Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.
Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.
Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.
Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.
Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.
Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.
Introduction
Over last years, a number of effective protocols has been developed for treatment of oncohematological diseases (leukemias and lymphomas) based on application of cytoreductive chemo- or radiation therapy. These treatment protocols, along with novel targeted drugs, bring about long-term remissions in these patients. However, quality of life in these patients is often disturbed, due to serious complications affecting different organs and systems. Dental complications, such as infectious and atrophy of oral mucosa and teeth occur quite often when treating oncological patients, especially children after chemo- or radiation treatment of leukemias and other malignancies [1, 2, 3, 4]. Treatment protocols in oncohematology usually include several rounds of cytoreductive therapy. Cytotoxic drugs or radiation treatment affect sensitive cells, both malignant and normal ones. Due to heavy insult to hematopoietic system, the leukocyte numbers begin to drop since day 5-6 after starting cytotoxic therapy cycle and recovers only at 2-3 weeks when the next round of therapy could be performed.
Quite intensive cytoreductive therapy, the so-called conditioning treatment, is administered before hematopoieticstem cell transplantation (HSCT) which causes a very deep suppression of hematopoiesis with entire depletion of granulocytes and most lymphoid cell population in peripheral blood, bone marrow and lymphoid organs. Their recovery occurs within weeks and months [5]. Along with blood cells, the cytoreductive treatment causes massive death of epithelial stem cells in oral cavity, intestines, lungs, urogenital tract etc. The therapy-induced epithelial damage manifests by early mucosites, colitis and other organ-specific syndromes. Intensive death of normal cells due to cytoreductive treatment followed by HSCT is, therefore, connected with repeated rounds of chemo-and radiation therapy which lead to maximal cytoreduction in epithelial organs as well.
The most common oral complications and main guidelines for managing dental disorders in the patients undergoing chemo/radiation therapy in children are well described in appropriate recommendations issued by American Academy of Pediatric Dentistry [6]. One should be noted that, by the time of HSCT, the patients already have marked immune deficiency cuased by previous courses of cytostatic therapy. Such immunocompromising condtions require all preventive dental programs to be performed before starting intensive anticancer treatment with following HSCT. If it is not possible, some provisional dental procedures are performed that should be continued upon stabilization of hematological and immune state of the patient. Over the period of post-transplant cytopenia, immune deficiency and concomitant oral complications, only local treatment is performed which is aimed for cytoprotection and accelerated healing of oral mucosae.
Hence, the aim of this review article was the discussion of epidemiology, pathogenesis, prevention and treatment of oral complications following intensive cytostatic therapy and hematopoietic stem cell transplantation. Disorders of oral mucosa represent several pathogenetic phases, from early toxic mucositis to late immune-induced atrophy of mucosal structures and salivary glands. Their treatment requires special approaches at every time period post-transplant.
Conditioning- and time-dependent features of oral complications in HSCT-procedure
Classical protocol for hematopoietic stem cell transplantation (HSCT) includes intensive chemo and/or radiation therapy (either myeloablative, or reduced conditioning regimens) delivered over limited terms (several days), thus causing a subsequent prolonged immune suppression. Such temporary immune deficiency is determined by several cytotoxic factors, i.e.:
1) High-dose cytoreductive therapy;
2) Long-term recovery of myelo- and lymphopoiesis posttransplant;
3) Antibacterial and antiviral treatment;
4) Acute graft-versus-host disease (aGVHD);
5) Long-term immunosuppressive therapy
(Cyclosporin etc.);
6) Chronic GVHD
Time course of bacterial and viral complications observed after intensive chemotherapy and hematopoietic stem cell transplantation is well presented in appropriate reviews [7,8]. The dental and mucosal complications are dependent on distinct time periods of conditioning therapy and subsequent transplantation [6]:
Phase I: Dental care before conditioning therapy
At this stage, oral complications are determined by the patient’s age, his/her general condition and oral health. In cases of hematological malignancies, the risk of posttransplant disorders depends on extent of local oral pathology, total intensity of previous cytoreductive therapy. Oral pathology at the pre-transplant stage may include oral infections, gingival leukemic infiltration, ulcers, bleeding, temporo-mandibular dysfunction.
Most principles of dental care before HSCT are similar to those applied to children suffering with malignancies. The two main differences are as follows: 1) in HSCT, the patient receives entire course of chemo- or radiation therapy several days before transplant; 2) HSCT is accompanied by a longterm immune suppression. Therefore, any elective dental care should be postponed until the immune restoration, i.e., at least 100 days after HSCT and even later, in cases of severe chronic GVHD or other complications. Vice versa, all urgent dental treatment should be completed before development of immune suppression in the patient.
Phase II: Neutropenic period following HSCT
The major oral complications at this time period, from the patient admission to HSCT clinic, and up to day +30 post-transplant, are caused by the cytostatic treatment and supporting therapy. They include oral mucositis, xerostomia, local pain, hemorrhages, taste anomalies, neurotoxicity (toothache, muscle tremor, temporo-mandibular pain, head ache etc.) may be registered, associated with common oral infections.
Oral mucositis develops within 7 to 10 days after starting of intensive treatment, and its symptoms are traceable for ca. 2 weeks after its completion. The patients should be observed thoroughly, and their oral condition should be traced. Optimal oral care is of crucial importance at this stage. Any kind of dental treatment should be avoided, due to severe immune suppression in the patient over this time period. Urgent dental interventions should be performed in close co-ordination with attending oncohematologists.
Phase III: Engraftment and recovery of hematopoiesis
Severity of the oral symptoms decreases by 3 to 4 weeks posttransplant, with domination of fungal invasion and herpes simplex infection. The infections are often combined with acute graft-versus-host disease, which may present sufficient problems after allogeneic HSCT. Differential histopathological features of oral infections and aGVHD should be considered. I.e., sometimes, one may observe xerostomia, hemorrhages, neurotoxicity, temporo-mandibular dysfunction, granulomas, papillomas etc. Examination of oral cavity and teeth as well as invasive stomatological procedures, e.g., tooth cleaning and soft tissue curettage should be agreed with transplantation team, due to continuous immune suppression in the patients. They should be encouraged to optimize their dental hygiene and avoid caryogenic diet, also being alert for xerostomia (“dry mouth”) and oral GVHD signs. For unclear reasons, oral cavity in transplanted patients shows increased temperature sensitivity for 2 to 4 months after HSCT. Local application of neutral fluoride or desensitizing tooth pastes may alleviate these symptoms.
Phase IV: Long-term restoration of immunity after systemic cytotoxic treatment
At later terms (over 100 days post-transplant), most oral complications are caused by chronic effects of preceding cytostatic therapy, including dysfunction of salivary glands, chronic GVHD affecting oral mucosa, as well as late viral infections. Oral squamous cell carcinoma may develop in oral cavity, like as other secondary malignancies. Relapse of the disease may be associated with xerostomia and injuries of oral cavity. However, late bacterial infections are less common, despite common neutropenia or severe chronic GVHD in the patients. Occasional dental examination with X-ray studies could be performed. Invasive dental care should be avoided in immunocompromised patients. Orthodontic care should be consulted with attending doctor and relatives of the patient, concerning risks and benefits of such treatment.
Phase V: Long-term survival following HSCT
Problems with development of orofacial, skeletal structures or teeth have similar origin for any complications observed in children who survived treatment of malignant diseases. In children, delayed growth of jaws and skull bones is observed months and years after intensive chemo-and radiotherapy. Such problems, generally, manifest in children under 6 years old and occur due to osteoblast suppression caused by prolonged cytostatic therapy. Long-term effects of the anticancer treatment may also include dental agenesis, microdontia, altered size and form of teeth, hypoplastic enamel, malformations of pulp cavity and dental roots as well as underdevelopment of jaws. Severity of such anomalies will depend on the patients’ age at the time of cytotoxic treatment. The patients may suffer of permanent dysfunction of salivary glands or xerostomia. Moreover, relapses of primary malignancies, or secondary cancer may also develop several years later.
Hence, the cancer survivors, especially younger patients, need routine dental examination and optimal oral care. The attending dentist should perform regular careful inspection of teeth, gingivae, tongue and oral mucosae, as well as adjacent areas. X ray studies and accessory cytological diagnostics should be performed in order to detect any head and neck malignancy. Dental treatment in such cohort needs a multidisciplinary approach with cooperation of different dental specialists in order to administer optimal treatment for any distinct case. Steady contact and consulting with attending oncologists is required, especially in case of relapse or immune deficiency suspected in the patient.
Most pathological changes of oral mucosae and epithelium (mucositis, gVHD, infections, later chronic complications) are accompanied by inflammation of mucosae and salivary glands. Role and pathogenetic mechanisms of inflammatory events are discussed, e.g., by Havermann et al. [9].
According to Fabuel et al. [10], the most common early oral complications in HSCT patients are as follows:
1. Acute mucositis caused by direct toxic action upon progenitor epithelial and bone cells of oral cavity. WHO classification distinguishes 5 grades of mucositis, from mild erythema to severe ulceration of oral mucosa. This pathology is associated with xerostomia, viscous saliva, intensive pain syndrome when eating, drinking or swallowing. Oral mucositis becomes clinically sound soon after HSCT reaching its maximum 5 to 7 days post-transplant and fades away gradually, within 2-3 weeks after HSCT. Focal necrosis of mucosae and labial skin is observed. In addition, caries new caries lesions may occur. For practical purposes, three stages of posttransplant oral mucositis are distinguished, depending on severity of mucositis, local pains and feeding difficulties [11].
2. Infectious complications mostly manifest as stomatitis caused by pathogenic bacteria, viruses or fungi.
3. Oral bleedings may occur in the patients due to suppression of hematopoiesis and thrombocytopenia, as well as primary disorder (e.g., acute leukemia).
4. Acute graft-versus-host disease (aGVHD) is observed within 100 days post-HSCT being a pathological immune reaction induced by the donor autoaggressive lymphocytes against some recipient antigens. aGVHD proceeds as a systemic inflammatory response involving cytokine activation. aGVHD affects mostly epithelial cell populations, including oral epithelium, thus representing a leading factor of severe complications and mortality among HSCT patients. Oral aGVHD presents as xerostomia, erythema, lichenoids, papular lesions, atrophy, and ulceration of mucosal surfaces.
Stepwise development of oral histopathology after conditioning therapy and hematopoietic transplantation
The first step of cytotoxic lesion, oral mucositis (OM) is a serious complication which depends on the total dose of chemotherapy and types of cytostatic drugs. E.g., Chaudhry et al. [12] have performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and their occurrence at various conditioning regimens. Grade of OM was analyzed based on the standard WHO Criteria for Adverse Events scales. Severe mucositis was defined as grades 2-3-4. A total of 624 studies were taken for analysis. In general, 73% experienced any signs of OM, whereas severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% after reduced-intensity-conditioning. In comparing graft-versus-host disease (GVHD) prophylaxis, the non-methotrexate regimens caused OM in 55.4%, thus being lower than among patients who received methotrexate (83.4%).
Primary insult to oral mucosa induced by intensive cytostatic treatment was described as early as in 1988 [13]. The workers analyzed early oral changes after HSCT. These changes included altered mucosal color (white and red) with subsequent atrophy, ulceration, accompanied by more viscous saliva, hyposecretion of salivary glands, causing xerostomia. This pathology determines subjective complaints of oral pain and dryness. The histological and clinical changes were most evident at ventral tongue, buccal and labial mucosa, and marginal gingival beginning just after conditioning treatment, peaking at 2 weeks after HSCT with following gradual mucosal repair. This complex pathology occurs due to conditioning chemoradiotherapy, immunosuppression after HSCT, occasional traumas posttransplant immunosuppressive chemotherapy, as well as due to activationg infections (mostly viral activation) local trauma, oral infections (especially those caused by HSV), and possibly acute GVHD. The viral and GVHD mechanisms should be considered in cases of worsening oral lesions at 3 weeks or later post-transplant.
These pathological findings were supported by several other studies [14]. A group of 54 children with oncohematological disorders were subjected to allo-HSCT, with 62% exhibiting clinical oral side effects upon treatment. These lesions were observed over first 2 weeks after conditioning therapy, transplantation, and until engraftment of the donor marrow having been ascribed to preceding chemo- and radiotherapy. Oral ulcers were seen in 34% of the cases. Administration of methotrexate for GVHD prophylaxis seemed to cause more common oral ulcerations rather than cyclosporin. HSV reactivation was observed in 35% of the children who were seropositive prior to BMT. Oral candidiasis was also a common finding (15% of the patients).
Early infections and inflammatory conditions of oral cavity following HSCT
Clinical infections of teeth and oral mucosa are widely spread in general population. E.g., colonization with Streptococcus mutans and parodonthogenic bacteria is revealed in gingival mucosa and dental plaque since pre-school age, becoming more common in later life [15]. The long-term immune deficiency after cytostatic chemo- and radiation therapy is widely known to promote a more active growth of odontogenic microflora. Incidence of oral HSCT complications was summarized using databases of the USA transplantation centers from 2004 to 2010 [16]. Over this time period, HSCT was performed in 101462 patients. Gingivitis or periodontitis was diagnosed in only 0.22% of the cases. Such low incidence, when compared to general population, may be connected with optimal dental care and full mouth debridement carried out before HSCT. Meanwhile, this study shows that gingival and periodontal problems in HSCT patients implies higher treatment costs, longer hospitalization period, and increased risks of infectious complications. E.g., septicemia, bacterial infections and mycoses in the patients with periodontitis were observed significantly more often than in cases without gingival problems before HSCT.
Several studies from 90’s support a defnite role of human herpesvirus type 6 (HHV6) in oral pathology occurring after HSCT [17]. This study was performed using a golden standard, the virus isolation, in 15 allogeneic and 11 autologous marrow transplantation patients. HHV6 type B was isolated posttransplant from peripheral blood mononuclears of 12 of 26 patients. Interestingly, 11 of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA both before and after transplantation. In sum, 23 of 26 patients showed evidence of active HHV-6 infection either by the virus isolation, salivary shedding, or increased antibody titers. Active human cytomegalovirus infection was associated with HHV-6 isolation, as also confirmed in later studies. However, no association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression in this study. The initial results of HHV6 studies were confirmed by Cone et al. [18].
Oral immune pathology in chronic GVHD
Histological changes observed at later stages post-HSCT, the s.c. chronic GVHD, seems to be of mostly autoimmune origin, due to cytotoxic damage of vascular structures and mucosal epithelium induced by donor effector cells. In cases of chronic GVHD, the changes in oral mucosa developing 12 months or later after transplantation comprise erythema of mucous membranes, tongue atrophy and also lichenoid changes in the buccal mucosa [14]. The study by Motta to al. [19] was performed in 12 patients undergoing allo-HSCT. The paired oral cGVHD biopsies obtained before and 1 month after treatment with topical dexamethasone (n=8), or tacrolimus (n=4) were subjected to immunohistochemistry of main immune markers (CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3) as compared to bioptates from aGVHD, oral lichen planus, and normal tissues. The oral bioptates in cGVHD were characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating immune cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+, and FoxP3+ cells, exceeding the levels of normal tissues thus presuming a largely T-cell-driven inflammation with macrophage participation. Topical dexamethasone or tacrolimus reduced the mentioned cell pathology in oral cGVHD, while reducing the number of CD4+ and CD103+ cells.
Clinical signs of chronic oral GVHD develop at later terms post-transplant (>100 days after HSCT), being observed in 50-80% of total cases. The cGVHD symptoms include erythema, atrophy of the tongue surfaces, lichenoid changes of buccal mucosae accompanied by ulcers and increased oral cancer risk [10]. Salivary gland dysfunction causes xerostomia, clinical pattern of parotitis, excess of mucous substances and lower saliva production. These symptoms may persist, at least, for 1 year after HSCT.
The cGVHD, like as acute GVHD, develops by immune mechanisms. It affects different organs and tissues including oral cavity. Clinical pattern of oral cGVHD, generally, is similar to the Sjogren disease, a well-known autoimmune disorder [20].
So far, there are no validated cGVHD biomarkers correlating with clinical except of relatively unspecific parameters, e.g., altered albumin or high complement levels [21]. Increased albumin, Na+ , Cl− concentrations, changes of lactoferrin an protease inhibitors may be observed in oral fluid of the cGVHD patients [22].
Treatment of early post-transplant oral disorders (mucositis and aGVHD)
Oral mucositis, being a very common complication of intensive chemotherapy followed by HSCT occurring in ca.70-80% of the cases, thus needing novel management strategies which include both preventive measures and therapeutic approaches. Pathophysiology of acute oral includes complex interactions between the products of tissue damage, reactive oxygen species, local microbiota and host immune system, which determines the grade of inflammatory response in oral mucosa and salivary glands. Genetic factors plays a major role in the development of this toxicity [23]. Although only few therapeutic agents are available, several promising drugs are under clinical trials.
Palifermin (keratinocyte growth factor) is the only pharmacological drug approved by the European Medicines Agency and the US Food and Drug Administration (FDA) for mucositis. Palifermin is administered intravenously prior to the initiation of chemotherapy and for an additional 3 days beginning since the day of HSCT [24].
Pathogenetic treatment also includes a number of anti-inflammatory drugs, either cytokine-based therapy, or non-steroid anti-inflammatory drugs, pentoxifylline etc. [23]. Biological cell-containing preparations are also tried to this purpose. Recently, Piccin et al. [25] has reported a lymphoma patient with severe oral and esophageal mucositis developed after high-dose chemotherapy, auto-HSCT, severe sepsis, viral infection and neutropenia. Platelet gel from cord blood was topically administered daily to the oral cavity. After 8 consecutive days, full recovery of mucositis was seen without any side effects. Therefore, controlled studies are required to compare efficacy of autologous and allogeneic platelet gels in severe mucositis.
A study in pediatric patients has also shown some efficiency of low-level laser therapy (LLT) in oral mucositis [26]. The authors have developed a specialized oral care protocol that included LLT for pediatric HSCT patients. Data from OM-related morbidity were collected from 51 HSCT pediatric patients treated daily with LLT, followed by standard oral care protocols. All the patients, even at younger ages, tolerated the LLT therapy well. The maximum OM degree was WHO II. Patients after autologous and HLA-haploidentical transplants showed less severe OM, and better clinical outcomes are reported with LLT which could be included into the specialized oral care in this cohort of children.
Novel treatments of mucosal aGVHD
Oral immune-like syndromes are sometimes observed in acute GVHD after HSCT. E.g., Ion et al. [27] has studied twenty-one such GVHD cases of which 5 demonstrated only oral features; the remaining 16 had variable involvement of skin (n=14), liver (n=7), and gut (n=5). The median time for onset of oral aGVHD was 35 days (11 to 159 days). The sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21) tongue (18 of 21 dorsum in 8), labial mucosa (16 of 21, palatal mucosa (15 of 21; hard palate in 7), and floor of mouth (7 of 21). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for additional support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and nonkeratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing.
Previous successful experience with blood platelet gels was based on regenerative effects upon diabetic or surgical wounds, due to local release of growth factors such as fibroblast – derived growth factor, platelet-derived growth factor etc. [28]. Their study was aimed for assessing efficacy and safety of allogeneic platelet gel for treating ulcers in the skin or oral aGVHD. Platelet-rich fibrin was obtained by automated process (Vivostat system, Vivostat A/S). Six patients with multiple lesions involving dermis (Grade I, n=2), subcutaneous (Grade II, n=4), or oral mucosa related to GVHD were administered the gel as local therapy. After the second gel application, the pain faded away, and granulation tissue was observed in four cases with Grade II lesions. After a median of eight PLT gel applications (range, -10), five of six patients showed a complete response, without any side effects documented.
Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. Induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), was suggested to potentiate intestinal crypt proliferation and mucosal repair [29]. A pilot study included 20 patients with steroid refractory intestinal GVHD who were given oral lithium carbonate against a group treated with glucocorticoids. As a result, 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients.
Therapy of chronic oral GVHD
Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy with minimal side effects which alleviates cGVHD in most patients. Its curative effects are explained by immunomodulatory action upon T-regulatory lymphocytes. Recent data suggest that favorable effects of extracorporeal photopheresis (UVA irradiation) upon cGVHD may be also caused by inactivation and apoptosis of peripheral blood neutrophils [30]. Meanwhile, chronic GVHD is often refractory to systemic therapies. Some workers draw attention to intraoral narrow-band ultraviolet B (NB-UVB) irradiation in oral cGVHD delivered as a course of 24 phototherapy sessions, at a single dose of >50 mJ/cm [31]. Median symptom scores (0-10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. In sum, 7/11 patients had improvement and 2/11 worsened. Hence, NB-UVB may be considered a treatment option in refractory oral cGVHD, however, requiring clinical trials with appropriate control groups.
A supplementary topical treatment of oral cGVHD is proposed by means the glucocorticoid inhalers [32]. The authors compared different formulations showing pharmacological superiority of Budesonide for topical application in oral cGVHD. Marked local anti-inflammatory effects of Budesonide are based on its very low absorption through mucosal surfaces, thus increasing the potential role in oral cGVHD management. Moreover, its viscous formulation increases mucosal contact time and provides greater pharmacological effect in mucosal inflammation [33].
Second-line treatment in refractory cGVHD may include low doses of alemtuzumab plus low doses of rituximab as suggested by Gutiérrez-Aguirre et al. [34]. The authors have observed 15 patients who received one cycle of subcutaneous alemtuzumab (10 mg/day/3 days), and intravenous rituximab 100 mg on D+4, +11, +18 and +25 post-transplant (the protocol is under clinical trial). The therapeutic response was measured on Days +30, +90 and +365 of the protocol. The main site involved was the oral mucosa (86.7%). The overall response to the treatment was 100% at Day +30 evaluation, i.e., 10 patients had partial remission and 5, complete remission. At D+90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. Adverse effects were mainly infections in 67% of patients; these were usually quickly solved.
Specific cautions for drug therapy following HSCT
First of all, one should take into account those anticancer drugs that carry the highest risk for mucositis, i.e., methotrexate, cyclophosphamide, cisplatin, and fluorouracil (Villa, Sonis, 2015).
Risk of mucositis is dose-dependent and increases with higher intensity of chemo- and/or radiation therapy. One should be cautious when administering some drugs to such patients, as follows [10]:
– General anesthetics;
– Non-steroid anti-inflammatory drugs (NSAIDs) since these drugs may augment cyclosporine and tacrolimus nephrotoxicity, and they may increase bleeding and aggravate peptic ulcers in the corticosteroid-treated patients;
– Aspirin dosage should be adjusted since it increases bleeding risks;
– Antibiotics (erythromycin, clarithromycin, tetracycline, aminoglycosides, chinolones), as well as azol antifungal azoles (ketonazol, fluconazole and itroconazol), like as NSAIDs could aaalter cyclosporine lebels in blood serum thus causing more expressed immunosuppression.
– Usage of Sirolimus, and probably, of other mTOR inhibitors for the GVHD prophylaxis, may cause acute ulcerative stomatitis affecting the non-keratinized mucosa, mainly, with tongue involvement, at median onset time of 55 days after HCST [35]. Topical corticosteroid treatment is successful in these cases.
Potential diagnostic markers
Dozens of salivary components may reflect different diseases of periodont and oral cavity, including inflammatory mediators, reactive oxidative products, cellular enzymes, tissue-breakdown products etc. [36]. Over last decade, a number of reviews have been dedicated to potential clinical significance of salivary markers for diagnostics of different somatic and infectious disorders. E.g., salivary diagnostics of cancer proteins in oral fluid is now an evolving field of diagnostics as reported by Kaur et al. [37]. However, most of current studies are directed to novel applications of salivary using the "omics" approach, studying genomic, transcriptomic, proteomic, microbiomic, and metabolomic parameters, thus bringing the solution to a big data analysis [38]. Meanwhile, a search may be focused on single specific markers showing distinct pathological disorders of oral cavity or in the entire host organism.
DNA markers
Salivary biomarkers for infectious diseases were extensively studied earlier [39]. The issue is that the infectious agents were detected by different laboratory tests (by specific antibodies, antigens or nucleic acid markers) in salivary samples. These include a large range of Herpes viruses, Hepatitis viruses, HIV, Human Papillomavirus (HPV), Influenza virus, and Poliovirus.
Moreover, hundreds of bacterial species could be found in saliva, at the oral mucosa, dental plaques and tongue surface including Escherichia coli, Mycobacterium tuberculosis, Helicobacter pylori, Treponema pallidum and a wide range of streptococcal species. Concerning fungal presentation in oral rinses, Candida species were the most frequently cultured fungi (in 75% of samples), followed by Cladosporium (65%), Aureobasidium, Saccharomycetales (50% for both), Aspergillus (35%), Fusarium (30%), and Cryptococcus (20%). [40].
Post-cytostatic immune deficiency is regularly associated with viral infections. In this view, the levels of herpesvirus type VI (HHVVI) in saliva were suggested to be a probable severity marker of chemotherapy-induced oral damage [41]. However, excessive HHV6 activation was not confirmed at later terms post-HSCT, in chronic GVHD patients [42]. The authors tested for HHV6 peripheral blood, different oral fluids from cGVHD patients and oral tissue samples from healthy blood donors. HHV6 was detected by nested polymerase chain reaction. The virus was detected in whole saliva in 13 cGVHD patients (68%) and in 19 blood donors (67%) but not in gingival crevicular fluid or parotid gland saliva. Only two oral tissue samples of cGVHD patients of 12 were positive for HHV6. In sum, these data do not support the importance of HHV6 in oral lesions of cGVHD.
Over 40 years, it has been well known that oral cavity and intestinal microbiota contain similar bacterial species as shown, e.g., by Hamilton et al. [43]. Large numbers of similar organisms (>106/m1) were recovered by microbiological cultures from oral samples and jejunal aspirate of 16 subjects, in five of whom the same organisms were present in similar relative proportions in the saliva, e.g., Fusobacteria, whereas in other cases jejunal organisms differed from those in saliva. In eight of them, jejunal flora showed a typical 'faecal' pattern usually associated with small bowel bacterial overgrowth but, in three, the jejunal floral was somewhat similar to that of saliva.
Nowadays, with development of high-throughput NGS and 16S RNA sequencing, these ratios are studied in more details [44]. Human microbiota from three different compartments, i.e., saliva, feces, and cancer tissue (CT), of patients with colorectal cancer (CRC) vs. 10 healthy controls (saliva and feces). Taxonomic analysis based on 16S rRNA gene, revealed the presence of three main bacterial phyla, which includes about 80% of sequence reads: Firmicutes, Bacteroidetes, and Proteobacteria. Differences in bacterial composition, F. nucleatum abundance in healthy controls vs. colon cancer patients, and the association of F. nucleatum with clinical parameters were observed. Hence, Fusobacterium species are part of the both oral and intestinal microbiota, especially of colon tissue. Metagenomic analyses have shown that F. nucleatum detection in saliva may be predictive for development of colorectal cancer (Nosho et al., 2016).
The leukocytes shed to saliva may be also used even for detection of specific mutations in the patients with myeloproliferative diseases. E.g., Strati et al. [45] have performed a comparative study of JAK2V617F mutation in blood and saliva taken from the patients with primary myelofibrosis. Analysis of results from 167 patients has shown that the concordance between JAK2V617F detection in blood and saliva was 96%, with a sensitivity of 100% and a specificity of 90%. This biological material seems to have, at least, as sensitive as blood analysis for this mutation.
Protein markers
Like as DNA markers, immune protein molecules, like specific immunoglobulins , may be measured in saliva and salivary gland secretions in order to detect some latent and activable viruses [46].
Searching novel markers of acute GVHD is an important issue. E.g., one may check such potential salivary biomarkers as S100 protein family members (S100A8, S100A9, and S100A7) performed by Chiusolo et al. [47]. By means of HPLC, the authors have shown S100A8 in 14 of 23 cases of GVHD in allo-HSCT patients as compared with 2 GVHDfree parients and in none case of control group ( (P<0.001). Similar trend was registered for S100A9 protein. Multiple analysis of salivary proteome allows to detect some candidate proteins specific to acute GVHD as shown by Souza et al. [48] who carried out a preliminary study of salivary proteins using PAGE gel electrophoresis, liquid chromatograpy, and modern mass spectrometry. The most relevant proteins recognized exclusively in GVHD patients were: CSF2RB, protocadherin Fat 2 precursor, protein capicua homolog isoform CIC-S, MUC16 and RGPD8_HUMAN RANBP2. Their physiological role in this complication is not clear and needs further studies.
Diagnostic and prognostic markers of acute or chronic chronic GVHD are currently searched by means of proteomic analysis performed with mass-spectrometry or other methods of protein analysis. For example, saliva collected from oral cavity of allo-HSCT patients with chronic oral GVHD and cGVHD-free cases using isobaric Tags for quantification labeling, followed by tandem mass spectrometry. The method allowed identify up to 249 salivary proteins. Of them, 82 proteins were differently expressed in oral cGVHD patients compared to GVHD-free patients. Of these proteins, most played role in immunity, proteolytic functions, or as cytoskeleton components. Salivary IL-1 receptor antagonist and Cystatin B proved to exhibit decreased expression in oral chronic GVHD (P<0.003), thus, probably, being of some diagnostic significance [49].
Conclusions
1. Intensive chemotherapy and radiation treatment of the oncohematological patients followed by hematopoietic stem cell transplantation (HSCT) brings about early inflammation and acute necrosis of oral mucosa and gingivae, atrophy of salivary glands
2. Immune deficiency is evident at all post-transplant phases and later, at the stage of immunesuppressive therapy. At early terms, it is complicated by infections, at later phase, by autoimmune affection of oral mucosae. Over next years, a risk of secondary cancers is increased.
3. Bacterial and fungal infections of oral cavity and gastrointestinal tract are especially common at early terms, whereas viral activation (including secondary tumors) is detected at later terms after HSCT. The diagnosis of infections in immunocompromised patients represents an important task for the dentist that should be resolved in close contact with attending physician.
4. Late oral pathology after HSCT in children is presented, mainly, by developmental anomalies of dental system in young patients.
5. Chronic graft-versus-host disease (cGVHD) is accompanied by the Sjogren-like problems with oral mucosa and salivary glands.
6. There is no effective etiological treatment for acute mucositis, oral GVHD, both acute and chronic clinical forms. Appropriate pathogenetic therapy is aimed for release of painful symptoms and anti-inflammatory treatment. Some new promising drugs are still used as experimental therapy.
6. By the present time, there are no recognized salivary markers for early diagnostic and prediction of severe damage of oral mucosa expected after intensive cytostatic therapy, as well as GVHD following allogeneic transplantation. However, some promising salivary tests are to be studied, to detect infections of oral cavity, local and systemic malignancies.
Conflict of interest
No conflict of interest reported.
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Introduction
Over last years, a number of effective protocols has been developed for treatment of oncohematological diseases (leukemias and lymphomas) based on application of cytoreductive chemo- or radiation therapy. These treatment protocols, along with novel targeted drugs, bring about long-term remissions in these patients. However, quality of life in these patients is often disturbed, due to serious complications affecting different organs and systems. Dental complications, such as infectious and atrophy of oral mucosa and teeth occur quite often when treating oncological patients, especially children after chemo- or radiation treatment of leukemias and other malignancies [1, 2, 3, 4]. Treatment protocols in oncohematology usually include several rounds of cytoreductive therapy. Cytotoxic drugs or radiation treatment affect sensitive cells, both malignant and normal ones. Due to heavy insult to hematopoietic system, the leukocyte numbers begin to drop since day 5-6 after starting cytotoxic therapy cycle and recovers only at 2-3 weeks when the next round of therapy could be performed.
Quite intensive cytoreductive therapy, the so-called conditioning treatment, is administered before hematopoieticstem cell transplantation (HSCT) which causes a very deep suppression of hematopoiesis with entire depletion of granulocytes and most lymphoid cell population in peripheral blood, bone marrow and lymphoid organs. Their recovery occurs within weeks and months [5]. Along with blood cells, the cytoreductive treatment causes massive death of epithelial stem cells in oral cavity, intestines, lungs, urogenital tract etc. The therapy-induced epithelial damage manifests by early mucosites, colitis and other organ-specific syndromes. Intensive death of normal cells due to cytoreductive treatment followed by HSCT is, therefore, connected with repeated rounds of chemo-and radiation therapy which lead to maximal cytoreduction in epithelial organs as well.
The most common oral complications and main guidelines for managing dental disorders in the patients undergoing chemo/radiation therapy in children are well described in appropriate recommendations issued by American Academy of Pediatric Dentistry [6]. One should be noted that, by the time of HSCT, the patients already have marked immune deficiency cuased by previous courses of cytostatic therapy. Such immunocompromising condtions require all preventive dental programs to be performed before starting intensive anticancer treatment with following HSCT. If it is not possible, some provisional dental procedures are performed that should be continued upon stabilization of hematological and immune state of the patient. Over the period of post-transplant cytopenia, immune deficiency and concomitant oral complications, only local treatment is performed which is aimed for cytoprotection and accelerated healing of oral mucosae.
Hence, the aim of this review article was the discussion of epidemiology, pathogenesis, prevention and treatment of oral complications following intensive cytostatic therapy and hematopoietic stem cell transplantation. Disorders of oral mucosa represent several pathogenetic phases, from early toxic mucositis to late immune-induced atrophy of mucosal structures and salivary glands. Their treatment requires special approaches at every time period post-transplant.
Conditioning- and time-dependent features of oral complications in HSCT-procedure
Classical protocol for hematopoietic stem cell transplantation (HSCT) includes intensive chemo and/or radiation therapy (either myeloablative, or reduced conditioning regimens) delivered over limited terms (several days), thus causing a subsequent prolonged immune suppression. Such temporary immune deficiency is determined by several cytotoxic factors, i.e.:
1) High-dose cytoreductive therapy;
2) Long-term recovery of myelo- and lymphopoiesis posttransplant;
3) Antibacterial and antiviral treatment;
4) Acute graft-versus-host disease (aGVHD);
5) Long-term immunosuppressive therapy
(Cyclosporin etc.);
6) Chronic GVHD
Time course of bacterial and viral complications observed after intensive chemotherapy and hematopoietic stem cell transplantation is well presented in appropriate reviews [7,8]. The dental and mucosal complications are dependent on distinct time periods of conditioning therapy and subsequent transplantation [6]:
Phase I: Dental care before conditioning therapy
At this stage, oral complications are determined by the patient’s age, his/her general condition and oral health. In cases of hematological malignancies, the risk of posttransplant disorders depends on extent of local oral pathology, total intensity of previous cytoreductive therapy. Oral pathology at the pre-transplant stage may include oral infections, gingival leukemic infiltration, ulcers, bleeding, temporo-mandibular dysfunction.
Most principles of dental care before HSCT are similar to those applied to children suffering with malignancies. The two main differences are as follows: 1) in HSCT, the patient receives entire course of chemo- or radiation therapy several days before transplant; 2) HSCT is accompanied by a longterm immune suppression. Therefore, any elective dental care should be postponed until the immune restoration, i.e., at least 100 days after HSCT and even later, in cases of severe chronic GVHD or other complications. Vice versa, all urgent dental treatment should be completed before development of immune suppression in the patient.
Phase II: Neutropenic period following HSCT
The major oral complications at this time period, from the patient admission to HSCT clinic, and up to day +30 post-transplant, are caused by the cytostatic treatment and supporting therapy. They include oral mucositis, xerostomia, local pain, hemorrhages, taste anomalies, neurotoxicity (toothache, muscle tremor, temporo-mandibular pain, head ache etc.) may be registered, associated with common oral infections.
Oral mucositis develops within 7 to 10 days after starting of intensive treatment, and its symptoms are traceable for ca. 2 weeks after its completion. The patients should be observed thoroughly, and their oral condition should be traced. Optimal oral care is of crucial importance at this stage. Any kind of dental treatment should be avoided, due to severe immune suppression in the patient over this time period. Urgent dental interventions should be performed in close co-ordination with attending oncohematologists.
Phase III: Engraftment and recovery of hematopoiesis
Severity of the oral symptoms decreases by 3 to 4 weeks posttransplant, with domination of fungal invasion and herpes simplex infection. The infections are often combined with acute graft-versus-host disease, which may present sufficient problems after allogeneic HSCT. Differential histopathological features of oral infections and aGVHD should be considered. I.e., sometimes, one may observe xerostomia, hemorrhages, neurotoxicity, temporo-mandibular dysfunction, granulomas, papillomas etc. Examination of oral cavity and teeth as well as invasive stomatological procedures, e.g., tooth cleaning and soft tissue curettage should be agreed with transplantation team, due to continuous immune suppression in the patients. They should be encouraged to optimize their dental hygiene and avoid caryogenic diet, also being alert for xerostomia (“dry mouth”) and oral GVHD signs. For unclear reasons, oral cavity in transplanted patients shows increased temperature sensitivity for 2 to 4 months after HSCT. Local application of neutral fluoride or desensitizing tooth pastes may alleviate these symptoms.
Phase IV: Long-term restoration of immunity after systemic cytotoxic treatment
At later terms (over 100 days post-transplant), most oral complications are caused by chronic effects of preceding cytostatic therapy, including dysfunction of salivary glands, chronic GVHD affecting oral mucosa, as well as late viral infections. Oral squamous cell carcinoma may develop in oral cavity, like as other secondary malignancies. Relapse of the disease may be associated with xerostomia and injuries of oral cavity. However, late bacterial infections are less common, despite common neutropenia or severe chronic GVHD in the patients. Occasional dental examination with X-ray studies could be performed. Invasive dental care should be avoided in immunocompromised patients. Orthodontic care should be consulted with attending doctor and relatives of the patient, concerning risks and benefits of such treatment.
Phase V: Long-term survival following HSCT
Problems with development of orofacial, skeletal structures or teeth have similar origin for any complications observed in children who survived treatment of malignant diseases. In children, delayed growth of jaws and skull bones is observed months and years after intensive chemo-and radiotherapy. Such problems, generally, manifest in children under 6 years old and occur due to osteoblast suppression caused by prolonged cytostatic therapy. Long-term effects of the anticancer treatment may also include dental agenesis, microdontia, altered size and form of teeth, hypoplastic enamel, malformations of pulp cavity and dental roots as well as underdevelopment of jaws. Severity of such anomalies will depend on the patients’ age at the time of cytotoxic treatment. The patients may suffer of permanent dysfunction of salivary glands or xerostomia. Moreover, relapses of primary malignancies, or secondary cancer may also develop several years later.
Hence, the cancer survivors, especially younger patients, need routine dental examination and optimal oral care. The attending dentist should perform regular careful inspection of teeth, gingivae, tongue and oral mucosae, as well as adjacent areas. X ray studies and accessory cytological diagnostics should be performed in order to detect any head and neck malignancy. Dental treatment in such cohort needs a multidisciplinary approach with cooperation of different dental specialists in order to administer optimal treatment for any distinct case. Steady contact and consulting with attending oncologists is required, especially in case of relapse or immune deficiency suspected in the patient.
