Introduction
The number of allogeneic hematopoietic stem cell transplantations (HSCT) continues to increase, including transplants from alternative donors. Therefore, an uncommon HSCT complication called a posttransplant lymphoproliferative disease (PTLD) should be in focus, due to its extreme danger to patients.
Since 60’s, lymphoid-derived posttransplant neoplasias were first described in renal transplant patients who received immunosuppressive drugs to prevent graft rejection [45]. PTLD is a common complication in solid organ transplant settings, occuring at a rate of 1 to 20%, being dependent on the graft type [7]. Similarly, PTLD may develop after allo-HSCT presenting many factors predisposing for deficient immune surveillance over proliferating B cells. PLTD incidence following allo-HSCT varies between 0.8 and 1.5% [2]. Some PTLD cases are described after umbilical blood transplantation [18], and allo-HSCT with nonmyeloablative conditioning [5, 52]. PTLD comprises a group of disorders ranging from benign polyclonal hyperplasia to alignant clonal proliferation [42, 25, 8, 30, 38]. PTLD is historically recognized as uncontrolled B cell proliferation caused by Epstein-Barr virus (EBV). However, EBV-negative PTLD are described as well [29].
Classification
All the posttransplant lymphoid neoplasias were previously called immunoblastic sarcomas until PTLD discretion, as a certain clinical entity. In 1987, Frizzera et al. [17] described some distinct polymorphic changes in patients after renal transplantation, and proposed a classification including a non-specific hyperplasia, polymorphic hyperplasia, and polymorphic lymphoma. In 1988, Nalesnik et al. coined a term polymorphic PTLD for the mentioned disorder [39]. Monomorphic PTLD was also described but it could not be differed from a non-Hodgkin’s lymphoma. However, mere morphological findings did not provide complete and reliable prognostic information. Knowles et al. [27] added combined molecular genetics criteria to classical morphological features in order to determine cellular clonality, thus developing a PTLD classification including a polyclonal plasmatic hyperplasia, monoclonal polymorphic B cell hyperplasia, or lymphoma, as well as monoclonal pleiomorphic immunoblastic lymphoma, or multiple myeloma.
By 1997, Society for Hematopathology developed a novel classification which initially pointed to differences between early and late PTLD’s [24]. In 2001, The World Health Organization (WHO) published current PTLD classification which is used up to present time: 1) initial disturbance, e.g., reactive lymphoplasmacytic hyperplasia, and a syndrome similar to infectious mononucleosis, 2) polymorphic PTLD; 3) monomorphic PTLD, and, 4) Hodgkin’s disease-like PTLD (Table 1) [26, 33]. In 2008, this classification was supplemented by additional histological criteria.
Table 1. PTLD categories according to WHO Classification of Tumours [26]
Notes: WHO, World Health Organization; PTLD, posttransplant lymphoproliferative disease; NHL, non-Hodgkin’s lymphomas.
Etiology and Pathogenesis
Primary EBV infection after transplantation is the main factor of PTLD. I.e., the PTLD risk after EBV infection is shown to be increased 10- to 76-fold [7]. EBV, herpesvirus family member may cause of infectious mononucleosis. Human fluids and secretions, e.g., saliva, are a usual transfection source. Over 90% of humans develop anti-EBV immunity by the age of 40 years. Following primary infection, a long-lasting viral latency is established. An immunocompetent organism has several control mechanisms against EBV proliferation after primary infection, especially, cytotoxic T cell response, and, to lesser degree, humoral (antibody) immune response; NK cell activity, cytokine regulatory pathways [51, 35]. EBV transmission to the HSCT recipients occurs mainly via blood products, however, exact incidence of this transfection is undetermined. In cases of B cell PTLD, B cell proliferation and inhibition of specific immune surveillance are the main causal factors [1]. EBV is known to primarily affect naïve B cells which migrate to germinative centers. Specific EBV proteins are stimulating differentiation of B cells to memory B cells that become the EBV depots. In summary, expression of EBV markers (LMP1, 2A-B), and nuclear proteins (EBNA-1, 2, 3A-C) is accompained by development of the virus latency. These latent gene expression is associated with ongoing EBV infection of B cells, and, accordingly, with different kinds of PTLD [37] (Table 2). Hence, EBV genome in immunocompetent subjects exists as episomes providing latency in memory B cells. Under inhibited immunity, the T cell control is also lost, thus causing proliferation of EBV-infected В cells, lymphoid cell hyperplasia, and evolving malignancy [32]. T cell recovery does not yet occur within 6 months post-HSCT, thus predisposing for higher PTLD risk during this time period. [4]. However, an increase in late PTLD cases is observed over last years [50]. As a rule, this trend is associated, with low CD4+ lymphocyte levels as it occurs in HIV-infected patients [20].
Table 2. EBV-associated PTLD and viral programs [37]
In early PTLD (1 st year after HSCT) EBV is found in >90% of В cells. With time, a year or later after HSCT, the EBV detectability decreases gradually, reaching an average of 21-32% of
total [16]. Over last years, growing number of EBV-negative PTLD’s has been registered: from 10% in 90’s to 48% over 2008-2013 [34]. Nevertheless, EBV presence is recommended for every bioptate taken using in situ hybridization since EBV status determines appropriate therapeutic approaches. Cytomegalovirus and human herpesvirus could be also detected in blood and tissues of the patients, being, however, an epiphenomenon rather than a disease trigger. [6, 62]. When transplanting solid organ, the PTLD emerges from recipient cells. Meanwhile, both donor and recipient in allogeneic HSCT, are EBV-seropositive in most cases. Hence, lymphoproliferation after allo-HSCT originates from donor cells because lymphoid system in recipient is often virtually destroyed by conditioning treatment. Even in cases of EBV-seronegativity in donor, PTLD develop, due to infection of donor lymphocytes from EBV-positive recipient.
Risk factors
In addition to EBV infection, a number of other HSCT-associated risk factors for PTLD are reported, e.g.: HLA-compatible donor (RR 3,8-9); T cell depletion (RR 4-12,7), treatment with CD3 antibodies; usage of antithymocyte globulin (ATG) (RR 3.1-6.4), severe acute GvHD, grade ≥2 (RR 1.9-6.5); extensive chronic GvHD (risk factor for a late PTLD) [2, 53]. As reported by Uhlin et al. [59], incidence of the EBV-associated PTLD may increase to 10-20% upon combination of some known risk factors: HLA mismatch, different EBV serology in donor/recipient pairs; reduced intensity conditioning; acute GvHD; splenectomy before HSCT; mesenchymal stem cell infusions. The EBV viral load in cases of viral reactivation does not play a sufficient role. E.g., PTLD was registered in 50% of the patients with blood EBV contents of ≥4,000 copies per mL [60]. Meanwhile, current European Guidelines recommend weekly quantitative PCR screening for EBV in allo-HSCT recipients for a minimum of 3 months post-HSCT [55]. Despite donor origin of proliferating B cells in most HSCT cases, high prevalence of PTLD is described in pediatric population among patients receiving ATG- or Alemtuzumab-containing conditioning, due to persistence of recipient B cells in this setting [9, 5].
One should not underestimate EBV-negative PTLDs which occur at later terms post-HSCT, showing a more aggressive clinical course [40]. Some authors suggest to consider them as “classic” lymphomas developing in transplanted patients [36]. Interestingly, the results of an international multicentric prospective study (Phase 2) do not consider EBV status a significant factor influencing overall survival and progression terms [57].
Clinical Features
PTLD manifestations may be quite diverse. Lymphadenopathy, or limited affection of lymphoid tissue are most common. Diffuse lesions similar to fulminant septic syndrome may occur more rarely [19]. The disorder may manifest like an acute respiratory viral infection, sometimes exhibiting functional affection of a distinct organ. Many cases could be complicated by cytomegalovirus infection, or by invasive aspergillosis. In some instances, PTLD proceeds symptomless, being detectable as an occasional finding at autopsy. Any HSCT patient presenting with notable adenopathy, bulky lesions, fever, unexplained pain, weight loss, or organ dysfunction should be examined, e.g., for PTLD [32]. Mortality with PTLD reaches 40-70% after solid organ transplantation. Early mortality from PTLD pst HSCT comprised 90% a decade ago. Overall five-year survival has increased to 40-60% by the present time, due to implementation of adoptive cell therapy [11]. Most lethal outcomes are associated with disease progression. Other 40% of deaths are attributed to infections and therapeutic toxicity. Unfavorable prognosis is associated with older age of the patient, advanced disease stages, bad somatic status, CNS affection, as well as increased LDH levels and ypoalbuminaemia.An International Prognostic Index (IPI) may be used as a predictor in PTLD patients. parameters of lesion and its response to therapy. Extreme importance of PET/CT is proven, in order to justify terms of treatment, especially for the patients with incomplete response to therapy [56].
Diagnostics The best way to manage PTLD patients is to minimize potential risk factors. E.g., the PTLD risk is sufficiently increased upon usage of anti-CD3 or ATG preparations for T cell depletion, aiming for GvHD control. Respectively, an option of B cell depletion should be considered if such approaches cannot be avoided. Testing anti-EBV antibodies in donors is an obligate requirement. A seropositive donor is a risk factor in case of seronegative recipient. Additional leucocyte reduction of RBC preparations is recommended, thus allowing to decrease risk for EBV-positive blood products [47]. CMV infection is considered to be a cofactor of PTLD development following solid organ transplantation. Therefore, CMV status of donor and recipient is also of great significance.
To assess proper diagnosis, EBV detection in blood by means of PCR technique should be used, along with studies of biopsies taken from affected tissues being performed with combined histology, immunophenotyping, immunohistochemistry, molecular techmiques, e.g., in situ hybridization of early EBV DNA (EBER), and PCR for EBV. The disorder should be clearly proven, since some treatment modes could cause severe complications in the patients. In some cases, polymorphic PTLDs is difficult to discern from infectious mononucleosis or odgkin’s disease which may manifest with similar disorders [12]. Cell infiltrate in pathological samples consists of lymphocytes, histiocytes and plasmocytes. The latters comprise transformed B blasts expressing CD20 and CD30, bieng CD15-negative. Monomorphic PTLD comply with histological criteria of lymphoma, mostly, B phenotype (especially, B cell lymphoma, diffuse large cell lymphoma, plasmoblastic lymphoma). However, T cell variants are also described (e.g., hepatolienal T cell lymphoma), and combined-type lymphomas. Hodgkin’s lymphoma after HSCT occurs sporadically, with Hodgkin and Reed-Sternberg cells being an obligate component of cellular substrate containing plasmocytes, eosinophils and histiocytes. The marker cells exhibit high CD30 and CD15 expression with absence of CD20 and weak PAX5 expression [58]. In Hodgkin’s-like PTLD, they are more aggressively presented, being in most cases associated with unfavorable prognosis [28, 48, 46]. These four categories are sometimes hardly discernable, due to cross-presentation of different cellular subsets. Lesions at different sites may exhibit distinct pathohistological pattern. Therefore, correlation with clinical and visualization data should be used to make the diagnosis more correct.
Clonality studies help to confirm the diagnosis. I.e., monomorphic PTLD usually exhibits clonal immunoglobulins or TCR rearrangements, respectively, in B and T cell populations. Due to immune suppression, the B cell PTLDs often express oligoclonal reactive T cell populations detectable by PCR for distinct T cell receptors. They could not be considered classical T cell lymphomas despite their lymphoma pattern revealed by histological criteria. For PTLD staging, they use computer tomography (CT) of chest, abdomen and pelvis minor areas, as well serum LDH determination.
To conduct early monitoring of EBV burden before clinical symptoms of the disorder, quantitative PCR of viral DNA from blood serum is performed. However, it does not substitute requirements for local biopsies to perform adequate diagnostics.
Positron emission tomography with fluorodeoxyglucose (F-FDG-PET/CT) is a golden standard, aiming to assess parameters of lesion and its response to therapy. Extreme importance of PET/CT is proven, in order to justify terms of treatment, especially for the patients with incomplete response to therapy [56].
Prophylaxis
The best way to manage PTLD patients is to minimize potential risk factors. E.g., the PTLD risk is sufficiently increased upon usage of anti-CD3 or ATG preparations for T cell depletion, aiming for GvHD control. Respectively, an option of B cell depletion should be considered if such approaches cannot be avoided. Testing anti-EBV antibodies in donors is an obligate requirement. A seropositive donor is a risk factor in case of seronegative recipient. Additional leucocyte reduction of RBC preparations is recommended, thus allowing to decrease risk for EBV-positive blood products [47]. CMV infection is considered to be a cofactor of PTLD development following solid organ transplantation. Therefore, CMV status of donor and recipient is also of great significance.
Rapid T cell reconstitution is a favorable factor. E.g., incidence of EBV viremia, and, accordigly, PTLD risk in ATG-treated HSCТ patients proved to be suffificiently lower at T cell levels
of >50/mcL by D+30 [44]. Rituximab (an anti-CD20 monoclonal antibody) could be used as prophylaxis [61] and preventive treatment of PTLD. E.g., a weekly qPCR EBV monitoring at the City of Hope Clinics (USA) is performed since D+21 after HSCT [33]. In case if EBV levels exceed 1000 copies/mL, the patient is administered a single Rituximab dose. In case of EBV per-
sistence for 6 other weeks, three Rituximab infusions are preformed in addition. Acyclovir or Gancyclovir usage was also of some interest. Gancyclovir is active in vitro against EBV, however, it may cause a sufficient myelosuppression [31]. The data on its clinical efficiency in PTLD prevention are controversial. Early studies of EBV-cytotoxic T cell infusions have shown their efficiency for viral load reduction, and those may be used to prevent and treat PTLD [49, 10, 21].