Most pathological changes of oral mucosae and epithelium (mucositis, gVHD, infections, later chronic complications) are accompanied by inflammation of mucosae and salivary glands. Role and pathogenetic mechanisms of inflammatory events are discussed, e.g., by Havermann et al. [9].
According to Fabuel et al. [10], the most common early oral complications in HSCT patients are as follows:
1. Acute mucositis caused by direct toxic action upon progenitor epithelial and bone cells of oral cavity. WHO classification distinguishes 5 grades of mucositis, from mild erythema to severe ulceration of oral mucosa. This pathology is associated with xerostomia, viscous saliva, intensive pain syndrome when eating, drinking or swallowing. Oral mucositis becomes clinically sound soon after HSCT reaching its maximum 5 to 7 days post-transplant and fades away gradually, within 2-3 weeks after HSCT. Focal necrosis of mucosae and labial skin is observed. In addition, caries new caries lesions may occur. For practical purposes, three stages of posttransplant oral mucositis are distinguished, depending on severity of mucositis, local pains and feeding difficulties [11].
2. Infectious complications mostly manifest as stomatitis caused by pathogenic bacteria, viruses or fungi.
3. Oral bleedings may occur in the patients due to suppression of hematopoiesis and thrombocytopenia, as well as primary disorder (e.g., acute leukemia).
4. Acute graft-versus-host disease (aGVHD) is observed within 100 days post-HSCT being a pathological immune reaction induced by the donor autoaggressive lymphocytes against some recipient antigens. aGVHD proceeds as a systemic inflammatory response involving cytokine activation. aGVHD affects mostly epithelial cell populations, including oral epithelium, thus representing a leading factor of severe complications and mortality among HSCT patients. Oral aGVHD presents as xerostomia, erythema, lichenoids, papular lesions, atrophy, and ulceration of mucosal surfaces.
Stepwise development of oral histopathology after conditioning therapy and hematopoietic transplantation
The first step of cytotoxic lesion, oral mucositis (OM) is a serious complication which depends on the total dose of chemotherapy and types of cytostatic drugs. E.g., Chaudhry et al. [12] have performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and their occurrence at various conditioning regimens. Grade of OM was analyzed based on the standard WHO Criteria for Adverse Events scales. Severe mucositis was defined as grades 2-3-4. A total of 624 studies were taken for analysis. In general, 73% experienced any signs of OM, whereas severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% after reduced-intensity-conditioning. In comparing graft-versus-host disease (GVHD) prophylaxis, the non-methotrexate regimens caused OM in 55.4%, thus being lower than among patients who received methotrexate (83.4%).
Primary insult to oral mucosa induced by intensive cytostatic treatment was described as early as in 1988 [13]. The workers analyzed early oral changes after HSCT. These changes included altered mucosal color (white and red) with subsequent atrophy, ulceration, accompanied by more viscous saliva, hyposecretion of salivary glands, causing xerostomia. This pathology determines subjective complaints of oral pain and dryness. The histological and clinical changes were most evident at ventral tongue, buccal and labial mucosa, and marginal gingival beginning just after conditioning treatment, peaking at 2 weeks after HSCT with following gradual mucosal repair. This complex pathology occurs due to conditioning chemoradiotherapy, immunosuppression after HSCT, occasional traumas posttransplant immunosuppressive chemotherapy, as well as due to activationg infections (mostly viral activation) local trauma, oral infections (especially those caused by HSV), and possibly acute GVHD. The viral and GVHD mechanisms should be considered in cases of worsening oral lesions at 3 weeks or later post-transplant.
These pathological findings were supported by several other studies [14]. A group of 54 children with oncohematological disorders were subjected to allo-HSCT, with 62% exhibiting clinical oral side effects upon treatment. These lesions were observed over first 2 weeks after conditioning therapy, transplantation, and until engraftment of the donor marrow having been ascribed to preceding chemo- and radiotherapy. Oral ulcers were seen in 34% of the cases. Administration of methotrexate for GVHD prophylaxis seemed to cause more common oral ulcerations rather than cyclosporin. HSV reactivation was observed in 35% of the children who were seropositive prior to BMT. Oral candidiasis was also a common finding (15% of the patients).
Early infections and inflammatory conditions of oral cavity following HSCT
Clinical infections of teeth and oral mucosa are widely spread in general population. E.g., colonization with Streptococcus mutans and parodonthogenic bacteria is revealed in gingival mucosa and dental plaque since pre-school age, becoming more common in later life [15]. The long-term immune deficiency after cytostatic chemo- and radiation therapy is widely known to promote a more active growth of odontogenic microflora. Incidence of oral HSCT complications was summarized using databases of the USA transplantation centers from 2004 to 2010 [16]. Over this time period, HSCT was performed in 101462 patients. Gingivitis or periodontitis was diagnosed in only 0.22% of the cases. Such low incidence, when compared to general population, may be connected with optimal dental care and full mouth debridement carried out before HSCT. Meanwhile, this study shows that gingival and periodontal problems in HSCT patients implies higher treatment costs, longer hospitalization period, and increased risks of infectious complications. E.g., septicemia, bacterial infections and mycoses in the patients with periodontitis were observed significantly more often than in cases without gingival problems before HSCT.
Several studies from 90’s support a defnite role of human herpesvirus type 6 (HHV6) in oral pathology occurring after HSCT [17]. This study was performed using a golden standard, the virus isolation, in 15 allogeneic and 11 autologous marrow transplantation patients. HHV6 type B was isolated posttransplant from peripheral blood mononuclears of 12 of 26 patients. Interestingly, 11 of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA both before and after transplantation. In sum, 23 of 26 patients showed evidence of active HHV-6 infection either by the virus isolation, salivary shedding, or increased antibody titers. Active human cytomegalovirus infection was associated with HHV-6 isolation, as also confirmed in later studies. However, no association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression in this study. The initial results of HHV6 studies were confirmed by Cone et al. [18].
Oral immune pathology in chronic GVHD
Histological changes observed at later stages post-HSCT, the s.c. chronic GVHD, seems to be of mostly autoimmune origin, due to cytotoxic damage of vascular structures and mucosal epithelium induced by donor effector cells. In cases of chronic GVHD, the changes in oral mucosa developing 12 months or later after transplantation comprise erythema of mucous membranes, tongue atrophy and also lichenoid changes in the buccal mucosa [14]. The study by Motta to al. [19] was performed in 12 patients undergoing allo-HSCT. The paired oral cGVHD biopsies obtained before and 1 month after treatment with topical dexamethasone (n=8), or tacrolimus (n=4) were subjected to immunohistochemistry of main immune markers (CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3) as compared to bioptates from aGVHD, oral lichen planus, and normal tissues. The oral bioptates in cGVHD were characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating immune cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+, and FoxP3+ cells, exceeding the levels of normal tissues thus presuming a largely T-cell-driven inflammation with macrophage participation. Topical dexamethasone or tacrolimus reduced the mentioned cell pathology in oral cGVHD, while reducing the number of CD4+ and CD103+ cells.
Clinical signs of chronic oral GVHD develop at later terms post-transplant (>100 days after HSCT), being observed in 50-80% of total cases. The cGVHD symptoms include erythema, atrophy of the tongue surfaces, lichenoid changes of buccal mucosae accompanied by ulcers and increased oral cancer risk [10]. Salivary gland dysfunction causes xerostomia, clinical pattern of parotitis, excess of mucous substances and lower saliva production. These symptoms may persist, at least, for 1 year after HSCT.
The cGVHD, like as acute GVHD, develops by immune mechanisms. It affects different organs and tissues including oral cavity. Clinical pattern of oral cGVHD, generally, is similar to the Sjogren disease, a well-known autoimmune disorder [20].
So far, there are no validated cGVHD biomarkers correlating with clinical except of relatively unspecific parameters, e.g., altered albumin or high complement levels [21]. Increased albumin, Na+ , Cl− concentrations, changes of lactoferrin an protease inhibitors may be observed in oral fluid of the cGVHD patients [22].
Treatment of early post-transplant oral disorders (mucositis and aGVHD)
Oral mucositis, being a very common complication of intensive chemotherapy followed by HSCT occurring in ca.70-80% of the cases, thus needing novel management strategies which include both preventive measures and therapeutic approaches. Pathophysiology of acute oral includes complex interactions between the products of tissue damage, reactive oxygen species, local microbiota and host immune system, which determines the grade of inflammatory response in oral mucosa and salivary glands. Genetic factors plays a major role in the development of this toxicity [23]. Although only few therapeutic agents are available, several promising drugs are under clinical trials.
Palifermin (keratinocyte growth factor) is the only pharmacological drug approved by the European Medicines Agency and the US Food and Drug Administration (FDA) for mucositis. Palifermin is administered intravenously prior to the initiation of chemotherapy and for an additional 3 days beginning since the day of HSCT [24].
Pathogenetic treatment also includes a number of anti-inflammatory drugs, either cytokine-based therapy, or non-steroid anti-inflammatory drugs, pentoxifylline etc. [23]. Biological cell-containing preparations are also tried to this purpose. Recently, Piccin et al. [25] has reported a lymphoma patient with severe oral and esophageal mucositis developed after high-dose chemotherapy, auto-HSCT, severe sepsis, viral infection and neutropenia. Platelet gel from cord blood was topically administered daily to the oral cavity. After 8 consecutive days, full recovery of mucositis was seen without any side effects. Therefore, controlled studies are required to compare efficacy of autologous and allogeneic platelet gels in severe mucositis.
A study in pediatric patients has also shown some efficiency of low-level laser therapy (LLT) in oral mucositis [26]. The authors have developed a specialized oral care protocol that included LLT for pediatric HSCT patients. Data from OM-related morbidity were collected from 51 HSCT pediatric patients treated daily with LLT, followed by standard oral care protocols. All the patients, even at younger ages, tolerated the LLT therapy well. The maximum OM degree was WHO II. Patients after autologous and HLA-haploidentical transplants showed less severe OM, and better clinical outcomes are reported with LLT which could be included into the specialized oral care in this cohort of children.
Novel treatments of mucosal aGVHD
Oral immune-like syndromes are sometimes observed in acute GVHD after HSCT. E.g., Ion et al. [27] has studied twenty-one such GVHD cases of which 5 demonstrated only oral features; the remaining 16 had variable involvement of skin (n=14), liver (n=7), and gut (n=5). The median time for onset of oral aGVHD was 35 days (11 to 159 days). The sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21) tongue (18 of 21 dorsum in 8), labial mucosa (16 of 21, palatal mucosa (15 of 21; hard palate in 7), and floor of mouth (7 of 21). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for additional support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and nonkeratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing.
Previous successful experience with blood platelet gels was based on regenerative effects upon diabetic or surgical wounds, due to local release of growth factors such as fibroblast – derived growth factor, platelet-derived growth factor etc. [28]. Their study was aimed for assessing efficacy and safety of allogeneic platelet gel for treating ulcers in the skin or oral aGVHD. Platelet-rich fibrin was obtained by automated process (Vivostat system, Vivostat A/S). Six patients with multiple lesions involving dermis (Grade I, n=2), subcutaneous (Grade II, n=4), or oral mucosa related to GVHD were administered the gel as local therapy. After the second gel application, the pain faded away, and granulation tissue was observed in four cases with Grade II lesions. After a median of eight PLT gel applications (range, -10), five of six patients showed a complete response, without any side effects documented.
Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. Induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), was suggested to potentiate intestinal crypt proliferation and mucosal repair [29]. A pilot study included 20 patients with steroid refractory intestinal GVHD who were given oral lithium carbonate against a group treated with glucocorticoids. As a result, 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients.
Therapy of chronic oral GVHD
Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy with minimal side effects which alleviates cGVHD in most patients. Its curative effects are explained by immunomodulatory action upon T-regulatory lymphocytes. Recent data suggest that favorable effects of extracorporeal photopheresis (UVA irradiation) upon cGVHD may be also caused by inactivation and apoptosis of peripheral blood neutrophils [30]. Meanwhile, chronic GVHD is often refractory to systemic therapies. Some workers draw attention to intraoral narrow-band ultraviolet B (NB-UVB) irradiation in oral cGVHD delivered as a course of 24 phototherapy sessions, at a single dose of >50 mJ/cm [31]. Median symptom scores (0-10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. In sum, 7/11 patients had improvement and 2/11 worsened. Hence, NB-UVB may be considered a treatment option in refractory oral cGVHD, however, requiring clinical trials with appropriate control groups.
A supplementary topical treatment of oral cGVHD is proposed by means the glucocorticoid inhalers [32]. The authors compared different formulations showing pharmacological superiority of Budesonide for topical application in oral cGVHD. Marked local anti-inflammatory effects of Budesonide are based on its very low absorption through mucosal surfaces, thus increasing the potential role in oral cGVHD management. Moreover, its viscous formulation increases mucosal contact time and provides greater pharmacological effect in mucosal inflammation [33].
Second-line treatment in refractory cGVHD may include low doses of alemtuzumab plus low doses of rituximab as suggested by Gutiérrez-Aguirre et al. [34]. The authors have observed 15 patients who received one cycle of subcutaneous alemtuzumab (10 mg/day/3 days), and intravenous rituximab 100 mg on D+4, +11, +18 and +25 post-transplant (the protocol is under clinical trial). The therapeutic response was measured on Days +30, +90 and +365 of the protocol. The main site involved was the oral mucosa (86.7%). The overall response to the treatment was 100% at Day +30 evaluation, i.e., 10 patients had partial remission and 5, complete remission. At D+90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. Adverse effects were mainly infections in 67% of patients; these were usually quickly solved.
Specific cautions for drug therapy following HSCT
First of all, one should take into account those anticancer drugs that carry the highest risk for mucositis, i.e., methotrexate, cyclophosphamide, cisplatin, and fluorouracil (Villa, Sonis, 2015).
Risk of mucositis is dose-dependent and increases with higher intensity of chemo- and/or radiation therapy. One should be cautious when administering some drugs to such patients, as follows [10]:
– General anesthetics;
– Non-steroid anti-inflammatory drugs (NSAIDs) since these drugs may augment cyclosporine and tacrolimus nephrotoxicity, and they may increase bleeding and aggravate peptic ulcers in the corticosteroid-treated patients;
– Aspirin dosage should be adjusted since it increases bleeding risks;
– Antibiotics (erythromycin, clarithromycin, tetracycline, aminoglycosides, chinolones), as well as azol antifungal azoles (ketonazol, fluconazole and itroconazol), like as NSAIDs could aaalter cyclosporine lebels in blood serum thus causing more expressed immunosuppression.
– Usage of Sirolimus, and probably, of other mTOR inhibitors for the GVHD prophylaxis, may cause acute ulcerative stomatitis affecting the non-keratinized mucosa, mainly, with tongue involvement, at median onset time of 55 days after HCST [35]. Topical corticosteroid treatment is successful in these cases.
Potential diagnostic markers
Dozens of salivary components may reflect different diseases of periodont and oral cavity, including inflammatory mediators, reactive oxidative products, cellular enzymes, tissue-breakdown products etc. [36]. Over last decade, a number of reviews have been dedicated to potential clinical significance of salivary markers for diagnostics of different somatic and infectious disorders. E.g., salivary diagnostics of cancer proteins in oral fluid is now an evolving field of diagnostics as reported by Kaur et al. [37]. However, most of current studies are directed to novel applications of salivary using the "omics" approach, studying genomic, transcriptomic, proteomic, microbiomic, and metabolomic parameters, thus bringing the solution to a big data analysis [38]. Meanwhile, a search may be focused on single specific markers showing distinct pathological disorders of oral cavity or in the entire host organism.
DNA markers
Salivary biomarkers for infectious diseases were extensively studied earlier [39]. The issue is that the infectious agents were detected by different laboratory tests (by specific antibodies, antigens or nucleic acid markers) in salivary samples. These include a large range of Herpes viruses, Hepatitis viruses, HIV, Human Papillomavirus (HPV), Influenza virus, and Poliovirus.
Moreover, hundreds of bacterial species could be found in saliva, at the oral mucosa, dental plaques and tongue surface including Escherichia coli, Mycobacterium tuberculosis, Helicobacter pylori, Treponema pallidum and a wide range of streptococcal species. Concerning fungal presentation in oral rinses, Candida species were the most frequently cultured fungi (in 75% of samples), followed by Cladosporium (65%), Aureobasidium, Saccharomycetales (50% for both), Aspergillus (35%), Fusarium (30%), and Cryptococcus (20%). [40].
Post-cytostatic immune deficiency is regularly associated with viral infections. In this view, the levels of herpesvirus type VI (HHVVI) in saliva were suggested to be a probable severity marker of chemotherapy-induced oral damage [41]. However, excessive HHV6 activation was not confirmed at later terms post-HSCT, in chronic GVHD patients [42]. The authors tested for HHV6 peripheral blood, different oral fluids from cGVHD patients and oral tissue samples from healthy blood donors. HHV6 was detected by nested polymerase chain reaction. The virus was detected in whole saliva in 13 cGVHD patients (68%) and in 19 blood donors (67%) but not in gingival crevicular fluid or parotid gland saliva. Only two oral tissue samples of cGVHD patients of 12 were positive for HHV6. In sum, these data do not support the importance of HHV6 in oral lesions of cGVHD.
Over 40 years, it has been well known that oral cavity and intestinal microbiota contain similar bacterial species as shown, e.g., by Hamilton et al. [43]. Large numbers of similar organisms (>106/m1) were recovered by microbiological cultures from oral samples and jejunal aspirate of 16 subjects, in five of whom the same organisms were present in similar relative proportions in the saliva, e.g., Fusobacteria, whereas in other cases jejunal organisms differed from those in saliva. In eight of them, jejunal flora showed a typical 'faecal' pattern usually associated with small bowel bacterial overgrowth but, in three, the jejunal floral was somewhat similar to that of saliva.
Nowadays, with development of high-throughput NGS and 16S RNA sequencing, these ratios are studied in more details [44]. Human microbiota from three different compartments, i.e., saliva, feces, and cancer tissue (CT), of patients with colorectal cancer (CRC) vs. 10 healthy controls (saliva and feces). Taxonomic analysis based on 16S rRNA gene, revealed the presence of three main bacterial phyla, which includes about 80% of sequence reads: Firmicutes, Bacteroidetes, and Proteobacteria. Differences in bacterial composition, F. nucleatum abundance in healthy controls vs. colon cancer patients, and the association of F. nucleatum with clinical parameters were observed. Hence, Fusobacterium species are part of the both oral and intestinal microbiota, especially of colon tissue. Metagenomic analyses have shown that F. nucleatum detection in saliva may be predictive for development of colorectal cancer (Nosho et al., 2016).
The leukocytes shed to saliva may be also used even for detection of specific mutations in the patients with myeloproliferative diseases. E.g., Strati et al. [45] have performed a comparative study of JAK2V617F mutation in blood and saliva taken from the patients with primary myelofibrosis. Analysis of results from 167 patients has shown that the concordance between JAK2V617F detection in blood and saliva was 96%, with a sensitivity of 100% and a specificity of 90%. This biological material seems to have, at least, as sensitive as blood analysis for this mutation.
Protein markers
Like as DNA markers, immune protein molecules, like specific immunoglobulins , may be measured in saliva and salivary gland secretions in order to detect some latent and activable viruses [46].
Searching novel markers of acute GVHD is an important issue. E.g., one may check such potential salivary biomarkers as S100 protein family members (S100A8, S100A9, and S100A7) performed by Chiusolo et al. [47]. By means of HPLC, the authors have shown S100A8 in 14 of 23 cases of GVHD in allo-HSCT patients as compared with 2 GVHDfree parients and in none case of control group ( (P<0.001). Similar trend was registered for S100A9 protein. Multiple analysis of salivary proteome allows to detect some candidate proteins specific to acute GVHD as shown by Souza et al. [48] who carried out a preliminary study of salivary proteins using PAGE gel electrophoresis, liquid chromatograpy, and modern mass spectrometry. The most relevant proteins recognized exclusively in GVHD patients were: CSF2RB, protocadherin Fat 2 precursor, protein capicua homolog isoform CIC-S, MUC16 and RGPD8_HUMAN RANBP2. Their physiological role in this complication is not clear and needs further studies.
Diagnostic and prognostic markers of acute or chronic chronic GVHD are currently searched by means of proteomic analysis performed with mass-spectrometry or other methods of protein analysis. For example, saliva collected from oral cavity of allo-HSCT patients with chronic oral GVHD and cGVHD-free cases using isobaric Tags for quantification labeling, followed by tandem mass spectrometry. The method allowed identify up to 249 salivary proteins. Of them, 82 proteins were differently expressed in oral cGVHD patients compared to GVHD-free patients. Of these proteins, most played role in immunity, proteolytic functions, or as cytoskeleton components. Salivary IL-1 receptor antagonist and Cystatin B proved to exhibit decreased expression in oral chronic GVHD (P<0.003), thus, probably, being of some diagnostic significance [49].
Conclusions
1. Intensive chemotherapy and radiation treatment of the oncohematological patients followed by hematopoietic stem cell transplantation (HSCT) brings about early inflammation and acute necrosis of oral mucosa and gingivae, atrophy of salivary glands
2. Immune deficiency is evident at all post-transplant phases and later, at the stage of immunesuppressive therapy. At early terms, it is complicated by infections, at later phase, by autoimmune affection of oral mucosae. Over next years, a risk of secondary cancers is increased.
3. Bacterial and fungal infections of oral cavity and gastrointestinal tract are especially common at early terms, whereas viral activation (including secondary tumors) is detected at later terms after HSCT. The diagnosis of infections in immunocompromised patients represents an important task for the dentist that should be resolved in close contact with attending physician.
4. Late oral pathology after HSCT in children is presented, mainly, by developmental anomalies of dental system in young patients.
5. Chronic graft-versus-host disease (cGVHD) is accompanied by the Sjogren-like problems with oral mucosa and salivary glands.
6. There is no effective etiological treatment for acute mucositis, oral GVHD, both acute and chronic clinical forms. Appropriate pathogenetic therapy is aimed for release of painful symptoms and anti-inflammatory treatment. Some new promising drugs are still used as experimental therapy.
6. By the present time, there are no recognized salivary markers for early diagnostic and prediction of severe damage of oral mucosa expected after intensive cytostatic therapy, as well as GVHD following allogeneic transplantation. However, some promising salivary tests are to be studied, to detect infections of oral cavity, local and systemic malignancies.
Conflict of interest
No conflict of interest reported.
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2Центральный научно-исследовательский институт стоматологии, Москва, Россия
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Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.
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2Central Research Institute of Stomatology, Moscow, Russia
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The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.
Keywords
Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.
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Grigoriants<sup>1</sup>, Ilya M. Rabinowitch<sup>2</sup>, Alexey B. Chukhlovin<sup>1</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(103) "Artur P. Grigoriants1, Ilya M. Rabinowitch2, Alexey B. Chukhlovin1" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(103) "Artur P. Grigoriants1, Ilya M. Rabinowitch2, Alexey B. Chukhlovin1
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20183" ["VALUE"]=> array(2) { ["TEXT"]=> string(3049) "<p style="text-align: justify;"> The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.<br> There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2977) "
The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.
Keywords
Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2977) "
The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.
Keywords
Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(175) "1The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
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" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20177" ["VALUE"]=> array(2) { ["TEXT"]=> string(177) "Артур П. Григорьянц<sup>1</sup>, Илья М. Рабинович<sup>2</sup>, Алексей Б. Чухловин<sup>1</sup>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(141) "Артур П. Григорьянц1, Илья М. Рабинович2, Алексей Б. Чухловин1" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(141) "Артур П. Григорьянц1, Илья М. Рабинович2, Алексей Б. Чухловин1" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20179" ["VALUE"]=> array(2) { ["TEXT"]=> string(3121) "<p style="text-align: justify;"> Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3055) "
Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3055) "Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.
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Introduction
Modern chemotherapy protocols and optimal radiotherapy allow to achieve stable remission in ~80% newly diagnosed Hodgkin’s lymphoma (HL) patients [1]. However, a proportion of HL patients has chemoresistant disease or relapse after initial objective response [1, 2]. Further strategy with HL patients includes salvage treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), and/or antibody-drug conjugate brentuximab vedotin [3, 4]. The patients with failure of second-line treatment have poor prognosis and limited therapeutic options [5]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated for the patients with relapsed and refractory (R/R) disease, being able to improve long-term survival and control of the disease [5]. Although allo-HSCT is a potentially curative approach in these patients, a substantial fraction of patients develops relapses and disease progression in posttransplant period, showing strong dependence on the disease status at the time of transplantation [5]. The dysfunction of immune surveillance mechanisms with alteration of PD-1 ligand (PDL-1)-to-PD-1 signaling is considered a defining feature of classical Hodgkin’s lymphoma [6]. nivolumab, a PD-1-blocking antibody, is an immune checkpoint inhibitor, showing high efficiency in patients with relapsed/refractory HL patients after ASCT and brentuximab vedotin treatment with benign toxicity profile. The most specific complications include autoimmune disorders such as pneumonitis, autoimmune hepatitis, hypothyroidism and other disorders [5]. Retrospective data demonstrated that nivolumab treatment for post-allo-HSCT may cause graft-versus-host disease (GVHD) manifestation and aggravation [7, 8, 9]. By contrary, some reports show no signs of GVHD after initiation of anti-PD-1 therapy [10]. Moreover, earlier observations show that, in HL patients after allo-HSCT, nivolumab may lead to profound clinical benefit even if applied at low doses [11]. With respect to previous reports we present retrospective results on seven HL patients relapsing after allo-HSCT subjected to nivolumab administered at different dosing regimens. In all the patients, nivolumab showed clinical efficiency with objective response and considerable toxicity, i.e., immune adverse effects, irrespective of nivolumab dosage, with no cases of GVHD manifestation.
Patients and methods
Our single-center study included seven patients (3 men and 4 women) with relapsed/refractory HL who underwent allo- HSCT. Their median age was 29 years (21 to 43 years old). Baseline characteristics of the patients are shown in Table 1. When entering the study, all the patients signed an informed consent for the use of their medical data for research purposes. The median number of prior therapeutic lines was 9 (8 to 9) including autologous stem cell transplantation (performed in 5/7 patients), and allo-HSCT. Matched HLA-related siblings were used for 3 patients. Four patients had unrelated donors: three of them were HLA-identical and one with 9/10-locus mismatch. Peripheral blood stem cells were transplanted in four patients, and bone marrow, in rest of the cases. Six patients received reduced intensity conditioning (RIC): fludarabine 30 mg/m2/bendamustine 130 mg/m2 per day for 3 days (FluBe) regimen was used in 3 patients, Flu/2 Gy TBI, in 2 patients, and Flu/8 mg/kg busulfan was used in 1 case. In 5/7 patients, the post-transplant cyclophosphamide based regimen was used for GVHD prophylaxis, i.e., cyclophosphamide 50 mg/kg on day +3 and +4 after alloHSCT (PTC) in 2 patients, PTC in combination with tacrolimus started on day + 5 (PTC-Tx) in 1 patient, PTC-Tx with addition of mycophenolate mofetil (MMF) in 2 patients, methotrexate/tacrolimus in 1 case, and antithymocyte globulin/methotrexate/ MMF/cyclosporine A in 1 patient. Objective response determined as CR or PR before allo-HSCT was documented in four patients (3 CR, 1 PR), two patients received transplant during the disease progression. Acute GVHD was reported in 6 patients, with no severe (grade III-IV) cases, and 3 patients had a limited chronic skin GVHD. Median time between the allo-HSCT and disease relapse/progression was 3.3 months (1.5-10). As salvage therapy after allo-HSCT, all patients have received the treatment with brentuximab vedotin, six of them received treatment with bendamustine. Five patients received donor lymphocyte infusions before nivolumab initiation. Median time from allo-HSCT to first injection of nivolumab was 26.7 months (range 7-42.4). One patient has received nivolumab before allo-HSCT, but treatment was discontinued due to grade 4 adverse event (bacterial meningitis). Transplantation modalities and complications are shown in Table 2. By the moment of nivolumab initiation, six patients had disease progression, one patient had stabilization of disease, 6/7 of patients presented with extranodal disease and 3/7 with B-symptoms. None of the patients had signs of GVHD at the moment of treatment initiation. Nivolumab was given as monotherapy at the dose of 3 mg/kg of body weight intravenously every two weeks for two patients. Due to concerns regarding the manifestation of GVHD and immune-related adverse events, the dose were reduced to 1 mg/kg and to the dose of 0.5 mg/kg i.v. every two weeks for 1 patient and for 4 patients, respectively. A median number of nivolumab injections was 7 (1 to 20). The treatment efficacy was assessed by total body PET/CT scan [12] every 3 months after nivolumab initiation or earlier in the event of treatment discontinuation. Toxicities were graded retrospectively according to the National Cancer Institute Common Toxicity Criteria for AEs (version 4.03).
Results
Treatment efficiency
Response to the nivolumab-based therapy was evaluated at a median follow-up time of 14.5 (3.3-22.5) months. Objective response was noted in all the patients at either nivolumab dosage. Complete metabolic response was observed in two patients (28.6%) treated with, respectively, 0.5 and 1 mg/kg of the drug. The rest of this group exhibited partial clinical responses. The maximal response and tumor mass reduction at the best response are shown in Fig. 1. and Fig. 2. The specific B symptoms of lymphoma reported before the therapy were resolved in two of three patients. The objective response was observed after a median of 6 (1-6) nivolumab injections. Four patients (57%) have experienced the disease progression at a median of 6.7 months (5 to 8.5). Two of these patients were re-treated with the same dose of nivolumab, thus allowing to achieve an objective response (CR) in one patient. After monotherapy with nivolumab, three patients underwent further treatment, with addition of bendamustine or other cytostatic agents. At the time of this report, three patients (42.9%) still receive the nivolumab monotherapy. Clinical outcomes are presented in Table 3 and Fig. 3.
Toxicity
All the patients were alive at the time of report and were subject to the safety analysis. During nivolumab treatment, 3/7 (42.9%) of the patients experienced grade 3-4 adverse events (AEs), which included two cases of aseptic meningitis (28.6%) and one case of аutoimmune hepatitis, autoimmune hypophysitis. This adverse events manifested after median of 2 (1-2) infusions of the drug. Due to severe adverse events, the nivolumab treatment was discontinued, and patients received short courses of glucocorticoids (1 mg/kg methylprednisolone) with complete resolution of the event. There was no correlation with nivolumab dosing regimen, since severe AEs were observed in patients with different drug dosage (0.5, 1, or 3 mg/kg of body weight). There were no cases of GVHD onset. Notably, the patient who had discontinued nivolumab before allo-HSCT had no adverse events in post-transplant setting. Two patients who discontinued nivolumab treatment due to AE’s, received retreatment after the disease relapse. In one patient with meningitis and hypophisitis, no AE recurrence was revealed later, in another case, a recurrence of autoimmune hepatitis was noted after 2 infusions during the first retreatment. The therapy was again discontinued, and the patient received glucocorticoids followed by complete resolution of hepatitis. The second retreatment was performed with addition of low-dose glucocorticoids in both patients, without AE signs observed.
Discussion
Allo-HSCT is a potentially curative treatment strategy for relapsed and refractory HL patients. Despite novel therapeutic modalities in HL, allogeneic HSCT is remaining an important option. Transplant-related mortality continues to decline owing to lower intensity preparative regimens [13], improved GVHD prophylaxis [5] and novel treatment modalities [4]. At the same time, HL relapse continues to present a significant problem [5]. Therapeutic options are limited in this severely pre-treated group of patients. Common treatment modalities in patients with relapse after allo-HSCT include brentuximab vedotin [14], donor lymphocyte infusions [15] and chemotherapy regimens, such as bendamustine [16] and drug combinations [17-19] with modest results.Therefore, improved post allo-HSCT treatment strategies are needed. Based on biological features of HL, and described mechanisms of graft-versus-lymphoma (GVL) effect, the enhancement of GVL with PD-1 blockade was proposed and demonstrated with several murine models [20, 21] with no GVHD aggravation, and confirmed by early clinical observations [22, 23]. Two retrospective studies [7, 9] of nivolumab salvage treatment in HL relapse after allo-HSCT demonstrate profound activity of this drug (ORR 77%-95%, CR 42%-50%), but also significant toxicity, with high rate of GVHD manifestation (30%-50%) including steroid-refractory and lethal cases of GVHD. The authors conclude that administration of anti-PD-1 after allo-HSCT should be done with extreme caution. This multicenter retrospective studies included mixed population of patients with different types of conditioning regimens and GVHD prophylaxis. Therefore, a strong need for prospective studies with standardized preparative regimens is required.
Another aspect addressed in our retrospective analysis is the dosing regimen for nivolumab. Most data regarding efficiency of nivolumab after allo-HSCT were obtained at a standard dose of 3 mg/kg every two weeks [7, 9]. Meanwhile, its pharmacokinetic studies reveal that the PD-1 peripheral receptor occupancy was saturated at doses as low as 0.3 mg/kg. There are also reports of efficient treatment with lower doses of the drug (0.5 mg/kg) in post allo-HSCT setting [11]. Thus, there is rationale for testing different doses of nivolumab in patients after allo-HSCT.
Here we present a retrospective analysis of 7 patients with HL relapse after allo-HSCT treated with nivolumab at different dosing regimens (0,5-3 mg/kg). All the patients were severely pre-treated with previous therapy (a median of 9 infusions). Most of the patients included into the study (5/7) received the posttransplant cyclophosphamide (PTC)-based GVHD prophylaxis. We demonstrate high efficiency of treatment with 100% ORR in all assessed patients and 28.6% CR rate, irrespective of the nivolumab dosing regimen. Despite high initial response rates, 4 of 7 patients (57%) have experienced disease progression at the median of 6.7 months. Importantly, nivolumab retreatment in two patients was followed by CR achievement in one patient, and clinical improvement in both cases. After median follow up of 14.5 (3.3 to 22.5) months, all the patients are alive with good quality of life.
We did not observe any GVHD onset or exacerbation in our group of patients, possibly due to use of PTC based GVHD prophylaxis regimen and long median time of treatment initiation after alloSCT (26.7 mo), 3/7 patients were experienced grade 3-4 immune AE including aseptic meningitis, hypophysitis and hepatitis. Whether the hepatic involvement was due the autoimmune hepatitis or GVHD is not completely clear, as clinical and histologic differences between GVHD and anti-PD-1 toxicity are not strictly defined. We consider our case of hepatic toxicity as hepatitis associated with anti-PD-1 drug treatment, because it presented with asymptomatic, profound increase in transaminases, while bilirubin level was within reference ranges during the entire observation period, which corresponds to common hepatic AEs induced by PD-1/PD-L1 inhibitors presenting as asymptomatic increase of AST and ALT, and total bilirubin in rare instances [24].
Despite severity of the observed immune AE’s, they regressed shortly after nivolumab discontinuation and initiation of glucocorticoid therapy. Therefore, anti-PD-1 antibodies after allo-HSCT should be administered with caution, and careful monitoring of patient is needed, especially during the first month of anti-PD-1 treatment. Previous reports of treatment with ipilimumab [25, 26] and lower doses of anti-PD-1 antibodies [11], suggested a dose-dependent or context-dependent risk of developing toxicity after the apoptosis checkpoint blockade. During our analysis we did not observed the dependence of the toxicity and effect from nivolumab dosage. Complete metabolic response observed in two patients with 0.5 and 1 mg/kg dosing regimen, and severe AEs was experienced in patients with 0.5, 1, 3 mg/kg. The results obtained with anti-PD therapy of Hodgkin’s disease should be compared with efficiency of Brentuximab, an immunotoxic drug targeted for CD30 antigen on tumor cells [27]. It proved to be highly efficient in resistant/relapsed cases of HD being currently under extensive trials [28-30]. Its combined effects with anti-PD drugs deserve further studies.
Conclusion
Our retrospective analysis of nivolumab treatment at different single dosages concerned post-allo-HSCT patients who developed HL relapse. We have confirmed clinical efficacy of nivolumab, however, with induction of severe-grade 3-4 immune AEs in three patients subjected to different dosing regimens (0.5, 1, 3 mg/kg), but without any documented GVHD cases. The prospective studies are warranted, aiming for establishment of optimal dosing regimens, as well as potential effects of conditioning and GVHD prophylaxis upon the risks and benefits of nivolumab treatment after allo-HSCT.
Conflict of interest
The authors report no conflicts of interest.
References
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28. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II Study of Brentuximab Vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
29. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, Armand P, Fanale M, Ratanatharathorn V, Kuruvilla J, Cohen JB, Collins G, Savage KJ, Trneny M, Kato K, Farsaci B, Parker SM, Rodig S, Roemer MG, Ligon AH, Engert A. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294.
30. Afanasyev BV, Moiseev IS, Alekseev SM, Mikhailova NB, Kondakova EV, Ilyin NV, Belyaеv AM. Multicenter prospective escalation-de-escalation PET-guided clinical study in classical type Hodgkin disease in the North-East of Russian Federation (RNWOHG-HD1): rationale and design. Cell Ther Transplant. 2017; 6(4): 76-81.
Introduction
Modern chemotherapy protocols and optimal radiotherapy allow to achieve stable remission in ~80% newly diagnosed Hodgkin’s lymphoma (HL) patients [1]. However, a proportion of HL patients has chemoresistant disease or relapse after initial objective response [1, 2]. Further strategy with HL patients includes salvage treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), and/or antibody-drug conjugate brentuximab vedotin [3, 4]. The patients with failure of second-line treatment have poor prognosis and limited therapeutic options [5]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated for the patients with relapsed and refractory (R/R) disease, being able to improve long-term survival and control of the disease [5]. Although allo-HSCT is a potentially curative approach in these patients, a substantial fraction of patients develops relapses and disease progression in posttransplant period, showing strong dependence on the disease status at the time of transplantation [5]. The dysfunction of immune surveillance mechanisms with alteration of PD-1 ligand (PDL-1)-to-PD-1 signaling is considered a defining feature of classical Hodgkin’s lymphoma [6]. nivolumab, a PD-1-blocking antibody, is an immune checkpoint inhibitor, showing high efficiency in patients with relapsed/refractory HL patients after ASCT and brentuximab vedotin treatment with benign toxicity profile. The most specific complications include autoimmune disorders such as pneumonitis, autoimmune hepatitis, hypothyroidism and other disorders [5]. Retrospective data demonstrated that nivolumab treatment for post-allo-HSCT may cause graft-versus-host disease (GVHD) manifestation and aggravation [7, 8, 9]. By contrary, some reports show no signs of GVHD after initiation of anti-PD-1 therapy [10]. Moreover, earlier observations show that, in HL patients after allo-HSCT, nivolumab may lead to profound clinical benefit even if applied at low doses [11]. With respect to previous reports we present retrospective results on seven HL patients relapsing after allo-HSCT subjected to nivolumab administered at different dosing regimens. In all the patients, nivolumab showed clinical efficiency with objective response and considerable toxicity, i.e., immune adverse effects, irrespective of nivolumab dosage, with no cases of GVHD manifestation.