Certainly, B cell depletion of hematopoietic grafts (by means of Rituximab or CD19+ cell depletion) remains the most effective tool for PTLD prevention. Treatment Special guidelines for PTLD treatment were designed on the basis of WHO classification [26]. Type 1 PTLD, or early polyclonal disturbances, including reactive lymphoplasmocytic hyperplasia or infectious monucleosis-like syndromes, do not usually require any interventions, being self-limited. However, reduction of immunosuppressive therapy (IST) is recommended in such cases. Type 2 of the polyclonal PTLD usually needs immunosuppression reduction with variable clinical response. Type 3 (lymphoma) is a subject to treatment in case of reduced immunosuppression and chemotherapy applied. Type 4 PTLD requires aggressive therapeutic approach.
Efficiency of reduced immunosuppression in PTLD is described as early as in 1984 [54]. This approach works both in EBV-associated PTLD patients, and in EBV-negative conditions. Absence of clinical response is predicted by LDH increase >2.5-fold over normal values, organ dysfunction, multiple organ failure. However, development or aggravation of acute GvHD could occur due to IST reduction, thus sufficiently worsenig prognosis of the disorder.
Rituximab proved to be an effective preparation in PTLD [3, 41, 15]. It is considered to be a “golden standard” for treatment of CD20+ PTLD including mono- and polymorphic lesions. When transplanting solid organs, full clinical response to Rituximab monotherapy was registered in 53-86% patients [41, 15]. EBV positivity is a predictor of clinical response. The authors recommend reduced immunosuppression and Rituximab admonistration for the patients with
EBV-positive PTLD, whereas polychemotherapy (PChT) is reserved for EBV negative, or Rituximab-nonresponding cases. CHOP and ProMACE-CytaBOM are used as chemotherapy regimens for PTLD, like as in non-Hodgkin’s lymphoma. This treatment mode remains problematic, due to high risk of severe infections and increased mortality levels.
Despite the Rituximab efficiency, this drug is inefficient in a group of the PTLD patients, whereas PChT application is limited by it’s adverse reactions.
Efficiency of cytotoxic EBV-specific T cells was studied in PTLD patients, however, without distinct results [49, 23]. Infusions of native donor lymphocytes may promote restoration of B cell immunity and increase clinical response rates in PTLD to 60-90% [4]. However, only 41% of these patients achieved stable remission. HSCT from EBV-seronegative donors and umbilical blood cells are of limited use in this condition. At the present time, HLA-compatible EBV-specific third-party donor lymphocytes are preferrable, thus suggesting T cell recognition of tumor cells, due to selective restriction of HLA alleles absent from PTLD cells. [13]. However, generation of EBV-specific cytotoxic lymphocytes needs time and expenses, thus limiting clinical usage of this approach. Some workers attempted to develop rapid cultures of EBV-cytotoxic lymphocytes, but their clinical efficiency is not yet proven. At present, donor banks which contain EBV-specific cytotoxic lymphocytes from third-party are arranged. Possible adverse effects may include systemic inflammatory response and minimal GvHD signs. These symptoms fade away upon administration of corticosteroids and Etanecerpt [43]. Cytokine-blocking therapy, e.g., with antibodies against IL-6, a B cell growth stimulant, is described in a Phase I-II multicentric study, showing 41% of clinical response in early PTLD [14, 22]. A concise therapeutic protocol is shown in Fig. 1 [11]. Diverse therapeutic approaches in PTLD are featured in Table 3 [11].
Figure 1. Proposed treatment algorithm for PTLD after HSCT [Dierickx D, Tousseyn T, Gheysens O. How I treat posttransplant lymphoproliferative disorders. Blood. 2015 Nov 12;126(20):2274-83. doi: 10.1182/blood-2015-05-615872. Epub 2015 Sep 17. PMID: 26384356].
Table 3. Treatment options for PTLD [11].
Notes: GvHD, Graft Versus Host Disease; IVIG, intravenous immunoglobulins.
Our clinical experience and discussion
We have analyzed our experience in allogeneic HSCTs performed over 1994-2011 at the Bone Marrow Transplantation Department at the Republican Pediatric Hospital (RPH) and
Institute of Children Hematology, as well as allo-HSCTs carried out within 2012-2016 at the Dmitry Rogachev National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia). From 1994 to 2011, 361 allo-HSCT were performed at the BMT Department, with 27 cases of EBV reactivation (8% of total). Among them, 9 patients showed EBV viremia followed by spontaneous resolution, whereas, in twelve cases, EBV loads required preventive therapy with Rituximab.
In six patients, EBV-associated lymphoproliferative syndrome was observed. Of those PTLD cases, three children received Rituximab treatment with clinical effect; two children required combined therapy with Rituximab and cytostatic chemotherapy. In one child, the disorder proceeded in a fulminant manner, showing no response to Rituximab. Among the group with documented EBV reactivation, eight children have been lost, including three cases of primary disease (1 case was combined with PTLD). In two patients, death was caused by chronic GvHD complicated by infections; in 1 case, lethal outcome was due to heart insufficiency in PTLD with clinical response to Rituximab. One lethal outcome occurred due to multiorgan failure underlied by EBV viremia, and only one case of EBV-associated PTLD proceeded in fulminant manner, with liver and abdominal lymph node affection, thus becoming an immediate cause of death. Clinical characteristics of all patients with EBV reactivation is presented in Table 4. The data on PTLD patients are shown in Table 5.
Table 4. Clinical features of the patients with EBV reactivation
Table 5. Characteristics of the EBV-PTLD patients
Below, we would like to report a detailed description of the most severe clinical case where all available therapeutic options were applied (Patient 3).
Clinical case description
A boy with immune thrombocytopenia diagnosed at 6 years, received corticosteroids without effect; intravenous immunoglobulins (IVIG) with minimal effect. At the age of 10 years, the disorder was complicated by anemia and leukopenia. At the RPH Department of General Hematology, the diagnosis was formulated as follows: acquired idiopathic aplastic anemia, a supersevere form. Due to absence of related compatible donor, immunosupressive therapy was performed with cyclosporine, ATG (2 rounds), without any clinical effect. Multiple transfusions were complicated by hemosiderosis.
At the age of 12 years, the child underwent allogeneic hematopoietic stem cell transplantation from a compatible unrelated donor (9/10 antigens, mismatch for a B locus) with minor ABO incombatibility, and EBV VCA IgG positivity in both donor and recipient. Conditioning regimen consisted of thoraco-abdominal irradiation at a dose of 2 Gy; Fludarabine, 150 mg/m 2 , Cyclophosphamide, 100 mg/kg; Thymoglobulin, 10 mg/kg (total doses are shown). Graft characteristics: nucleated cells, 5х10 8 /kg; CD34+ cells, 3.14х10 6 /kg. GvHD prophylaxis was performed with Tacrolimus and Mycophenolate mofetil.
Engraftment was registered at the day +22. Early posttransplant period was complicated by febrile neutropenia. Donor chimerism was developed at 2 months; blood group was changed to donor RBCs. Stage 1/2 acute GvHD was registered as skin affection, thus requiring Prednisolone administration for 1 month. In parallel, cytomegalovirus in blood was detectable, having been treated by Gancyclovir. Three months after HSCT, the patient developed persistent fever without response to antibiotics, as well as enlargement of left cervical lymph nodes. EBV viremia (2000 copies/mL) was first registered 2 weeks after these manifestations. Enhanced antibiotic therapy was without effect, the patient’s condition became worse, febrile state persisted, accompanied by weakness, asthenia, cachexia. Lymph nodes at the neck area were enlarged, forming a solid conglomerate up to 5 cm in diameter. Lymph node biopsies were performed, followed by their examination at different reference centers (RPH, Moscow; Bureau for Pathology&Anatomy, St. Petersburg). EBV was detected there by means of PCR. Histological pattern corresponded to monomorphic (Moscow), or polymorphic PTLD (St. Petersburg).
In Fig. 2, the results obtained at the Pathology Laboratory in St. Petersburg (Chief, Dr. Yu. A. Krivolapov). A lymphoid tissue fragment exhibited a pattern of lost organ structure. The tissue consisted of diffuse lymphoid cell fields with detectable small and medium-sized lymphocytes, plasmoblasts
and immunoblasts, large atypical cells with giant, sometimes deformed nuclei with large homogenous nucleoli. Nearly all cells in the field have intensively basophilic cytoplasm
(Fig. 3). Mitotic figures are observed. Numerous necrotic foci are revealed, with nuclear fragments (karyorrhexis). Upon immunohistochemical study, vast majority of proliferating cells expressed CD79a (JCB117) and MuM1(Mum1p), with lesser amounts of CD20 (L26)- positive lymphoid cells (Fig. 4). Activated lymphoid cells expressed CD30 (Ber-H2) (Fig. 5). Immunoglobulin light lambda chain-expressing lymphoid cells prevailed over kappa-positive cells in the samples of proliferating tissues (Fig. 6, 7). Large deformed immunoblasts are found there, being both kappa- and lambda-positive. Their cytoplasm showed intensive expression of latent EBV membrane LMP-1(CS1-4) protein (Fig. 8). A proliferative KiS5 antigen was expressed in nuclei of ca. 70% of lymphoid cells. Few CD3+ T cells were seen (Fig. 9), with CD8(1A5) cells being prevalent over CD4(4B12)+ lymphocytes. The proliferating tissue did not contain detectable lymphoid cells expressing CALLA CD10 (56C6), or (ALK-1). Ziel-Nilsen Acid fast stain of slices with carbol fuchsin did not show acid-resistant bacteria. Staining with antibodies for M.bovis did not show this antigen. Clinical pattern of the disease, histological structure of lymphoid tissue under study, and immune histochemistry results correspond to polymorphic post-transplant lymphoproliferative disease.
Immunosuppression was discontinued as a first-line therapeutic measure, and treatment with Rituximab was started. Following 4 injections, clinical effect was not reached. Therefore, we undertook a second-line therapy which consisted of a single-block CHOP chemotherapy, which was complicated by enteroparesis. Within first days of chemotherapy, a decrease and softening of the lymph node conglomerate was registered, then followed by the tumor stabilization, with persisting febrile state.
We then started block A (Dexamethasone+Ifosfamide+Methotrexate, 1 g/m 2 over 24 h + Cytosar + Vepeside, without Vincristine, due to recently observed neuropathy), accompanied by combined anti-infectious therapy. Despite treatment, the neck conglomerate was enlarged, along with continuous febrility. However, EBV was not more detectable in blood by means of PCR. Hence, this case of EBV-associated PTLD was considered refractory. A third block of polychemotherapy was scheduled, as follows: Gemsar, 1 g/m 2 (days 1-6); Carboplatine, 200 mg/m 2 (days 2-5); Vepesid, 150 mg/m 2 (days 2-5); Dexamethasone, 6 mg/m 2 (days 1-6), followed by subsequent transfusion of donor hematopoietic cells (boost without conditioning): on day 3 after finishing therapy, the patient received СD34+ cells at a dose of 11х10 6 / kg, and CD3+ cells at a dose of 1х10 4 /kg. Two weeks later, the fever faded away, and hematopoiesis recovered. However, the boy showed signs of GvHD: dry skin, exfoliation, hyperpigmentation, weak itching. Nevertheless, a decision was taken to continue donor lymphocyte infusions (DLI). Three weeks after first lymphocyte infusion, a second DLI was performed (CD3+ cells, 5х10 4 /kg). Febrile state did resume, but the neck lymph node conglomerate was reduced in size, and hepatosplenomegaly retained. Liver enzyme markers became increased to 400 U/L (ALT and AST); alcaline phosphatase, to 1400 U/L). Toxic hepatitis was diagnosed, and hepatotoxic drugs were withdrawn. However, the condition
of patient became worse, i.e., loss of appetite and weight, enteric symptomes occurred, along with icterus and hepatosplenomegaly (liver +8 cm, spleen +2 cm). Blood biochemistry: total bilirubin of 84 mcmol/L; ALT, 1060 U/L, AST, 2217 U/L, alcaline phosphatase, 2630 U/L. Spot/papule eruptions developed at the the skin of head, trunk, as well as mucosal leukoplakia, and intestinal syndrome considered as grade 3 GvHD, with skin, mucosae, liver, intestinal tract lesions consequent to DLI. Corticosteroid treatment was resumed, at 2 mg/kg/day. As result, eruptions were entirely reduced, like as fever, vomitimg and nausea. However, fatigue, low appetite, intestinal syndrome, signs of sinusitis, lung and intestinal infections (cytomegaloviral and adenoviral colitis). The patient received massive combined antibacterial and antiviral therapy (Cydofovir), antifungal treatment.
PTLD features were still detectable in MRI: heterogenous, thickened, soft, contrast-accumulating tissue retained in nasopharinx area, posterior nasal passages; posterior oropharynx (more at right side) looks deformed, mandibular lymph nodes were enlarged on the right. A heterogenous soft tissue mass persisted in lateral part of neck (left side, 18х9х31 mm in size), containing highly dense inclusions (microcalcinates), without proven contrast accumulation. Later on, a volumic decrease in lymphoproliferative changes was noted.
One month later, glucocorticoids were gradually tapered and fully discontinued. Rapamycin was administered as a basic immunosuppressive drug, aiming for immunotherapy, along with gamma-Interferon (2 injections). Clinical condition of the patient remained quite severe being characterized by cachexia, fever, adynamia, graft hypofunction with transfusion demands and requirements for hematopoiesis stimulation. Remarkable cholestasis was also documented (total bilirubin, 256 mcmol/L (direct,162); ALT, 147 U/L; AST, 174 U/L; alcaline phosphatase, 1224 U/L; GGTP, 1372 U/L), like as hemosiderosis (ferritin, 46545 mcg/L).
From these data, we suggested a secondary hemophagocytic syndrome underlied by EBV infection in immunocompromised patient subjected to unrelated allo-HSCT. Dexamethasone therapy was started (10 mg/m 2 No12), Vepesid
(150 mg/m 2 twice a week). Fever was stopped, and the size of liver and spleen was diminished. However, infectiuos complications still progressed, along with hypoalbuminemia and oedemas. Antibacterial and accessory treatment was further modified. E.g., grafting of CD34+ cells (10х10 6 / kg) was performed, aiming for acceleration of hematopoiesis recovery. During the therapy, small positive changes were documented as decrease of febrile rises, reduced abdominal pains. IST was continued with Rapamycin, and substitutive IVIG transfusions at higher doses were performed, biphosphonates were also administered.