Patients and methods
Our single-center study included seven patients (3 men and 4 women) with relapsed/refractory HL who underwent allo- HSCT. Their median age was 29 years (21 to 43 years old). Baseline characteristics of the patients are shown in Table 1. When entering the study, all the patients signed an informed consent for the use of their medical data for research purposes. The median number of prior therapeutic lines was 9 (8 to 9) including autologous stem cell transplantation (performed in 5/7 patients), and allo-HSCT. Matched HLA-related siblings were used for 3 patients. Four patients had unrelated donors: three of them were HLA-identical and one with 9/10-locus mismatch. Peripheral blood stem cells were transplanted in four patients, and bone marrow, in rest of the cases. Six patients received reduced intensity conditioning (RIC): fludarabine 30 mg/m2/bendamustine 130 mg/m2 per day for 3 days (FluBe) regimen was used in 3 patients, Flu/2 Gy TBI, in 2 patients, and Flu/8 mg/kg busulfan was used in 1 case. In 5/7 patients, the post-transplant cyclophosphamide based regimen was used for GVHD prophylaxis, i.e., cyclophosphamide 50 mg/kg on day +3 and +4 after alloHSCT (PTC) in 2 patients, PTC in combination with tacrolimus started on day + 5 (PTC-Tx) in 1 patient, PTC-Tx with addition of mycophenolate mofetil (MMF) in 2 patients, methotrexate/tacrolimus in 1 case, and antithymocyte globulin/methotrexate/ MMF/cyclosporine A in 1 patient. Objective response determined as CR or PR before allo-HSCT was documented in four patients (3 CR, 1 PR), two patients received transplant during the disease progression. Acute GVHD was reported in 6 patients, with no severe (grade III-IV) cases, and 3 patients had a limited chronic skin GVHD. Median time between the allo-HSCT and disease relapse/progression was 3.3 months (1.5-10). As salvage therapy after allo-HSCT, all patients have received the treatment with brentuximab vedotin, six of them received treatment with bendamustine. Five patients received donor lymphocyte infusions before nivolumab initiation. Median time from allo-HSCT to first injection of nivolumab was 26.7 months (range 7-42.4). One patient has received nivolumab before allo-HSCT, but treatment was discontinued due to grade 4 adverse event (bacterial meningitis). Transplantation modalities and complications are shown in Table 2. By the moment of nivolumab initiation, six patients had disease progression, one patient had stabilization of disease, 6/7 of patients presented with extranodal disease and 3/7 with B-symptoms. None of the patients had signs of GVHD at the moment of treatment initiation. Nivolumab was given as monotherapy at the dose of 3 mg/kg of body weight intravenously every two weeks for two patients. Due to concerns regarding the manifestation of GVHD and immune-related adverse events, the dose were reduced to 1 mg/kg and to the dose of 0.5 mg/kg i.v. every two weeks for 1 patient and for 4 patients, respectively. A median number of nivolumab injections was 7 (1 to 20). The treatment efficacy was assessed by total body PET/CT scan [12] every 3 months after nivolumab initiation or earlier in the event of treatment discontinuation. Toxicities were graded retrospectively according to the National Cancer Institute Common Toxicity Criteria for AEs (version 4.03).
Results
Treatment efficiency
Response to the nivolumab-based therapy was evaluated at a median follow-up time of 14.5 (3.3-22.5) months. Objective response was noted in all the patients at either nivolumab dosage. Complete metabolic response was observed in two patients (28.6%) treated with, respectively, 0.5 and 1 mg/kg of the drug. The rest of this group exhibited partial clinical responses. The maximal response and tumor mass reduction at the best response are shown in Fig. 1. and Fig. 2. The specific B symptoms of lymphoma reported before the therapy were resolved in two of three patients. The objective response was observed after a median of 6 (1-6) nivolumab injections. Four patients (57%) have experienced the disease progression at a median of 6.7 months (5 to 8.5). Two of these patients were re-treated with the same dose of nivolumab, thus allowing to achieve an objective response (CR) in one patient. After monotherapy with nivolumab, three patients underwent further treatment, with addition of bendamustine or other cytostatic agents. At the time of this report, three patients (42.9%) still receive the nivolumab monotherapy. Clinical outcomes are presented in Table 3 and Fig. 3.
Toxicity
All the patients were alive at the time of report and were subject to the safety analysis. During nivolumab treatment, 3/7 (42.9%) of the patients experienced grade 3-4 adverse events (AEs), which included two cases of aseptic meningitis (28.6%) and one case of аutoimmune hepatitis, autoimmune hypophysitis. This adverse events manifested after median of 2 (1-2) infusions of the drug. Due to severe adverse events, the nivolumab treatment was discontinued, and patients received short courses of glucocorticoids (1 mg/kg methylprednisolone) with complete resolution of the event. There was no correlation with nivolumab dosing regimen, since severe AEs were observed in patients with different drug dosage (0.5, 1, or 3 mg/kg of body weight). There were no cases of GVHD onset. Notably, the patient who had discontinued nivolumab before allo-HSCT had no adverse events in post-transplant setting. Two patients who discontinued nivolumab treatment due to AE’s, received retreatment after the disease relapse. In one patient with meningitis and hypophisitis, no AE recurrence was revealed later, in another case, a recurrence of autoimmune hepatitis was noted after 2 infusions during the first retreatment. The therapy was again discontinued, and the patient received glucocorticoids followed by complete resolution of hepatitis. The second retreatment was performed with addition of low-dose glucocorticoids in both patients, without AE signs observed.
Discussion
Allo-HSCT is a potentially curative treatment strategy for relapsed and refractory HL patients. Despite novel therapeutic modalities in HL, allogeneic HSCT is remaining an important option. Transplant-related mortality continues to decline owing to lower intensity preparative regimens [13], improved GVHD prophylaxis [5] and novel treatment modalities [4]. At the same time, HL relapse continues to present a significant problem [5]. Therapeutic options are limited in this severely pre-treated group of patients. Common treatment modalities in patients with relapse after allo-HSCT include brentuximab vedotin [14], donor lymphocyte infusions [15] and chemotherapy regimens, such as bendamustine [16] and drug combinations [17-19] with modest results.Therefore, improved post allo-HSCT treatment strategies are needed. Based on biological features of HL, and described mechanisms of graft-versus-lymphoma (GVL) effect, the enhancement of GVL with PD-1 blockade was proposed and demonstrated with several murine models [20, 21] with no GVHD aggravation, and confirmed by early clinical observations [22, 23]. Two retrospective studies [7, 9] of nivolumab salvage treatment in HL relapse after allo-HSCT demonstrate profound activity of this drug (ORR 77%-95%, CR 42%-50%), but also significant toxicity, with high rate of GVHD manifestation (30%-50%) including steroid-refractory and lethal cases of GVHD. The authors conclude that administration of anti-PD-1 after allo-HSCT should be done with extreme caution. This multicenter retrospective studies included mixed population of patients with different types of conditioning regimens and GVHD prophylaxis. Therefore, a strong need for prospective studies with standardized preparative regimens is required.
Another aspect addressed in our retrospective analysis is the dosing regimen for nivolumab. Most data regarding efficiency of nivolumab after allo-HSCT were obtained at a standard dose of 3 mg/kg every two weeks [7, 9]. Meanwhile, its pharmacokinetic studies reveal that the PD-1 peripheral receptor occupancy was saturated at doses as low as 0.3 mg/kg. There are also reports of efficient treatment with lower doses of the drug (0.5 mg/kg) in post allo-HSCT setting [11]. Thus, there is rationale for testing different doses of nivolumab in patients after allo-HSCT.
Here we present a retrospective analysis of 7 patients with HL relapse after allo-HSCT treated with nivolumab at different dosing regimens (0,5-3 mg/kg). All the patients were severely pre-treated with previous therapy (a median of 9 infusions). Most of the patients included into the study (5/7) received the posttransplant cyclophosphamide (PTC)-based GVHD prophylaxis. We demonstrate high efficiency of treatment with 100% ORR in all assessed patients and 28.6% CR rate, irrespective of the nivolumab dosing regimen. Despite high initial response rates, 4 of 7 patients (57%) have experienced disease progression at the median of 6.7 months. Importantly, nivolumab retreatment in two patients was followed by CR achievement in one patient, and clinical improvement in both cases. After median follow up of 14.5 (3.3 to 22.5) months, all the patients are alive with good quality of life.
We did not observe any GVHD onset or exacerbation in our group of patients, possibly due to use of PTC based GVHD prophylaxis regimen and long median time of treatment initiation after alloSCT (26.7 mo), 3/7 patients were experienced grade 3-4 immune AE including aseptic meningitis, hypophysitis and hepatitis. Whether the hepatic involvement was due the autoimmune hepatitis or GVHD is not completely clear, as clinical and histologic differences between GVHD and anti-PD-1 toxicity are not strictly defined. We consider our case of hepatic toxicity as hepatitis associated with anti-PD-1 drug treatment, because it presented with asymptomatic, profound increase in transaminases, while bilirubin level was within reference ranges during the entire observation period, which corresponds to common hepatic AEs induced by PD-1/PD-L1 inhibitors presenting as asymptomatic increase of AST and ALT, and total bilirubin in rare instances [24].
Despite severity of the observed immune AE’s, they regressed shortly after nivolumab discontinuation and initiation of glucocorticoid therapy. Therefore, anti-PD-1 antibodies after allo-HSCT should be administered with caution, and careful monitoring of patient is needed, especially during the first month of anti-PD-1 treatment. Previous reports of treatment with ipilimumab [25, 26] and lower doses of anti-PD-1 antibodies [11], suggested a dose-dependent or context-dependent risk of developing toxicity after the apoptosis checkpoint blockade. During our analysis we did not observed the dependence of the toxicity and effect from nivolumab dosage. Complete metabolic response observed in two patients with 0.5 and 1 mg/kg dosing regimen, and severe AEs was experienced in patients with 0.5, 1, 3 mg/kg. The results obtained with anti-PD therapy of Hodgkin’s disease should be compared with efficiency of Brentuximab, an immunotoxic drug targeted for CD30 antigen on tumor cells [27]. It proved to be highly efficient in resistant/relapsed cases of HD being currently under extensive trials [28-30]. Its combined effects with anti-PD drugs deserve further studies.
Conclusion
Our retrospective analysis of nivolumab treatment at different single dosages concerned post-allo-HSCT patients who developed HL relapse. We have confirmed clinical efficacy of nivolumab, however, with induction of severe-grade 3-4 immune AEs in three patients subjected to different dosing regimens (0.5, 1, 3 mg/kg), but without any documented GVHD cases. The prospective studies are warranted, aiming for establishment of optimal dosing regimens, as well as potential effects of conditioning and GVHD prophylaxis upon the risks and benefits of nivolumab treatment after allo-HSCT.
Conflict of interest
The authors report no conflicts of interest.
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Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.
Ключевые слова
Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.
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Lepik, Andrey V. Kozlov, Evgeniya S. Borzenkova, Marina O. Popova, Ivan S. Moiseev, Elena I. Darskaya, Asmik G. Gevorgyan, Luibov A. Tsvetkova, Sergey N. Bondarenko, Alexander L. Alyanskiy, Elena V. Kondakova, Natalya B. Mikhailova, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(263) "Kirill V. Lepik, Andrey V. Kozlov, Evgeniya S. Borzenkova, Marina O. Popova, Ivan S. Moiseev, Elena I. Darskaya, Asmik G. Gevorgyan, Luibov A. Tsvetkova, Sergey N. Bondarenko, Alexander L. Alyanskiy, Elena V. Kondakova, Natalya B. Mikhailova, Boris V. 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M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. P. Pavlov Medical University, Roentgen St. 12; 197022, St. Petersburg,Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(257) "R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. P. 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There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1806) "Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.
Keywords
Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.
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There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1806) "Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.
Keywords
Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1806) "Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.
Keywords
Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.
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Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3272) "Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.
Ключевые слова
Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3272) "Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.
Ключевые слова
Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option in a number of high-risk oncohematological patients [1]. Availability of HLA-identical siblings or compatible unrelated donors is a common limiting factor for broader allo-HSCT practice, especially among ethnical minorities [2, 3, 4]. Sufficient growth of allo HSCT worldwide activities occurs because of lowering limitations by the stage of diseases, patients’ age and comorbidities, due to introduction of fludarabin-containing conditioning regimens (RICs), thus reducing intensity of cytostatic load and transplantation-associated mortality while retaining efficiency and of treatment, along with immunoadoptive effects [5, 6, 7]. Meanwhile, nearly all patients have a potential haploidentical family donor. However, early attempts of haplo-HSCT using a native graft without T cell purging using standard immunosuppression shedules resulted into unacceptable graft-versus-host disease (GVHD) rates whereas ex vivo T cell depletion for GVHD control was accomplished by high risk of non-engraftment and infectious complications causing high mortality [8, 9, 10, 11]. In Russia, approximately 80% of patients requiring allo-HSCT do not have a compatible sibling donor, whereas a chance to find an unrelated donor do not exceed 60-70%, requiring high financial costs, thus presenting the main obstacle for timely performance of allo-HSCT [3]. Search for alternative stem cell sources, such as umbilical blood cells, or haploidentical donor is quite challenging. To control HSCT risks and to prevent non-engraftment, the workers form Perugia (Italy) have used megadoses of CD34+ cells after their positive selection (a median of >10×106/ kg weight), with minimal T cell contamination (a median of 1×104/kg weight) combined with intensive conditioning regimen [11]. This study reported engraftment in 94 of 101 patients with good GVHD control. However, the rates of non-relapse-associated mortality proved to be very high (36.5%) which were largely determined by infections associated with slow immunological recovery. Event-free survival was satisfactory in the patients transplanted in remission, being, however, extremely poor for the patients treated in resistant or relapsing cases. Complexity of this transplantation approach and high costs of the method limited its approval by other transplantation centers. A group of Chinese workers has used a method avoiding ex vivo T cell depletion based on intensive pre-transplant treatment using myeloablative GIAC conditioning regimens (MAC) combined with anti-thymocyte gobulin as in vivo T cell depletion. The research team used a combined non-manipulated graft containing stimulated peripheral HCSs and bone marrow HSCs. 250 patients with acute leukemias were reported to achieve full donor chimerism, whereas acute and chronic GVHD frequencies were, respectively, 46% and 54%. Despite satisfactory relapse-free survival rates, the standard-risk patients often suffered with opportunistic infections, Transplant-related mortality rates for standard-risk and high-risk groups were, respectively, 19.5% и 29.5% for acute myeloid leukemia (AML), or 21% and 51% for acute lymphoblastic leukemia (ALL) [13]. Another approach to allo-HSCT was developed in Baltimore (USA) included usage of non-manipulated graft followed by post-transplant cyclophosphamide injection (PtCy) to control T cell reactivity after HSCT seems to overcome most obstacles historically connected with haplo-HSCT [14, 22]. Over last years, the haplo-HSCT methodology has experienced sufficient changes, i.e., novel conditioning protocols were developed with decreased toxicity and low dose intensity; the ex vivo T cell depletion options were designed, i.e., CD34+ cell selection, CD3+/CD19+ cell depletion, γ/β TCR chain depletion. The in vivo trials, suggest favorable effects from usage of anti-thymocyte globulins (ATG), cyclophosphamide at at high doses on D+3, D+4 after the haploidentical transplant. An immune response modification could be carried out as reduction of T cell reactivity by changing the Th1/Th2 balance, by means of hematopoiesis stimulation with G-CSF before myeloexfusion. Pharmacological prophylaxis of acute GVHD (aGVHD) is accomplished by new therapies, e.g., with rapamycin, the mTOR inhibitor [14, 15, 16]. Good efficiency of haploidentical HSCT is shown for the 1st and 2nd remissions of AML, with 5-year relapse-free survival of 82.5%, and 59.4%. Appropriate figures for ALL were 68.9% and 56.6% [15]. The results of relapsed and resistant clinical forms were unsatisfactory if using allo-HSCT, or hapolo-HSC, i.e., the 5-year overall survival in AML was 42.9% and 22.2% in ALL [15, 16, 17, 18]. The aim of our study was to assess efficiency of haplo-HSCT performed with non-manipulated grafts of children and adolescents with high-risk acute leukemias. In this respect an efficiency study of haploidentical GVHD was performed at our clinic in children and adolescents with high-risk ALL and AML, at maximal observation terms of 10 years.
Patients and methods
The study included 106 children and adolescents 0 to 18 years old (median age, 7 y.o.). with primary diagnosis of ALL in 63 cases (59.4%), and AML (43 patients, 41%), who underwent allo-HSCT from haploidentical donors within a time period of December 2006 to December 2016 года. The patients were followed up for a maximum of 10 years.
Haploidentical HSCT was performed in remission state for 43 patients (40.6%), i.e., 21 patients were transplanted in 1st remission, 13 patients, in 2nd remission, and nine children were treated in 3rd remission. Sixty-three relapsed/ therapy-resistant (R/R) patients with AL were transplanted (59.4% of total). Several MAC schedules were applied for conditioning treatment, i.e., GIAC protocol (39 cases, 36.8% of total) including busulfan (16 mg/kg body weight), cyclophosphamide (Cy) at a dose of 2000 mg/m2, cytosar (8000 mg/m2), lomustin (120 mg/kg). Other MACs were based on busulfan (12 mg/kg) and Fludarabin (150 mg/m2), being applied in 2 patients (2%), and a regimen based on Treosulfan (42 g/m2) was used in 6 cases (5.7%). The reduced-intensity conditioning regimens (RICs) based on melphalan (140 mg/m2) were applied in 40 recipients (37.7%), whereas RICs containing busulfan (8 mg/kg) were used in 18 patients (17%).
All the patients underwent aGHVD prophylaxis, i.e., antithymocyte globulin (ATGAM) was injected at 60 mg/kg weight in 39 cases (36.8%); whereas post-transplant cyclophosphamide (PtCy, 50 mg/kg) was injected on D+3 and D+4 in 67 recipients (63.2%). Basic immune suppressive therapy (IST) included Tacrolimus (0.03 mg/kg/d) for 47 patients (44.3%); cyclosporine A (3 mg/kg/d was used in 59 cases (55.7%). In addition to tacrolimus, an mTOR inhibitor at 1 mg/m2 was administered since D+3. Clinical parameters of the patients enrolled into the study, are summarized in Table 1.
Two methods were used for yielding the haploidentical donor grafts, i.e.:
1. A combined graft containing bone marrow and peripheral hematopoietic stem cells (PHSCs) obtained after G-CSF priming (5 mg/kg/d, for 4 days) then followed by positive selection of CD34+ клеток with a CliniMACS device (Miltenyi Biotec). This cell product was applied in 27 cases (25.5%).
2. Non-manipulated marrow graft primed with G-CSF (5 mg/kg/d for 3 days) was obtained and used in 79 patients (74.5%). The median cellularity as for transfused CD34+ cells comprised 5.9х106/kg weight for non-manipulated bone marrow (1.0 to 9х106/kg), and 5.9х106/kg for the combined graft (2.5 to 30.9х106/kg).
Results
Hematopoiesis recovery
Stem cell engraftment after haplo-HSCT was documented in 80 total group of patients (75.7% of total). Median engraftment term was D+24 (D+14 to D+34). Primary non-engraftment was revealed in 26 patients (24.5%) due to chemoresistance and/or relapsed AL. The median recovery terms for granulocytes (>0.5x109/L) was D+19 (D+10 to D+34); for leukocytes (>1.0x109/L), D+17 (D+10 to D+34); for platelets reconstitution (>20x109/L), D+17 (D+10–D+41). Median recovery time for lymphocytes (>30x109/L) was D+29 (D+14 to D+50). Full donor chimerism was registered in 67 cases (83.8%) by day +30 posttransplant. Thirteen patients (16.2%) developed full chimerism by day +60 after HSCT.
Survival data
Ten-year overall survival (OS) in total group proved to be 33.3% after haplo-HSCT (Fig. 1). In particular, the ten-year OS in patients transplanted in 1st and 2nd remissions was 64.7% as compared to 18.1% for the patients transplanted beyond the remission. (р=0.01; Fig. 2). Overall survival for the patients who received G-CSF-primed, non-manipulated bone marrow and in those who got combined marrow/peripheral grafts was, respectively, 38% and 18.5% (р=0.03, Fig. 3). The AL type did not influence the 10-year survival, i.e., 36.5% vs 27.9% respectively, for ALL and AML subgroups. The OS values in ALL versus AML patients transplanted in 1st or 2nd remissions have shown comparable OS rates, respectively, 68.2% and 58.3%. We could not show any significant correlations between the 10-year survival and recovery kinetics of leukocytes, neutrophils and platelets post-transplant.
Figure 1. Ten-year overall survival in children and adolescents with acute leukemias after haplo-HSCT
Figure 2. Ten-year overall survival in children and adolescents after haplo-HSCT performed in 1st and 2nd remission (р=0.01)
Figure 3. Ten-year overall survival in children and adolescents after haplo-HSCT for the groups receiving a G-CSF-primed nonmanipulated bone marrow (blue graph), or a combined hematopoietic graft (green graph). The difference is significant at р=0.03
Comparative OS values are presented in Table 2. The 10-year OS did not statistically differ between the groups receiving different conditioning regimens. It could be explained by small numbers of cases and inability to tolerate the full-dose conditioning regimens in resistant AL cases. Hence, OS rates among patients who received MAC regimens comprised 36.2% as compared to 30.5% for the RIC group. The OS values upon more detailed evaluation and subgroup division were as follows: MAC, 28.6%; MAC+PtCy treatment, 40%; RIC, 16.7%, and RIC+PtCy, 38.1% (р>0.05).
Posttransplant complications
Acute graft-versus-host disease (GVHD) is a major immunological disorder developing early after allo-HSCT. Of 80 patients who achieved engraftment, aGVHD grade II was observed in 21 cases (26.3%); severe GVHD (grade III to IV) was diagnosed in 15 patients (18.6%). Leukemia relapses were registered in 51 of 106 patients (48.1%), with a mediane of D+91 after haplo-HSCT (D+17 to D+1101). Occurrence of relapses post haplo-HSCT, if performed in 1st or 2nd remission was 23.5%, with a median of D+88 (D+30 to D+301). The disease recurrence was more common in recipients with resistant or relapsing disease (56,9%, with a median development on D+81 post-transplant). The overall transplant-associated mortality was 21.6% in the studied group. Fatal infectious complications in the early post-transplant period were registered in 14 patients (13.2%). Acute GVHD caused death of 7 patients (8.8%), lethal toxic conditions, in 2 cases (1.9%). Meanwhile, the leukemia relapses proved to prevail in post-engraftment lethality among children and adolescents undergoing haplo-HSCT (39 patients, 48.8%). Posttransplant relapses among the patients transplanted in 1st and 2nd remissions resulted into lethal outcome in 6 cases (17.6%). Meanwhile, the AL recurrence with lethal outcome was registered in 33 cases (45.8%) among patients who received haploidentical grafts in resistant or relapsing disease upon engraftment.
Discussion
At the present time, HSCT from haploidentical donors is known to be an effective and safe treatment approach for the high-risk leukemia patients, requiring allo-HSCT for urgent reasons, especially in absence of a compatible donors, either related or unrelated ones. Fast preparation of a donor and HSC isolation, good chances for repeated graft harvest if required, as well as minimal financial costs comprise clear benefits of haplo-HSCT. However, some cautions exist, due to risks of posttransplant complications, such as acute GVHD and severe infections determined by marked immunosuppression and prolonged immune recovery after haplo-HSCT. Moreover, a specific graft-versus-leukemia (GvL) response after haplo-HSCT and persistence of this effect is still in question, being subject to different studies [20]. Application of RIC regimens as a platform for the post-transplant immunonadoptive therapy may provide an additional tool for enhancement of the GvL immune reaction without increasing the transplant-related mortality. Some promising data on the subject are published by a study team at the John Hopkins and Fred Hutchinson Cancer Research Center on the patients with high-risk acute leukemia who underwent reduced-intensity conditioning followed by haplo-HSCT and post-transplant cyclophosphamide injections on D+3 and D+4. According to this study, clinical engraftment was registered in 87% of the cases, with OS values of 41%. Clinically sound aGHVD (grade II-IV) was registered in <27%, with chronic GVHD documented in 15% of the cases. However, frequency of post-transplant relapses remained high (55%), with relatively low transplant-related mortality (18%) [20, 22]. Our own data on haplo-HSCT confirm the high rates of transplant engraftment (80%), while reaching full donor chimerism by day+30 in 84% of the cases. The rest of this group developed full chimerism by day +60 post-HSCT. Overall survival with a maximal observation term of 10 years was 33.3% for the total group. Frequency of clinical aGVHD in our study is also comparable to the previously reported data,i.e., prevalence of aGVHD grade II was 26.3%, aGVHD grade III-IV, 18.6%, which does not exceed the published values [20]. We have obtained encouraging results on the 10-year overall survival (64.7%) for the haplo-HSCT patients who received their graft during 1st and 2nd remissions. Absence of severe lethal infectious complications before D+100 seems to be connected with faster T cell reconstitution. Post-transplant relapses represent the main problem for these patients. High percentage of such dismal outcomes (48.1%) may be explained by the disease status at the time of haplo-HSCT. The majority of patients (72 cases, 68%) were transplanted beyond the registered remission. According to the data published by Italian workers, the relapse rates may reach 50% in such patient groups [7, 12].
Conclusion
Allo-HSCT of the non-manipulated primed bone marrow from a haploidentical donor proved to be an effective approach, in order to achieve clinical remission in children and adolescents with high-risk AL. At the present time, one may discuss relative benefits of different stem cell separation techniques for haplo-HSCT in childhood. Implementation of post-transplant cyclophosphamide (PtCy) proved to be an available and effective regimen improving clinical results of haplo-HSCT. State of the disease is the main factor influencing overall survival after haplo-HSCT. First or second remission of ALL or AML is the optimal time-point for haplo- HSCT. To improve the results of haplo-HSCT in Russia, the appropriate cooperative multicentric studies are required in this research area.
Conflict of interest
The authors report no conflicts of interest.
References
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Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option in a number of high-risk oncohematological patients [1]. Availability of HLA-identical siblings or compatible unrelated donors is a common limiting factor for broader allo-HSCT practice, especially among ethnical minorities [2, 3, 4]. Sufficient growth of allo HSCT worldwide activities occurs because of lowering limitations by the stage of diseases, patients’ age and comorbidities, due to introduction of fludarabin-containing conditioning regimens (RICs), thus reducing intensity of cytostatic load and transplantation-associated mortality while retaining efficiency and of treatment, along with immunoadoptive effects [5, 6, 7]. Meanwhile, nearly all patients have a potential haploidentical family donor. However, early attempts of haplo-HSCT using a native graft without T cell purging using standard immunosuppression shedules resulted into unacceptable graft-versus-host disease (GVHD) rates whereas ex vivo T cell depletion for GVHD control was accomplished by high risk of non-engraftment and infectious complications causing high mortality [8, 9, 10, 11]. In Russia, approximately 80% of patients requiring allo-HSCT do not have a compatible sibling donor, whereas a chance to find an unrelated donor do not exceed 60-70%, requiring high financial costs, thus presenting the main obstacle for timely performance of allo-HSCT [3]. Search for alternative stem cell sources, such as umbilical blood cells, or haploidentical donor is quite challenging. To control HSCT risks and to prevent non-engraftment, the workers form Perugia (Italy) have used megadoses of CD34+ cells after their positive selection (a median of >10×106/ kg weight), with minimal T cell contamination (a median of 1×104/kg weight) combined with intensive conditioning regimen [11]. This study reported engraftment in 94 of 101 patients with good GVHD control. However, the rates of non-relapse-associated mortality proved to be very high (36.5%) which were largely determined by infections associated with slow immunological recovery. Event-free survival was satisfactory in the patients transplanted in remission, being, however, extremely poor for the patients treated in resistant or relapsing cases. Complexity of this transplantation approach and high costs of the method limited its approval by other transplantation centers. A group of Chinese workers has used a method avoiding ex vivo T cell depletion based on intensive pre-transplant treatment using myeloablative GIAC conditioning regimens (MAC) combined with anti-thymocyte gobulin as in vivo T cell depletion. The research team used a combined non-manipulated graft containing stimulated peripheral HCSs and bone marrow HSCs. 250 patients with acute leukemias were reported to achieve full donor chimerism, whereas acute and chronic GVHD frequencies were, respectively, 46% and 54%. Despite satisfactory relapse-free survival rates, the standard-risk patients often suffered with opportunistic infections, Transplant-related mortality rates for standard-risk and high-risk groups were, respectively, 19.5% и 29.5% for acute myeloid leukemia (AML), or 21% and 51% for acute lymphoblastic leukemia (ALL) [13]. Another approach to allo-HSCT was developed in Baltimore (USA) included usage of non-manipulated graft followed by post-transplant cyclophosphamide injection (PtCy) to control T cell reactivity after HSCT seems to overcome most obstacles historically connected with haplo-HSCT [14, 22]. Over last years, the haplo-HSCT methodology has experienced sufficient changes, i.e., novel conditioning protocols were developed with decreased toxicity and low dose intensity; the ex vivo T cell depletion options were designed, i.e., CD34+ cell selection, CD3+/CD19+ cell depletion, γ/β TCR chain depletion. The in vivo trials, suggest favorable effects from usage of anti-thymocyte globulins (ATG), cyclophosphamide at at high doses on D+3, D+4 after the haploidentical transplant. An immune response modification could be carried out as reduction of T cell reactivity by changing the Th1/Th2 balance, by means of hematopoiesis stimulation with G-CSF before myeloexfusion. Pharmacological prophylaxis of acute GVHD (aGVHD) is accomplished by new therapies, e.g., with rapamycin, the mTOR inhibitor [14, 15, 16]. Good efficiency of haploidentical HSCT is shown for the 1st and 2nd remissions of AML, with 5-year relapse-free survival of 82.5%, and 59.4%. Appropriate figures for ALL were 68.9% and 56.6% [15]. The results of relapsed and resistant clinical forms were unsatisfactory if using allo-HSCT, or hapolo-HSC, i.e., the 5-year overall survival in AML was 42.9% and 22.2% in ALL [15, 16, 17, 18]. The aim of our study was to assess efficiency of haplo-HSCT performed with non-manipulated grafts of children and adolescents with high-risk acute leukemias. In this respect an efficiency study of haploidentical GVHD was performed at our clinic in children and adolescents with high-risk ALL and AML, at maximal observation terms of 10 years.
Patients and methods
The study included 106 children and adolescents 0 to 18 years old (median age, 7 y.o.). with primary diagnosis of ALL in 63 cases (59.4%), and AML (43 patients, 41%), who underwent allo-HSCT from haploidentical donors within a time period of December 2006 to December 2016 года. The patients were followed up for a maximum of 10 years.
Haploidentical HSCT was performed in remission state for 43 patients (40.6%), i.e., 21 patients were transplanted in 1st remission, 13 patients, in 2nd remission, and nine children were treated in 3rd remission. Sixty-three relapsed/ therapy-resistant (R/R) patients with AL were transplanted (59.4% of total). Several MAC schedules were applied for conditioning treatment, i.e., GIAC protocol (39 cases, 36.8% of total) including busulfan (16 mg/kg body weight), cyclophosphamide (Cy) at a dose of 2000 mg/m2, cytosar (8000 mg/m2), lomustin (120 mg/kg). Other MACs were based on busulfan (12 mg/kg) and Fludarabin (150 mg/m2), being applied in 2 patients (2%), and a regimen based on Treosulfan (42 g/m2) was used in 6 cases (5.7%). The reduced-intensity conditioning regimens (RICs) based on melphalan (140 mg/m2) were applied in 40 recipients (37.7%), whereas RICs containing busulfan (8 mg/kg) were used in 18 patients (17%).
All the patients underwent aGHVD prophylaxis, i.e., antithymocyte globulin (ATGAM) was injected at 60 mg/kg weight in 39 cases (36.8%); whereas post-transplant cyclophosphamide (PtCy, 50 mg/kg) was injected on D+3 and D+4 in 67 recipients (63.2%). Basic immune suppressive therapy (IST) included Tacrolimus (0.03 mg/kg/d) for 47 patients (44.3%); cyclosporine A (3 mg/kg/d was used in 59 cases (55.7%). In addition to tacrolimus, an mTOR inhibitor at 1 mg/m2 was administered since D+3. Clinical parameters of the patients enrolled into the study, are summarized in Table 1.
Two methods were used for yielding the haploidentical donor grafts, i.e.:
1. A combined graft containing bone marrow and peripheral hematopoietic stem cells (PHSCs) obtained after G-CSF priming (5 mg/kg/d, for 4 days) then followed by positive selection of CD34+ клеток with a CliniMACS device (Miltenyi Biotec). This cell product was applied in 27 cases (25.5%).
2. Non-manipulated marrow graft primed with G-CSF (5 mg/kg/d for 3 days) was obtained and used in 79 patients (74.5%). The median cellularity as for transfused CD34+ cells comprised 5.9х106/kg weight for non-manipulated bone marrow (1.0 to 9х106/kg), and 5.9х106/kg for the combined graft (2.5 to 30.9х106/kg).
Results
Hematopoiesis recovery
Stem cell engraftment after haplo-HSCT was documented in 80 total group of patients (75.7% of total). Median engraftment term was D+24 (D+14 to D+34). Primary non-engraftment was revealed in 26 patients (24.5%) due to chemoresistance and/or relapsed AL. The median recovery terms for granulocytes (>0.5x109/L) was D+19 (D+10 to D+34); for leukocytes (>1.0x109/L), D+17 (D+10 to D+34); for platelets reconstitution (>20x109/L), D+17 (D+10–D+41). Median recovery time for lymphocytes (>30x109/L) was D+29 (D+14 to D+50). Full donor chimerism was registered in 67 cases (83.8%) by day +30 posttransplant. Thirteen patients (16.2%) developed full chimerism by day +60 after HSCT.
Survival data
Ten-year overall survival (OS) in total group proved to be 33.3% after haplo-HSCT (Fig. 1). In particular, the ten-year OS in patients transplanted in 1st and 2nd remissions was 64.7% as compared to 18.1% for the patients transplanted beyond the remission. (р=0.01; Fig. 2). Overall survival for the patients who received G-CSF-primed, non-manipulated bone marrow and in those who got combined marrow/peripheral grafts was, respectively, 38% and 18.5% (р=0.03, Fig. 3). The AL type did not influence the 10-year survival, i.e., 36.5% vs 27.9% respectively, for ALL and AML subgroups. The OS values in ALL versus AML patients transplanted in 1st or 2nd remissions have shown comparable OS rates, respectively, 68.2% and 58.3%. We could not show any significant correlations between the 10-year survival and recovery kinetics of leukocytes, neutrophils and platelets post-transplant.
Figure 1. Ten-year overall survival in children and adolescents with acute leukemias after haplo-HSCT
Figure 2. Ten-year overall survival in children and adolescents after haplo-HSCT performed in 1st and 2nd remission (р=0.01)
Figure 3. Ten-year overall survival in children and adolescents after haplo-HSCT for the groups receiving a G-CSF-primed nonmanipulated bone marrow (blue graph), or a combined hematopoietic graft (green graph). The difference is significant at р=0.03
Comparative OS values are presented in Table 2. The 10-year OS did not statistically differ between the groups receiving different conditioning regimens. It could be explained by small numbers of cases and inability to tolerate the full-dose conditioning regimens in resistant AL cases. Hence, OS rates among patients who received MAC regimens comprised 36.2% as compared to 30.5% for the RIC group. The OS values upon more detailed evaluation and subgroup division were as follows: MAC, 28.6%; MAC+PtCy treatment, 40%; RIC, 16.7%, and RIC+PtCy, 38.1% (р>0.05).
Posttransplant complications
Acute graft-versus-host disease (GVHD) is a major immunological disorder developing early after allo-HSCT. Of 80 patients who achieved engraftment, aGVHD grade II was observed in 21 cases (26.3%); severe GVHD (grade III to IV) was diagnosed in 15 patients (18.6%). Leukemia relapses were registered in 51 of 106 patients (48.1%), with a mediane of D+91 after haplo-HSCT (D+17 to D+1101). Occurrence of relapses post haplo-HSCT, if performed in 1st or 2nd remission was 23.5%, with a median of D+88 (D+30 to D+301). The disease recurrence was more common in recipients with resistant or relapsing disease (56,9%, with a median development on D+81 post-transplant). The overall transplant-associated mortality was 21.6% in the studied group. Fatal infectious complications in the early post-transplant period were registered in 14 patients (13.2%). Acute GVHD caused death of 7 patients (8.8%), lethal toxic conditions, in 2 cases (1.9%). Meanwhile, the leukemia relapses proved to prevail in post-engraftment lethality among children and adolescents undergoing haplo-HSCT (39 patients, 48.8%). Posttransplant relapses among the patients transplanted in 1st and 2nd remissions resulted into lethal outcome in 6 cases (17.6%). Meanwhile, the AL recurrence with lethal outcome was registered in 33 cases (45.8%) among patients who received haploidentical grafts in resistant or relapsing disease upon engraftment.
Discussion
At the present time, HSCT from haploidentical donors is known to be an effective and safe treatment approach for the high-risk leukemia patients, requiring allo-HSCT for urgent reasons, especially in absence of a compatible donors, either related or unrelated ones. Fast preparation of a donor and HSC isolation, good chances for repeated graft harvest if required, as well as minimal financial costs comprise clear benefits of haplo-HSCT. However, some cautions exist, due to risks of posttransplant complications, such as acute GVHD and severe infections determined by marked immunosuppression and prolonged immune recovery after haplo-HSCT. Moreover, a specific graft-versus-leukemia (GvL) response after haplo-HSCT and persistence of this effect is still in question, being subject to different studies [20]. Application of RIC regimens as a platform for the post-transplant immunonadoptive therapy may provide an additional tool for enhancement of the GvL immune reaction without increasing the transplant-related mortality. Some promising data on the subject are published by a study team at the John Hopkins and Fred Hutchinson Cancer Research Center on the patients with high-risk acute leukemia who underwent reduced-intensity conditioning followed by haplo-HSCT and post-transplant cyclophosphamide injections on D+3 and D+4. According to this study, clinical engraftment was registered in 87% of the cases, with OS values of 41%. Clinically sound aGHVD (grade II-IV) was registered in <27%, with chronic GVHD documented in 15% of the cases. However, frequency of post-transplant relapses remained high (55%), with relatively low transplant-related mortality (18%) [20, 22]. Our own data on haplo-HSCT confirm the high rates of transplant engraftment (80%), while reaching full donor chimerism by day+30 in 84% of the cases. The rest of this group developed full chimerism by day +60 post-HSCT. Overall survival with a maximal observation term of 10 years was 33.3% for the total group. Frequency of clinical aGVHD in our study is also comparable to the previously reported data,i.e., prevalence of aGVHD grade II was 26.3%, aGVHD grade III-IV, 18.6%, which does not exceed the published values [20]. We have obtained encouraging results on the 10-year overall survival (64.7%) for the haplo-HSCT patients who received their graft during 1st and 2nd remissions. Absence of severe lethal infectious complications before D+100 seems to be connected with faster T cell reconstitution. Post-transplant relapses represent the main problem for these patients. High percentage of such dismal outcomes (48.1%) may be explained by the disease status at the time of haplo-HSCT. The majority of patients (72 cases, 68%) were transplanted beyond the registered remission. According to the data published by Italian workers, the relapse rates may reach 50% in such patient groups [7, 12].
Conclusion
Allo-HSCT of the non-manipulated primed bone marrow from a haploidentical donor proved to be an effective approach, in order to achieve clinical remission in children and adolescents with high-risk AL. At the present time, one may discuss relative benefits of different stem cell separation techniques for haplo-HSCT in childhood. Implementation of post-transplant cyclophosphamide (PtCy) proved to be an available and effective regimen improving clinical results of haplo-HSCT. State of the disease is the main factor influencing overall survival after haplo-HSCT. First or second remission of ALL or AML is the optimal time-point for haplo- HSCT. To improve the results of haplo-HSCT in Russia, the appropriate cooperative multicentric studies are required in this research area.
Conflict of interest
The authors report no conflicts of interest.
References
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Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.
Цель
Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.
Материалы и методы
106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.
Результаты
Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.
Выводы
Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.
Ключевые слова
Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».
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Paina, Polina V. Kozhokar, Anastasia S. Borovkova, Anastasia S. Frolova, Kirill A. Ekushov, Tatyana A. Bykova, Zhemal Z. Rakhmanova, Mariya A. Galas, Aigul G. Khabirova, Inna V. Markova, Elena V. Semenova, Sergey N. Bondarenko, Elena V. Babenko, Tatyana L. Gindina, Alexander L. Alyanskiy, Ildar M. Barkhatov, Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev " ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(383) "Olesya V. Paina, Polina V. Kozhokar, Anastasia S. Borovkova, Anastasia S. Frolova, Kirill A. Ekushov, Tatyana A. Bykova, Zhemal Z. Rakhmanova, Mariya A. Galas, Aigul G. Khabirova, Inna V. Markova, Elena V. Semenova, Sergey N. Bondarenko, Elena V. Babenko, Tatyana L. Gindina, Alexander L. Alyanskiy, Ildar M. Barkhatov, Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. 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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State I. Pavlov Medical University; St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(241) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State I. 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During 10 years in R/G/Memorial Institute of children oncology,<br> hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients. </p> <h3 style="text-align: justify;">Materials and methods</h3> <p style="text-align: justify;"> 106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w. </p> <h3 style="text-align: justify;">Statistical analysis</h3> <p style="text-align: justify;"> SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike. </p> <h3 style="text-align: justify;">Conclusion</h3> <p style="text-align: justify;"> Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100. </p> <h3 style="text-align: justify;">Keywords</h3> <p style="text-align: justify;"> Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3258) "
Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.
Materials and methods
106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.
Statistical analysis
SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.
Conclusion
Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.
Keywords
Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.
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Afanasyev" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20193" ["VALUE"]=> array(2) { ["TEXT"]=> string(3462) "<p style="text-align: justify;"> Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,<br> hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients. </p> <h3 style="text-align: justify;">Materials and methods</h3> <p style="text-align: justify;"> 106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w. </p> <h3 style="text-align: justify;">Statistical analysis</h3> <p style="text-align: justify;"> SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike. </p> <h3 style="text-align: justify;">Conclusion</h3> <p style="text-align: justify;"> Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100. </p> <h3 style="text-align: justify;">Keywords</h3> <p style="text-align: justify;"> Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3258) "
Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.
Materials and methods
106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.
Statistical analysis
SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.
Conclusion
Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.
Keywords
Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3258) "
Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.
Materials and methods
106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.
Statistical analysis
SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.
Conclusion
Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.
Keywords
Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.
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Афанасьев" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20189" ["VALUE"]=> array(2) { ["TEXT"]=> string(7222) "<p style="text-align: justify;"> Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ. </p> <h3 style="text-align: justify;">Цель</h3> <p style="text-align: justify;"> Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии. </p> <h3 style="text-align: justify;">Материалы и методы</h3> <p style="text-align: justify;"> 106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х10<sup>6</sup>/кг (медиана 5,9х10<sup>6</sup>/кг), клеточность КМ+ПСКК от 2,5 до 30,9х10<sup>6</sup>/ кг (медиана 5,9х10<sup>6</sup>/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x10<sup>6</sup>/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x10<sup>6</sup>/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x10<sup>6</sup>/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек. </p> <h3 style="text-align: justify;">Выводы</h3> <p style="text-align: justify;"> Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина». </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6876) "
Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.
Цель
Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.
Материалы и методы
106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.
Результаты
Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.
Выводы
Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.
Ключевые слова
Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(6876) "Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.
Цель
Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.
Материалы и методы
106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.
Результаты
Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.
Выводы
Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.
Ключевые слова
Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».
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Introduction
Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, W. Dameshek (1967) has noticed that severe AA may transform into paroxysmal nocturnal hemoglobinuria (PNH), secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [1]. At the present time, this dependence is confirmed by numerous studies [2-15]. Moreover, recent data show high incidence up to 50% somatic mutations in patients with acquired AA, involving genes commonly mutated in myeloid malignancies [4]. Previously, most patients died within a year after primary diagnosis of SAA, until 1980’s when implementation of antithymocyte globulin (ATG) combined with cyclosporin A (CsA) proved to be an effective immunosuppressive therapy (IST). Therefore, secondary clonal disorders in AA have become more common, due to longer survival of the patients. From 10 to 30% of AA patients treated with IST were shown to develop secondary clonal diseases, i.e., MDS/AML or PNH, with a cumulative risk of 8 to 18% within next 10 years [2-6, 7, 8, 14]. The patients with secondary disorders have worse prognosis than de novo AML or MDS cases, with a median survival of <1 year [11, 12, 13]. Diagnosis of NSAA, shorter telomere length, splenectomy, two or more ATG courses is related to increase risk for subsequent clonal complications [2, 6, 9, 10, 15, 16]. By contrary, allogeneic bone marrow transplantation aimed for AA treatment causes a sufficiently reduced risk of such secondary disorders [11]. Therapeutic experience for these patients is limited, due to their rarity in common hematological practice. Clinical remissions achieved in such patients usually short and accompanied by high minimal residual disease levels. Moreover, these patients poorly tolerate chemotherapy; they develop longer cytopenia and often die from complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative method for these conditions. The aim of present study was to evaluate efficiency of allo-HSCT in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes.
Patients and methods
The retrospective study included 26 patients with MDS/AML, previously treated with IST due to acquired AA. The patients were observed in First St. Petersburg State I. Pavlov Medical University and Novosibirsk Institute of Clinical Immunology from July 1998 to June 2018. The survival assessment was completed at 15.06.2018. Acquired AA was diagnosed according to standard criteria (International Agranulocytosis and Aplastic Anemia Study Group, 1987). The AA severity grade was evaluated by common criteria [17, 18]. The degree of response corresponded to standard definitions [19]. Fanconi anemia and other inherited AA were not included into the study. Majority of patients (19/26), received as a combination of ATG and CsA, six patients received CsA as monotherapy. Splenectomy has been performed in other centers in seven cases. The patients were observed for a median of 6 years (range, 0.9 to 33) from the AA diagnosis. Sixteen patients were enrolled into the study group at the stage of clonal disorders. The median age at the time of AA diagnosis was 17 (range, 5 to 41) and 25 (range, 9 to 45) years at MDS/AML transformation, respectively. MDS transformation was diagnosed by characteristic morphological changes in bone marrow, increasing blast cell numbers, and typical chromosome aberrations (International Working Group on Morphology of Myelodysplastic Syndrome, 2008). Clinical MDS variant was determined according to the WHO classification (WHO classification of the myeloid neoplasms, 2016). AML was diagnosed when the ratio of blast cells in bone marrow exceeded 20%. The AML phenotype was determined by means of morphological, cytochemical, mmunophenotyping assays, as well as cytogenetic methods and molecular markers. Eight patients were treated with chemotherapy and/or hypomethylating treatment. All the patients provided informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. Eighteen patients received allo-HSCT, either from matched related donor (MRD) (n=6), matched unrelated donor (MUD) (n=9) or haploidentical donor (n=3). Most patients underwent the non-myeloablative conditioning regimen consisting of fludarabine 180 mg/m2 and busulfan 10 mg/kg (n=14). Graft-versus-host disease (GVHD) prophylaxis included the combination tacrolimus (Tx) and mycophenolate mofetil (MMF) (n=6), CsA/methotrexate combined therapy (n=6) and post-transplant cyclophosphamide (PtCy) at a dose of 50 mg/kg on D+3, D+4 (n=6). Engraftment criteria were absolute neutrophil counts of >0.5х109/L for 3 subsequent days and platelet numbers to >20х109/L in absence of preceding platelet transfusions for 7 days. The GvHD severity and grade were assessed according to Przepiorka D. et al., 1995 [20]. Clinical relapse was diagnosed upon hematological recurrence of MDS or AML signs. The overall survival parameters were evaluated by Kaplan-Meier approach, calculating the confidence interval values (CI 95%) using a log-rank test for evaluation of differences between the survival curves. Descriptive inter-group differences were evaluated with exact Fisher criterion for categorical characteristics, and Mann-Whitney U test (for 2 groups) and Kruskal-Wallis criterion (>2 groups). Univariate and multivariate survival analyses were carried out using the Cox proportional hazard model. All significant variables among those assessed in univariate analysis were considered for the multivariate model. The STATISTICA 10.0 (StatSoft Inc., USA) software was used.
Results
Clinical characteristics
A total of 26 patients were included, male/female 15/11, with median age of 25 years at the moment of MDS/AML diagnosis. More than a half of patients (n=14) had the history of non-severe AA (NSAA). Cytogenetic study was performed in twelve cases upon primary diagnostics, showing normal karyotype in all cases. The PNH clone was tested in 17 patients as a part of AA diagnostics, and a minor PNH clone was revealed in 7 cases. Moreover, three patients with partial AA remission showed signs of hemolytic PNH (resp., 4, 6 and 14 years after the debut), with subsequent PNH clone disappearance and evolution to MDS/AML, respectively, 10, 13 and 22 years later. In 7 out of 26 patients, even partial AA remission was achieved. The most common cytogenetic abnormality was monosomy 7. The demographic and clinical characteristics of the patients are presented in Table 1.
Treatment results
Eight patients with secondary AML who had no available compatible donors, received chemotherapy: «7+3» (n=3), low-dose cytarabine (n=2), FLAG (n=1) and high-dose cytarabine (n=2). MDS patients were treated with 5-azacytidine or low-dose cytarabine. All patients initially diagnosed with MDS developed AML within 24 months. All patients treated by chemotherapy/hypomethylating agents alone (n=8), died with median survival time of 6 (1 to 25) months since the malignant transformation. They all were scheduled for unrelated HSCT which, however, could not be timely performed. Among the patients subjected to allo-HSCT (n=18), eight patients are still alive, at a median follow-up time of 4.8 years (0.5 to 12 years). The 2-year overall survival (OS) in the chemotherapy alone group was 0 %, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024] as shown in Fig. 1.
Allo-HSCT for secondary MDS/AML
A total of 26 allo-HSCTs were perfo
rmed in 18 patients. Median age at the HSCT was 23 (11-44) years. The median time from MDS/AML diagnosis to HSCT was 7 (2 to 18) months. For the first HSCT, HLA-identical siblings were used for 6 patients (33%), a MUD in 9 (50 %) of cases, whereas haploidentical familial donor was used for three patients (17%). Repeated HSCT was in most cases performed from haploidentical donors (n=5). Before allo-HSCT, eight patients received hypomethylating agents (5-azacytidine, decitabine). Four of six patients achieved first complete remission after «7+3» chemotherapy. One patient was treated at low-dose cytarabine and 3 patients with myelodysplastic syndrome with multilineage dysplasia (MDS-MLD), received only supportive care. All the patients had multiple transfusions of RBC and platelets in their past history. The median of ferritin level at the time of HSCT was 1430 (205-10500) ng/mL.
Biological and clinical characteristics of transplanted patients and HSCT procedure are presented in Table 2. Successful engraftment was documented in 12 patients, with a median at D+16 (D+12 to D+25), platelet recovery, at D+17 (D+11 to D+20). Seven patients (39%) developed acute GVHD grade II-IV, resulted in death in 2 cases. All the HSCT survivors have clinical signs of moderate or severe chronic GVHD. Primary graft failure was registered in six patients (33%): 3 after haploidentical, 2 after unrelated and 2 after related HSCT. A secondary graft rejection was revealed in 2 patients after unrelated HSCT. Two patients developed relapse of MDS/AML. Seven patients with primary graft failure/graft rejection were subjected to repeated HSCT from haploidentical donor (n=5), related (n=1), or unrelated donors (n=1). However, the engraftment after repeated HSCT was not achieved in 5 cases, patients died in cytopenia from hemorrhagic and infectious complications. One patient after repeated MUD HSCT developed a fatal GVHD grade IV. Two patients developed the disease relapse (respectively, D+56 after related HSCT in 2 cases, and D+380 after unrelated HSCT). The causes of post-transplant mortality are presented in Table 3. Seven transplanted patients have got hypomethylating drugs at a mean of 6 courses (5-azacytidine, in 4 cases; decitabine in 3 patients) aiming to prevent relapses.
Analysis of prognostic factors
Assessment of prognostic significance for distinct biological and clinical parameters is presented in Table 4. According to further statistical evaluation, such factors as patient’s gender, age, conditioning regimen, GVHD prophylaxis, CMV status, ABO mismatch, numbers of CD34+ and mononuclear cells did not have a significant effect on overall survival (p>0,1). The use of peripheral blood as a source of graft was associated with higher overall survival (p=0.014). The overall post-transplant survival proved to be significantly dependent only on remission state at the time of HSCT (Fig. 2). HSCT timing seems to be important in patients with MDSMLD. Of the three patients only one survived, who received hematopoietic graft 2 months after the MDS diagnosis (monosomy 7, marrow dysplasia). Two deceased patients were transplanted much later, >1 year after the diagnosis, when the patients continued to receive replacement transfusions. High ferritin levels did not significantly impair survival. Of note, the transfusion load for these patients was quite significant (median RBC transfusions 23 units; platelets, 44 units by the time of HSCT).
Discussion
Treatment of the patients with secondary MDS/AML remains unresolved problem, and its results are worse to those in primary patients. Especially, one should consider high rates of severe cytopenia-associated complications after standard therapy of the patients with previously diagnosed AA, probably, due to reduced regenerative ability of bone marrow. In most patients, unstable clinical remission could be obtained after chemotherapy, with high levels of minimal residual disease. In some patients remission is not achieved, or they die from hemorrhagic and infectious complications after 1st induction course. Meanwhile, with increased life duration of IST-treated AA patients, the number of patients with secondary MDS/AML will increase. Therefore, novel algorithm is required for management of such patients.
In our study, all the non-transplanted patients have developed acute leukemia within 2 years since the MDS diagnosis. Overall 4-year survival of the patients subjected to HSCT was 40% (95% CI, 38-52) compared to zero survival among non-transplanted patients. For the patients being in remission state at the time of HSCT, the 4-year OS comprised 80 % (95% CI, 65-95), thus being in accordance with results presented by European Bone Marrow Transplantation Group [21]. Our study has confirmed that allogeneic HSCT is the only option able to cure the patient with secondary MDS/AML evolving after AA. The time interval from diagnosis of secondary disorder to HSCT is the critical factor for success, due to rapid transformation of MDS to AML, poor chemotherapy tolerance, and high risk of lethal outcome before HSCT. To provide HSCT within short terms for these patients, itis necessary to perform HLA typing of the patients at the stage of AA, in order to assess availability of potential donors (for NSAA patients as well), regular examination after IST, including cytogenetic studies of bone marrow, especially, in resistant and relapsing AA conditions. It was shown that the probability of arising pathological clones with chromosomal aberrations makes up to 40% in non-responders to IST, in 6% with partial response, and in 10% of patients well responding to the treatment. Risk for clonal disorders in the patients non-responding to IST, and in cases of preceding NSAA sufficiently exceeds appropriate hazards in the patients with partial response, full response to the therapy, and severe AA [8, 9, 10]. Our study, though performed in a small group, has detected a significantly increased OS in the patients subjected to allo-HSCT, as compared to the patients who received chemotherapy only (40% among transplanted patients versus 0 % in the non-transplanted cases), thus again stressing the role of remission state as the main factor of favorable prognosis in HSCT series. Prognostic significance of remission state was confirmed in our multifactorial analysis. However, one may suppose that, when increasing the number of patients, this factor will significantly influence the results as it was shown in other studies dealing with greater cohorts [21]. Moreover, we have noted a tendency towards better HSCT outcomes in the persons <21 years old, as well as when using the mobilized hematopoietic stem cells as a source of graft. The type of conditioning regimen also did not have significant impact on the HSCT results, but some studies declare benefits of myeloablative conditioning for treatment of secondary MDS [21, 23]. In our study, only 3 out of 16 patients were subjected to myeloablative conditioning, with engraftment in 2 of 3 cases. However, the most patients were admitted to the BMT Center after prolonged conservative therapy, and their comorbid state did not allow to performing myeloablative conditioning. Frequency of aGVHD in total was 27%, severe aGVHD (grade III-IV) was 19% and caused lethal outcome in two cases. Chronic GVHD of different grade was observed in all survivors; however, it did not result into severe disability. According to our data, primary graft failure is the most common cause for HSCT failure (33% of total group in our study). This is a significantly higher incidence compared with data reported by other authors [21, 23]. To our mind, heavy pre-treatment, multiple blood transfusions, as well as numerous courses of chemotherapy and demethylating treatment predisposing for infections, may cause this post-transplant complication. It is difficult to determine efficiency оf haploidentical HSCT in this study because of few clinical cases (n=3), however, primary non-engraftment seems to be the main problem in this HSCT option. Carrying out repeated HSCTs following primary non-engraftment allowed achieving hematopoietic recovery in two cases (25%), with one lethal outcome due to grade IV aGVHD. Therapy with hypomethylating drugs during the post-transplant period is used to prevent and treat relapses in the patients with high risk AML [24]. Our study has shown promising results of such strategy in cases of secondary MDS/AML as well.
Conclusions
Allogeneic hematopoietic stem cell transplantation is the only potentially curative method for treatment of MDS/AML occurring in the patients previously treated with immunosuppressive therapy for AA. Remission state at the time of HSCT is the main predictor for a successful transplantation. Using peripheral blood as a source of graft improves overall survival in patients with secondary MDS/AML from AA. Allo-HSCT is indicated as soon as possible in the case of registered evolution of AA to MDS/AML.
Conflict of interest
No conflicts of interests are reported.
References
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Introduction
Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, W. Dameshek (1967) has noticed that severe AA may transform into paroxysmal nocturnal hemoglobinuria (PNH), secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [1]. At the present time, this dependence is confirmed by numerous studies [2-15]. Moreover, recent data show high incidence up to 50% somatic mutations in patients with acquired AA, involving genes commonly mutated in myeloid malignancies [4]. Previously, most patients died within a year after primary diagnosis of SAA, until 1980’s when implementation of antithymocyte globulin (ATG) combined with cyclosporin A (CsA) proved to be an effective immunosuppressive therapy (IST). Therefore, secondary clonal disorders in AA have become more common, due to longer survival of the patients. From 10 to 30% of AA patients treated with IST were shown to develop secondary clonal diseases, i.e., MDS/AML or PNH, with a cumulative risk of 8 to 18% within next 10 years [2-6, 7, 8, 14]. The patients with secondary disorders have worse prognosis than de novo AML or MDS cases, with a median survival of <1 year [11, 12, 13]. Diagnosis of NSAA, shorter telomere length, splenectomy, two or more ATG courses is related to increase risk for subsequent clonal complications [2, 6, 9, 10, 15, 16]. By contrary, allogeneic bone marrow transplantation aimed for AA treatment causes a sufficiently reduced risk of such secondary disorders [11]. Therapeutic experience for these patients is limited, due to their rarity in common hematological practice. Clinical remissions achieved in such patients usually short and accompanied by high minimal residual disease levels. Moreover, these patients poorly tolerate chemotherapy; they develop longer cytopenia and often die from complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative method for these conditions. The aim of present study was to evaluate efficiency of allo-HSCT in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes.
Patients and methods
The retrospective study included 26 patients with MDS/AML, previously treated with IST due to acquired AA. The patients were observed in First St. Petersburg State I. Pavlov Medical University and Novosibirsk Institute of Clinical Immunology from July 1998 to June 2018. The survival assessment was completed at 15.06.2018. Acquired AA was diagnosed according to standard criteria (International Agranulocytosis and Aplastic Anemia Study Group, 1987). The AA severity grade was evaluated by common criteria [17, 18]. The degree of response corresponded to standard definitions [19]. Fanconi anemia and other inherited AA were not included into the study. Majority of patients (19/26), received as a combination of ATG and CsA, six patients received CsA as monotherapy. Splenectomy has been performed in other centers in seven cases. The patients were observed for a median of 6 years (range, 0.9 to 33) from the AA diagnosis. Sixteen patients were enrolled into the study group at the stage of clonal disorders. The median age at the time of AA diagnosis was 17 (range, 5 to 41) and 25 (range, 9 to 45) years at MDS/AML transformation, respectively. MDS transformation was diagnosed by characteristic morphological changes in bone marrow, increasing blast cell numbers, and typical chromosome aberrations (International Working Group on Morphology of Myelodysplastic Syndrome, 2008). Clinical MDS variant was determined according to the WHO classification (WHO classification of the myeloid neoplasms, 2016). AML was diagnosed when the ratio of blast cells in bone marrow exceeded 20%. The AML phenotype was determined by means of morphological, cytochemical, mmunophenotyping assays, as well as cytogenetic methods and molecular markers. Eight patients were treated with chemotherapy and/or hypomethylating treatment. All the patients provided informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. Eighteen patients received allo-HSCT, either from matched related donor (MRD) (n=6), matched unrelated donor (MUD) (n=9) or haploidentical donor (n=3). Most patients underwent the non-myeloablative conditioning regimen consisting of fludarabine 180 mg/m2 and busulfan 10 mg/kg (n=14). Graft-versus-host disease (GVHD) prophylaxis included the combination tacrolimus (Tx) and mycophenolate mofetil (MMF) (n=6), CsA/methotrexate combined therapy (n=6) and post-transplant cyclophosphamide (PtCy) at a dose of 50 mg/kg on D+3, D+4 (n=6). Engraftment criteria were absolute neutrophil counts of >0.5х109/L for 3 subsequent days and platelet numbers to >20х109/L in absence of preceding platelet transfusions for 7 days. The GvHD severity and grade were assessed according to Przepiorka D. et al., 1995 [20]. Clinical relapse was diagnosed upon hematological recurrence of MDS or AML signs. The overall survival parameters were evaluated by Kaplan-Meier approach, calculating the confidence interval values (CI 95%) using a log-rank test for evaluation of differences between the survival curves. Descriptive inter-group differences were evaluated with exact Fisher criterion for categorical characteristics, and Mann-Whitney U test (for 2 groups) and Kruskal-Wallis criterion (>2 groups). Univariate and multivariate survival analyses were carried out using the Cox proportional hazard model. All significant variables among those assessed in univariate analysis were considered for the multivariate model. The STATISTICA 10.0 (StatSoft Inc., USA) software was used.
Results
Clinical characteristics
A total of 26 patients were included, male/female 15/11, with median age of 25 years at the moment of MDS/AML diagnosis. More than a half of patients (n=14) had the history of non-severe AA (NSAA). Cytogenetic study was performed in twelve cases upon primary diagnostics, showing normal karyotype in all cases. The PNH clone was tested in 17 patients as a part of AA diagnostics, and a minor PNH clone was revealed in 7 cases. Moreover, three patients with partial AA remission showed signs of hemolytic PNH (resp., 4, 6 and 14 years after the debut), with subsequent PNH clone disappearance and evolution to MDS/AML, respectively, 10, 13 and 22 years later. In 7 out of 26 patients, even partial AA remission was achieved. The most common cytogenetic abnormality was monosomy 7. The demographic and clinical characteristics of the patients are presented in Table 1.
Treatment results
Eight patients with secondary AML who had no available compatible donors, received chemotherapy: «7+3» (n=3), low-dose cytarabine (n=2), FLAG (n=1) and high-dose cytarabine (n=2). MDS patients were treated with 5-azacytidine or low-dose cytarabine. All patients initially diagnosed with MDS developed AML within 24 months. All patients treated by chemotherapy/hypomethylating agents alone (n=8), died with median survival time of 6 (1 to 25) months since the malignant transformation. They all were scheduled for unrelated HSCT which, however, could not be timely performed. Among the patients subjected to allo-HSCT (n=18), eight patients are still alive, at a median follow-up time of 4.8 years (0.5 to 12 years). The 2-year overall survival (OS) in the chemotherapy alone group was 0 %, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024] as shown in Fig. 1.
Allo-HSCT for secondary MDS/AML
A total of 26 allo-HSCTs were perfo
rmed in 18 patients. Median age at the HSCT was 23 (11-44) years. The median time from MDS/AML diagnosis to HSCT was 7 (2 to 18) months. For the first HSCT, HLA-identical siblings were used for 6 patients (33%), a MUD in 9 (50 %) of cases, whereas haploidentical familial donor was used for three patients (17%). Repeated HSCT was in most cases performed from haploidentical donors (n=5). Before allo-HSCT, eight patients received hypomethylating agents (5-azacytidine, decitabine). Four of six patients achieved first complete remission after «7+3» chemotherapy. One patient was treated at low-dose cytarabine and 3 patients with myelodysplastic syndrome with multilineage dysplasia (MDS-MLD), received only supportive care. All the patients had multiple transfusions of RBC and platelets in their past history. The median of ferritin level at the time of HSCT was 1430 (205-10500) ng/mL.
Biological and clinical characteristics of transplanted patients and HSCT procedure are presented in Table 2. Successful engraftment was documented in 12 patients, with a median at D+16 (D+12 to D+25), platelet recovery, at D+17 (D+11 to D+20). Seven patients (39%) developed acute GVHD grade II-IV, resulted in death in 2 cases. All the HSCT survivors have clinical signs of moderate or severe chronic GVHD. Primary graft failure was registered in six patients (33%): 3 after haploidentical, 2 after unrelated and 2 after related HSCT. A secondary graft rejection was revealed in 2 patients after unrelated HSCT. Two patients developed relapse of MDS/AML. Seven patients with primary graft failure/graft rejection were subjected to repeated HSCT from haploidentical donor (n=5), related (n=1), or unrelated donors (n=1). However, the engraftment after repeated HSCT was not achieved in 5 cases, patients died in cytopenia from hemorrhagic and infectious complications. One patient after repeated MUD HSCT developed a fatal GVHD grade IV. Two patients developed the disease relapse (respectively, D+56 after related HSCT in 2 cases, and D+380 after unrelated HSCT). The causes of post-transplant mortality are presented in Table 3. Seven transplanted patients have got hypomethylating drugs at a mean of 6 courses (5-azacytidine, in 4 cases; decitabine in 3 patients) aiming to prevent relapses.
Analysis of prognostic factors
Assessment of prognostic significance for distinct biological and clinical parameters is presented in Table 4. According to further statistical evaluation, such factors as patient’s gender, age, conditioning regimen, GVHD prophylaxis, CMV status, ABO mismatch, numbers of CD34+ and mononuclear cells did not have a significant effect on overall survival (p>0,1). The use of peripheral blood as a source of graft was associated with higher overall survival (p=0.014). The overall post-transplant survival proved to be significantly dependent only on remission state at the time of HSCT (Fig. 2). HSCT timing seems to be important in patients with MDSMLD. Of the three patients only one survived, who received hematopoietic graft 2 months after the MDS diagnosis (monosomy 7, marrow dysplasia). Two deceased patients were transplanted much later, >1 year after the diagnosis, when the patients continued to receive replacement transfusions. High ferritin levels did not significantly impair survival. Of note, the transfusion load for these patients was quite significant (median RBC transfusions 23 units; platelets, 44 units by the time of HSCT).
Discussion
Treatment of the patients with secondary MDS/AML remains unresolved problem, and its results are worse to those in primary patients. Especially, one should consider high rates of severe cytopenia-associated complications after standard therapy of the patients with previously diagnosed AA, probably, due to reduced regenerative ability of bone marrow. In most patients, unstable clinical remission could be obtained after chemotherapy, with high levels of minimal residual disease. In some patients remission is not achieved, or they die from hemorrhagic and infectious complications after 1st induction course. Meanwhile, with increased life duration of IST-treated AA patients, the number of patients with secondary MDS/AML will increase. Therefore, novel algorithm is required for management of such patients.
In our study, all the non-transplanted patients have developed acute leukemia within 2 years since the MDS diagnosis. Overall 4-year survival of the patients subjected to HSCT was 40% (95% CI, 38-52) compared to zero survival among non-transplanted patients. For the patients being in remission state at the time of HSCT, the 4-year OS comprised 80 % (95% CI, 65-95), thus being in accordance with results presented by European Bone Marrow Transplantation Group [21]. Our study has confirmed that allogeneic HSCT is the only option able to cure the patient with secondary MDS/AML evolving after AA. The time interval from diagnosis of secondary disorder to HSCT is the critical factor for success, due to rapid transformation of MDS to AML, poor chemotherapy tolerance, and high risk of lethal outcome before HSCT. To provide HSCT within short terms for these patients, itis necessary to perform HLA typing of the patients at the stage of AA, in order to assess availability of potential donors (for NSAA patients as well), regular examination after IST, including cytogenetic studies of bone marrow, especially, in resistant and relapsing AA conditions. It was shown that the probability of arising pathological clones with chromosomal aberrations makes up to 40% in non-responders to IST, in 6% with partial response, and in 10% of patients well responding to the treatment. Risk for clonal disorders in the patients non-responding to IST, and in cases of preceding NSAA sufficiently exceeds appropriate hazards in the patients with partial response, full response to the therapy, and severe AA [8, 9, 10]. Our study, though performed in a small group, has detected a significantly increased OS in the patients subjected to allo-HSCT, as compared to the patients who received chemotherapy only (40% among transplanted patients versus 0 % in the non-transplanted cases), thus again stressing the role of remission state as the main factor of favorable prognosis in HSCT series. Prognostic significance of remission state was confirmed in our multifactorial analysis. However, one may suppose that, when increasing the number of patients, this factor will significantly influence the results as it was shown in other studies dealing with greater cohorts [21]. Moreover, we have noted a tendency towards better HSCT outcomes in the persons <21 years old, as well as when using the mobilized hematopoietic stem cells as a source of graft. The type of conditioning regimen also did not have significant impact on the HSCT results, but some studies declare benefits of myeloablative conditioning for treatment of secondary MDS [21, 23]. In our study, only 3 out of 16 patients were subjected to myeloablative conditioning, with engraftment in 2 of 3 cases. However, the most patients were admitted to the BMT Center after prolonged conservative therapy, and their comorbid state did not allow to performing myeloablative conditioning. Frequency of aGVHD in total was 27%, severe aGVHD (grade III-IV) was 19% and caused lethal outcome in two cases. Chronic GVHD of different grade was observed in all survivors; however, it did not result into severe disability. According to our data, primary graft failure is the most common cause for HSCT failure (33% of total group in our study). This is a significantly higher incidence compared with data reported by other authors [21, 23]. To our mind, heavy pre-treatment, multiple blood transfusions, as well as numerous courses of chemotherapy and demethylating treatment predisposing for infections, may cause this post-transplant complication. It is difficult to determine efficiency оf haploidentical HSCT in this study because of few clinical cases (n=3), however, primary non-engraftment seems to be the main problem in this HSCT option. Carrying out repeated HSCTs following primary non-engraftment allowed achieving hematopoietic recovery in two cases (25%), with one lethal outcome due to grade IV aGVHD. Therapy with hypomethylating drugs during the post-transplant period is used to prevent and treat relapses in the patients with high risk AML [24]. Our study has shown promising results of such strategy in cases of secondary MDS/AML as well.
Conclusions
Allogeneic hematopoietic stem cell transplantation is the only potentially curative method for treatment of MDS/AML occurring in the patients previously treated with immunosuppressive therapy for AA. Remission state at the time of HSCT is the main predictor for a successful transplantation. Using peripheral blood as a source of graft improves overall survival in patients with secondary MDS/AML from AA. Allo-HSCT is indicated as soon as possible in the case of registered evolution of AA to MDS/AML.
Conflict of interest
No conflicts of interests are reported.
References
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Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.
Ключевые слова
Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.
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Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(246) "Irina K. Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. 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Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(289) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20215" ["VALUE"]=> array(2) { ["TEXT"]=> string(2022) "<p style="text-align: justify;"> Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1956) "Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.
Keywords
Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.
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However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1956) "Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.
Keywords
Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1956) "Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.
Keywords
Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.
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Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(289) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(289) "R. 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Афанасьев" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20209" ["VALUE"]=> array(2) { ["TEXT"]=> string(3868) "<p style="text-align: justify;"> Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3802) "Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.
Ключевые слова
Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3802) "Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.
Ключевые слова
Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.
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Hematopoietic stem cell transplantation (HSCT) is a rapidly developing method for the treatment of various malignant and non-malignant diseases [1]. However, it requires synchronization between donor preparation to donation, conditioning regimen, donation and graft-versus-host disease (GVHD) prophylaxis. Thus situations occur, like unexpected infection in a recipient or fulminate relapse of the underling disease, when there is a dilemma whether to transplant a patient with these unexpected conditions or postpone the transplant and administer appropriate treatment . It is well known that grafting in relapse is the worst predictive factor for long-term survival [2]. On the other hand, active infections at the start of the conditioning also impact the outcome adversely [3, 4]. Thus in the majority of cases like these the decision is made to postpone the HSCT, however this is not possible in certain situations with unrelated donors, and also when a related donor has started the stimulation with granulocyte-colony stimulating factor. In these case the graft is usually cryopreserved before infusion. The other situation leading to cryopreservation is the poor graft cellularity collected from a donor. It is well known that low number of CD3 and CD34-positive cells in the graft significantly affect the incidence of primary graft failure and poor graft function after HSCT, which are associated with significant non-relapse mortality [5, 6]. Unlike the related setting when CD34-selected boost could be collected after unrelated transplantation this might be difficult due to donor decision or logistics. Thus several centers prefer to receive and access the graft quality before the start of the conditioning, and then transfuse the cryopreserved graft. Despite the safe use of freezing stage during autologous HSCT procedure, there is a lack of large comparative studies evaluating the effects of graft cryopreservation on the outcome of allogeneic HSCT. Despite the evidence that engraftment of the cryopreserved bone marrow is comparable [7, 8], there are reports that the risk of graft failure is increased with frozen peripheral blood stem cell (PBSC) graft [9], or the risk of the GVHD might be altered after thawing [10, 11]. We conducted a single-institution pair-matched retrospective study to evaluate the impact of graft cryopreservation on the outcomes and toxicity of allogeneic stem cell transplantation.
Patients and Methods
Patients and transplantation procedures
162 patients transplanted in 2006-2017 at the I. Pavlov First St. Petersburg State Medical University were included into the study. All patients signed informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. 81 patients received the cryopreserved graft. The graft was stored with 10% DMSO at -180⁰C until the day of the transplant. The reasons for freezing were: infection before the start of the conditioning (38.3%), relapse of the underlying disease (32.2%), unavailability of a related donor at the time of HSCT (17.2%), availability of the cryopreserved graft after the first donation due to restriction of CD34 cell count (11.1%), pregnancy before the conditioning (1.2%). The study group (Cryo group) comprised predominantly adult patients with unrelated donors, leukemia as an underlying disease and reduced intensity conditioning. The study group was represented by high-risk disease with 42% of patients having DRI 3 or 4 and active disease in 40% of patients. The control group (native group) comprised 81 pairmatched patients. The criteria for matching were type of the donor, graft source (bone marrow or PBSC), diagnosis, stage of the disease at the time of the performed HSCT, intensity of the conditioning, age ±5 years, CD34 count ± 1x106/kg and graft versus host disease prophylaxis. The significance of the matching factors was in the order listed above. The resulting groups were well matched and were not significantly different in any of the patient- or transplantation-related factors (Table 1). Median follow up was 25 months, thus the two year outcomes were used in the study.
Transplantation procedures
Myeloablative conditioning (MAC) was performed with oral busulfan 16 mg/kg and cyclophosphamide 100-120 mg/kg. Reduced intensity conditioning (RIC) was performed with fludarabine 180 mg/m2 and busulfan 8-10 mg/kg. Patients were assigned to RIC if they were 40 years or older, had hematopoietic cell transplantation-specific comorbidity index (HCT-CI)≥2, exbited, at least, grade 3 hepatic toxicity during previous therapy, or uncontrolled infection at the start of the conditioning. Patients subjected to second HSCT also received RIC. GVHD prophylaxis in the post-transplantation cyclophosphamide (PTCy) group consisted of cyclophosphamide (50 mg/kg) administered at days +3, +4, tacrolimus 0.03 mg/kg and mycophenolate mofetil (MMF) 30-45 mg/kg from day +5. The classical GVHD prophylaxis included either tacrolimus with target concentrations of 5-15 ng/ml, or cyclosporine A with target concentrations of 150-350 ng/ml from day -1. As second agents in the prophylaxis regimen we used short-course methotrexate 10-15 mg/m2 at days +1, +3, +6 or mycophenolate mofetil (MMF) 30 mg/kg from day -1 to day +30.
Clinical definitions
Time to disease relapse, acute GVHD (aGVHD), moderate to severe chronic GVHD (cGVHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GVHD-relapse free survival (GRFS) were defined as the time from transplantation to the event. All these parameters were calculated for the two-year interval. Incidence of aGVHD was calculated at 125 days after HSCT, and the time frame for the other outcomes was two years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grades III-IV acute GVHD or systemic therapy-requiring chronic GVHD. The Consensus Conference criteria and NIH criteria were used for aGVHD and cGVHD grading, respectively [12,13]. Primary graft failure was defined as the complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraftment was calculated as time from HSCT to unsupported neutrophil count > 500/ul and white blood cell count >1000/ul for 3 consecutive days.
Toxicity was assessed with CTCAE ver. 4.03. Sepsis in the study was defined as systemic inflammatory reaction with microbiologically confirmed bacteremia. The risk of the disease was accessed with disease risk index (DRI) by Armand et al. [14].
AML=acute myeloid leukeina; ALL=acute lymphoblastic leukemia; MDS=myelodysplastic syndrome; MPN=myeloprolipherative neoplasm; CML=chronic myeloid leukemia; AA=aplastic anemia; BM=bone marrow; PBSC=peripheral blood stem cells; RIC=reduced-intensity conditioning; MAC=myeloablative conditioning; PTCy=post-transplantation cyclophosphamide.