MRI of laryngo-pharyngeal area 8 months after starting PTLD therapy, showed that the right oropharinx, left nasal passages, and left cervical area retain soft tissue lesions; some features of lymphoproliferative lesions in maxillar sinus are also present. By the present, EBV viremia comprised 600 copies/mL, followed by increase to 4320 copies/mL. In parallel, CMV-viremia did also elevate. Therapy with EBV-specific lymphocytes from the same donor was scheduled.
During the waiting period, due to problems with breathing and swallowing, the mass in oropharynx was removed preceded by tracheostoma mounting. Clinical state remained
very severe due to infectious complications underlied by pancytopenia and cholestasis syndromes. A month later, the tracheostome was removed. Therapy with EBV-specific do-
nor cytotoxic lymphocytes was commenced (a total of five injections weekly). The therapy was associated with diminished lymph nodes, gradual improvement of blood counts, as well as slow decrease in liver toxicity markers, EBV viremia. Immune reconstitution seemed to proceed with time.
1.5 years after HSCT, there were no additional data for active PTLD (i.e., a year and 3 months after beginning the therapy), main problems concerned hepatic dysfunction and hepatosplenomegaly, along with liver fidrosis and hemochromatosis. The patient has received a long-term therapy with Budenofalk and Exjade. Subsequently, gradual recovery of somatic status was observed, the boy underwent regular control examinations, replacement therapy with IVIG. His state stabilized 2 years after HSCT. There retaine hepatosplenomegaly, slight increase in hepatic transaminases and alcaline phosphatase. Budenofalk was continued for 3 years. Age-dependent vaccination was performed. At the present time, 10 years after allogeneic HSCT, clinical state of the adolescent is satisfactory, he is learning and keeps active life.
The above clinical description demonstrates an extremely aggressive course of some PTLD cases, thus requiring rapid and precise actions from the doctors. The pathological process developed within typical terms (3 months after HSCT), in absence of immune reconstitution, and exhibited and manifested as an infectious condition with fever and lymphadenopathy. Despite limited localization (oropharynx and cervical regions), the disorder proved to be refractory and threatened with asphyxia at certain stage of disease. Appropriate diagnostics required combined diagnostic measures with dominating histochemical results. Despite a divergent interpretation of mono- or polymorphic lesions in the given EBV-associated PTLD, clinical course and somatic status of the patient determined a vitla demand for changes and careful selection of adequate therapy. One should note professionalism of the medical team, as well as precise actions, patience and insistence of the doctor that determined favorable outcome of this case which initially presented a life-threatening situation.
Meanwhile, the first case presented in Table 5 concerns fulminant course of EBV-PTLD. A 3-year old girl with acute lymphoblastic leukemia (ALL) was subject to allo-HSCT
from HLA-compatible, EBV-positive unrelated donor with partial CD34+ graft enrichment. EBV viremia in the patient was registered at 4 months posttransplant, reaching 12,000 copies/mL. A week later, the viremia was increased to 500,000 copies/mL, accompanied by fever; liver damage as documented by growth in transaminases, rising bilirubin; enlarged abdominal lymph nodes. After two Rituximab injections, no positive effect was reached, her condition deteriorated rapidly, and the patient died due to progressing hepatic and respiratory failure. Only three weeks passed since EBV viremia was registered in the girl. Two-week therapy with Rituximab proved to be without any effect. This type of EBV-PTLD (any histology data are not available, due to lacking autopsy) showed a quite aggressive and rapid course, thus preventing alternative therapeutic options. Other PTLD cases observed (see Table 5) depict more favorable variants of the disorder, with positive response to the IST reduction and Rituximab treatment. Interestingly, the patient No.6 developed EBV-associated PTLD despite EBV-seronegativity in his donor, may be, due to endogenous infection of donor cells from recipient.
Another unusual presentation of PTLD was connected with affection of central nervous system. However, there was no opportunity to perform stereotactic brain biopsy at the time of encephalitis manifestation. Later on, a biopsy did not reveal an initial cellular substrate. However, a marked response to Rituximab, e.g., its endolumbar injections, and to Methotrexate therapy are indicative for malignant origin of primary CNS lesions in the given patient.
A study of the second cohort of patients who received allo-HSCT from 2012 to 2016 at the NCPHOI has revealed only two EBV-PTLD cases among 911 children (Table 6).
This cohort was analysed separately, because the transplants were performed mostly by a novel protocol with a CD19 depletion and inclusion of Rituximab into the conditioning regimen. Among 483 patients after HSCT with alpha/beta depletion and CD19-negative selection, as well as among 316 children who received Rituximab, no single case of PTLD was registered. However, B cell depletion was not performed in the two belowmentioned cases: the first patient was grafted with umbilical blood from unrelated donor. The second patient received bone marrow from a sibling. Therefore, their conditioning regimens were classic, with Thymoglobulin application which is considered an accessory risk factor for PTLD. Description, of these 2 cases, PTLD manifestations and their treatment are seen from Table 6.
Table 6. Characteristics of the two patients with monomorphic B cell PTLD
These two cases also refer to aggressive and malignant clinical forms of PTLD. The first case concerned a girl with acutemyeloblastic leukemia following allografting and development of refractory acute and chronic GvHD without any options of immunotherapy. The B cell monomorphic PTLD did partially respond to Rituximab treatment. More active treatment modes were impossible, due to poor somatic condition of thefemale patient.
In the boy with aplastic anemia, we have documented all stages of EBV-PTLD emergence, including progression from EBV viremia and lymphadenopathy to mucosal lesions (bleeding gastric ulceration requiring partial stomach resection, tonsillar involvement) followed by outgrowth of parapharyngeal tumor mass. We were also able to confirm histologically a transition from polymorphic PTLD to monomorphic aggressive form being similar to malignant large-cell lymphoma by B cell origin (Fig. 10). Such clinical course is rarely described in details, both for clinical and histological pattern, hencethis case seems to be original, due to concordance between evolution of modifying pathological pattern and specific treatment mode. At the stage of EBV-associated lymphoadenopathy, a standard approach with Rituximab therapy was applied, however, without effect. This monomorphic PTLD was refractory to therapy with anti-CD20 antibodies. At the next stage, the EBV-PTLD proceeded as a malignant B cell large-cell lymphoma (Fig. 11), this requiring a highdose chemotherapy. In future, standard polychemotherapy proved to be insuffisient, and clinical effect was obtained only from combined chemotherapy, immune drugs and donor lymphocyte infusion. Nivolumab and Brentuximab were used as a pioneering approach to treatment of such condition. In both children, antibodies against IL-6 were also used with proven effect, in order to ameliorate clinical symptoms.
Figure 10. Pathomorphosis of PTLD in one patient.
а. hematoxylin and eosin stain; х10, х40. Early PTLD lymph node lesion. The loss of topographic structure, focuses of necrosis, polymorphic cell infiltrate with large EBV-positive cells.
b. hematoxylin and eosin stain; х10, х40. Polymorhic PTLD, mucocutaneous ulcer of the antral stomach. The mucose of the antral stomach with ulceration and a massive transmural infiltration of lamina propria. Polymorphic cell infiltrate with numerous EBV-positive large cells, plasmacytic cells and plasmoblasts, small CD3/CD8 reactive Т-lymphocytes.
c. hematoxylin and eosin stain; х20, х40. Monomorphic B-cell PTLD, diffuse large cell B-cell lymphoma. Monomorphic large cell infiltrate with the diffuse distribution among the muscled fibers. Cells with a high mytotic activity – immunoblasts and centroblasts.
Conclusion
Hence, PTLD is a challenging pathological process which lets a lot of open questions be answered by appropriate specialists. This complication still bears a risk of high mortality, thus requiring further activities for studying pathogenesis and treatment modes for PTLD. Multicenter research and clinical studies are necessary to evaluate this clinical entity. The PTLD therapy represents an excellent clinical model for combined application of immune therapy, cellular therapy, and standard cytostatic treatment of malignancies which may be used for treatment of other neoplasias and severe viral infections.
Conflict of interest
No conflict of interests is declared.
References
1. Andreone P, Gramenzi A, Lorenzini S, Biselli M, Cursaro C, Pileri S, Bernardi M. Posttransplantation lymphoproliferative disorders. Arch Intern Med. 2003;163(17):1997-2004.
2. Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stemcell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003 ; 21(7):1352-1358.
3. Blaes AH, Peterson BA, Bartlett N, Dunn DL, Morrison VA. Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial. Cancer. 2005;104(8):1661-1667.
4. Bollard CM, Rooney CM, Heslop HE. T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat Rev Clin Oncol. 2012 Sep;9(9):510-519.
5. Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, Wagner JE. Marked increased risk of Epstein-Barr virus-related complications with the addition of
antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood. 2006;108(8):2874-2880.
6. Chen W, Huang Q, Zuppan CW, Rowsell EH, Cao JD, Weiss LM, Wang J. Complete absence of KSHV/HHV-8 in posttransplant lymphoproliferative disorders: an immuno
histochemical and molecular study of 52 cases. Am J Clin Pathol. 2009;131(5):632-9.
7. Cockfield SM. Identifying the patient at risk for posttransplant lymphoproliferative disorder. Transpl Infect Dis. 2001 ; 3(2):70-78. Review.
8. Cohen J.I. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore), 1991;70:137–160.
9. Cohen JM, Cooper N, Chakrabarti S, Thomson K, Samarasinghe S, Cubitt D, Lloyd C, Woolfrey A, Veys P, Amrolia PJ. EBV-related disease following haematopoietic stem
cell transplantation with reduced intensity conditioning. Leuk Lymphoma. 2007;48(2):256-269.
10. Comoli P, Labirio M, Basso S, Baldanti F, Grossi P, Furione M, Viganò M, Fiocchi R, Rossi G, Ginevri F, Gridelli B, Moretta A, Montagna D, Locatelli F, Gerna G, Maccario
R. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood. 2002 ; 99(7):2592-2598.
11. Dierickx D, Tousseyn T, Gheysens O. How I treat posttransplant lymphoproliferative disorders. Blood. 2015;126(20):2274-2283.
12. Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, Brepoels L, Kuypers D, Vanhaecke J, Nevens F, Verleden G, Van Damme-Lombaerts R, Renard M, Pirenne J, De Wolf-Peeters C, Verhoef G. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymphoma. 2013;54(11):2433-2440. ford DH., et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360(9331):436-442.
13. Doubrovina E, Oflaz-Sozmen B, Prockop SE, Kernan NA, Abramson S, Teruya-Feldstein J, Hedvat C, Chou JF, Heller G, Barker JN, Boulad F, Castro-Malaspina H, George D, Jakubowski A, Koehne G, Papadopoulos EB, Scaradavou A, Small TN, Khalaf R, Young JW, O’Reilly RJ. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood. 2012;119(11):2644-2656. 24. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol. 1997;14(1):8-14.
14. Durandy A. Anti-B cell and anti-cytokine therapy for the treatment of post-transplant lymphoproliferative disorder: past, present, and future. Transpl Infect Dis. 2001;3(2):104-107.
15. Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, Olthoff KM, Schuster SJ, Nasta SD, Stadtmauer EA, Tsai DE. Treatment of PTLD with rituximab or
chemotherapy. Am J Transplant. 2006;6(3):569-576.
25. Hoover R.N. Lymphoma risks in populations with altered immunity – a search for mechanism. Cancer Res 1992; 52: 5477s.
26. Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues. In: World Health Organization Classification of Tumours, vol.3, Lyon, France: IARC Press, 2001:264-269.
27. Knowles DM, Cesarman E, Chadburn A. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphopro-
liferative disorders. Blood. 1995 ;85(2) :552-565.
16. Epstein-Barr virus and lymphoproliferative disorders after transplantation. [No authors listed] Am J Transplant. 2004; 4 (Suppl 10):59-65. 28. Krishnamurthy S, Hassan A, Frater JL, Paessler ME, Kreisel FH. Pathologic and clinical features of Hodgkin lymphoma-like posttransplant lymphoproliferative disease. Int J Surg Pathol. 2010; 18(4): 278-285.
17. Frizzera G, Hanto DW, Gajl-Peczalska KJ, Rosai J, McKenna RW, Sibley RK, Holahan KP, Lindquist LL. Polymorphic diffuse B-cell hyperplasias and lymphomas in renal
transplant recipients. Cancer Res. 1981;41(11, Pt 1):4262-4279. 29. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, Gandjbakhch I, Binet JL, Raphael M. Post-
transplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16(6):2052-2059.
18. Gong JZ, Bayerl MG, Sandhaus LM, Sebastian S, Rehder CW, Routbort M, Lagoo AS, Szabolcs P, Chiu J, Comito M, Buckley PJ. Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children. Am J Surg Pathol. 2006; 30(3): 328-336. 30. Liebowitz D. Epstein-Barr virus and a cellular signaling
pathway in lymphomas from immunosuppressed patients. N Engl J Med 1998; 338: 1413–1421.
19. Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annu Rev Med. 2005; 56:29-44.
20. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59-67.
21. Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG. Epstein-Barr virus (EBV) load in bone marrow trans-
plant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood. 2000;95(3):807-814.
22. Haddad E, Paczesny S, Leblond V, Seigneurin JM, Stern M, Achkar A, Bauwens M, Delwail V, Debray D, Duvoux C, Hubert P, Hurault de Ligny B, Wijdenes J, Durandy A, Fischer A. Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial. Blood. 2001;97(6):1590-1597.
23. Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A, Dombagoda D, Britton KM, Swerdlow AJ, Crawford DH., et al. Treatment of Epstein-Barr-virus-positive
post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360(9331):436-442.
24. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol. 1997;14(1):8-14.
25. Hoover R.N. Lymphoma risks in populations with altered immunity – a search for mechanism. Cancer Res 1992; 52: 5477s.
26. Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues. In: World Health Organization Classification of Tumours, vol.3, Lyon, France: IARC Press, 2001:264-269.