Statistical Analysis
Comparison between the groups was performed by Chisquare test. The comparison of the quantitative parameters between groups were preformed with log-normalized t-test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGVHD, cGVHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate analysis was not performed, because patients were matched by the majority of significant variables. The subgroup analysis was performed for OS. Heterogeneities between the hazard ratios in the subgroup analysis were tested for significance using the Cochran’s Q test, with df degrees of freedom. Incidence and severity of complications were compared using Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).
Results
Engraftment
There was a trend towards higher incidence of graft failure in the Cryo group (15.7% vs 6.3%, p=0.0588). When the graft source was analyzed separately, there was a significant increase in graft failure for BM (26% vs 0%, p=0.025), but no difference for peripheral blood (12% vs 9%, p=0.483). Among patients who engrafted there was no difference for the time of neutrophil engraftment (median 19 vs 18 days, p=0.345 in the Cryo and control groups, respectively), white blood cell recovery (18 vs 16 days, p=0.419) and platelet engraftment (17 vs 14 days, p=0.442).
Graft-versus-host disease, mortality and survival
No differences were observed in the incidence of acute GVHD grade II-IV (39%, 95%CI 28-50% vs 37%, 95%CI 26-48% in the Cryo and control groups, respectively, p=0.8865, Fig. 1A) and grade III-IV acute GVHD (25%, 95%CI 16-36% vs 19%, 95%CI 11-29% in the Cryo and control groups, respectively, p=0.4708). Incidence of grade I GVHD (14.8% vs 13,5%, p=0.873) as well as the incidence of steroid-refractory GVHD (9.9% vs 9.9%, p=1.0) were also not different. The incidence of moderate and severe chronic GVHD was also comparable in the study groups: Cryo group, 29% (95%CI 17-42%) vs Control group, 30% (95%CI 14-48%), p=0.3918, Fig. 1B. A significantly higher non-relapse mortality was observed for patients with cryopreserved graft: 45% (95%CI 34-56%) vs 28% (95% CI 18-39%), p=0.0145, Fig. 1C. However, the incidence of relapse was reduced the Cryo group: 21% (95% CI 12-30%) vs 34% (95% CI 23-45%), p=0.0481, Fig. 1D. This bidirectional differences resulted in absence of statistically significant impact of graft thawing on overall survival (37%, 95% CI 27-48% vs 44%, 95% CI 32-55% in the Cryo Figure 2. Subgroup analysis of overall survival and control groups, respectively, p=0.2384, Fig. 1E), EFS (35%, 95% CI 24-45% vs 40%, 95% CI 29-51%, respectively, p=0.38) and GFRS (19% ,95% CI 10-28% vs 25% , 95% CI 15-26, respectively, p=0.2041, Fig. 1F). The subgroup analysis of the OS outcome revealed no differences between cryopreserved and native graft irrespective of the conditioning intensity, graft source, age of the patients, underlying disease, status of the disease and type of donor (p>0.2, Fig. 2).
Complications of transplantation
In general, toxicity of HSCT was comparable between the groups (Fig. 3), but we observed a significant increase in the incidence of acute clinically significant renal toxicity (30% vs 10%, p=0.0046). The mean maximal creatinine observed after HSCT was 143±108 vs 114±65 μmol/l in the Cryo and control groups, respectively. Borderline differences were observed in the incidence of sepsis before engraftment (24% vs 13%, p=0.0681) and severe sepsis before engraftment (17% vs 8%, p=0.0981). Although relatively high incidence of VOD (15%) for predominantly RIC regimen was observed in the Cryo group, the difference was not statistically significant.
Discussion
In this well-matched cohort of patients, we have shown that the survival of patients after HSCT with cryopreserved graft is not significantly compromised. Also we have not observed any differences in the incidence of acute and chronic GVHD. These results are comparable to the ones previously reported by Medd et al. [11], despite their cohort included predominantly matched related donors and PBSC only. Despite the comparable OS levels, we observed that NRM was significantly higher in the Cryo group, which was compensated by lower relapse risk. To our knowledge, this observation hadnot been previously reported in the literature. The increment in non-relapse mortality was primary driven by higher incidence of graft failures. This corresponds to the data previously reported by M. Lioznov et al. [9]. In our study we observed increased incidence in the BM, but not in PBSC group. However, the number of graft failures in our dataset is relatively low to draw a definitive conclusion. Since primary graft failure is a multifactorial event [6] with significant impact of anti-HLA antibodies [15], other antibody types [16], microenvironment abnormalities, particularly in MDS and MPN [17], and other potential factors, this difference in graft failure should be confirmed in large registry studies. Nonetheless, the current understanding of immune mechanisms behind graft failure might partially explain the increased Figure 3. Complications of stem cell transplantation incidence of this complication after freezing the graft. The release of specific antigens during thawing, particularly from granulocytes, might trigger both the antibody-mediated and T-cell-mediated rejection [18]. The other complication leading to non-relapse mortality was the tendency to higher incidence of sepsis. It is unlikely that the mechanisms behind this observation are related to the cryopreservation of the graft. It was rather due to difference between groups. For the majority of patients in the Cryo group, the reason for freezing the graft was an unexpected infection. This indicates that this group might have been more prone to infections. In allo HSCT recipients this is usually associated by iron overload [19], and the groups were not matched by this parameter. Also the Cryo group included patients in whom the remissions were reinduced before HSCT, using high-dose cytarabine with fludarabine. This mode of chemotherapy is usually associated with relatively high incidence of bloodstream infections [20], and recurrence of septic episodes after HSCT has previously been reported [21]. The finding about reduced risk of relapse in the study group also lacks logical explanation, since the incidence of acute and chronic GVHD was not different between the groups, and it is hard to speculate about the augmentation of graft-versus-leukemia affect. Despite the groups were matched by the disease type and stage, the abovementioned mechanism of re-induction close to the start of the conditioning might play a role. Although chemotherapy and conditioning were not sequential like in certain protocols for high-risk leukemia [22], the factor of timing is likely to play a role in the observed results.
Conclusion
Despite certain differences between the groups compared and non-randomized study design, we have demonstrated that cryopreservation of allogeneic graft is a viable option in case of complications that increase the risk of HSCT, however the benefit from postponing a transplant should be weighed against the possible risk of primary graft failure. The results of the study require confirmation in the muticenter setting or in the studies with international registry data.
Acknowledgements
The authors declare no conflict of interest.
References
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9. Lioznov M, Dellbrügger C, Sputtek A, Fehse B, Kröger N, Zander AR. Transportation and cryopreservation may impair haematopoietic stem cell function and engraftment of allogeneic PBSCs, but not BM. Bone Marrow Transplant. 2008 Jul;42(2):121-128.
10. Frey NV, Lazarus HM, Goldstein SC. Has allogeneic stem cell cryopreservation been given the 'cold shoulder'? An analysis of the pros and cons of using frozen versus fresh stem cell products in allogeneic stem cell transplantation. Bone Marrow Transplant. 2006; 38(6):399-405.
11. Medd P, Nagra S, Hollyman D, Craddock C, Malladi R. Cryopreservation of allogeneic PBSC from related and unrelated donors is associated with delayed platelet engraftment but has no impact on survival. Bone Marrow Transplant. 2013;48(2):243-248.
12. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828.
13. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–956.
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20. Estey E, Thall P, Andreeff M, Beran M, Kantarjian H, O'Brien S, Escudier S, Robertson LE, Koller C, Kornblau S, et al. Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J Clin Oncol. 1994;12(4):671-678.
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Introduction
Hematopoietic stem cell transplantation (HSCT) is a rapidly developing method for the treatment of various malignant and non-malignant diseases [1]. However, it requires synchronization between donor preparation to donation, conditioning regimen, donation and graft-versus-host disease (GVHD) prophylaxis. Thus situations occur, like unexpected infection in a recipient or fulminate relapse of the underling disease, when there is a dilemma whether to transplant a patient with these unexpected conditions or postpone the transplant and administer appropriate treatment . It is well known that grafting in relapse is the worst predictive factor for long-term survival [2]. On the other hand, active infections at the start of the conditioning also impact the outcome adversely [3, 4]. Thus in the majority of cases like these the decision is made to postpone the HSCT, however this is not possible in certain situations with unrelated donors, and also when a related donor has started the stimulation with granulocyte-colony stimulating factor. In these case the graft is usually cryopreserved before infusion. The other situation leading to cryopreservation is the poor graft cellularity collected from a donor. It is well known that low number of CD3 and CD34-positive cells in the graft significantly affect the incidence of primary graft failure and poor graft function after HSCT, which are associated with significant non-relapse mortality [5, 6]. Unlike the related setting when CD34-selected boost could be collected after unrelated transplantation this might be difficult due to donor decision or logistics. Thus several centers prefer to receive and access the graft quality before the start of the conditioning, and then transfuse the cryopreserved graft. Despite the safe use of freezing stage during autologous HSCT procedure, there is a lack of large comparative studies evaluating the effects of graft cryopreservation on the outcome of allogeneic HSCT. Despite the evidence that engraftment of the cryopreserved bone marrow is comparable [7, 8], there are reports that the risk of graft failure is increased with frozen peripheral blood stem cell (PBSC) graft [9], or the risk of the GVHD might be altered after thawing [10, 11]. We conducted a single-institution pair-matched retrospective study to evaluate the impact of graft cryopreservation on the outcomes and toxicity of allogeneic stem cell transplantation.
Patients and Methods
Patients and transplantation procedures
162 patients transplanted in 2006-2017 at the I. Pavlov First St. Petersburg State Medical University were included into the study. All patients signed informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. 81 patients received the cryopreserved graft. The graft was stored with 10% DMSO at -180⁰C until the day of the transplant. The reasons for freezing were: infection before the start of the conditioning (38.3%), relapse of the underlying disease (32.2%), unavailability of a related donor at the time of HSCT (17.2%), availability of the cryopreserved graft after the first donation due to restriction of CD34 cell count (11.1%), pregnancy before the conditioning (1.2%). The study group (Cryo group) comprised predominantly adult patients with unrelated donors, leukemia as an underlying disease and reduced intensity conditioning. The study group was represented by high-risk disease with 42% of patients having DRI 3 or 4 and active disease in 40% of patients. The control group (native group) comprised 81 pairmatched patients. The criteria for matching were type of the donor, graft source (bone marrow or PBSC), diagnosis, stage of the disease at the time of the performed HSCT, intensity of the conditioning, age ±5 years, CD34 count ± 1x106/kg and graft versus host disease prophylaxis. The significance of the matching factors was in the order listed above. The resulting groups were well matched and were not significantly different in any of the patient- or transplantation-related factors (Table 1). Median follow up was 25 months, thus the two year outcomes were used in the study.
Transplantation procedures
Myeloablative conditioning (MAC) was performed with oral busulfan 16 mg/kg and cyclophosphamide 100-120 mg/kg. Reduced intensity conditioning (RIC) was performed with fludarabine 180 mg/m2 and busulfan 8-10 mg/kg. Patients were assigned to RIC if they were 40 years or older, had hematopoietic cell transplantation-specific comorbidity index (HCT-CI)≥2, exbited, at least, grade 3 hepatic toxicity during previous therapy, or uncontrolled infection at the start of the conditioning. Patients subjected to second HSCT also received RIC. GVHD prophylaxis in the post-transplantation cyclophosphamide (PTCy) group consisted of cyclophosphamide (50 mg/kg) administered at days +3, +4, tacrolimus 0.03 mg/kg and mycophenolate mofetil (MMF) 30-45 mg/kg from day +5. The classical GVHD prophylaxis included either tacrolimus with target concentrations of 5-15 ng/ml, or cyclosporine A with target concentrations of 150-350 ng/ml from day -1. As second agents in the prophylaxis regimen we used short-course methotrexate 10-15 mg/m2 at days +1, +3, +6 or mycophenolate mofetil (MMF) 30 mg/kg from day -1 to day +30.
Clinical definitions
Time to disease relapse, acute GVHD (aGVHD), moderate to severe chronic GVHD (cGVHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GVHD-relapse free survival (GRFS) were defined as the time from transplantation to the event. All these parameters were calculated for the two-year interval. Incidence of aGVHD was calculated at 125 days after HSCT, and the time frame for the other outcomes was two years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grades III-IV acute GVHD or systemic therapy-requiring chronic GVHD. The Consensus Conference criteria and NIH criteria were used for aGVHD and cGVHD grading, respectively [12,13]. Primary graft failure was defined as the complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraftment was calculated as time from HSCT to unsupported neutrophil count > 500/ul and white blood cell count >1000/ul for 3 consecutive days.
Toxicity was assessed with CTCAE ver. 4.03. Sepsis in the study was defined as systemic inflammatory reaction with microbiologically confirmed bacteremia. The risk of the disease was accessed with disease risk index (DRI) by Armand et al. [14].
AML=acute myeloid leukeina; ALL=acute lymphoblastic leukemia; MDS=myelodysplastic syndrome; MPN=myeloprolipherative neoplasm; CML=chronic myeloid leukemia; AA=aplastic anemia; BM=bone marrow; PBSC=peripheral blood stem cells; RIC=reduced-intensity conditioning; MAC=myeloablative conditioning; PTCy=post-transplantation cyclophosphamide.
Statistical Analysis
Comparison between the groups was performed by Chisquare test. The comparison of the quantitative parameters between groups were preformed with log-normalized t-test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGVHD, cGVHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate analysis was not performed, because patients were matched by the majority of significant variables. The subgroup analysis was performed for OS. Heterogeneities between the hazard ratios in the subgroup analysis were tested for significance using the Cochran’s Q test, with df degrees of freedom. Incidence and severity of complications were compared using Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).
Results
Engraftment
There was a trend towards higher incidence of graft failure in the Cryo group (15.7% vs 6.3%, p=0.0588). When the graft source was analyzed separately, there was a significant increase in graft failure for BM (26% vs 0%, p=0.025), but no difference for peripheral blood (12% vs 9%, p=0.483). Among patients who engrafted there was no difference for the time of neutrophil engraftment (median 19 vs 18 days, p=0.345 in the Cryo and control groups, respectively), white blood cell recovery (18 vs 16 days, p=0.419) and platelet engraftment (17 vs 14 days, p=0.442).
Graft-versus-host disease, mortality and survival
No differences were observed in the incidence of acute GVHD grade II-IV (39%, 95%CI 28-50% vs 37%, 95%CI 26-48% in the Cryo and control groups, respectively, p=0.8865, Fig. 1A) and grade III-IV acute GVHD (25%, 95%CI 16-36% vs 19%, 95%CI 11-29% in the Cryo and control groups, respectively, p=0.4708). Incidence of grade I GVHD (14.8% vs 13,5%, p=0.873) as well as the incidence of steroid-refractory GVHD (9.9% vs 9.9%, p=1.0) were also not different. The incidence of moderate and severe chronic GVHD was also comparable in the study groups: Cryo group, 29% (95%CI 17-42%) vs Control group, 30% (95%CI 14-48%), p=0.3918, Fig. 1B. A significantly higher non-relapse mortality was observed for patients with cryopreserved graft: 45% (95%CI 34-56%) vs 28% (95% CI 18-39%), p=0.0145, Fig. 1C. However, the incidence of relapse was reduced the Cryo group: 21% (95% CI 12-30%) vs 34% (95% CI 23-45%), p=0.0481, Fig. 1D. This bidirectional differences resulted in absence of statistically significant impact of graft thawing on overall survival (37%, 95% CI 27-48% vs 44%, 95% CI 32-55% in the Cryo Figure 2. Subgroup analysis of overall survival and control groups, respectively, p=0.2384, Fig. 1E), EFS (35%, 95% CI 24-45% vs 40%, 95% CI 29-51%, respectively, p=0.38) and GFRS (19% ,95% CI 10-28% vs 25% , 95% CI 15-26, respectively, p=0.2041, Fig. 1F). The subgroup analysis of the OS outcome revealed no differences between cryopreserved and native graft irrespective of the conditioning intensity, graft source, age of the patients, underlying disease, status of the disease and type of donor (p>0.2, Fig. 2).
Complications of transplantation
In general, toxicity of HSCT was comparable between the groups (Fig. 3), but we observed a significant increase in the incidence of acute clinically significant renal toxicity (30% vs 10%, p=0.0046). The mean maximal creatinine observed after HSCT was 143±108 vs 114±65 μmol/l in the Cryo and control groups, respectively. Borderline differences were observed in the incidence of sepsis before engraftment (24% vs 13%, p=0.0681) and severe sepsis before engraftment (17% vs 8%, p=0.0981). Although relatively high incidence of VOD (15%) for predominantly RIC regimen was observed in the Cryo group, the difference was not statistically significant.
Discussion
In this well-matched cohort of patients, we have shown that the survival of patients after HSCT with cryopreserved graft is not significantly compromised. Also we have not observed any differences in the incidence of acute and chronic GVHD. These results are comparable to the ones previously reported by Medd et al. [11], despite their cohort included predominantly matched related donors and PBSC only. Despite the comparable OS levels, we observed that NRM was significantly higher in the Cryo group, which was compensated by lower relapse risk. To our knowledge, this observation hadnot been previously reported in the literature. The increment in non-relapse mortality was primary driven by higher incidence of graft failures. This corresponds to the data previously reported by M. Lioznov et al. [9]. In our study we observed increased incidence in the BM, but not in PBSC group. However, the number of graft failures in our dataset is relatively low to draw a definitive conclusion. Since primary graft failure is a multifactorial event [6] with significant impact of anti-HLA antibodies [15], other antibody types [16], microenvironment abnormalities, particularly in MDS and MPN [17], and other potential factors, this difference in graft failure should be confirmed in large registry studies. Nonetheless, the current understanding of immune mechanisms behind graft failure might partially explain the increased Figure 3. Complications of stem cell transplantation incidence of this complication after freezing the graft. The release of specific antigens during thawing, particularly from granulocytes, might trigger both the antibody-mediated and T-cell-mediated rejection [18]. The other complication leading to non-relapse mortality was the tendency to higher incidence of sepsis. It is unlikely that the mechanisms behind this observation are related to the cryopreservation of the graft. It was rather due to difference between groups. For the majority of patients in the Cryo group, the reason for freezing the graft was an unexpected infection. This indicates that this group might have been more prone to infections. In allo HSCT recipients this is usually associated by iron overload [19], and the groups were not matched by this parameter. Also the Cryo group included patients in whom the remissions were reinduced before HSCT, using high-dose cytarabine with fludarabine. This mode of chemotherapy is usually associated with relatively high incidence of bloodstream infections [20], and recurrence of septic episodes after HSCT has previously been reported [21]. The finding about reduced risk of relapse in the study group also lacks logical explanation, since the incidence of acute and chronic GVHD was not different between the groups, and it is hard to speculate about the augmentation of graft-versus-leukemia affect. Despite the groups were matched by the disease type and stage, the abovementioned mechanism of re-induction close to the start of the conditioning might play a role. Although chemotherapy and conditioning were not sequential like in certain protocols for high-risk leukemia [22], the factor of timing is likely to play a role in the observed results.
Conclusion
Despite certain differences between the groups compared and non-randomized study design, we have demonstrated that cryopreservation of allogeneic graft is a viable option in case of complications that increase the risk of HSCT, however the benefit from postponing a transplant should be weighed against the possible risk of primary graft failure. The results of the study require confirmation in the muticenter setting or in the studies with international registry data.
Acknowledgements
The authors declare no conflict of interest.
References
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Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.
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Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20223" ["VALUE"]=> array(2) { ["TEXT"]=> string(2128) "<p style="text-align: justify;"> Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2062) "Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.
Keywords
Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.
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Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(278) "Elena V. Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(278) "Elena V. Babenko, Ivan S. Moiseev, Mikhail M. 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We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2062) "Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.
Keywords
Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2062) "Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.
Keywords
Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.
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Бабенко, Иван С. Моисеев, Михаил М. Канунников, Александр Л. Алянский, Дмитрий Э. Певцов, Анастасия В. Фролова, Анна А. Осипова, Татьяна А. Быкова, Олеся В. Паина, Елена И. Дарская, Людмила С. Зубаровская, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(478) "Елена В. Бабенко, Иван С. Моисеев, Михаил М. Канунников, Александр Л. Алянский, Дмитрий Э. Певцов, Анастасия В. Фролова, Анна А. Осипова, Татьяна А. Быкова, Олеся В. Паина, Елена И. Дарская, Людмила С. Зубаровская, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(478) "Елена В. Бабенко, Иван С. Моисеев, Михаил М. 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Афанасьев " } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20219" ["VALUE"]=> array(2) { ["TEXT"]=> string(4474) "<p style="text-align: justify;"> Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4408) "Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4408) "Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.
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The t(3;21)(q26.2;q22) translocation, as well as trisomy 13 are rare but recurrent chromosome abnormalities which, to our best knowledge, have not yet encountered simultaneously in MDS/AML patients and, hence, have not been treated by means of allo-HSCT. The t(3;21) translocation is not rarely found in patients with therapy-related MDS/AML [1-7]. This disorder is, generally, characterized by aggressive clinical course [8, 9] and short event-free survival [10]. The t(3;21)(q26.2;q22) translocation results into a fusion between the RUNT domain of RUNX1, and EVI1 gene [11]. The EVI1 gene is known to encode a dual domain of the zinc-finger transcription factor which exhibits DNA binding activity acting together with a histone methyltransferase (SET) domain [12-14]. This molecule promotes self-renewal in hematopoietic stem cells. The t(3;21) translocation has been reported to occur in approximately 1% of AML or MDS cases [15]. Its clinical significance in MDS has been poorly determined, though poor prognosis appears to be proven in CML patients with t(3;21) [16-18]. It has been recently shown that t-MDS and t-AML positive for t(3;21) (q26.2;q22) are resistant both to cytostatic chemotherapy, and to allo-HSCT treatment [19]. Moreover, according to multicentric cytogenetic studies, trisomy 13 was observed in 0.2% patients, detectable as an single aberration, or combined with an additional abnormality [20]. A sufficient gender imbalance was reported for this condition (21 males of 27 cases). The median age of patients was 73 years. Isolated trisomy 13 was revealed in 96% of the cases. Of note, these patients with higher-risk MDS did not respond to therapy with hypomethylating agents. In general, trisomy 13 rarely occurs in MDS (0.2 to 0.8% of total), mostly as an isolated event, being something more frequent in AML (1-2%). Most of these patients are males over 70 years old. Typically, MDS proceeds with blast excess and moderate pancytopenia having poor prognosis, with median survival ranging between <6 months and 1 year. The patients with AML and trisomy 13 do not respond to standard intensive chemotherapy. For instance, treatment with hypomethylating agents is inefficient in this MDS type, though high-dose lenolidomide could be an option here. It should be also kept in mind, that trisomy 13 is associated with overexpression of FLT3 gene located at the extra chromosome. Besides, a close association between trisomy 13 and mutations of RUNX1 have been recently found [21, 22].
Materials and methods
Cytogenetic and molecular techniques
Serial cytogenetic investigations were carried out by a standard G-banding technique which has been recently published [23]. Identification of chromosomes and chromosomal aberrations was carried out according to International System Human Cytogenetic Nomenclature (ISCN) [24]. A serial molecular biological testing of donor chimerism was done on peripheral blood or bone marrow samples at the time of hematologic engraftment, as well as every 2 weeks between 1 and 3 months and every month between 3 and 12 months after transplantation were obtained and processed. Shortly, the evaluation was done by means of PCR-based Chimerix FA Kit (Inogene, Russia), by analyzing selected polymorphic short tandem repeat (STR) loci: D11S488, HUMVWFA31, D13S317, D8S639, D19S246, D4S2366, D12S1064, D16S539 and the sex determination marker Amelogenin. The amplified sample was analyzed by capillary electrophoresis using an ABI Prism 3500xl Genetic Analyser (Applied Biosystems). Quantification of the mixed chimerism (calculated as percent of recipient DNA) was performed by analyzing the proportion of the fluorescent peak areas corresponding to donor and patient genotypes.
Clinical case description
The patient was a 22-year-old male, initially presented in August 2006 with complaints for moderate fatigue and fever (37.4°C). Peripheral blood examination showed pancytopenia. Bone marrow aspirate was hypocellular with features of aplastic anemia. Cyclosporin A (CSA) was given, but it was taken by the patient only for two weeks due to hepatic discomfort. During the following three years, the patient did not visit a hematologist, and his condition was stable. In January of 2009 he noted exacerbation of fatigue and skin hemorrhages which required hospitalization to the Hematology Department. Peripheral blood counts were as follows: Hb, 55 g/L; WBC, 1.5x109/L; platelets, 4x109/L. The bone marrow aspirate was hypocellular, contained 15.5% blasts with diffuse-type periodic acid Schiff (PAS) staining, and 30% ring sideroblasts, whereas most neutrophilic cells were peroxidase-deficient. Immunophenotyping of the blast cells showed positivity for CD34, CD13, CD33, and HLA-DRA. The results of serial cytogenetic investigations and chimerism testing using molecular biology approaches are presented in Table 1.
Figure 1. Karyogram of bone marrow cell 47, XY, t(3;21) (q26;q22),+13 from patient with primary myelodysplastic syndrome (RAEB-II)
Initial marrow karyotype was as following: 47, XY, t(3;21) (q26.2;q22),+13, (Fig. 1) with involvement into arrangement EVI1 gene (Fig. 2), whereas 10% metaphases had normal chromosome complement. Meanwhile, a standard molecular investigation with primers for common chromosome translocations did not show any oncogene anomalies. Therefore, a diagnosis of MDS RAEB -II IPSS 3.0 was established. Since the patient was transfusion-dependent for a long time, his ferritine level reached 2500 mg/mm3.
Figure 2. Fluorescence in situ hybridization (FISH) with BreakApart EVI1 probe (CytoCell, UK) showing one normal EVI1 gene (one fusion yellow signal) and one abnormal EVI1 gene (one green and one red split signals on interphase cells) in the patient with translocation t(3;21)(q26.2;q22) RUNX1/EVI1
Figure 3. Karyotype of donor’s bone marrow cell 46,XY from a patient with primary myelodysplastic syndrome after allogeneic bone marrow transplantation prepared during a short-term hematological and cytogenetic remission
Figure 4. Schematic presentation of clinical course in a patient with primary myelodysplastic syndrome with karyotype 47,XY,t(3;21)(q26.2;q22),+13 associated with resistance to standard chemotherapy, hypomethylating agents and allo-HSCT
Before bone marrow transplantation, the patient obtained one 5-day course of Dacogen (Decitabine) as demethylating therapy. It did not change common blood parameters, but allowed to reduce his transfusion dependence. Since the patient had an HLA-DQB1-mismatched related donor (Table 1), allo-HSCT was considered. The patient was enrolled into the RIC/MAC study protocol, and randomized to RIC branch (Busulfan + Fludarabine – 800 and 300 mg, respectively). Graft-versus-host-disease (GvHD) prophylaxis included CSA and Methotrexate (MTX). Following the allo-HSCT, stem cell engraftment was detected on day +15, when mixed chimerism was 45-55%. By this time, bone marrow contained only 2.4% of blasts, and the previously detected chromosomal abnormalities were not found (Fig. 3, Table 1). GvHD symptoms were absent, but a cytogenetic relapse was documented two weeks later (on day +29), due to appearance of the marker chromosomal aberrations and decreasing donor chimerism which could be caused by small number of CD34+ stem cells in the graft. Therefore, cyclosporine A was stopped on day +38, and, a week later, a donor lymphocyte infusion (DLI) was performed at a dose of 5.0х107 cells/kg, however, without any clinical effect. The graft rejection was diagnosed on day D+50 (Fig. 4). By that time, the patient had hemoglobin levels of 57 g/L; WBC, 1.7x109/L; and platelets, l3.0x109/L. Bone marrow aspirate was hypocellular with 3.4% blasts, and the donor chimerism faded away (<5%). Because of allo-BMT failure, a second allo-HSCT was administered, using peripheral blood stem cells from the same donor. It was performed after RIC preparative regimen containing Fludarabine 350 mg, Thiotepa 960 mg, and Campath 40 mg. GvHD prophylaxis included Tacrolymus and CellCept (Mycophenolate Mofetyl). Engraftment was registered since day D+10. Two days later, acute GvHD of gut and skin (grade I) was diagnosed. Steroids were added to the treatment schedule which resulted into a significant improvement of GvHD. Peripheral blood findings on the day +16 after 2nd transplant were as follows: Hb, 92.0 g/L; WBC, 4.3x109/L, and platelets, 35.0x109/L. Bone marrow aspirate was hypocellular without blast excess, and full donor chimerism was achieved. Cytogenetic study has shown a repeated karyotype normalization. Due to high risk of relapse, another DLI procedure was performed. Despite the immunotherapy, a new cytogenetic relapse, along with reduced donor chimerism levels, was diagnosed in July 2010. An attempt to achieve another remission with hypomethylating agents (5 courses of Dacogen) was not successful. A repeated cytogenetic relapse has been diagnosed in December 2010, causing his death at the BMT Center two months later.
Discussion
To our knowledge, it is the first clinical description of primary MDS with t(3;21)(q26.2;q22), combined with trisomy 13, and treated by two subsequent allo-HSCTs from a partially HLA-mismatched sibling (brother). The first earliest relapse occurred on the day 29, which could be, in part, explained by low cellularity of transplant. Since a second transplant was required, a reduced-intensity conditioning was chosen again, but peripheral blood stem cells were used for the 2nd transplant. The second engraftment was longer. A new cytological relapse was diagnosed 2 months later as evidenced by increased blast counts in bone marrow up to 12% accompanied by recurrence of the above cytogenetic aberrations, as well as decreasing donor chimerism. Moreover, the patient did not respond to hypomethylating agents (5 courses of Dacogen), aiming to correct the hematopoietic disorder. Recent studies have shown that distinct portions of RUNX1 gene may fuse in variable manner to MDS1 and EVI1 genes located within the 3q26 region. On the other hand, these different fusion products are capable of blocking myeloid differentiation interfering with normal transcriptional regulatory functions of RUNX1 [14]. As a result, our MDS case with combined t(3;21) chromosome anomalies and trisomy 13, showing poor clinical prognosis, appears to be related to imbalance of GATA, ERG, MEIS1, HOXA9 and FLT3 genes at the stem cell level which could be responsible for leukemia cells resistance to both chemotherapy and allo-HSCT.
Acknowledgements
The authors are grateful to colleagues for their excellent support.
Conflict of interest
No conflicts of interests are declared.
References
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9. Park TS, Choi JR, Yoon SH, Song J, Kim J, Kim SJ, Kwon O, Min YH. Acute promyelocytic leukemia relapsing as secondary acute myelogenous leukemia with translocation t(3;21)(q26;q22) and RUNX1-MDS1-EVI1 fusion transcript. Cancer Genet Cytogenet 2008; 187(2):61-73.
10. Lugthart S, Groschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Bergde Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Kohne CH, Pfeundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Dohner K, Lowenber B, Dohner H. Clinical,
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Introduction
The t(3;21)(q26.2;q22) translocation, as well as trisomy 13 are rare but recurrent chromosome abnormalities which, to our best knowledge, have not yet encountered simultaneously in MDS/AML patients and, hence, have not been treated by means of allo-HSCT. The t(3;21) translocation is not rarely found in patients with therapy-related MDS/AML [1-7]. This disorder is, generally, characterized by aggressive clinical course [8, 9] and short event-free survival [10]. The t(3;21)(q26.2;q22) translocation results into a fusion between the RUNT domain of RUNX1, and EVI1 gene [11]. The EVI1 gene is known to encode a dual domain of the zinc-finger transcription factor which exhibits DNA binding activity acting together with a histone methyltransferase (SET) domain [12-14]. This molecule promotes self-renewal in hematopoietic stem cells. The t(3;21) translocation has been reported to occur in approximately 1% of AML or MDS cases [15]. Its clinical significance in MDS has been poorly determined, though poor prognosis appears to be proven in CML patients with t(3;21) [16-18]. It has been recently shown that t-MDS and t-AML positive for t(3;21) (q26.2;q22) are resistant both to cytostatic chemotherapy, and to allo-HSCT treatment [19]. Moreover, according to multicentric cytogenetic studies, trisomy 13 was observed in 0.2% patients, detectable as an single aberration, or combined with an additional abnormality [20]. A sufficient gender imbalance was reported for this condition (21 males of 27 cases). The median age of patients was 73 years. Isolated trisomy 13 was revealed in 96% of the cases. Of note, these patients with higher-risk MDS did not respond to therapy with hypomethylating agents. In general, trisomy 13 rarely occurs in MDS (0.2 to 0.8% of total), mostly as an isolated event, being something more frequent in AML (1-2%). Most of these patients are males over 70 years old. Typically, MDS proceeds with blast excess and moderate pancytopenia having poor prognosis, with median survival ranging between <6 months and 1 year. The patients with AML and trisomy 13 do not respond to standard intensive chemotherapy. For instance, treatment with hypomethylating agents is inefficient in this MDS type, though high-dose lenolidomide could be an option here. It should be also kept in mind, that trisomy 13 is associated with overexpression of FLT3 gene located at the extra chromosome. Besides, a close association between trisomy 13 and mutations of RUNX1 have been recently found [21, 22].
Materials and methods
Cytogenetic and molecular techniques
Serial cytogenetic investigations were carried out by a standard G-banding technique which has been recently published [23]. Identification of chromosomes and chromosomal aberrations was carried out according to International System Human Cytogenetic Nomenclature (ISCN) [24]. A serial molecular biological testing of donor chimerism was done on peripheral blood or bone marrow samples at the time of hematologic engraftment, as well as every 2 weeks between 1 and 3 months and every month between 3 and 12 months after transplantation were obtained and processed. Shortly, the evaluation was done by means of PCR-based Chimerix FA Kit (Inogene, Russia), by analyzing selected polymorphic short tandem repeat (STR) loci: D11S488, HUMVWFA31, D13S317, D8S639, D19S246, D4S2366, D12S1064, D16S539 and the sex determination marker Amelogenin. The amplified sample was analyzed by capillary electrophoresis using an ABI Prism 3500xl Genetic Analyser (Applied Biosystems). Quantification of the mixed chimerism (calculated as percent of recipient DNA) was performed by analyzing the proportion of the fluorescent peak areas corresponding to donor and patient genotypes.
Clinical case description
The patient was a 22-year-old male, initially presented in August 2006 with complaints for moderate fatigue and fever (37.4°C). Peripheral blood examination showed pancytopenia. Bone marrow aspirate was hypocellular with features of aplastic anemia. Cyclosporin A (CSA) was given, but it was taken by the patient only for two weeks due to hepatic discomfort. During the following three years, the patient did not visit a hematologist, and his condition was stable. In January of 2009 he noted exacerbation of fatigue and skin hemorrhages which required hospitalization to the Hematology Department. Peripheral blood counts were as follows: Hb, 55 g/L; WBC, 1.5x109/L; platelets, 4x109/L. The bone marrow aspirate was hypocellular, contained 15.5% blasts with diffuse-type periodic acid Schiff (PAS) staining, and 30% ring sideroblasts, whereas most neutrophilic cells were peroxidase-deficient. Immunophenotyping of the blast cells showed positivity for CD34, CD13, CD33, and HLA-DRA. The results of serial cytogenetic investigations and chimerism testing using molecular biology approaches are presented in Table 1.
Figure 1. Karyogram of bone marrow cell 47, XY, t(3;21) (q26;q22),+13 from patient with primary myelodysplastic syndrome (RAEB-II)
Initial marrow karyotype was as following: 47, XY, t(3;21) (q26.2;q22),+13, (Fig. 1) with involvement into arrangement EVI1 gene (Fig. 2), whereas 10% metaphases had normal chromosome complement. Meanwhile, a standard molecular investigation with primers for common chromosome translocations did not show any oncogene anomalies. Therefore, a diagnosis of MDS RAEB -II IPSS 3.0 was established. Since the patient was transfusion-dependent for a long time, his ferritine level reached 2500 mg/mm3.
Figure 2. Fluorescence in situ hybridization (FISH) with BreakApart EVI1 probe (CytoCell, UK) showing one normal EVI1 gene (one fusion yellow signal) and one abnormal EVI1 gene (one green and one red split signals on interphase cells) in the patient with translocation t(3;21)(q26.2;q22) RUNX1/EVI1
Figure 3. Karyotype of donor’s bone marrow cell 46,XY from a patient with primary myelodysplastic syndrome after allogeneic bone marrow transplantation prepared during a short-term hematological and cytogenetic remission
Figure 4. Schematic presentation of clinical course in a patient with primary myelodysplastic syndrome with karyotype 47,XY,t(3;21)(q26.2;q22),+13 associated with resistance to standard chemotherapy, hypomethylating agents and allo-HSCT
Before bone marrow transplantation, the patient obtained one 5-day course of Dacogen (Decitabine) as demethylating therapy. It did not change common blood parameters, but allowed to reduce his transfusion dependence. Since the patient had an HLA-DQB1-mismatched related donor (Table 1), allo-HSCT was considered. The patient was enrolled into the RIC/MAC study protocol, and randomized to RIC branch (Busulfan + Fludarabine – 800 and 300 mg, respectively). Graft-versus-host-disease (GvHD) prophylaxis included CSA and Methotrexate (MTX). Following the allo-HSCT, stem cell engraftment was detected on day +15, when mixed chimerism was 45-55%. By this time, bone marrow contained only 2.4% of blasts, and the previously detected chromosomal abnormalities were not found (Fig. 3, Table 1). GvHD symptoms were absent, but a cytogenetic relapse was documented two weeks later (on day +29), due to appearance of the marker chromosomal aberrations and decreasing donor chimerism which could be caused by small number of CD34+ stem cells in the graft. Therefore, cyclosporine A was stopped on day +38, and, a week later, a donor lymphocyte infusion (DLI) was performed at a dose of 5.0х107 cells/kg, however, without any clinical effect. The graft rejection was diagnosed on day D+50 (Fig. 4). By that time, the patient had hemoglobin levels of 57 g/L; WBC, 1.7x109/L; and platelets, l3.0x109/L. Bone marrow aspirate was hypocellular with 3.4% blasts, and the donor chimerism faded away (<5%). Because of allo-BMT failure, a second allo-HSCT was administered, using peripheral blood stem cells from the same donor. It was performed after RIC preparative regimen containing Fludarabine 350 mg, Thiotepa 960 mg, and Campath 40 mg. GvHD prophylaxis included Tacrolymus and CellCept (Mycophenolate Mofetyl). Engraftment was registered since day D+10. Two days later, acute GvHD of gut and skin (grade I) was diagnosed. Steroids were added to the treatment schedule which resulted into a significant improvement of GvHD. Peripheral blood findings on the day +16 after 2nd transplant were as follows: Hb, 92.0 g/L; WBC, 4.3x109/L, and platelets, 35.0x109/L. Bone marrow aspirate was hypocellular without blast excess, and full donor chimerism was achieved. Cytogenetic study has shown a repeated karyotype normalization. Due to high risk of relapse, another DLI procedure was performed. Despite the immunotherapy, a new cytogenetic relapse, along with reduced donor chimerism levels, was diagnosed in July 2010. An attempt to achieve another remission with hypomethylating agents (5 courses of Dacogen) was not successful. A repeated cytogenetic relapse has been diagnosed in December 2010, causing his death at the BMT Center two months later.