27. Knowles DM, Cesarman E, Chadburn A. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphopro-
liferative disorders. Blood. 1995 ;85(2) :552-565.
28. Krishnamurthy S, Hassan A, Frater JL, Paessler ME, Kreisel FH. Pathologic and clinical features of Hodgkin lymphoma-like posttransplant lymphoproliferative disease. Int J Surg Pathol. 2010; 18(4): 278-285.
29. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, Gandjbakhch I, Binet JL, Raphael M. Posttransplant lymphoproliferative disorders not associated
with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16(6):2052-2059.
32. Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant. 2003;31(3):145-155.
33. Lowe T., S.Bhatia, G.Somlo. Second malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007; 13:1121-1134.
34. Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, Porter DL, Vonderheide RH, Bagg A, Heitjan DF, Tsai DE, Reshef R. The impact of EBV status on characteristics and outcomes of posttransplantation lymphoproliferative disorder. Am J Transplant. 2015;15(10):2665-2673.
35. Mathur A, Kamat DM, Filipovich AH, Steinbuch M, Shapiro RS. Immunoregulatory abnormalities in patients with Epstein-Barr virus-associated B cell lymphoprolifera-
tive disorders. Transplantation. 1994; 57(7):1042-1045.
36. Morscio J, Dierickx D, Ferreiro JF, Herreman A, Van Loo P, Bittoun E, Verhoef G, Matthys P, Cools J, Wlodarska I, De Wolf-Peeters C, Sagaert X, Tousseyn T. Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders. Am J Transplant. 2013;13(5):1305-1316.
37. Morscio J, Tousseyn T. Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders. World J Transplant. 2016; 6(3):505-516. kin-like post-transplant lymphoproliferative disease. Pediatr Transplant. 2008;12(4):426-431.
38. Nalesnik M.A., L. Makowka, T.E. Starzl. The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg, 1988; 25: 367–472. 49. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, Heslop HE. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood. 1998; 92(5):1549-1555.
39. Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol. 1988;133(1):173-192.
40. Nelson BP, Nalesnik MA, Bahler DW, Locker J, Fung JJ, Swerdlow SH. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol. 2000;24(3):375-385.
41. Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Váry M, Babel N, Trappe RU, Jonas S, Hummel M, Anagnostopoulos I, Dörken B, Riess HB. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. 2005;5(12):2901-2906.
42. Orazi A, Hromas RA, Neiman RS, Greiner TC, Lee CH, Rubin L, Haskins S, Heerema NA, Gharpure V, Abonour R, Srour EF, Cornetta K. Posttransplantation lymphoproliferative disorders in bone marrow transplant recipients are aggressive diseases with a high incidence of adverse histologic and immunobiologic features. Am J Clin Pathol. 1997; 107:419–429.
43. Orazi A, Hromas RA, Neiman RS, Greiner TC, Lee CH, Rubin L, Haskins S, Heerema NA, Gharpure V, Abonour R, Srour EF, Cornetta K. Systemic inflammatory response syndrome after administration of unmodified T lymphocytes. Mol Ther. 2014 ;22(6):1134-1138.
44. Patriarca F, Medeot M, Isola M, Battista ML, Sperotto A, Pipan C, Toffoletti E, Dozzo M, Michelutti A, Gregoraci G, Geromin A, Cerno M, Savignano C, Rinaldi C, Barbone F, Fanin R. Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab. Transpl Infect Dis. 2013;15(3):259-267.
45. Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients.Transplant Proc. 1969; 1:106-112.
46. Pitman SD, Huang Q, Zuppan CW, Rowsell EH, Cao JD, Berdeja JG, Weiss LM, Wang J. Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically. Am J Surg Pathol. 2006 ;30(4):470-476.
47. Qu L, Xu S, Rowe D, Triulzi D. Efficacy of Epstein-Barr virus removal by leukoreduction of red blood cells. Transfusion. 2005;45(4):591-595.
48. Rohr JC, Wagner HJ, Lauten M, Wacker HH, Jüttner E, Hanke C, Pohl M, Niemeyer CM. Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodg-kin-like post-transplant lymphoproliferative disease. Pediatr Transplant. 2008;12(4):426-431.
49. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, Heslop HE. Infusion of cytotoxic T cells for the preven-
tion and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood. 1998; 92(5):1549-1555.
50. Rowlings PA, Curtis RE, Passweg JR, Deeg HJ, Socié G, Travis LB, Kingma DW, Jaffe ES, Sobocinski KA, Horowitz MM. Increased incidence of Hodgkin’s disease
after allogeneic bone marrow transplantation. J Clin Oncol. 1999;17(10):3122-3127.
51. Shapiro RS, McClain K, Frizzera G, Gajl-Peczalska KJ, Kersey JH, Blazar BR, Arthur DC, Patton DF, Greenberg JS, Burke B, et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood. 1988;71(5):1234-1243.
52. Snyder MJ, Stenzel TT, Buckley PJ, Lagoo AS, Rizzieri DA, Gasparetto C, Vredenburgh JJ, Chao NJ, Gong JZ. Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation. Am J Surg Pathol. 2004;28(6):794-800.
53. Socié G, Curtis RE, Deeg HJ, Sobocinski KA, Filipovich AH, Travis LB, Sullivan KM, Rowlings PA, Kingma DW, Banks PM, Travis WD, Witherspoon RP, Sanders J, Jaffe
ES, Horowitz MM. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18(2):348-357.
54. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BW Jr, Hardesty RL, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984; 1(8377):583-587.
55. Styczynski J, Reusser P, Einsele H, de la Camara R, Cordonnier C, Ward KN, Ljungman P, Engelhard D. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant. 2009;43(10):757-770.
56. Takehana CS, Twist CJ, Mosci C, Quon A, Mittra E, Iagaru A. (18)F-FDG PET/CT in the management of patients with post-transplant lymphoproliferative disorder. Nucl
Med Commun. 2014;35(3):276-281.
57. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithäuser M, Zimmer-
mann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S; German PTLD Study Group; European PTLD Network. Sequential treatment with rituximab followed by CHOP
chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012;13(2):196-206.
58. Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med. 2007;131(8):1209-1218.
59. Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O, Winiarski J, Ljungman P, Remberger M, Mattsson J. Risk factors for Epstein-Barr virus-related posttransplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99(2):346-352.
60. Wagner HJ, Cheng YC, Huls MH, Gee AP, Kuehnle I, Krance RA, Brenner MK, Rooney CM, Heslop HE. Prompt versus preemptive intervention for EBV lymphoproliferative disease. Blood. 2004;103(10):3979-3981.
61. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE, Jakubowski A. Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transplant.
2006;37(6):539-546.
62. Zallio F, Primon V, Tamiazzo S, Pini M, Baraldi A, Corsetti MT, Gotta F, Bertassello C, Salvi F, Rocchetti A, Levis A. Epstein-Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation. Clin Transplant. 2013;27(4):E491-497.
Introduction
The number of allogeneic hematopoietic stem cell transplantations (HSCT) continues to increase, including transplants from alternative donors. Therefore, an uncommon HSCT complication called a posttransplant lymphoproliferative disease (PTLD) should be in focus, due to its extreme danger to patients.