Discussion
To our knowledge, it is the first clinical description of primary MDS with t(3;21)(q26.2;q22), combined with trisomy 13, and treated by two subsequent allo-HSCTs from a partially HLA-mismatched sibling (brother). The first earliest relapse occurred on the day 29, which could be, in part, explained by low cellularity of transplant. Since a second transplant was required, a reduced-intensity conditioning was chosen again, but peripheral blood stem cells were used for the 2nd transplant. The second engraftment was longer. A new cytological relapse was diagnosed 2 months later as evidenced by increased blast counts in bone marrow up to 12% accompanied by recurrence of the above cytogenetic aberrations, as well as decreasing donor chimerism. Moreover, the patient did not respond to hypomethylating agents (5 courses of Dacogen), aiming to correct the hematopoietic disorder. Recent studies have shown that distinct portions of RUNX1 gene may fuse in variable manner to MDS1 and EVI1 genes located within the 3q26 region. On the other hand, these different fusion products are capable of blocking myeloid differentiation interfering with normal transcriptional regulatory functions of RUNX1 [14]. As a result, our MDS case with combined t(3;21) chromosome anomalies and trisomy 13, showing poor clinical prognosis, appears to be related to imbalance of GATA, ERG, MEIS1, HOXA9 and FLT3 genes at the stem cell level which could be responsible for leukemia cells resistance to both chemotherapy and allo-HSCT.
Acknowledgements
The authors are grateful to colleagues for their excellent support.
Conflict of interest
No conflicts of interests are declared.
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Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.
Ключевые слова
Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.
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Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(160) "Nikolay N. Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. 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He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1112) "We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.
Keywords
Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.
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Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(160) "Nikolay N. Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(160) "Nikolay N. Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev " } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20246" ["VALUE"]=> array(2) { ["TEXT"]=> string(1178) "<p style="text-align: justify;"> We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1112) "We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.
Keywords
Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1112) "We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.
Keywords
Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.
" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20240" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2018-7-2-64-69" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2018-7-2-64-69" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2018-7-2-64-69" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20243" ["VALUE"]=> string(199) "Primary myelodysplastic syndrome with two rare recurrent chromosome abnormalities [t(3q26.2;q22) and trisomy 13] associated with resistance to chemotherapy and hematopoietic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(199) "Primary myelodysplastic syndrome with two rare recurrent chromosome abnormalities [t(3q26.2;q22) and trisomy 13] associated with resistance to chemotherapy and hematopoietic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(199) "Primary myelodysplastic syndrome with two rare recurrent chromosome abnormalities [t(3q26.2;q22) and trisomy 13] associated with resistance to chemotherapy and hematopoietic stem cell transplantation" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20242" ["VALUE"]=> array(2) { ["TEXT"]=> string(194) "R. 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Мамаев, Татьяна Л. Гиндина, Елена В. Морозова, Юлия В. Рудницкая, Мария В. Губина, Ильдар М. Бархатов, Сергей Н. Бондаренко, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(272) "Николай Н. Мамаев, Татьяна Л. Гиндина, Елена В. Морозова, Юлия В. Рудницкая, Мария В. Губина, Ильдар М. Бархатов, Сергей Н. Бондаренко, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(272) "Николай Н. Мамаев, Татьяна Л. Гиндина, Елена В. Морозова, Юлия В. Рудницкая, Мария В. Губина, Ильдар М. Бархатов, Сергей Н. Бондаренко, Борис В. Афанасьев " } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20239" ["VALUE"]=> array(2) { ["TEXT"]=> string(1650) "<p style="text-align: justify;"> Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1584) "Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.
Ключевые слова
Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1584) "Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.
Ключевые слова
Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.
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Acute myeloid leukemia (AML) is a clinically heterogenous clonal blood malignancy. Stratification of the patients into certain AML risk group is primarily based on the presence or absence of cytogenetic aberrations specific to certain leukemic cell clones [1]. Meanwhile, there are challenging issues for the intermediate-risk AML group, which is defined as a non-homogeneous clinical entity, due to a variety of encountered gene mutations (FLT3, NPM1, CEBPA, etc.) coupled to appropriate differences in clinical course, relapse risk, and adequate treatment choice. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) was proven to be an optimal approach to AML therapy [2]. However, leukemia relapses develop in 33-78% of AML patients following allo-HSCT, mainly, due to post-treatment persistence of residual leukemic cells in hematopoietic tissues defined as minimal residual disease (MRD). Therefore, a search for new molecular markers able to predict the relapse risk in AML cases, especially those lacking evident cytogenetic abnormalities, represents a high-priority task for clinical molecular oncohematology. In this respect, the BAALC (brain and acute leukemia, cytoplasmic) gene is a useful molecular marker showing enhanced expression in AML malignant cells, being also associated with unfavorable disease prognosis after the induction chemotherapy [3, 4, 5]. In earlier studies, the high BAALC expression level was observed as a single abnormality in AML patients associated with chromosome 8 trisomy [6]. Later on, the BAALC overexpression was shown to be a negative prognostic factor in AML patients with normal karyotype (NK-AML) [7, 8]. The cases of leukemia with primary chemoresistance, high relapse risk and lower overall survival (OS) rates were more common among the patients with BAALC over-expression, if compared to the patient groups with low BAALC expression [7, 9]. BAALC gene is located in the 8q22.3 locus (chromosome 8). In normal hematopoiesis, BAALC expression is limited by a population of early CD34+ progenitor cells, being, however, associated with the most immature blasts in acute leukemia (AL) [7, 8]. The BAALC overexpression frequency is about 40-60%, similarly to other AML expression markers. But, despite such high prevalence, the functional role of BAALC gene product was only recently specified for the leukemia pathogenesis. Morita and co-authors [10] have shown that BAALC overexpression in leukemic cell lines is associated with a cell cycle progression through the ERK-kinase intracellular signaling cascade activation. In addition, more abundant BAALC protein in the cytoplasm interacts with KLF4 transcription factor, thus causing blockage of KLF4 nuclear transport and inhibition of the specific tumor cell suppression. At the same time, a constitutive BAALC expression/ activation in normal hematopoietic stem cells does not influence their proliferative activity [11]. This fact suggests that an additional genetic defect may promote AML in patients with over-expressed BAALC associated with a relapse before allo-HSCT. Ability of BAALC to block myeloid differentiation of hematopoietic stem cells, due to interaction with HoxA9 oncogene, could be one of such tumor-promoting factors [11]. Hence, some recent data point to certain interrelations between the BAALC over-expression and functional changes in malignant AML cells, thus assisting the disease progression. Interestingly, BAALC expression is regulated by the SP1/ NF-κB transcription factor complex. Its pharmacological inhibitor (Bortezomib) reduces the BAALC transcripts abundance in AML cell line KG1α [12]. Suppression of BAALC expression by shRNA in KG1α cells leads to a decrease of the proliferative activity and apoptosis induction [13]. Further studying of the complex genetic abnormalities, associated with intracellular signaling in BAALC-positive AML, may assist both with selection of therapeutic approach, and opens new opportunities in targeted therapy of resistant AML and prevention of post-transplant relapses. The aim of this study was to analyze prognostic significance of BAALC gene over-expression in AML patients during the post-transplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assays, as a tool for MRD monitoring.
Patients and Methods
Clinical data
The study included ninety-three AML patients who have undergone 94 allo-HSCTs (one transplantation was repeated) at the R. Gorbacheva Memorial Institute Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2014. A median follow-up time after HSCT was 7 (0.5 to 52.5) months. The detailed patient characteristics are shown in Table 1. Bone marrow sampling for molecular studies was performed before and after allo- HSCT on 15-720 days posttransplant.
RNA extraction and reverse transcription
RNA was isolated from the fresh bone marrow samples by the guanidine-phenol-chloroform extraction method using the “Ribo-zol-D” kit reagent (InterLabService, Russia), according to the manufacturer’s instructions. Eleven microliters of extracted RNA were used for reverse transcription and cDNA synthesis, being performed with RevertAid First Strand cDNA Synthesis Kit (LifeTechnologies, USA).
Quantitative evaluation of BAALC gene expression
For each cDNA sample, multiplex PCR was performed for BAALC and ABL genes. The reaction conditions were as follows: 10 μl of PCR reaction mixture (“Syntol”, Russia), containing dNTP mix 2.5 mM each, 10xPCR buffer, 5 Units of Taq-DNA polymerase and 2.5μl of 25 mM MgCl2, supplemented with 7 pmol of each gene-specific primers, 5 pmol of Taqman probes for the both BAALC and ABL genes. The primer and TaqMan probe sequences for the quantitative real- time PCR are shown in Table 2. Finally, 5μl of cDNA template, or calibrator for BAALC and ABL (“Inogene”, Russia) were added to the individual tubes, at a total PCR reaction volume of 25μl. Quantitative real-time PCR was performed with a BioRad iQ5 instrument (“BioRad”, USA). The amplification protocol was 95°С for 10 min followed by 50 cycles of heating at 95°С (15 sec), and annealing at 60°С (1 min). The relative BAALC expression levels, or BAALC copy numbers (CN) were determined against the housekeeping reference gene ABL1 to adjust for variations in mRNA quality and different efficiencies of cDNA synthesis. [14]. The gene expression ratio was calculated by the formula CN(BAALC)/CN (ABL)x100%, and the results were expressed in percents.
Statistical methods
Statistical evaluation was performed using descriptive statistics and non-parametric correlation analysis (Spearman rank correlation quotient). In order to reveal the basal BAALC cut-off expression level for MRD monitoring, the analysis of its specificity and sensitivity compared to the reference methods was calculated using ROC-analysis. The prognostic significance of BAALC expression level estimated by plotting of OS, RFS and relapse risk curves, according to Kaplan-Meier. SPSS software version 22.0 (IBM corporation, Armonk, NY, USA) and SAS9 were used for statistical analysis.Results
Correlation between BAALC expression level and clinical scores
In the present study, we have observed positive correlations between BAALC expression level and the number of blast cells in bone marrow (R=0.417, N=93, p=0.000), and with chimeric transcripts in the favorable cytogenetic risk group (RUNX1-RUNX1T1, PML-RARα and CBFB-MYH11) (R=0.388, N=16, p=0.000). A stronger correlation was revealed between BAALC and chimeric transcript RUNX1-RUNX1T1 expression (R=0.521, N=9, p=0.000). Besides, in three patients, who displays PML-RARα transcript, we observed relative lower BAALC expression profile (BAALC expression level ranged from 0.05% to 12.87% with a median 1.84%). In addition, a negative correlation was revealed for BAALC and donor chimerism level which was determined by analysis of short tandem repeats (R=-0.257, N=93, p=0.0001).
Posttransplant BAALC expression monitoring for the relapse risk estimation
The terms of relapse for the patients included into this study ranged from 24 to 400 (a median of 101) days post-transplant. BAALC expression level in the cases of posttransplant relapse was higher than in non-relapsing patients, except for the early posttransplant period (Fig. 1). The most significant difference was detected at D+60 (p=0.006), D+90 (p=0.022), D+120 (p=0.008), D+150 (p=0.006), and D+270 (p=0.006) after allo-HSCT.
Figure 1. Time course and magnitude of BAALC expression reflects a relapse risk in subgroups of AML patients over the posttransplant period. Abscissa: days after HSCT and number of cases at each timepoint. Ordinate: Relative BAALC expression levels, %. Red graph – patients with clinical relapse in posttransplant period. Blue graph – patients without clinical relapse in posttransplant period. * – p<0.05. The grey-shaded space represents 95% confidence intervals
Our data indicate that BAALC expression levels in relapse-free patients did not differ significantly from those in remission state before allo-HSCT (N=69, p=0.308), also being independent on the conditioning regimen (N=69, p=0.199). The median of BAALC expression levels in the patients without post-transplant relapse was 2.6%, with a maximal value of 56.7% (Fig. 2). At early terms after HSCT (D+15 to D+30), the levels of BAALC expression in these patients were comparable to those in remission before HSCT (p=0.515 (N=17) and p=0.212 (N=37), respectively). In this respect, the basal BAALC expression level of 60% was chosen as a common cut-off value in order to assess the BAALC prognostic significance in AML patients over the post-transplant period, because such cut-off reflects a maximal BAALC expression in non-relapsed patients.
Figure 2. A variety of BAALC expression levels over posttransplant period in the patients without relapse after allo-HSCT. Asterisks represent extreme values, circles represent outlying values
We have also undertaken a study with individual pre-transplant cut-off values, in order to predict probability of post-transplant remission. The patients with relative BAALC expression level of >0.5% in remission before HSCT were taken into analysis. Appropriate group of 51 patients was studied, including 16 cases of posttransplant relapse. The median BAALC expression level in patients in pre-transplant remission was 3.7, as compared to the patients relapsed after HSCT who exhibited a median pre-transplant value of 120.5 (p=0.0001, according to the Wilcoxon test). In absence of post-transplant relapse, 97.1% of patients did not show an increased BAALC expression by more than 0.5 log10 (fivefold) over the post-transplant period (Fig. 3).
Figure 3. Changes of individual BAALC expression level in patients without relapse or in relapse after the allo-HSCT relatively to the period before transplantation. Abscissa: orders of BAALC overexpression (log10)
In 88.2% patients with relapse, we observed BAALC expression level of more than for 0.5 log10 above the individual threshold. Moreover, a rise of individual BAALC expression levels by more than one order of magnitude was registered in 80% of post-transplant relapsed patients. Such an increase was not observed in patients with relapse-free post-transplant course. Therefore, BAALC overexpression of >1 log10 has been chosen as an individual cut-off level for studying prognostic significance of BAALC during the post-transplant period in AML patients.
BAALC overexpression: prediction for survivaland relapse risk
In the study group, expression of BAALC above the cut-off level of 60% was observed in 51.9% of relapse cases (14 of 27 patients), whereas individual increases over the cut-off value were registered in 11 relapsed patients of 14 (78.6%). When studying the prognostic significance of BAALC over-expression, we have revealed significant correlations between both individual and common cut-off excess and overall survival, relapse-free survival and relapse risk over a 2-year period after HSCT (Fig. 4). In cases of BAALC overexpression > 60%, both OS and RFS rates were decreased to 7.1% and 0%, respectively, and the relapse risk was 100%. In case of BAALC over-expression above 1 log10 higher than individual cut-offs, the OS and RFS factors were 11.1% and the relapse risk was 88.9%. In particular, BAALC overexpression by >1 log10 over individual cutoff allows assignment of the patients to prognostically unfavorable risk group for high OS, RFS and relapse risk (Fig. 5). Moreover, we have revealed that the pre-relapse increase of individual cutoff values proved to occur sooner than an increased common cut-off value (>60%). For example, BAALC expression by more than 1 log10 over individual basal expression levels was observed in 6 of 14 relapse cases in this group (42.9%) and it developed at 51 days (3-115) prior to clinical relapse. BAALC expression of >60% before the clinical relapse was registered in 2 cases from 21 (9.52%), and in both cases it was developed in 9 days before clinical symptoms of relapse.
Assessing the BAALC cut-off level for reliable MRD monitoring
Minimal residual disease (MRD) is the one of basic reasons of posttransplant relapses in AML. The most sensitive method for MRD detection is the monitoring of the patient-specific cytogenetic aberrations in leukemic cells, resulting in fusion transcripts, or genetic point mutations. However, more than a half of AML patients lack such informative genetic markers [15]. Such patient cohorts represent an ideal group for studying the significance of BAALC overexpression for MRD detection and estimation of relapse risk in post-transplant period.
Our study included assessment of cut-off level for BAALC expression aimed for MRD monitoring in the patients with chimeric transcripts. Appropriate expression levels were based on results of quantitative real-time PCR (N=17). By comparing BAALC expression in molecular remission (MRD=0%) and relapse (MRD>0%) using the receiveroperating characteristic curve (ROC) plotting method, a range of the most sensitive and specific cut-off level values was determined for clinical relapse prediction (Fig. 6A). The area under the curve (AUC) was 0.698. The BAALC expression level at maximal sensitivity and specificity for detection of residual tumor cell was adjusted to 5.2% (sensitivity of 0.495, and specificity of 0.914).
Figure 5. Prognostic significance of posttransplant BAALC expression over individual cut-offs for intermediate-risk AML group, as compared to the group of cytogenetic-based unfavorable prognosis (N=54, p=0.000)
Using the generated cut-off value of 5.2% for the entire patient cohort, we have shown that the BAALC expression exceeding such value did not significantly influence the relapse risk (p=0.071), overall (p=0.422) and relapse-free survival (p=0.244) after the HSCT (Fig. 6 B-D). At the same time, the amounts of positive chimeric gene transcripts in favorable-risk patient group (N=17) ranging from 0.002 to 231%, with a median of 0.09%, were observed at the BAALC<5.2% expression level (Fig. 7).
Discussion
Our study aimed for evaluation of prognostic significance for the BAALC overexpression after allo-HSCT, as well as BAALC monitoring for relapse risk estimation after HSCT, and calculation of sensitivity and specificity indexes of MRD testing in AML patients with normal karyotype.
We have found positive correlations between BAALC expression levels and amounts of blast cells in bone marrow samples, and correlations with molecular cytogenetic markers in favorable AML risk group, especially, with chimeric RUNX1-RUNX1T transcript. These data well conform to the previously published analyses [16]. The low correlation quotient may be explained by the fact that BAALC expression is more typical to the least differentiated hematopoietic progenitors and blast cells that express the CD34 surface marker. However, leukemic cells in 20% of AML cases are more differentiated, being CD34-negative, thus exhibiting lower BAALC expression [7, 17, 18]. Stronger correlation of BAALC and RUNX1-RUNX1T1 compared to other translocations in favorable cytogenetic group can be explained by the presence of a G424T polymorphism (rs62527607) in BAALC promoter region which is found in 15% of cases. This nucleotide substitution creates an additional site for high affinity RUNX1 transcription factor binding [19, 20]. The RUNX1 transcription factor and RUNX1-RUNX1T1 chimeric protein have a similar target gene activation profile, due to identical DNA-binding domain structure, thus potentially leading to increased BAALC expression by the RUNX1-RUNX1T1 in cases of 424T allele [21]. Additional experiments are required to confirm this hypothesis.
Figure 6. Graph A: estimation of basal BAALC cut-off level for MRD detection by means of ROC-analysis; B, influence of BAALC overexpression (BAALC>5.2%) on the clinical relapse risk in AML patients with normal karyotype (NK-AML) after allo-HSCT; C, influence of BAALC overexpression (BAALC>5.2%) on the 2-year OS values of NK-AML patients; D, influence of BAALC overexpression (BAALC>5.2%) on the 2-year RFS values of NK-AML patients after HSCT
Figure 7. Expression range of mRNA fusion transcripts typical to favorable cytogenetic risk group at the BAALC expression levels of <5.2%
A negative correlation between the BAALC expression level and PML-RARα fusion transcript was also discussed previously. BAALC expression level is significantly lower in acute promyelocytic leukemia (APL), exhibiting a specific PMLRARα translocation [22, 23]. A functional role of BAALC gene in APL induction is still open to debates. However, BAALC overexpression allows to distinguish a sub-group with unfavorable disease prognosis within the high-risk APL cohort [23, 24]. According to several studies, BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. Interestingly, in the cases of BAALC-positive AML status before HSCT, this marker remained to be informative in 89% of posttransplant relapses (8 from 9 cases). Overexpression of WT1 and PRAME markers in the exceptional BAALC-positive case was observed in the bone marrow sample at the posttransplant relapse. This fact is absolutely consistent with literature data [25], where BAALC gene expression is discussed as an early event in the dominant clone, which remains relatively stable through clonal evolution. We have also used studied individual threshold values of BAALC expression before transplant, in order to predict a risk of clinical relapse after allo-HSCT. A ten-fold increase of individual BAALC expression over the median has been chosen as a cut-off value for results obtained in clinical remission before HSCT. Elevation over general cut-off value of 60% correlated with maximal risk of clinical relapse during the 1st year post-transplant. Increased BAALC expression by one to four log10 (10-10 000 fold) over individual cut-off values suggested a transfer of the patient to unfavorable risk group. A feasibility of the individual BAALC expression monitoring is confirmed by increased expression of BAALC over general cut-off levels in only 51.9% of relapsed patients, whereas individual thresholds were exceeded at earlier terms before relapse, being informative in 78.6% of relapses. Such findings are in accordance with the literature data, where only 53.9% of relapsed patients had BAALC/ABL1 ratio over than 60% [25]. Referring to the scientific publications, monitoring of the BAALC expression may be useful for therapy efficiency estimation in the patients lacking specific genetic markers of tumor cells, and for prediction of molecular and clinical relapse [4, 22, 25, 26]. Applicability of BAALC expression as a MRD marker is based on its sufficient overexpression in relapse if compared to the remission values and its correlation with gene expression of AML markers, such as RUNX1-RUNX1T1, WT1 expression, other markers of normal-karyotype AML (RUNX1, FLT3-ITD, NPM1, CEBPA, MLL-PTD etc.). Our data confirm a significant difference of BAALC expression for the remission and relapse states. However, a more detailed analysis of BAALC as an MRD marker, and its comparison to the reference techniques for MRD monitoring (i.e., qPCR-based detection of chimeric gene transcripts) was performed, showing lower sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. In the absence of BAALC overexpression (BAALC<5.2%), positive MRD values can be observed, whereas BAALC over-expression (BAALC>5.2%) did not significantly correlate with relapse risk, overall and relapse-free survival. Therefore, quantitative monitoring of BAALC expression could not be recommended as a universal marker of therapy efficiency in the patients with normal-karyotype AML after allo-HSCT, since a specificity of BAALC for CD34+ leukemic blasts is reduced, due to its basal expression in early hematopoietic progenitors [7, 27].
Conclusion
Summarizing our results obtained with a representative group of AML patients, we may recommend the serial quantitative BAALC monitoring for clinical relapse prediction following allogeneic hematopoietic stem cell transplantation. Tracing of BAALC expression levels and individual assignment of cut-off values can be useful not only for stratification of patients into different risk groups, but also for selection of appropriate AML therapy after allo-HSCT.
Conflict of interest
No conflicts of interest are reported.
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13. Xu B, Chen G, Shi P, Guo X, Xiao P, Wang W, Zhou S. shRNA-Mediated BAALC knockdown affects proliferation and apoptosis in human acute myeloid leukemia cells. Hematology. 2012;17(1):35-40.
14. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-1108.
15. Saultz JN, Garzon R. Acute myeloid leukemia: A concise review. J Clin Med. 2016; 5(3). pii: E33. doi: 10.3390/jcm5030033.
16. Qi X, Shen Y, Cen J, Chen H, Sun Y, Sheng H, Wang Y, and Chena Z. Up-regulation of BAALC gene may be an important alteration in AML-M2 patients with t(8;21) translocation. J Cell Mol Med. 2008; 12(6a): 2301–2304.
17. Oyan AM, TH, Jonassen I, Ulvestad E, Gjertsen BT, Kalland KH, Bruserud O. CD34 expression in native human acute myelogenous leukemia blasts: differences in CD34 membrane molecule expression are associated with different gene expression profiles. Cytometry B Clin Cytom. 2005;64(1):18-27.
18. Schuurhuis GJ, Kelder A, Terwijn M, Rutten AP, Smit L, Zweegman S, Ossenkoppele G. The prognostic value of CD34 expression in acute myeloid leukemia. A mystery solved. Blood. 2010; 116 (21):2725.
19. Eisfeld AK, Marcucci G, Liyanarachchi S, Döhner K, Schwind S, Maharry K, Leffel B, Döhner H, Radmacher MD, Bloomfield CD, Tanner SM,and de la Chapellea A. Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia. Proc Natl Acad Sci USA. 2012; 109(17): 6668–6673.
20. Nadimi M, Rahgozar S, Moafi A, Tavassoli M, Mesrian Tanha H. Evaluation of rs62527607 [GT] single nucleotide polymorphism located in BAALC gene in children with acute leukemia using mismatch PCR-RFLP. Cancer Genet. 2016;209(7-8):348-353.
21. Lam K and Zhang DE. RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci. 2012;17:1120–1139.
22. Najima Y, Ohashi K, Kawamura M, Onozuka Y, Yamaguchi T, Akiyama H, Sakamaki H. Molecular monitoring of BAALC expression in patients with CD34-positive acute leukemia. Int J Hematol. 2010;91(4):636-645.
23. Lucena-Araujo AR, Pereira-Martins DA, Koury LS, Franca-Neto PL, Coelho-Silva JL, de Deus Wagatsuma VM, elo RAM, Bittencourt R, Pagnano K, Pasquini R, Chiattone CS, Fagundes EM, Chauffaille ML, Schrier SL, Tallman MS, Ribeiro RC, Grimwade D, Ganser A, Löwenberg B, Lo-Coco F,Sanz MA, Berliner N, Rego EM. Clinical impact of BAALC expression in high-risk acute promyelocytic leukemia. Blood Adv. 2017; 1(21): 1807–1814.
24. Nolte F, Hecht A, Reinwald M, Nowak D, Nowak V, Hanfstein B, Faldum A, Büchner T, Spiekermann K, Sauerland C, Hofmann WK, Lengfelder E. In acute promyelocytic leukemia (APL) low BAALC gene expression identifies a patient group with favorable overall survival and improved relapse free survival. Leuk Res. 2013;37(4):378-382.
25. Weber S, Haferlach T, Alpermann T, Perglerová K, Schnittger S, Haferlach C, Kern W. Feasibility of BAALC gene expression for detection of minimal residual disease and risk stratification in normal karyotype acute myeloid leukaemia. Br J Haematol. 2016;175(5):904-916.
26. Weber S, Alpermann T, Dicker F, Jeromin S, Nadarajah N, Eder C, Fasan A, Kohlmann A, Meggendorfer M,Haferlach C, Kern W, Haferlach T, Schnittger S. BAALC expression: a suitable marker for prognostic risk stratification and detection of residual disease in cytogenetically normal acute myeloid leukemia. Blood Cancer J. 2014; 4(1): e173.
27. Eid MA, Attia M, Abdou S, El-Shazly SF, Elahwal L, Farrag W, Mahmoud L. BAALC and ERG expression in acute myeloid leukemia with normal karyotype: impact on prognosis. Int J Lab Hematol. 2010;32(2):197-205.
Introduction
Acute myeloid leukemia (AML) is a clinically heterogenous clonal blood malignancy. Stratification of the patients into certain AML risk group is primarily based on the presence or absence of cytogenetic aberrations specific to certain leukemic cell clones [1]. Meanwhile, there are challenging issues for the intermediate-risk AML group, which is defined as a non-homogeneous clinical entity, due to a variety of encountered gene mutations (FLT3, NPM1, CEBPA, etc.) coupled to appropriate differences in clinical course, relapse risk, and adequate treatment choice. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) was proven to be an optimal approach to AML therapy [2]. However, leukemia relapses develop in 33-78% of AML patients following allo-HSCT, mainly, due to post-treatment persistence of residual leukemic cells in hematopoietic tissues defined as minimal residual disease (MRD). Therefore, a search for new molecular markers able to predict the relapse risk in AML cases, especially those lacking evident cytogenetic abnormalities, represents a high-priority task for clinical molecular oncohematology. In this respect, the BAALC (brain and acute leukemia, cytoplasmic) gene is a useful molecular marker showing enhanced expression in AML malignant cells, being also associated with unfavorable disease prognosis after the induction chemotherapy [3, 4, 5]. In earlier studies, the high BAALC expression level was observed as a single abnormality in AML patients associated with chromosome 8 trisomy [6]. Later on, the BAALC overexpression was shown to be a negative prognostic factor in AML patients with normal karyotype (NK-AML) [7, 8]. The cases of leukemia with primary chemoresistance, high relapse risk and lower overall survival (OS) rates were more common among the patients with BAALC over-expression, if compared to the patient groups with low BAALC expression [7, 9]. BAALC gene is located in the 8q22.3 locus (chromosome 8). In normal hematopoiesis, BAALC expression is limited by a population of early CD34+ progenitor cells, being, however, associated with the most immature blasts in acute leukemia (AL) [7, 8]. The BAALC overexpression frequency is about 40-60%, similarly to other AML expression markers. But, despite such high prevalence, the functional role of BAALC gene product was only recently specified for the leukemia pathogenesis. Morita and co-authors [10] have shown that BAALC overexpression in leukemic cell lines is associated with a cell cycle progression through the ERK-kinase intracellular signaling cascade activation. In addition, more abundant BAALC protein in the cytoplasm interacts with KLF4 transcription factor, thus causing blockage of KLF4 nuclear transport and inhibition of the specific tumor cell suppression. At the same time, a constitutive BAALC expression/ activation in normal hematopoietic stem cells does not influence their proliferative activity [11]. This fact suggests that an additional genetic defect may promote AML in patients with over-expressed BAALC associated with a relapse before allo-HSCT. Ability of BAALC to block myeloid differentiation of hematopoietic stem cells, due to interaction with HoxA9 oncogene, could be one of such tumor-promoting factors [11]. Hence, some recent data point to certain interrelations between the BAALC over-expression and functional changes in malignant AML cells, thus assisting the disease progression. Interestingly, BAALC expression is regulated by the SP1/ NF-κB transcription factor complex. Its pharmacological inhibitor (Bortezomib) reduces the BAALC transcripts abundance in AML cell line KG1α [12]. Suppression of BAALC expression by shRNA in KG1α cells leads to a decrease of the proliferative activity and apoptosis induction [13]. Further studying of the complex genetic abnormalities, associated with intracellular signaling in BAALC-positive AML, may assist both with selection of therapeutic approach, and opens new opportunities in targeted therapy of resistant AML and prevention of post-transplant relapses. The aim of this study was to analyze prognostic significance of BAALC gene over-expression in AML patients during the post-transplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assays, as a tool for MRD monitoring.
Patients and Methods
Clinical data
The study included ninety-three AML patients who have undergone 94 allo-HSCTs (one transplantation was repeated) at the R. Gorbacheva Memorial Institute Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2014. A median follow-up time after HSCT was 7 (0.5 to 52.5) months. The detailed patient characteristics are shown in Table 1. Bone marrow sampling for molecular studies was performed before and after allo- HSCT on 15-720 days posttransplant.
RNA extraction and reverse transcription
RNA was isolated from the fresh bone marrow samples by the guanidine-phenol-chloroform extraction method using the “Ribo-zol-D” kit reagent (InterLabService, Russia), according to the manufacturer’s instructions. Eleven microliters of extracted RNA were used for reverse transcription and cDNA synthesis, being performed with RevertAid First Strand cDNA Synthesis Kit (LifeTechnologies, USA).
Quantitative evaluation of BAALC gene expression
For each cDNA sample, multiplex PCR was performed for BAALC and ABL genes. The reaction conditions were as follows: 10 μl of PCR reaction mixture (“Syntol”, Russia), containing dNTP mix 2.5 mM each, 10xPCR buffer, 5 Units of Taq-DNA polymerase and 2.5μl of 25 mM MgCl2, supplemented with 7 pmol of each gene-specific primers, 5 pmol of Taqman probes for the both BAALC and ABL genes. The primer and TaqMan probe sequences for the quantitative real- time PCR are shown in Table 2. Finally, 5μl of cDNA template, or calibrator for BAALC and ABL (“Inogene”, Russia) were added to the individual tubes, at a total PCR reaction volume of 25μl. Quantitative real-time PCR was performed with a BioRad iQ5 instrument (“BioRad”, USA). The amplification protocol was 95°С for 10 min followed by 50 cycles of heating at 95°С (15 sec), and annealing at 60°С (1 min). The relative BAALC expression levels, or BAALC copy numbers (CN) were determined against the housekeeping reference gene ABL1 to adjust for variations in mRNA quality and different efficiencies of cDNA synthesis. [14]. The gene expression ratio was calculated by the formula CN(BAALC)/CN (ABL)x100%, and the results were expressed in percents.
Statistical methods
Statistical evaluation was performed using descriptive statistics and non-parametric correlation analysis (Spearman rank correlation quotient). In order to reveal the basal BAALC cut-off expression level for MRD monitoring, the analysis of its specificity and sensitivity compared to the reference methods was calculated using ROC-analysis. The prognostic significance of BAALC expression level estimated by plotting of OS, RFS and relapse risk curves, according to Kaplan-Meier. SPSS software version 22.0 (IBM corporation, Armonk, NY, USA) and SAS9 were used for statistical analysis.Results
Correlation between BAALC expression level and clinical scores
In the present study, we have observed positive correlations between BAALC expression level and the number of blast cells in bone marrow (R=0.417, N=93, p=0.000), and with chimeric transcripts in the favorable cytogenetic risk group (RUNX1-RUNX1T1, PML-RARα and CBFB-MYH11) (R=0.388, N=16, p=0.000). A stronger correlation was revealed between BAALC and chimeric transcript RUNX1-RUNX1T1 expression (R=0.521, N=9, p=0.000). Besides, in three patients, who displays PML-RARα transcript, we observed relative lower BAALC expression profile (BAALC expression level ranged from 0.05% to 12.87% with a median 1.84%). In addition, a negative correlation was revealed for BAALC and donor chimerism level which was determined by analysis of short tandem repeats (R=-0.257, N=93, p=0.0001).
Posttransplant BAALC expression monitoring for the relapse risk estimation
The terms of relapse for the patients included into this study ranged from 24 to 400 (a median of 101) days post-transplant. BAALC expression level in the cases of posttransplant relapse was higher than in non-relapsing patients, except for the early posttransplant period (Fig. 1). The most significant difference was detected at D+60 (p=0.006), D+90 (p=0.022), D+120 (p=0.008), D+150 (p=0.006), and D+270 (p=0.006) after allo-HSCT.
Figure 1. Time course and magnitude of BAALC expression reflects a relapse risk in subgroups of AML patients over the posttransplant period. Abscissa: days after HSCT and number of cases at each timepoint. Ordinate: Relative BAALC expression levels, %. Red graph – patients with clinical relapse in posttransplant period. Blue graph – patients without clinical relapse in posttransplant period. * – p<0.05. The grey-shaded space represents 95% confidence intervals
Our data indicate that BAALC expression levels in relapse-free patients did not differ significantly from those in remission state before allo-HSCT (N=69, p=0.308), also being independent on the conditioning regimen (N=69, p=0.199). The median of BAALC expression levels in the patients without post-transplant relapse was 2.6%, with a maximal value of 56.7% (Fig. 2). At early terms after HSCT (D+15 to D+30), the levels of BAALC expression in these patients were comparable to those in remission before HSCT (p=0.515 (N=17) and p=0.212 (N=37), respectively). In this respect, the basal BAALC expression level of 60% was chosen as a common cut-off value in order to assess the BAALC prognostic significance in AML patients over the post-transplant period, because such cut-off reflects a maximal BAALC expression in non-relapsed patients.
Figure 2. A variety of BAALC expression levels over posttransplant period in the patients without relapse after allo-HSCT. Asterisks represent extreme values, circles represent outlying values
We have also undertaken a study with individual pre-transplant cut-off values, in order to predict probability of post-transplant remission. The patients with relative BAALC expression level of >0.5% in remission before HSCT were taken into analysis. Appropriate group of 51 patients was studied, including 16 cases of posttransplant relapse. The median BAALC expression level in patients in pre-transplant remission was 3.7, as compared to the patients relapsed after HSCT who exhibited a median pre-transplant value of 120.5 (p=0.0001, according to the Wilcoxon test). In absence of post-transplant relapse, 97.1% of patients did not show an increased BAALC expression by more than 0.5 log10 (fivefold) over the post-transplant period (Fig. 3).
Figure 3. Changes of individual BAALC expression level in patients without relapse or in relapse after the allo-HSCT relatively to the period before transplantation. Abscissa: orders of BAALC overexpression (log10)
In 88.2% patients with relapse, we observed BAALC expression level of more than for 0.5 log10 above the individual threshold. Moreover, a rise of individual BAALC expression levels by more than one order of magnitude was registered in 80% of post-transplant relapsed patients. Such an increase was not observed in patients with relapse-free post-transplant course. Therefore, BAALC overexpression of >1 log10 has been chosen as an individual cut-off level for studying prognostic significance of BAALC during the post-transplant period in AML patients.
BAALC overexpression: prediction for survivaland relapse risk
In the study group, expression of BAALC above the cut-off level of 60% was observed in 51.9% of relapse cases (14 of 27 patients), whereas individual increases over the cut-off value were registered in 11 relapsed patients of 14 (78.6%). When studying the prognostic significance of BAALC over-expression, we have revealed significant correlations between both individual and common cut-off excess and overall survival, relapse-free survival and relapse risk over a 2-year period after HSCT (Fig. 4). In cases of BAALC overexpression > 60%, both OS and RFS rates were decreased to 7.1% and 0%, respectively, and the relapse risk was 100%. In case of BAALC over-expression above 1 log10 higher than individual cut-offs, the OS and RFS factors were 11.1% and the relapse risk was 88.9%. In particular, BAALC overexpression by >1 log10 over individual cutoff allows assignment of the patients to prognostically unfavorable risk group for high OS, RFS and relapse risk (Fig. 5). Moreover, we have revealed that the pre-relapse increase of individual cutoff values proved to occur sooner than an increased common cut-off value (>60%). For example, BAALC expression by more than 1 log10 over individual basal expression levels was observed in 6 of 14 relapse cases in this group (42.9%) and it developed at 51 days (3-115) prior to clinical relapse. BAALC expression of >60% before the clinical relapse was registered in 2 cases from 21 (9.52%), and in both cases it was developed in 9 days before clinical symptoms of relapse.
Assessing the BAALC cut-off level for reliable MRD monitoring
Minimal residual disease (MRD) is the one of basic reasons of posttransplant relapses in AML. The most sensitive method for MRD detection is the monitoring of the patient-specific cytogenetic aberrations in leukemic cells, resulting in fusion transcripts, or genetic point mutations. However, more than a half of AML patients lack such informative genetic markers [15]. Such patient cohorts represent an ideal group for studying the significance of BAALC overexpression for MRD detection and estimation of relapse risk in post-transplant period.
Our study included assessment of cut-off level for BAALC expression aimed for MRD monitoring in the patients with chimeric transcripts. Appropriate expression levels were based on results of quantitative real-time PCR (N=17). By comparing BAALC expression in molecular remission (MRD=0%) and relapse (MRD>0%) using the receiveroperating characteristic curve (ROC) plotting method, a range of the most sensitive and specific cut-off level values was determined for clinical relapse prediction (Fig. 6A). The area under the curve (AUC) was 0.698. The BAALC expression level at maximal sensitivity and specificity for detection of residual tumor cell was adjusted to 5.2% (sensitivity of 0.495, and specificity of 0.914).
Figure 5. Prognostic significance of posttransplant BAALC expression over individual cut-offs for intermediate-risk AML group, as compared to the group of cytogenetic-based unfavorable prognosis (N=54, p=0.000)
Using the generated cut-off value of 5.2% for the entire patient cohort, we have shown that the BAALC expression exceeding such value did not significantly influence the relapse risk (p=0.071), overall (p=0.422) and relapse-free survival (p=0.244) after the HSCT (Fig. 6 B-D). At the same time, the amounts of positive chimeric gene transcripts in favorable-risk patient group (N=17) ranging from 0.002 to 231%, with a median of 0.09%, were observed at the BAALC<5.2% expression level (Fig. 7).
Discussion
Our study aimed for evaluation of prognostic significance for the BAALC overexpression after allo-HSCT, as well as BAALC monitoring for relapse risk estimation after HSCT, and calculation of sensitivity and specificity indexes of MRD testing in AML patients with normal karyotype.
We have found positive correlations between BAALC expression levels and amounts of blast cells in bone marrow samples, and correlations with molecular cytogenetic markers in favorable AML risk group, especially, with chimeric RUNX1-RUNX1T transcript. These data well conform to the previously published analyses [16]. The low correlation quotient may be explained by the fact that BAALC expression is more typical to the least differentiated hematopoietic progenitors and blast cells that express the CD34 surface marker. However, leukemic cells in 20% of AML cases are more differentiated, being CD34-negative, thus exhibiting lower BAALC expression [7, 17, 18]. Stronger correlation of BAALC and RUNX1-RUNX1T1 compared to other translocations in favorable cytogenetic group can be explained by the presence of a G424T polymorphism (rs62527607) in BAALC promoter region which is found in 15% of cases. This nucleotide substitution creates an additional site for high affinity RUNX1 transcription factor binding [19, 20]. The RUNX1 transcription factor and RUNX1-RUNX1T1 chimeric protein have a similar target gene activation profile, due to identical DNA-binding domain structure, thus potentially leading to increased BAALC expression by the RUNX1-RUNX1T1 in cases of 424T allele [21]. Additional experiments are required to confirm this hypothesis.
Figure 6. Graph A: estimation of basal BAALC cut-off level for MRD detection by means of ROC-analysis; B, influence of BAALC overexpression (BAALC>5.2%) on the clinical relapse risk in AML patients with normal karyotype (NK-AML) after allo-HSCT; C, influence of BAALC overexpression (BAALC>5.2%) on the 2-year OS values of NK-AML patients; D, influence of BAALC overexpression (BAALC>5.2%) on the 2-year RFS values of NK-AML patients after HSCT
Figure 7. Expression range of mRNA fusion transcripts typical to favorable cytogenetic risk group at the BAALC expression levels of <5.2%
A negative correlation between the BAALC expression level and PML-RARα fusion transcript was also discussed previously. BAALC expression level is significantly lower in acute promyelocytic leukemia (APL), exhibiting a specific PMLRARα translocation [22, 23]. A functional role of BAALC gene in APL induction is still open to debates. However, BAALC overexpression allows to distinguish a sub-group with unfavorable disease prognosis within the high-risk APL cohort [23, 24]. According to several studies, BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. Interestingly, in the cases of BAALC-positive AML status before HSCT, this marker remained to be informative in 89% of posttransplant relapses (8 from 9 cases). Overexpression of WT1 and PRAME markers in the exceptional BAALC-positive case was observed in the bone marrow sample at the posttransplant relapse. This fact is absolutely consistent with literature data [25], where BAALC gene expression is discussed as an early event in the dominant clone, which remains relatively stable through clonal evolution. We have also used studied individual threshold values of BAALC expression before transplant, in order to predict a risk of clinical relapse after allo-HSCT. A ten-fold increase of individual BAALC expression over the median has been chosen as a cut-off value for results obtained in clinical remission before HSCT. Elevation over general cut-off value of 60% correlated with maximal risk of clinical relapse during the 1st year post-transplant. Increased BAALC expression by one to four log10 (10-10 000 fold) over individual cut-off values suggested a transfer of the patient to unfavorable risk group. A feasibility of the individual BAALC expression monitoring is confirmed by increased expression of BAALC over general cut-off levels in only 51.9% of relapsed patients, whereas individual thresholds were exceeded at earlier terms before relapse, being informative in 78.6% of relapses. Such findings are in accordance with the literature data, where only 53.9% of relapsed patients had BAALC/ABL1 ratio over than 60% [25]. Referring to the scientific publications, monitoring of the BAALC expression may be useful for therapy efficiency estimation in the patients lacking specific genetic markers of tumor cells, and for prediction of molecular and clinical relapse [4, 22, 25, 26]. Applicability of BAALC expression as a MRD marker is based on its sufficient overexpression in relapse if compared to the remission values and its correlation with gene expression of AML markers, such as RUNX1-RUNX1T1, WT1 expression, other markers of normal-karyotype AML (RUNX1, FLT3-ITD, NPM1, CEBPA, MLL-PTD etc.). Our data confirm a significant difference of BAALC expression for the remission and relapse states. However, a more detailed analysis of BAALC as an MRD marker, and its comparison to the reference techniques for MRD monitoring (i.e., qPCR-based detection of chimeric gene transcripts) was performed, showing lower sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. In the absence of BAALC overexpression (BAALC<5.2%), positive MRD values can be observed, whereas BAALC over-expression (BAALC>5.2%) did not significantly correlate with relapse risk, overall and relapse-free survival. Therefore, quantitative monitoring of BAALC expression could not be recommended as a universal marker of therapy efficiency in the patients with normal-karyotype AML after allo-HSCT, since a specificity of BAALC for CD34+ leukemic blasts is reduced, due to its basal expression in early hematopoietic progenitors [7, 27].
Conclusion
Summarizing our results obtained with a representative group of AML patients, we may recommend the serial quantitative BAALC monitoring for clinical relapse prediction following allogeneic hematopoietic stem cell transplantation. Tracing of BAALC expression levels and individual assignment of cut-off values can be useful not only for stratification of patients into different risk groups, but also for selection of appropriate AML therapy after allo-HSCT.
Conflict of interest
No conflicts of interest are reported.
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23. Lucena-Araujo AR, Pereira-Martins DA, Koury LS, Franca-Neto PL, Coelho-Silva JL, de Deus Wagatsuma VM, elo RAM, Bittencourt R, Pagnano K, Pasquini R, Chiattone CS, Fagundes EM, Chauffaille ML, Schrier SL, Tallman MS, Ribeiro RC, Grimwade D, Ganser A, Löwenberg B, Lo-Coco F,Sanz MA, Berliner N, Rego EM. Clinical impact of BAALC expression in high-risk acute promyelocytic leukemia. Blood Adv. 2017; 1(21): 1807–1814.
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Резюме
Острый миелоидный лейкоз (ОМЛ) представляет собой гетерогенное клональное заболевание крови опухолевой природы. Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь.
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There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2228) "Summary
Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients.
Keywords
Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease.
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Shakirova, Ildar M. Barkhatov, Anna I. Churkina, Ivan S. Moiseev, Tatiana L. Gindina, Sergey N. Bondarenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(137) "Alena I. Shakirova, Ildar M. Barkhatov, Anna I. Churkina, Ivan S. Moiseev, Tatiana L. Gindina, Sergey N. Bondarenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(137) "Alena I. Shakirova, Ildar M. Barkhatov, Anna I. Churkina, Ivan S. Moiseev, Tatiana L. Gindina, Sergey N. Bondarenko, Boris V. Afanasyev " } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20233" ["VALUE"]=> array(2) { ["TEXT"]=> string(2316) "<h2 style="text-align: justify;">Summary</h2> <p style="text-align: justify;"> Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2228) "Summary
Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients.
Keywords
Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2228) "Summary
Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients.
Keywords
Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease.
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Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(170) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(170) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State I. 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Шакирова, Ильдар М. Бархатов, Анна И. Чуркина, Иван С. Моисеев, Татьяна Л. Гиндина, Сергей Н. Бондаренко, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(235) "Алена И. Шакирова, Ильдар М. Бархатов, Анна И. Чуркина, Иван С. Моисеев, Татьяна Л. Гиндина, Сергей Н. Бондаренко, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(235) "Алена И. Шакирова, Ильдар М. Бархатов, Анна И. Чуркина, Иван С. Моисеев, Татьяна Л. Гиндина, Сергей Н. Бондаренко, Борис В. 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Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4331) "Резюме
Острый миелоидный лейкоз (ОМЛ) представляет собой гетерогенное клональное заболевание крови опухолевой природы. Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь.
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Острый миелоидный лейкоз (ОМЛ) представляет собой гетерогенное клональное заболевание крови опухолевой природы. Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь.
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Worldwide, prostate cancer is known to be the third leading cause of cancer-associated deaths among elderly men. Whereas the survival rate for patients diagnosed with stage I-II prostate cancer approaches 85% due to impressive efficacy of surgery, chemotherapy, and radiotherapy, this is not the case for late-stage prostate cancer patients. As with many other cancers, prostate cancer typically remains unnoticed and asymptomatic at early stages, and about 90% of patients first present with stage III-IV prostate cancer, which is lethal in over 50% cases [1]. Pancreatic cancer is also among the top most frequent causes of cancer-related deaths [2], with patients having few if any therapeutic options. Clearly, there is a pressing need for developing novel therapeutic modalities for metastatic prostate cancer and pancreatic cancer.
One of the cell surface protein molecules that has been reported to be overexpressed by both prostate and pancreatic tumors as well as metastases in a fraction of patients is PSCA (prostate stem cell antigen), a 123 aa-long GPI-anchored protein of largely unknown function and limited expression in normal tissues [3-6]. Targeting this cancer-associated marker therefore presents an attractive opportunity.
One of the recent advances in the field of cancer immunotherapy is based on the administration of cancer-specific T cells into the patients. In this approach, T cell retargeting is achieved via their ex vivo engineering with chimeric antigen receptors (CARs). Following adoptive transfer, CAR T cells specifically destroy malignant cells, proliferate and persist in vivo thereby mediating prolonged antitumor control.
CARs typically encompass four structural modules: i) antigen recognition module most frequently composed of an scFv; ii) spacer region, which provides adequate positioning of the antigen recognition module relatively to the target antigen as well as optimal spacing between contacting effector and target cells. This module is typically derived from CD8а, CD28, and IgG1/IgG4; iii) transmembrane domain, which helps anchor the CAR on the cell surface; and iv) intracellular signaling domain, which functions to activate the CAR-bearing effector cell upon encounter of the target cancer cell [7, 8]. Two most common signaling domain designs tested in the clinical trials incorporate CD3ζ signaling domain in combination with either CD28 or 4-1BB co-stimulatory sequences [9]. Thus, CAR brings together the selectivity of antibodies and potent cytotoxicity of effector T cells. Yet, the design of clinically successful CARs still remains a trial-and-error process, and so multiple rounds of structural optimization may be required to produce clinically viable CAR T cell products.
Recently, two autologous CAR T cell based products targeting CD19 have been approved by FDA for treating pediatric patients with r/r ALL and adults with r/r large B-cell lymphoma, and many more CARs against other molecules and combinations thereof are currently in clinical trials [10, 11]. It is hoped that this success can be translated to solid cancers as well, however a combination of immunosuppressive tumor microenvironment, inefficient tumor homing, and limited CAR T cell persistence makes this goal a difficult feat [12]. In contrast to most B-cell malignancies, solid tumors share a hostile milieu encompassing various immune cells (M2 macrophages, Tregs, etc), endothelial cells, fibroblasts, extracellular matrix proteins, and inhibitory cytokines. This not only physically limits the access of CAR T cells to the tumor interior, but also has a potent immunosuppressive effect [13-15]. Several experimental approaches partially addressing these issues have been described in the literature, for instance CAR T cells have been designed to secrete additional molecules to attract resident immune cells or reverse the inhibitory effects of tumor-derived factors to boost T cell proliferation [16-23]. Alternative cell sources for CAR therapies have also been explored. In this regard, NK cells seem to be particularly promising, as they have long been known to be more efficient at tissue and tumor trafficking, as well as more resistant to immunosuppressive tumor microenvironment. Further, use of NK-cells in CAR therapies holds promise of their application as off-the-shelf allogeneic cell products [24-27]. Finally, combining CAR T cell therapies with other anticancer modalities, such as radiation therapy [28], chemotherapy [29], oncolytic virotherapy [30, 31], and small molecules and antibodies [32, 33] is also an area of active ongoing research.
Multiple studies have also focused on optimization of CAR structure to enhance activity of CAR T cells. When effector and tumor cells interact to form an immunologic synapse, the distance between the cell membranes lies within a fixed range and was reported to be critical for optimal CAR T cell-mediated cytotoxicity [34]. Hence, the choice of the spacer region in a CAR dictates the appropriate positioning of the antigen-recognition region and the cognate epitope, and should ideally be customized for each epitope/scFv pair to provide optimal in vitro and in vivo CAR T cell activity, particularly in the context of solid tumors.
In this study, we developed a series of CAR constructs targeting PSCA, which differ only in the spacer region used. These CARs were expressed in an NK cell line, YT, which we test as a platform for allogeneic CAR-NK cell therapy. CAR-NK cell lines obtained were comparatively assayed for in vitro cytotoxicity and IFN-g release. This, to our knowledge, is the first study to explore the contribution of the spacer region of a CAR in an NK-cell background.
Materials and Methods
Cell lines and cell culture
HEK293T and PC3 cells were purchased from ATCC (USA). YT cell line was kindly provided by Dr. A.V. Filatov. PSCA-expressing PC3 cells were produced via lentiviral transduction of a PSCA-encoding construct co-expressing tdTomato, followed by monocloning. All cell lines were cultured in IMDM (Sigma) supplemented with 4 мМ L-glutamine, 10% FCS (HyClone), 100 U/ml penicillin and 100 ug/ml streptomycin in 5% CO2 at 37°С. Cells were passaged every other day or one day before transfection/transduction.
CAR design
Antigen-recognition module of the PSCA-specific CAR was derived from the parental version of the 2B3 antibody (humanized murine antibody) [35]. Coding sequence for scFv(2B3) flanked with AgeI and BamHI sites was obtained by gene synthesis (Genomatik) and inserted in-frame with the mIgk signal sequence and the c-myc epitope preceding hinge region (IgG1, CD8a, or none) of the pCDH-based lentiviral vectors described previously (GenBank acc. numbers KX757242.1, KX757244.1, KX757246.1) [36]. In these constructs, CAR expression was driven by a constitutive hybrid hEF1a-HTLV promoter.
Assembly of VSV-G-pseudotyped lentiviral particles
HEK293T cells were used for producing VSV-G- pseudotyped lentiviral particles. The cells were transfected following the standard Ca-phosphate transfection protocol [37]. DNA of lentiviral constructs was mixed with the DNA of packaging plasmids pMD.2G and psPAX2 [38] at a ratio of 4:1:3. Lentivirus-containing supernatants were collected 48 hours following transfection, filtered through 0.45-μm PES filters and used either fresh or frozen at -70°C.
Transduction of YT cells
YT cells were transduced using spinoculation [39]. Briefly, YT cells were seeded into 96-well plates (1×10[4] cells/well) in the presence of polybrene (8 ug/ml), followed by addition of pseudotyped lentiviral particles. Non-ransduced cells were kept as a control. Cells were centrifuged at 500 g for 40 minutes at 32°C and kept in the CO2 incubator for 16 hours. Next day, the supernatant was aspirated and replaced by the fresh culture medium.
FACS profiling
One hundred thousand cells were washed in PBS and incubated with mouse anti-c-myc (Abcam, clone 9E10) antibodies or protein L-bio (GenScript, M00097). PE-labeled donkey anti-mouse IgG conjugates (BioLegend) and SA-PE (Thermo Fisher Scientific) were used as secondary antibodies. 7AAD (Biolegend) was used to exclude dead cells from the analysis. The samples were analyzed using BD FACSCantо II instrument (Becton Dickinson and Company) and BD FACSDiva Software.
Flow cytometry-based cytotoxicity assay and IFN-g release assay
Target PC3(PSCA) or PC3 cells (T) were labeled with Cell Proliferation Dye eFluor® 670 (eBioscience), washed, and incubated with CAR-expressing YT cells (E) at 1:1, 2:1, and 3:1 E:T ratios for 4 hours in round-bottom 96 wells TPP plates (#92097, TPP). Then, the cells were stained with propidium iodide (PI) and analyzed by flow cytometry. Target cells left without effector cells were used as a negative control. The percentage of dead target cells (i.e. cytotoxicity) was calculated as follows: 100% * (PI+, eFluor+)count/(total eFluor+)count, as described previously [40, 41].
In order to measure IFN-g release, aPSCA-CAR YT or non-transduced YT cells were incubated with target PC3(PSCA) or control PC3 cells at a 1:1 ratio in 24-well plates for 4 hours. Following incubation, cell culture supernatants were filtered through 0.45-μm filters and IFN-g concentration in the supernatants was measured in duplicates using ELISA (IFA-best kit, Vektor-best, Russia).
Results
Design of PSCA-specific CARs encompassing distinct spacer regions
Three lentiviral constructs encoding second-generation PSCA-specific CARs were assembled using conventional cloning. Except for the spacer regions used, the structures of these CARs were identical as presented in Fig. 1. CopGFP reporter was used for labeling transduced effector cells, and c-myc epitope was placed downstream of the antigen-recognition module to conveniently detect CAR expression.
PSCA-specific CARs are expressed on the surface of YT cells
Human NK-cell lines such as NK-92, YT, KHYG-1, etc are an attractive cellular platform that may serve as a viable alternative to the autologous format of CAR T cell therapy [27, 42]. In our study, YT cell line [43] was selected as a carrier for CARs, as these cells are IL-2 independent and afford high transduction efficiency [41]. YT cells were transduced with lentiviral particles encoding three CAR variants described above and surface-stained with anti-myc antibodies to detect CAR expression (Fig. 2a). Pronounced CAR expression was detectable, yet spacerless CAR had an apparent reduction in surface expression. Given that viral titers used for transduction were very similar, we reasoned that this may have been caused by the proximity of c-myc epitope in this particular CAR variant to the cell membrane and its shielding from efficient recognition by anti-c-myc antibodies. This was indeed the case, as immunodetection of CARs using protein L, аn immunoglobulin kappa-chain binder [44], confirmed consistent CAR expression in all three cases (Fig. 2b).
Figure 1. Structure of the CAR-encoding lentiviral constructs. EF1a – constitutive hEF1a-HTLV promoter, SP – leader sequence of murine Igk, scFv(aPSCA) – antigen-recognition module derived from the humanized PSCA-specific antibody 2B3, CD8a and IgG1 – spacer modules derived from human CD8a and IgG1, CD28-СD3cyto – transmembrane and intracellular signaling region, IRES – internal ribosome entry site of cardiovirus A, copGFP – GFP from a copepod Pontellina plumata
Figure 2. Surface expression of CARs in the context of YT cells. A. anti-c-myc staining; B. protein L staining
CAR-YT cells display specific cytotoxicity against target cells and secrete IFN-g in vitro
Whether or not CAR-YT cells display PSCA-specific cytotoxicity, was tested using a FACS-based assay. Following incubation with PSCA-expressing target cells (PC3-PSCA) but not with isogenic PSCA-negative controls (PC3), CARYT cells displayed ~25% killing of target cells within the E:T ratios tested (Fig. 3a). This was observed for all three CAR designs regardless of the spacer region used. Next, we proceeded to analyze whether this was accompanied by IFN-g release. Upon co-incubation with target PC3-PSCA cells, we observed pronounced IFN-g secretion, and again it was overall comparable in all the CAR-YT cell lines obtained (Fig. 3b).
Discussion
To date, multiple PSCA-specific CARs have been created and validated both in vitro and in vivo. These CARs encompass various antigen-binding regions (derived from mAbs 1G8, 7F5, bm2B3, Ha1-4.117, etc), spacers (IgG4, IgG1, IgD, CH3, spacerless, CD8a), as well as signaling domains (CD3z, CD28-CD3z, CD28-4-1BB-CD3z, CD28-OX40-CD3z, and DAP12), and were expressed in primary human T cells, NK cells, and NK cell lines [6, 45-51]. Whenever the studies were structure-oriented and comparative by design, minor modifications in CAR architecture resulted in profound changes in CAR performance. However, to our knowledge, none of the above studies addressed the question whether the spacer region of PSCA-specific CARs should be tailored to the context of immunological synapse of NK-cells.
In our study, we asked whether PSCA-specific CARs may require structural optimization of the spacer region when expressed by NK-cells rather than conventional T cells. This optimization was reported to be necessary for adequate CAR performance in vitro and particularly in vivo in the context of primary T cells [50, 52]. In our in vitro assays, PSCA-specific CARs encompassing either long IgG1, short CD8a, or no spacer region behaved very similar. Whether this may apply to other in vitro tests and in vivo situation, remains to be explored.
PSCA is a relatively small protein, accordingly the epitope recognized by our CARs is found in a membrane-proximal position relatively to the tumor cell surface. Thus, the contribution of the length and flexibility of the spacer region of a CAR may have less of an effect on the sterical compatibility of the CAR and the target epitope, which may partially explain our in vitro results. The observed lack of effect of spacer region on CAR-NK cell functionality is unlike what was observed for PSCA-specific CAR T cells [50, 52]. We speculate that this may be attributable to some yet unknown peculiarities of immune synapse formation between CARNK and tumor cells.
In conclusion, the different PSCA-specific CAR designs assayed in the context of YT cells appear functional in vitro and may serve as a platform for developing allogeneic CARNK cell products for cell therapy of patients with PSCA-positive prostate and pancreatic tumors. Acknowledgements This work was supported by the Ministry of Education and Science of the Russian Federation, grant agreement № 14.604.21.0169 (unique project identifier RFMEFI60417X0169). The authors gratefully acknowledge the resources provided by the "Molecular and Cellular Biology" core facility of the IMCB SB RAS and the Collective Center for microscopic analysis of biological objects of the SB RAS.
Figure 3. A. CAR-YT cells are retargeted against PSCA-expressing prostate cancer cells and spare PSCA-negative isogenic controls at E:T ratios ranging from 1 to 3 regardless of the structure of the spacer region of the CAR. Irrelevant CAR-YT cells specific for PSMA fail to kill PSCA-expressing cells. Average percentage +/- standard deviation values from two technical replicas are plotted. B. CAR-YT cells secrete IFN-g upon co-incubation with cognate target cells
Conflict of interest
No conflict of interests is reported by the authors.
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Introduction
Worldwide, prostate cancer is known to be the third leading cause of cancer-associated deaths among elderly men. Whereas the survival rate for patients diagnosed with stage I-II prostate cancer approaches 85% due to impressive efficacy of surgery, chemotherapy, and radiotherapy, this is not the case for late-stage prostate cancer patients. As with many other cancers, prostate cancer typically remains unnoticed and asymptomatic at early stages, and about 90% of patients first present with stage III-IV prostate cancer, which is lethal in over 50% cases [1]. Pancreatic cancer is also among the top most frequent causes of cancer-related deaths [2], with patients having few if any therapeutic options. Clearly, there is a pressing need for developing novel therapeutic modalities for metastatic prostate cancer and pancreatic cancer.
One of the cell surface protein molecules that has been reported to be overexpressed by both prostate and pancreatic tumors as well as metastases in a fraction of patients is PSCA (prostate stem cell antigen), a 123 aa-long GPI-anchored protein of largely unknown function and limited expression in normal tissues [3-6]. Targeting this cancer-associated marker therefore presents an attractive opportunity.
One of the recent advances in the field of cancer immunotherapy is based on the administration of cancer-specific T cells into the patients. In this approach, T cell retargeting is achieved via their ex vivo engineering with chimeric antigen receptors (CARs). Following adoptive transfer, CAR T cells specifically destroy malignant cells, proliferate and persist in vivo thereby mediating prolonged antitumor control.
CARs typically encompass four structural modules: i) antigen recognition module most frequently composed of an scFv; ii) spacer region, which provides adequate positioning of the antigen recognition module relatively to the target antigen as well as optimal spacing between contacting effector and target cells. This module is typically derived from CD8а, CD28, and IgG1/IgG4; iii) transmembrane domain, which helps anchor the CAR on the cell surface; and iv) intracellular signaling domain, which functions to activate the CAR-bearing effector cell upon encounter of the target cancer cell [7, 8]. Two most common signaling domain designs tested in the clinical trials incorporate CD3ζ signaling domain in combination with either CD28 or 4-1BB co-stimulatory sequences [9]. Thus, CAR brings together the selectivity of antibodies and potent cytotoxicity of effector T cells. Yet, the design of clinically successful CARs still remains a trial-and-error process, and so multiple rounds of structural optimization may be required to produce clinically viable CAR T cell products.
Recently, two autologous CAR T cell based products targeting CD19 have been approved by FDA for treating pediatric patients with r/r ALL and adults with r/r large B-cell lymphoma, and many more CARs against other molecules and combinations thereof are currently in clinical trials [10, 11]. It is hoped that this success can be translated to solid cancers as well, however a combination of immunosuppressive tumor microenvironment, inefficient tumor homing, and limited CAR T cell persistence makes this goal a difficult feat [12]. In contrast to most B-cell malignancies, solid tumors share a hostile milieu encompassing various immune cells (M2 macrophages, Tregs, etc), endothelial cells, fibroblasts, extracellular matrix proteins, and inhibitory cytokines. This not only physically limits the access of CAR T cells to the tumor interior, but also has a potent immunosuppressive effect [13-15]. Several experimental approaches partially addressing these issues have been described in the literature, for instance CAR T cells have been designed to secrete additional molecules to attract resident immune cells or reverse the inhibitory effects of tumor-derived factors to boost T cell proliferation [16-23]. Alternative cell sources for CAR therapies have also been explored. In this regard, NK cells seem to be particularly promising, as they have long been known to be more efficient at tissue and tumor trafficking, as well as more resistant to immunosuppressive tumor microenvironment. Further, use of NK-cells in CAR therapies holds promise of their application as off-the-shelf allogeneic cell products [24-27]. Finally, combining CAR T cell therapies with other anticancer modalities, such as radiation therapy [28], chemotherapy [29], oncolytic virotherapy [30, 31], and small molecules and antibodies [32, 33] is also an area of active ongoing research.
Multiple studies have also focused on optimization of CAR structure to enhance activity of CAR T cells. When effector and tumor cells interact to form an immunologic synapse, the distance between the cell membranes lies within a fixed range and was reported to be critical for optimal CAR T cell-mediated cytotoxicity [34]. Hence, the choice of the spacer region in a CAR dictates the appropriate positioning of the antigen-recognition region and the cognate epitope, and should ideally be customized for each epitope/scFv pair to provide optimal in vitro and in vivo CAR T cell activity, particularly in the context of solid tumors.
In this study, we developed a series of CAR constructs targeting PSCA, which differ only in the spacer region used. These CARs were expressed in an NK cell line, YT, which we test as a platform for allogeneic CAR-NK cell therapy. CAR-NK cell lines obtained were comparatively assayed for in vitro cytotoxicity and IFN-g release. This, to our knowledge, is the first study to explore the contribution of the spacer region of a CAR in an NK-cell background.
Materials and Methods
Cell lines and cell culture
HEK293T and PC3 cells were purchased from ATCC (USA). YT cell line was kindly provided by Dr. A.V. Filatov. PSCA-expressing PC3 cells were produced via lentiviral transduction of a PSCA-encoding construct co-expressing tdTomato, followed by monocloning. All cell lines were cultured in IMDM (Sigma) supplemented with 4 мМ L-glutamine, 10% FCS (HyClone), 100 U/ml penicillin and 100 ug/ml streptomycin in 5% CO2 at 37°С. Cells were passaged every other day or one day before transfection/transduction.
CAR design
Antigen-recognition module of the PSCA-specific CAR was derived from the parental version of the 2B3 antibody (humanized murine antibody) [35]. Coding sequence for scFv(2B3) flanked with AgeI and BamHI sites was obtained by gene synthesis (Genomatik) and inserted in-frame with the mIgk signal sequence and the c-myc epitope preceding hinge region (IgG1, CD8a, or none) of the pCDH-based lentiviral vectors described previously (GenBank acc. numbers KX757242.1, KX757244.1, KX757246.1) [36]. In these constructs, CAR expression was driven by a constitutive hybrid hEF1a-HTLV promoter.
Assembly of VSV-G-pseudotyped lentiviral particles
HEK293T cells were used for producing VSV-G- pseudotyped lentiviral particles. The cells were transfected following the standard Ca-phosphate transfection protocol [37]. DNA of lentiviral constructs was mixed with the DNA of packaging plasmids pMD.2G and psPAX2 [38] at a ratio of 4:1:3. Lentivirus-containing supernatants were collected 48 hours following transfection, filtered through 0.45-μm PES filters and used either fresh or frozen at -70°C.
Transduction of YT cells
YT cells were transduced using spinoculation [39]. Briefly, YT cells were seeded into 96-well plates (1×10[4] cells/well) in the presence of polybrene (8 ug/ml), followed by addition of pseudotyped lentiviral particles. Non-ransduced cells were kept as a control. Cells were centrifuged at 500 g for 40 minutes at 32°C and kept in the CO2 incubator for 16 hours. Next day, the supernatant was aspirated and replaced by the fresh culture medium.
FACS profiling
One hundred thousand cells were washed in PBS and incubated with mouse anti-c-myc (Abcam, clone 9E10) antibodies or protein L-bio (GenScript, M00097). PE-labeled donkey anti-mouse IgG conjugates (BioLegend) and SA-PE (Thermo Fisher Scientific) were used as secondary antibodies. 7AAD (Biolegend) was used to exclude dead cells from the analysis. The samples were analyzed using BD FACSCantо II instrument (Becton Dickinson and Company) and BD FACSDiva Software.
Flow cytometry-based cytotoxicity assay and IFN-g release assay
Target PC3(PSCA) or PC3 cells (T) were labeled with Cell Proliferation Dye eFluor® 670 (eBioscience), washed, and incubated with CAR-expressing YT cells (E) at 1:1, 2:1, and 3:1 E:T ratios for 4 hours in round-bottom 96 wells TPP plates (#92097, TPP). Then, the cells were stained with propidium iodide (PI) and analyzed by flow cytometry. Target cells left without effector cells were used as a negative control. The percentage of dead target cells (i.e. cytotoxicity) was calculated as follows: 100% * (PI+, eFluor+)count/(total eFluor+)count, as described previously [40, 41].
In order to measure IFN-g release, aPSCA-CAR YT or non-transduced YT cells were incubated with target PC3(PSCA) or control PC3 cells at a 1:1 ratio in 24-well plates for 4 hours. Following incubation, cell culture supernatants were filtered through 0.45-μm filters and IFN-g concentration in the supernatants was measured in duplicates using ELISA (IFA-best kit, Vektor-best, Russia).
Results
Design of PSCA-specific CARs encompassing distinct spacer regions
Three lentiviral constructs encoding second-generation PSCA-specific CARs were assembled using conventional cloning. Except for the spacer regions used, the structures of these CARs were identical as presented in Fig. 1. CopGFP reporter was used for labeling transduced effector cells, and c-myc epitope was placed downstream of the antigen-recognition module to conveniently detect CAR expression.
PSCA-specific CARs are expressed on the surface of YT cells
Human NK-cell lines such as NK-92, YT, KHYG-1, etc are an attractive cellular platform that may serve as a viable alternative to the autologous format of CAR T cell therapy [27, 42]. In our study, YT cell line [43] was selected as a carrier for CARs, as these cells are IL-2 independent and afford high transduction efficiency [41]. YT cells were transduced with lentiviral particles encoding three CAR variants described above and surface-stained with anti-myc antibodies to detect CAR expression (Fig. 2a). Pronounced CAR expression was detectable, yet spacerless CAR had an apparent reduction in surface expression. Given that viral titers used for transduction were very similar, we reasoned that this may have been caused by the proximity of c-myc epitope in this particular CAR variant to the cell membrane and its shielding from efficient recognition by anti-c-myc antibodies. This was indeed the case, as immunodetection of CARs using protein L, аn immunoglobulin kappa-chain binder [44], confirmed consistent CAR expression in all three cases (Fig. 2b).
Figure 1. Structure of the CAR-encoding lentiviral constructs. EF1a – constitutive hEF1a-HTLV promoter, SP – leader sequence of murine Igk, scFv(aPSCA) – antigen-recognition module derived from the humanized PSCA-specific antibody 2B3, CD8a and IgG1 – spacer modules derived from human CD8a and IgG1, CD28-СD3cyto – transmembrane and intracellular signaling region, IRES – internal ribosome entry site of cardiovirus A, copGFP – GFP from a copepod Pontellina plumata
Figure 2. Surface expression of CARs in the context of YT cells. A. anti-c-myc staining; B. protein L staining
CAR-YT cells display specific cytotoxicity against target cells and secrete IFN-g in vitro
Whether or not CAR-YT cells display PSCA-specific cytotoxicity, was tested using a FACS-based assay. Following incubation with PSCA-expressing target cells (PC3-PSCA) but not with isogenic PSCA-negative controls (PC3), CARYT cells displayed ~25% killing of target cells within the E:T ratios tested (Fig. 3a). This was observed for all three CAR designs regardless of the spacer region used. Next, we proceeded to analyze whether this was accompanied by IFN-g release. Upon co-incubation with target PC3-PSCA cells, we observed pronounced IFN-g secretion, and again it was overall comparable in all the CAR-YT cell lines obtained (Fig. 3b).
Discussion
To date, multiple PSCA-specific CARs have been created and validated both in vitro and in vivo. These CARs encompass various antigen-binding regions (derived from mAbs 1G8, 7F5, bm2B3, Ha1-4.117, etc), spacers (IgG4, IgG1, IgD, CH3, spacerless, CD8a), as well as signaling domains (CD3z, CD28-CD3z, CD28-4-1BB-CD3z, CD28-OX40-CD3z, and DAP12), and were expressed in primary human T cells, NK cells, and NK cell lines [6, 45-51]. Whenever the studies were structure-oriented and comparative by design, minor modifications in CAR architecture resulted in profound changes in CAR performance. However, to our knowledge, none of the above studies addressed the question whether the spacer region of PSCA-specific CARs should be tailored to the context of immunological synapse of NK-cells.
In our study, we asked whether PSCA-specific CARs may require structural optimization of the spacer region when expressed by NK-cells rather than conventional T cells. This optimization was reported to be necessary for adequate CAR performance in vitro and particularly in vivo in the context of primary T cells [50, 52]. In our in vitro assays, PSCA-specific CARs encompassing either long IgG1, short CD8a, or no spacer region behaved very similar. Whether this may apply to other in vitro tests and in vivo situation, remains to be explored.
PSCA is a relatively small protein, accordingly the epitope recognized by our CARs is found in a membrane-proximal position relatively to the tumor cell surface. Thus, the contribution of the length and flexibility of the spacer region of a CAR may have less of an effect on the sterical compatibility of the CAR and the target epitope, which may partially explain our in vitro results. The observed lack of effect of spacer region on CAR-NK cell functionality is unlike what was observed for PSCA-specific CAR T cells [50, 52]. We speculate that this may be attributable to some yet unknown peculiarities of immune synapse formation between CARNK and tumor cells.
In conclusion, the different PSCA-specific CAR designs assayed in the context of YT cells appear functional in vitro and may serve as a platform for developing allogeneic CARNK cell products for cell therapy of patients with PSCA-positive prostate and pancreatic tumors. Acknowledgements This work was supported by the Ministry of Education and Science of the Russian Federation, grant agreement № 14.604.21.0169 (unique project identifier RFMEFI60417X0169). The authors gratefully acknowledge the resources provided by the "Molecular and Cellular Biology" core facility of the IMCB SB RAS and the Collective Center for microscopic analysis of biological objects of the SB RAS.
Figure 3. A. CAR-YT cells are retargeted against PSCA-expressing prostate cancer cells and spare PSCA-negative isogenic controls at E:T ratios ranging from 1 to 3 regardless of the structure of the spacer region of the CAR. Irrelevant CAR-YT cells specific for PSMA fail to kill PSCA-expressing cells. Average percentage +/- standard deviation values from two technical replicas are plotted. B. CAR-YT cells secrete IFN-g upon co-incubation with cognate target cells
Conflict of interest
No conflict of interests is reported by the authors.
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b Новосибирский государственный университет, Новосибирск
c Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск
# Оба автора внесли равный вклад в данную работу
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Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro.
Ключевые слова
Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA).
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Matvienko <sup>a</sup>, <sup>b</sup>, <sup>#</sup>, Sergey V. Kulemzin <sup>a</sup>, <sup>#</sup>, Anna S. Smagina <sup>a</sup>, <sup>b</sup>, Tatyana N. Belovezhets <sup>a</sup>, <sup>b</sup>, Anton N. Chikaev <sup>a</sup>, Olga Y. Volkova <sup>a</sup>, Nikolay A. Chikaev <sup>a</sup>, Olga A. Koval <sup>b</sup>, <sup>c</sup>, Elena V. Kuligina <sup>b</sup>, <sup>c</sup>, Alexandr V. Taranin <sup>a</sup>, <sup>b</sup>, Andrey A. Gorchakov <sup>a</sup>, <sup>b</sup>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(479) "Daria A. Matvienko a, b, #, Sergey V. Kulemzin a, #, Anna S. Smagina a, b, Tatyana N. Belovezhets a, b, Anton N. Chikaev a, Olga Y. Volkova a, Nikolay A. Chikaev a, Olga A. Koval b, c, Elena V. Kuligina b, c, Alexandr V. Taranin a, b, Andrey A. Gorchakov a, b" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20252" ["VALUE"]=> array(2) { ["TEXT"]=> string(416) "<sup>a</sup> Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia <sup>b</sup> Novosibirsk State University, Novosibirsk, Russia <sup>c</sup> Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia <sup>#</sup> equal contribution" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(368) "a Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia b Novosibirsk State University, Novosibirsk, Russia c Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia # equal contribution" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20253" ["VALUE"]=> array(2) { ["TEXT"]=> string(926) "<p style="text-align: justify;"> Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(860) "Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region.
Keywords
Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA).
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In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(860) "Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region.
Keywords
Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA).
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(860) "Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region.
Keywords
Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA).
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Горчаков a, b" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20249" ["VALUE"]=> array(2) { ["TEXT"]=> string(1612) "<p style="text-align: justify;"> Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro. </p> <h2 style="text-align: justify;"><span style="font-family: Arial, sans-serif;">Ключевые слова</span></h2> <p style="text-align: justify;"> Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1524) "Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro.
Ключевые слова
Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA).
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1524) "Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro.
Ключевые слова
Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA).
" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20248" ["VALUE"]=> array(2) { ["TEXT"]=> string(592) "<sup>a</sup> Институт молекулярной и клеточной биологии СО РАН, Новосибирск<br> <sup>b</sup> Новосибирский государственный университет, Новосибирск<br> <sup>c</sup> Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск<br> <sup>#</sup> Оба автора внесли равный вклад в данную работу<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(520) "a Институт молекулярной и клеточной биологии СО РАН, Новосибирскb Новосибирский государственный университет, Новосибирск
c Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск
# Оба автора внесли равный вклад в данную работу
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b Новосибирский государственный университет, Новосибирск
c Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск
# Оба автора внесли равный вклад в данную работу
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Dear Colleagues,
Since I am asked by the editor to prevent Dr. Gale and Dr. Moiseev from slugging it out, I would like to find positions where we can meet:
1) The informed consent for any treatment particularly with the risks for the patient will require a complete disclosure of risks and alternative treatments (Declaration of Helsinki, Belmont report). If we recommend a transplant to a patient with AML in first remission at intermediate risk, we have to tell them how they would fare with conventional treatment [1-3].
2) Knowing the dilemma of our prediction capability. Hematologists and transplanters work for more than 40 years on refinement of predictive models. The predictive model by Smith and Keating has been applied to a patient group with acute leukemia and could show a survival advantage for transplants in the high and intermediate, but not in the good risk group [4, 5].
3) The current EBMT recommendations state AML patients with good cytogenetic features are not: patients with intermediate and poor risk, are candidates for transplant in first CR [6-10].
4) Risk Assessment integrating cytogenetic and molecular profiling might improve the predictability [11].
5) Since the age represents one of the most adverse prognostic indicators for response to treatment and overall survival and since the results of transplant in patients older than 60 years have improved significantly, further emphasis should be directed towards elderly AML patients to sort out age risk factor versus molecular and cytogenetic markers [12].
6) As to the ornithological questions, how to overcome the black and white swans [13]. I would like to point to Cocoanuts
1929, the Marx Brothers: “Why a duck?”[14].
7) As to the slugging it out, I would like to recommend the Bavarian method to drown the dispute in beer until everything is clear and the question forgotten.
Sincerely,
Axel Rolf Zander, MD, Dr.h.c., FACP
Huntsman Cancer Institute, University of Utah,
Salt Lake City
E-mail: arzzander@aol.de
References
1. Gale RP. Transplants for acute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us. Cell Ther Transplant (CTT). 2017; 6 (4): 10-12.
2. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Department of Health, Education and Welfare (DHEW) (30 September 1978). The Belmont report (http://videocast.nih.gov\pdf\ohrpbelmont_report.pdf) (PDF). Washington, DC: United States Government Printing Office.
3. World Medical Association (2013). “Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects” (http://jama.jamanetwork.com\article.aspx?articleid=1760318). JAMA. 310 (20): 2191-2194. doi:10.1001\jama.2013.281053 (https:\\doi.org\10.1001%2Fjama.2013.281053). PMID 24141714 (https:\\www.ncbi.nlm.nih.gov\pubmed\24141714). Retrieved July 24, 2015.
4. Murray PM, The History of Informed Consent. Iowa Orthop J. 1990; 10: 104-109.
5. Smith TL, Gehan EA, Keating MJ, et al: Prediction of remission in adult acute leukemia: Development and testing of predictive models. Cancer. 1982; 50:466-472.
6. Zander AR, Keating M, Dicke K, et al: A comparison of marrow transplantation with chemotherapy for adults with acute leukemia or poor prognosis in first complete remission. J Clin Oncol. 1988; 6(10): 1548-1557.
7. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse. Results of the UK MRC AML 10 trial. Brit J Haematol. 2002; 118:385-400.
8. Zittoun RA, Madelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. New Engl J Med. 1995; 332: 217-223.
9. Koreth J, Schlenk R, Kpoecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: Systematic review and meta-analysis of prospective clinical trials. JAMA. 2009; 301: 2349-2361.
10. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhauser M, Juliusson G, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012; 9:579-590.
11. Moarii M, Papaemmanuil E. Classification and risk assessment in AML: integrating cytogenetics and molecular profiling. American Society of Hematology. 2017; 37.
12. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016; 127:62-70.
13. Moiseev IS. Transplants for аcute myeloid leukaemia in 1st remission: standard of care or something else? Cell Ther Transplant, 2018; 7(1):67-70.
14. The Cocoanuts 1929, The Marx Brothers: “Why A Duck?” www.marx-brothers.org/whyaduck/info/.../whyaduck.htm
" ["~DETAIL_TEXT"]=> string(5639) "
Dear Colleagues,
Since I am asked by the editor to prevent Dr. Gale and Dr. Moiseev from slugging it out, I would like to find positions where we can meet:
1) The informed consent for any treatment particularly with the risks for the patient will require a complete disclosure of risks and alternative treatments (Declaration of Helsinki, Belmont report). If we recommend a transplant to a patient with AML in first remission at intermediate risk, we have to tell them how they would fare with conventional treatment [1-3].
2) Knowing the dilemma of our prediction capability. Hematologists and transplanters work for more than 40 years on refinement of predictive models. The predictive model by Smith and Keating has been applied to a patient group with acute leukemia and could show a survival advantage for transplants in the high and intermediate, but not in the good risk group [4, 5].
3) The current EBMT recommendations state AML patients with good cytogenetic features are not: patients with intermediate and poor risk, are candidates for transplant in first CR [6-10].
4) Risk Assessment integrating cytogenetic and molecular profiling might improve the predictability [11].
5) Since the age represents one of the most adverse prognostic indicators for response to treatment and overall survival and since the results of transplant in patients older than 60 years have improved significantly, further emphasis should be directed towards elderly AML patients to sort out age risk factor versus molecular and cytogenetic markers [12].
6) As to the ornithological questions, how to overcome the black and white swans [13]. I would like to point to Cocoanuts
1929, the Marx Brothers: “Why a duck?”[14].
7) As to the slugging it out, I would like to recommend the Bavarian method to drown the dispute in beer until everything is clear and the question forgotten.
Sincerely,
Axel Rolf Zander, MD, Dr.h.c., FACP
Huntsman Cancer Institute, University of Utah,
Salt Lake City
E-mail: arzzander@aol.de
References
1. Gale RP. Transplants for acute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us. Cell Ther Transplant (CTT). 2017; 6 (4): 10-12.
2. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Department of Health, Education and Welfare (DHEW) (30 September 1978). The Belmont report (http://videocast.nih.gov\pdf\ohrpbelmont_report.pdf) (PDF). Washington, DC: United States Government Printing Office.
3. World Medical Association (2013). “Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects” (http://jama.jamanetwork.com\article.aspx?articleid=1760318). JAMA. 310 (20): 2191-2194. doi:10.1001\jama.2013.281053 (https:\\doi.org\10.1001%2Fjama.2013.281053). PMID 24141714 (https:\\www.ncbi.nlm.nih.gov\pubmed\24141714). Retrieved July 24, 2015.
4. Murray PM, The History of Informed Consent. Iowa Orthop J. 1990; 10: 104-109.
5. Smith TL, Gehan EA, Keating MJ, et al: Prediction of remission in adult acute leukemia: Development and testing of predictive models. Cancer. 1982; 50:466-472.
6. Zander AR, Keating M, Dicke K, et al: A comparison of marrow transplantation with chemotherapy for adults with acute leukemia or poor prognosis in first complete remission. J Clin Oncol. 1988; 6(10): 1548-1557.
7. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse. Results of the UK MRC AML 10 trial. Brit J Haematol. 2002; 118:385-400.
8. Zittoun RA, Madelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. New Engl J Med. 1995; 332: 217-223.
9. Koreth J, Schlenk R, Kpoecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: Systematic review and meta-analysis of prospective clinical trials. JAMA. 2009; 301: 2349-2361.
10. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhauser M, Juliusson G, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012; 9:579-590.
11. Moarii M, Papaemmanuil E. Classification and risk assessment in AML: integrating cytogenetics and molecular profiling. American Society of Hematology. 2017; 37.
12. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016; 127:62-70.
13. Moiseev IS. Transplants for аcute myeloid leukaemia in 1st remission: standard of care or something else? Cell Ther Transplant, 2018; 7(1):67-70.
14. The Cocoanuts 1929, The Marx Brothers: “Why A Duck?” www.marx-brothers.org/whyaduck/info/.../whyaduck.htm
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Ключевые слова
Острый миелобластный лейкоз, трансплантация гемопоэтических стволовых клеток, клинические исходы, предсказание
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Acute myeloblastic leukemia, hematopoietic stem cell transplantation, clinical outcomes, prediction.
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Дорогие коллеги!
Поскольку редакция просила меня вмешаться в выяснение отношений между проф. Р. Гэйлом и д-ром И. Моисеевым, то я бы хотел выделить те положения, по которым можно найти согласие:
1) Информированное согласие на любой вид лечения, особенно, связанного с риском для пациента, потребует полного информирования о рисках и альтернативных видах лечения (Декларация Хельсинки, доклад Белмонт). Если мы рекомендуем трансплантацию пациенту в первой ремиссии острого миелобластного лейкоза (ОМЛ) промежуточной степени риска, то мы должны сказать ему, каков был бы результат обычного лечения [1-3].
2) Относительно наших сложностей выбора прогностических вариантов: более 40 лет гематологи и трансплантологи работают над повышением точности предиктивных моделей. Так, прогнозная модель Smith and Keating была использована для группы больных с острыми лейкозами и смогла показать преимущества по выживаемости для трансплантаций при острых лейкозах промежуточного и высокого риска, но не для группы благоприятного риска [4, 5].
3) Существующие рекомендации EBMT не рассматривают в этом плане больных ОМЛ с благоприятными цитогенетическими маркерами; кандидатами на трансплантацию в первой полной ремиссии являются пациенты промежуточной и неблагоприятной групп риска [6-10].
4) Оценка риска, интегрирующая наборы цитогенетических и молекулярных маркеров могла бы улучшить предсказуемость терапии [11].
5) Поскольку возраст является одним из наиболее неблагоприятных прогностических показателей, в плане ответа на лечение и общей выживаемости и ввиду значительного улучшения результатов трансплантации у больных старше 60 лет, необходимо в дальнейшем акцентировать внимание на пожилых больных с ОМЛ, чтобы оценивать возраст как отдельный фактор риска, наряду с молекулярными и цитогенетическими факторами [12].
6) По поводу орнитологических вопросов о том, как обходиться с черными и белыми лебедями [13], я хотел бы упомянуть братьев Маркс в фильме Cocoanuts (1929 г.) [14]*.
7) Что касается выяснения отношений, то я бы хотел здесь посоветовать баварский метод: утопить диспут в пиве до той поры, пока все не выяснится, а вопрос будет забыт.
Искренне Ваш,
Аксель Рольф Цандер,
Профессор медицины, доктор honoris causa, FACP
Онкологический Институт Хантсмана, Университет
Юта, Солт-Лейк Сити, США
E-mail: arzzander@aol.de
Keywords
Acute myeloblastic leukemia, hematopoietic stem cell transplantation, clinical outcomes, prediction.
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Acute myeloblastic leukemia, hematopoietic stem cell transplantation, clinical outcomes, prediction.
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Острый миелобластный лейкоз, трансплантация гемопоэтических стволовых клеток, клинические исходы, предсказание
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" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20260" ["VALUE"]=> array(2) { ["TEXT"]=> string(4502) "<p style="text-align: justify;"> <b>Дорогие коллеги!</b><br> Поскольку редакция просила меня вмешаться в выяснение отношений между проф. Р. Гэйлом и д-ром И. Моисеевым, то я бы хотел выделить те положения, по которым можно найти согласие:<br> 1) Информированное согласие на любой вид лечения, особенно, связанного с риском для пациента, потребует полного информирования о рисках и альтернативных видах лечения (Декларация Хельсинки, доклад Белмонт). Если мы рекомендуем трансплантацию пациенту в первой ремиссии острого миелобластного лейкоза (ОМЛ) промежуточной степени риска, то мы должны сказать ему, каков был бы результат обычного лечения [1-3].<br> 2) Относительно наших сложностей выбора прогностических вариантов: более 40 лет гематологи и трансплантологи работают над повышением точности предиктивных моделей. Так, прогнозная модель Smith and Keating была использована для группы больных с острыми лейкозами и смогла показать преимущества по выживаемости для трансплантаций при острых лейкозах промежуточного и высокого риска, но не для группы благоприятного риска [4, 5].<br> 3) Существующие рекомендации EBMT не рассматривают в этом плане больных ОМЛ с благоприятными цитогенетическими маркерами; кандидатами на трансплантацию в первой полной ремиссии являются пациенты промежуточной и неблагоприятной групп риска [6-10].<br> 4) Оценка риска, интегрирующая наборы цитогенетических и молекулярных маркеров могла бы улучшить предсказуемость терапии [11].<br> 5) Поскольку возраст является одним из наиболее неблагоприятных прогностических показателей, в плане ответа на лечение и общей выживаемости и ввиду значительного улучшения результатов трансплантации у больных старше 60 лет, необходимо в дальнейшем акцентировать внимание на пожилых больных с ОМЛ, чтобы оценивать возраст как отдельный фактор риска, наряду с молекулярными и цитогенетическими факторами [12].<br> 6) По поводу орнитологических вопросов о том, как обходиться с черными и белыми лебедями [13], я хотел бы упомянуть братьев Маркс в фильме Cocoanuts (1929 г.) [14]*.<br> 7) Что касается выяснения отношений, то я бы хотел здесь посоветовать баварский метод: утопить диспут в пиве до той поры, пока все не выяснится, а вопрос будет забыт.<br> Искренне Ваш,<br> Аксель Рольф Цандер,<br> Профессор медицины, доктор <i>honoris causa</i>, FACP<br> Онкологический Институт Хантсмана, Университет<br> Юта, Солт-Лейк Сити, США<br> E-mail: <a href="mailto:arzzander@aol.de">arzzander@aol.de</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4350) "
Дорогие коллеги!
Поскольку редакция просила меня вмешаться в выяснение отношений между проф. Р. Гэйлом и д-ром И. Моисеевым, то я бы хотел выделить те положения, по которым можно найти согласие:
1) Информированное согласие на любой вид лечения, особенно, связанного с риском для пациента, потребует полного информирования о рисках и альтернативных видах лечения (Декларация Хельсинки, доклад Белмонт). Если мы рекомендуем трансплантацию пациенту в первой ремиссии острого миелобластного лейкоза (ОМЛ) промежуточной степени риска, то мы должны сказать ему, каков был бы результат обычного лечения [1-3].
2) Относительно наших сложностей выбора прогностических вариантов: более 40 лет гематологи и трансплантологи работают над повышением точности предиктивных моделей. Так, прогнозная модель Smith and Keating была использована для группы больных с острыми лейкозами и смогла показать преимущества по выживаемости для трансплантаций при острых лейкозах промежуточного и высокого риска, но не для группы благоприятного риска [4, 5].
3) Существующие рекомендации EBMT не рассматривают в этом плане больных ОМЛ с благоприятными цитогенетическими маркерами; кандидатами на трансплантацию в первой полной ремиссии являются пациенты промежуточной и неблагоприятной групп риска [6-10].
4) Оценка риска, интегрирующая наборы цитогенетических и молекулярных маркеров могла бы улучшить предсказуемость терапии [11].
5) Поскольку возраст является одним из наиболее неблагоприятных прогностических показателей, в плане ответа на лечение и общей выживаемости и ввиду значительного улучшения результатов трансплантации у больных старше 60 лет, необходимо в дальнейшем акцентировать внимание на пожилых больных с ОМЛ, чтобы оценивать возраст как отдельный фактор риска, наряду с молекулярными и цитогенетическими факторами [12].
6) По поводу орнитологических вопросов о том, как обходиться с черными и белыми лебедями [13], я хотел бы упомянуть братьев Маркс в фильме Cocoanuts (1929 г.) [14]*.
7) Что касается выяснения отношений, то я бы хотел здесь посоветовать баварский метод: утопить диспут в пиве до той поры, пока все не выяснится, а вопрос будет забыт.
Искренне Ваш,
Аксель Рольф Цандер,
Профессор медицины, доктор honoris causa, FACP
Онкологический Институт Хантсмана, Университет
Юта, Солт-Лейк Сити, США
E-mail: arzzander@aol.de
Дорогие коллеги!
Поскольку редакция просила меня вмешаться в выяснение отношений между проф. Р. Гэйлом и д-ром И. Моисеевым, то я бы хотел выделить те положения, по которым можно найти согласие:
1) Информированное согласие на любой вид лечения, особенно, связанного с риском для пациента, потребует полного информирования о рисках и альтернативных видах лечения (Декларация Хельсинки, доклад Белмонт). Если мы рекомендуем трансплантацию пациенту в первой ремиссии острого миелобластного лейкоза (ОМЛ) промежуточной степени риска, то мы должны сказать ему, каков был бы результат обычного лечения [1-3].
2) Относительно наших сложностей выбора прогностических вариантов: более 40 лет гематологи и трансплантологи работают над повышением точности предиктивных моделей. Так, прогнозная модель Smith and Keating была использована для группы больных с острыми лейкозами и смогла показать преимущества по выживаемости для трансплантаций при острых лейкозах промежуточного и высокого риска, но не для группы благоприятного риска [4, 5].
3) Существующие рекомендации EBMT не рассматривают в этом плане больных ОМЛ с благоприятными цитогенетическими маркерами; кандидатами на трансплантацию в первой полной ремиссии являются пациенты промежуточной и неблагоприятной групп риска [6-10].
4) Оценка риска, интегрирующая наборы цитогенетических и молекулярных маркеров могла бы улучшить предсказуемость терапии [11].
5) Поскольку возраст является одним из наиболее неблагоприятных прогностических показателей, в плане ответа на лечение и общей выживаемости и ввиду значительного улучшения результатов трансплантации у больных старше 60 лет, необходимо в дальнейшем акцентировать внимание на пожилых больных с ОМЛ, чтобы оценивать возраст как отдельный фактор риска, наряду с молекулярными и цитогенетическими факторами [12].
6) По поводу орнитологических вопросов о том, как обходиться с черными и белыми лебедями [13], я хотел бы упомянуть братьев Маркс в фильме Cocoanuts (1929 г.) [14]*.
7) Что касается выяснения отношений, то я бы хотел здесь посоветовать баварский метод: утопить диспут в пиве до той поры, пока все не выяснится, а вопрос будет забыт.
Искренне Ваш,
Аксель Рольф Цандер,
Профессор медицины, доктор honoris causa, FACP
Онкологический Институт Хантсмана, Университет
Юта, Солт-Лейк Сити, США
E-mail: arzzander@aol.de
04.06.2018 16:46:00
Афанасьев Б. В. (Санкт-Петербург, Россия)
Вагемакер Г. (Роттердам, Нидерланды)
Цандер А. Р. (Гамбург, Германия)
Фезе Б. (Гамбург, Германия)
Чухловин А. Б. (Санкт-Петербург, Россия)
Алейникова О. В. (Минск, Беларусь)
Борсет М. (Трондхейм, Норвегия)
Галибин О. В. (Санкт-Петербург, Россия)
Зубаровская Л. С. (Санкт-Петербург, Россия)
Климко Н. Н. (Санкт-Петербург, Россия)
Кольб Х. (Мюнхен, Германия)
Крегер Н. (Гамбург, Германия)
Кулагин А. Д. (Санкт-Петербург, Россия)
Ланге К. (Гамбург, Германия)
Мамаев Н. Н. (Санкт-Петербург, Россия)
Михайлова Н. Б. (Санкт-Петербург, Россия)
Моисеев И. С. (Санкт-Петербург, Россия)
Наглер А. (Тель-Авив, Израиль)
Немков А. С. (Санкт-Петербург, Россия)
Парамонов И. В. (Киров, Россия)
Румянцев А. Г. (Москва, Россия)
Савченко В. Г. (Москва, Россия)
Смирнов А. В. (Санкт-Петербург, Россия)
Усс А. Л. (Минск, Беларусь)
Фиббе В. (Лейден, Нидерланды)
Хельтцер Д. (Франкфурт-на-Майне, Германия)
Чечеткин А. В. (Санкт-Петербург, Россия)
Настоящий номер CTT начинается обзорной статьей д-ра А. Григорьянца и соавт., которая касается проблем полости рта у пациентов после аллогенной трансплантации гемопоэтических клеток (ТГСК), в частности – краткосрочных и отдаленных нарушений зубного аппарата у детей после интенсивной цитотоксической терапии и воспалительно-атрофических заболеваний слизистой рта, связанных с острой и хронической реакциями «трансплантат против хозяина» (РТПХ), инфекционными и аутоагрессивными процессами.
Международные исследования показывают хорошую эффективность ТГСК от гаплоидентичного донора при лечении острых лейкозов. Соответствующие клинические протоколы для детей и подростков с применением неманипулированных гемопоэтических транспантатов и оценка средне- и долгосрочных результатов описаны в работе д-ра О. Паиной и соавт. Авторы делают выводы о хорошей эффективности гаплоидентичной ТГСК в данной возрастной группе, сравнимой с результатами HLA-совместимой трансплантации.
Новые ингибиторы апоптотоза с участием PD-1 интенсивно изучаются в настоящее время, с целью усиления эффективности иммунотерапии при различных злокачественных заболеваниях. Статья д-ра К. Лепика и соавт. касается применения ниволумаба при рецидивах болезни Ходжкина (БХ) после аллогенной ТГСК. У большинства пациентов отмечен выраженный клинический ответ, что подтверждает эффективность этого препарата при БХ.
Лечение миелодиспластических синдромов и острых миелобластных лейкозов (ОМЛ), развивающихся из приобретенной апластической анемии обсуждается в статье д-ра И. Голубовской и соавт., где представлены клинические результаты, полученные при лечении этих редких состояний со сложным патогенезом. В частности, авторы обсужд ранние осложнения и общую выживаемость после иммуносупрессивной терапии и аллогенной ТГСК.
Статья д-ра Е. Бабенко и соавт. посвящена сравнительной статистической оценке результатов трансплантации криоконсервированных и нативных гемопоэтических клеток пациентам из гетерогенной клинической группы. Долгосрочный опыт показал, в целом, что результаты аллогенной ТГСК криоконсервированных клеток сравнимы с результатами применения нативных трансплантатов, в плане частоты острой и хронической РТПХ, общей выживаемости и выживаемости без рецидивов и РТПХ.
Анализ экспрессии генов, ассоциированных с лейкозами, таких, EVI 1, WT1, и др., важен как для первичной диагностики, так и, в особенности, для количественного учета минимальной остаточной болезни (МОД) после проведенного лечения. Исследование д-ра А. Шакировой и соавт. сфокусировано на прогностической значимости и диагностических порогах значений экспрессии гена BAALC, имеющих прогностическое значение для рецидивов острого миелобластного лейкоза после алло-ТГСК.
Клиническая значимость цитогенетических исследований для прослеживания клональной эволюции при миелодиспластическом синдроме хорошо иллюстрируется клиническим случаем, представленным профессором Н. Мамаевым и соавт. Этот случай весьма поучителен для онкогематологов, поскольку здесь сопоставляются киническое течение, цитогенетическая и молекулярная эволюция заболевания у данного пациента.
Хорошее экспериментальное исследование представлено группой из Новосибирска (д-р Д. Матвиенко и соавт.). Авторы работы создали клон клеток с химерным антигенным рецептором, которые могут быть потенциально использованы для иммунотерапии рака предстательной железы.
Данный выпуск содержит также краткий комментарий профессора Акселя Цандера, который излагает современные клинические критерии предсказания риска у пациентов с ОМЛ, которые живо обсуждались в предыдущих двух номерах журнала СТТ. Читатели журнала приглашаются к ознакомлению с подробностями этой дискуссии.
Редакционная статья
Обзорные статьи
Клинические исследования
Экспериментальные исследования
Письмо редактору
Редакционная статья
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Дорогие коллеги и читатели,<br>
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области<br>
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.<br>
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.<br>
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.<br>
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.
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Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.
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Dear Colleagues and Readers,<br>
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.<br>
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.<br>
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.<br>
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.
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Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.
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Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)
Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.
Обзорные статьи
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<sup>2</sup>Центральный научно-исследовательский институт стоматологии, Москва, Россия<br>
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Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.
</p>
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Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.
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Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.
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The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.<br>
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.
</p>
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Keywords
Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.
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Артур П. Григорьянц1, Илья М. Рабинович2, Алексей Б. Чухловин1
2Центральный научно-исследовательский институт стоматологии, Москва, Россия
Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.
Клинические исследования
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Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.
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Ключевые слова
Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.
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[TEXT] => R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. P. Pavlov Medical University, Roentgen St. 12; 197022, St. Petersburg,Russia
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Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.
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<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.
</p>
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Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.
Keywords
Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.
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Кирилл В. Лепик, Андрей В. Козлов, Евгения С. Борзенкова, Марина О. Попова, Иван С. Моисеев, Елена И. Дарская, Асмик Г. Геворгян, Любовь А. Цветкова, Сергей Н. Бондаренко, Александр Л. Алянский, Елена В. Кондакова, Наталья Б. Михайлова, Борис В. Афанасьев
Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.
Ключевые слова
Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.
Клинические исследования
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Первый Санкт-Петербургский государственный медицинский университет им. академика И. П. Павлова Министерства здравоохранения России;
Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия
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Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия
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Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.
</p>
<h3 style="text-align: justify;">Цель</h3>
<p style="text-align: justify;">
Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.
</p>
<h3 style="text-align: justify;">Материалы и методы</h3>
<p style="text-align: justify;">
106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х10<sup>6</sup>/кг (медиана 5,9х10<sup>6</sup>/кг), клеточность КМ+ПСКК от 2,5 до 30,9х10<sup>6</sup>/ кг (медиана 5,9х10<sup>6</sup>/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.
</p>
<h3 style="text-align: justify;">Результаты</h3>
<p style="text-align: justify;">
Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x10<sup>6</sup>/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x10<sup>6</sup>/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x10<sup>6</sup>/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.
</p>
<h3 style="text-align: justify;">Выводы</h3>
<p style="text-align: justify;">
Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».
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Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.
Цель
Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.
Материалы и методы
106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.
Результаты
Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.
Выводы
Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.
Ключевые слова
Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».
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Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,<br>
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.
</p>
<h3 style="text-align: justify;">Materials and methods</h3>
<p style="text-align: justify;">
106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.
</p>
<h3 style="text-align: justify;">Statistical analysis</h3>
<p style="text-align: justify;">
SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.
</p>
<h3 style="text-align: justify;">Conclusion</h3>
<p style="text-align: justify;">
Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.
</p>
<h3 style="text-align: justify;">Keywords</h3>
<p style="text-align: justify;">
Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.
</p>
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Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.
Materials and methods
106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.
Statistical analysis
SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.
Conclusion
Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.
Keywords
Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.
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Олеся В. Паина, Полина В. Кожокарь, Анастасия С. Боровкова, Анастасия С. Фролова, Кирилл А. Екушов, Татьяна А. Быкова, Жемаль З. Рахманова, Мария А. Галас, Айгуль Г. Хабирова, Инна В. Маркова, Елена В. Семенова, Сергей Н. Бондаренко, Елена В. Бабенко, Татьяна Л. Гиндина, Александр Л. Алянский, Ильдар М. Бархатов, Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев
Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.
Цель
Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.
Материалы и методы
106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.
Результаты
Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.
Выводы
Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.
Ключевые слова
Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».
Клинические исследования
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Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.
</p>
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Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.
Ключевые слова
Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.
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[TEXT] => R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University
*St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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*St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.
</p>
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Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.
Keywords
Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.
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)
Ирина К. Голубовская, Александр Д. Кулагин, Юлия В. Рудницкая, Елена В. Морозова, Анна А. Осипова, Варвара Н. Овечкина, Николай Ю. Цветков, Сергей Н. Бондаренко, *Борис И. Смирнов, Людмила С. Зубаровская, Инна В. Маркова, Борис В. Афанасьев
Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.
Ключевые слова
Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.
Клинические исследования
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Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.
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Ключевые слова
Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.
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Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.
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<h2 style="text-align: justify;">Keywords</h2>
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Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.
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Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.
Keywords
Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.
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Елена В. Бабенко, Иван С. Моисеев, Михаил М. Канунников, Александр Л. Алянский, Дмитрий Э. Певцов, Анастасия В. Фролова, Анна А. Осипова, Татьяна А. Быкова, Олеся В. Паина, Елена И. Дарская, Людмила С. Зубаровская, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев
Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.
Клинические исследования
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Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.
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Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.
Ключевые слова
Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.
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We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.
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We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.
Keywords
Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.
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Николай Н. Мамаев, Татьяна Л. Гиндина, Елена В. Морозова, Юлия В. Рудницкая, Мария В. Губина, Ильдар М. Бархатов, Сергей Н. Бондаренко, Борис В. Афанасьев
Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.
Ключевые слова
Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.
Клинические исследования
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<h2 style="text-align: justify;">Резюме</h2>
<p style="text-align: justify;">
Острый миелоидный лейкоз (ОМЛ) представляет собой гетерогенное клональное заболевание крови опухолевой природы. Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь.
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Резюме
Острый миелоидный лейкоз (ОМЛ) представляет собой гетерогенное клональное заболевание крови опухолевой природы. Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь.
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Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients.
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Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease.
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Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients.
Keywords
Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease.
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Алена И. Шакирова, Ильдар М. Бархатов, Анна И. Чуркина, Иван С. Моисеев, Татьяна Л. Гиндина, Сергей Н. Бондаренко, Борис В. Афанасьев
Резюме
Острый миелоидный лейкоз (ОМЛ) представляет собой гетерогенное клональное заболевание крови опухолевой природы. Для пациентов с ОМЛ промежуточной цитогенетической группы риска, которая является гетерогенной по мутационному статусу целого ряда генов (FLT3, NPM1, CEBPA и т.д.), прогнозирование течения заболевания, оценка риска развития рецидива и выбор оптимальной терапии затруднены. В связи с этим поиск новых молекулярных маркеров, имеющих большое прогностическое значение, а так же полезных в аспекте оценки риска развития рецидива у пациентов с ОМЛ, лишенных крупных цитогенетических аномалий, является одной из приоритетных задач молекулярной онкогематологии. Для оценки применимости мониторинга уровня экспрессии гена BAALC (Brain And Acute Leukemia, Cytoplasmic) для предикции развития рецидива, оценки чувствительности и специфичности метода мониторинга BAALC с целью оценки эффективности терапии, мы проанализировали прогностическое значение гиперэкспрессии гена BAALC у 93 пациентов с ОМЛ в посттрансплантационном периоде. В свежих образцах костного мозга пациентов методом количественной ПЦР в режиме реального времени определялся уровень экспрессии гена BAALC. Пациенты были подразделены на группы низкой и высокой экспрессии BAALC на основании общего и индивидуального пороговых уровней экспрессии. Мы заключили, что гиперэкспрессия BAALC выше индивидуального и общего порогового уровней является прогностически значимым фактором для оценки риска развития рецидива в посттрансплантационном периоде, общей и безрецидивной выживаемости. Однако более детальный анализ BAALC как маркера эффективности терапии и его сравнение с референтными методами мониторинга минимальной остаточной болезни (такими как детекция химерных транскриптов генов методом количественной ПЦР в режиме реального времени) показал более низкую чувствительность такого подхода к мониторингу МОБ в посттрансплантационном периоде, по меньшей мере на примере исследуемой выборки пациентов. Частый мониторинг уровня экспрессии гена BAALC может быть рекомендован для предикции развития клинико-гематологического рецидива в ходе посттрансплантационного периода у пациентов с ОМЛ.
Ключевые слова
Острый миелобластный лейкоз, BAALC, экспрессия гена, клинический прогноз, минимальная остаточная болезнь.
Экспериментальные исследования
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[TEXT] => <sup>a</sup> Институт молекулярной и клеточной биологии СО РАН, Новосибирск<br>
<sup>b</sup> Новосибирский государственный университет, Новосибирск<br>
<sup>c</sup> Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск<br>
<sup>#</sup> Оба автора внесли равный вклад в данную работу<br>
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b Новосибирский государственный университет, Новосибирск
c Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск
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Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro.
</p>
<h2 style="text-align: justify;"><span style="font-family: Arial, sans-serif;">Ключевые слова</span></h2>
<p style="text-align: justify;">
Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA).
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Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro.
Ключевые слова
Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA).
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<sup>b</sup> Novosibirsk State University, Novosibirsk, Russia
<sup>c</sup> Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
<sup>#</sup> equal contribution
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b Novosibirsk State University, Novosibirsk, Russia
c Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
# equal contribution
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Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region.
</p>
<h2 style="text-align: justify;">Keywords</h2>
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Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA).
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Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region.
Keywords
Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA).
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Дарья А. Матвиенко a, b, #, Сергей В. Кулемзин a, #, Анна С. Смагина a, b, Татьяна Н. Беловежец a, b, Антон Н. Чикаев a, Ольга Ю. Волкова a, Николай А. Чикаев a, Ольга А. Коваль b, c, Елена В. Кулигина b, c, Александр В. Таранин a, b, Андрей А. Горчаков a, b
b Новосибирский государственный университет, Новосибирск
c Институт химической биологии и фундаментальной медицины СО РАН, Новосибирск
# Оба автора внесли равный вклад в данную работу
Структурная оптимизация модульного состава химерных антигенных рецепторов (CAR) может иметь принципиальное значение для обеспечения активности CAR T-клеточных продуктов. Мы воспользовались разработанной ранее платформой лентивирусных векторов для сравнения различных вариантов дизайна CAR в унифицированном формате. В частности, было проведено исследование влияния шарнирного района на функционирование PSCA-специфичного CAR в контексте NK-клеточной линии YT. Было обнаружено, что независимо от природы и наличия шарнирного района (IgG1, CD8a и без шарнира) все три CAR обнаруживают сравнимые уровни активности in vitro.
Ключевые слова
Химерный антигенный рецептор (CAR), адоптивная иммунотерапия, рак простаты, антиген стволовых клеток простаты (PSCA).
Письмо редактору
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[TIMESTAMP_X] => 2015-09-02 18:02:59
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<p style="text-align: justify;">
Acute myeloblastic leukemia, hematopoietic stem cell transplantation, clinical outcomes, prediction.
</p>
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<b>Дорогие коллеги!</b><br>
Поскольку редакция просила меня вмешаться в выяснение отношений между проф. Р. Гэйлом и д-ром И. Моисеевым, то я бы хотел выделить те положения, по которым можно найти согласие:<br>
1) Информированное согласие на любой вид лечения, особенно, связанного с риском для пациента, потребует полного информирования о рисках и альтернативных видах лечения (Декларация Хельсинки, доклад Белмонт). Если мы рекомендуем трансплантацию пациенту в первой ремиссии острого миелобластного лейкоза (ОМЛ) промежуточной степени риска, то мы должны сказать ему, каков был бы результат обычного лечения [1-3].<br>
2) Относительно наших сложностей выбора прогностических вариантов: более 40 лет гематологи и трансплантологи работают над повышением точности предиктивных моделей. Так, прогнозная модель Smith and Keating была использована для группы больных с острыми лейкозами и смогла показать преимущества по выживаемости для трансплантаций при острых лейкозах промежуточного и высокого риска, но не для группы благоприятного риска [4, 5].<br>
3) Существующие рекомендации EBMT не рассматривают в этом плане больных ОМЛ с благоприятными цитогенетическими маркерами; кандидатами на трансплантацию в первой полной ремиссии являются пациенты промежуточной и неблагоприятной групп риска [6-10].<br>
4) Оценка риска, интегрирующая наборы цитогенетических и молекулярных маркеров могла бы улучшить предсказуемость терапии [11].<br>
5) Поскольку возраст является одним из наиболее неблагоприятных прогностических показателей, в плане ответа на лечение и общей выживаемости и ввиду значительного улучшения результатов трансплантации у больных старше 60 лет, необходимо в дальнейшем акцентировать внимание на пожилых больных с ОМЛ, чтобы оценивать возраст как отдельный фактор риска, наряду с молекулярными и цитогенетическими факторами [12].<br>
6) По поводу орнитологических вопросов о том, как обходиться с черными и белыми лебедями [13], я хотел бы упомянуть братьев Маркс в фильме Cocoanuts (1929 г.) [14]*.<br>
7) Что касается выяснения отношений, то я бы хотел здесь посоветовать баварский метод: утопить диспут в пиве до той поры, пока все не выяснится, а вопрос будет забыт.<br>
Искренне Ваш,<br>
Аксель Рольф Цандер,<br>
Профессор медицины, доктор <i>honoris causa</i>, FACP<br>
Онкологический Институт Хантсмана, Университет<br>
Юта, Солт-Лейк Сити, США<br>
E-mail: <a href="mailto:arzzander@aol.de">arzzander@aol.de</a>
</p>
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Дорогие коллеги!
Поскольку редакция просила меня вмешаться в выяснение отношений между проф. Р. Гэйлом и д-ром И. Моисеевым, то я бы хотел выделить те положения, по которым можно найти согласие:
1) Информированное согласие на любой вид лечения, особенно, связанного с риском для пациента, потребует полного информирования о рисках и альтернативных видах лечения (Декларация Хельсинки, доклад Белмонт). Если мы рекомендуем трансплантацию пациенту в первой ремиссии острого миелобластного лейкоза (ОМЛ) промежуточной степени риска, то мы должны сказать ему, каков был бы результат обычного лечения [1-3].
2) Относительно наших сложностей выбора прогностических вариантов: более 40 лет гематологи и трансплантологи работают над повышением точности предиктивных моделей. Так, прогнозная модель Smith and Keating была использована для группы больных с острыми лейкозами и смогла показать преимущества по выживаемости для трансплантаций при острых лейкозах промежуточного и высокого риска, но не для группы благоприятного риска [4, 5].
3) Существующие рекомендации EBMT не рассматривают в этом плане больных ОМЛ с благоприятными цитогенетическими маркерами; кандидатами на трансплантацию в первой полной ремиссии являются пациенты промежуточной и неблагоприятной групп риска [6-10].
4) Оценка риска, интегрирующая наборы цитогенетических и молекулярных маркеров могла бы улучшить предсказуемость терапии [11].
5) Поскольку возраст является одним из наиболее неблагоприятных прогностических показателей, в плане ответа на лечение и общей выживаемости и ввиду значительного улучшения результатов трансплантации у больных старше 60 лет, необходимо в дальнейшем акцентировать внимание на пожилых больных с ОМЛ, чтобы оценивать возраст как отдельный фактор риска, наряду с молекулярными и цитогенетическими факторами [12].
6) По поводу орнитологических вопросов о том, как обходиться с черными и белыми лебедями [13], я хотел бы упомянуть братьев Маркс в фильме Cocoanuts (1929 г.) [14]*.
7) Что касается выяснения отношений, то я бы хотел здесь посоветовать баварский метод: утопить диспут в пиве до той поры, пока все не выяснится, а вопрос будет забыт.
Искренне Ваш,
Аксель Рольф Цандер,
Профессор медицины, доктор honoris causa, FACP
Онкологический Институт Хантсмана, Университет
Юта, Солт-Лейк Сити, США
E-mail: arzzander@aol.de
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Аксель Рольф Цандер
Ключевые слова
Острый миелобластный лейкоз, трансплантация гемопоэтических стволовых клеток, клинические исходы, предсказание