Since 60’s, lymphoid-derived posttransplant neoplasias were first described in renal transplant patients who received immunosuppressive drugs to prevent graft rejection [45]. PTLD is a common complication in solid organ transplant settings, occuring at a rate of 1 to 20%, being dependent on the graft type [7]. Similarly, PTLD may develop after allo-HSCT presenting many factors predisposing for deficient immune surveillance over proliferating B cells. PLTD incidence following allo-HSCT varies between 0.8 and 1.5% [2]. Some PTLD cases are described after umbilical blood transplantation [18], and allo-HSCT with nonmyeloablative conditioning [5, 52]. PTLD comprises a group of disorders ranging from benign polyclonal hyperplasia to alignant clonal proliferation [42, 25, 8, 30, 38]. PTLD is historically recognized as uncontrolled B cell proliferation caused by Epstein-Barr virus (EBV). However, EBV-negative PTLD are described as well [29].
Classification
All the posttransplant lymphoid neoplasias were previously called immunoblastic sarcomas until PTLD discretion, as a certain clinical entity. In 1987, Frizzera et al. [17] described some distinct polymorphic changes in patients after renal transplantation, and proposed a classification including a non-specific hyperplasia, polymorphic hyperplasia, and polymorphic lymphoma. In 1988, Nalesnik et al. coined a term polymorphic PTLD for the mentioned disorder [39]. Monomorphic PTLD was also described but it could not be differed from a non-Hodgkin’s lymphoma. However, mere morphological findings did not provide complete and reliable prognostic information. Knowles et al. [27] added combined molecular genetics criteria to classical morphological features in order to determine cellular clonality, thus developing a PTLD classification including a polyclonal plasmatic hyperplasia, monoclonal polymorphic B cell hyperplasia, or lymphoma, as well as monoclonal pleiomorphic immunoblastic lymphoma, or multiple myeloma.
By 1997, Society for Hematopathology developed a novel classification which initially pointed to differences between early and late PTLD’s [24]. In 2001, The World Health Organization (WHO) published current PTLD classification which is used up to present time: 1) initial disturbance, e.g., reactive lymphoplasmacytic hyperplasia, and a syndrome similar to infectious mononucleosis, 2) polymorphic PTLD; 3) monomorphic PTLD, and, 4) Hodgkin’s disease-like PTLD (Table 1) [26, 33]. In 2008, this classification was supplemented by additional histological criteria.
Table 1. PTLD categories according to WHO Classification of Tumours [26]
Notes: WHO, World Health Organization; PTLD, posttransplant lymphoproliferative disease; NHL, non-Hodgkin’s lymphomas.
Etiology and Pathogenesis
Primary EBV infection after transplantation is the main factor of PTLD. I.e., the PTLD risk after EBV infection is shown to be increased 10- to 76-fold [7]. EBV, herpesvirus family member may cause of infectious mononucleosis. Human fluids and secretions, e.g., saliva, are a usual transfection source. Over 90% of humans develop anti-EBV immunity by the age of 40 years. Following primary infection, a long-lasting viral latency is established. An immunocompetent organism has several control mechanisms against EBV proliferation after primary infection, especially, cytotoxic T cell response, and, to lesser degree, humoral (antibody) immune response; NK cell activity, cytokine regulatory pathways [51, 35]. EBV transmission to the HSCT recipients occurs mainly via blood products, however, exact incidence of this transfection is undetermined. In cases of B cell PTLD, B cell proliferation and inhibition of specific immune surveillance are the main causal factors [1]. EBV is known to primarily affect naïve B cells which migrate to germinative centers. Specific EBV proteins are stimulating differentiation of B cells to memory B cells that become the EBV depots. In summary, expression of EBV markers (LMP1, 2A-B), and nuclear proteins (EBNA-1, 2, 3A-C) is accompained by development of the virus latency. These latent gene expression is associated with ongoing EBV infection of B cells, and, accordingly, with different kinds of PTLD [37] (Table 2). Hence, EBV genome in immunocompetent subjects exists as episomes providing latency in memory B cells. Under inhibited immunity, the T cell control is also lost, thus causing proliferation of EBV-infected В cells, lymphoid cell hyperplasia, and evolving malignancy [32]. T cell recovery does not yet occur within 6 months post-HSCT, thus predisposing for higher PTLD risk during this time period. [4]. However, an increase in late PTLD cases is observed over last years [50]. As a rule, this trend is associated, with low CD4+ lymphocyte levels as it occurs in HIV-infected patients [20].
Table 2. EBV-associated PTLD and viral programs [37]
In early PTLD (1 st year after HSCT) EBV is found in >90% of В cells. With time, a year or later after HSCT, the EBV detectability decreases gradually, reaching an average of 21-32% of
total [16]. Over last years, growing number of EBV-negative PTLD’s has been registered: from 10% in 90’s to 48% over 2008-2013 [34]. Nevertheless, EBV presence is recommended for every bioptate taken using in situ hybridization since EBV status determines appropriate therapeutic approaches. Cytomegalovirus and human herpesvirus could be also detected in blood and tissues of the patients, being, however, an epiphenomenon rather than a disease trigger. [6, 62]. When transplanting solid organ, the PTLD emerges from recipient cells. Meanwhile, both donor and recipient in allogeneic HSCT, are EBV-seropositive in most cases. Hence, lymphoproliferation after allo-HSCT originates from donor cells because lymphoid system in recipient is often virtually destroyed by conditioning treatment. Even in cases of EBV-seronegativity in donor, PTLD develop, due to infection of donor lymphocytes from EBV-positive recipient.
Risk factors
In addition to EBV infection, a number of other HSCT-associated risk factors for PTLD are reported, e.g.: HLA-compatible donor (RR 3,8-9); T cell depletion (RR 4-12,7), treatment with CD3 antibodies; usage of antithymocyte globulin (ATG) (RR 3.1-6.4), severe acute GvHD, grade ≥2 (RR 1.9-6.5); extensive chronic GvHD (risk factor for a late PTLD) [2, 53]. As reported by Uhlin et al. [59], incidence of the EBV-associated PTLD may increase to 10-20% upon combination of some known risk factors: HLA mismatch, different EBV serology in donor/recipient pairs; reduced intensity conditioning; acute GvHD; splenectomy before HSCT; mesenchymal stem cell infusions. The EBV viral load in cases of viral reactivation does not play a sufficient role. E.g., PTLD was registered in 50% of the patients with blood EBV contents of ≥4,000 copies per mL [60]. Meanwhile, current European Guidelines recommend weekly quantitative PCR screening for EBV in allo-HSCT recipients for a minimum of 3 months post-HSCT [55]. Despite donor origin of proliferating B cells in most HSCT cases, high prevalence of PTLD is described in pediatric population among patients receiving ATG- or Alemtuzumab-containing conditioning, due to persistence of recipient B cells in this setting [9, 5].
One should not underestimate EBV-negative PTLDs which occur at later terms post-HSCT, showing a more aggressive clinical course [40]. Some authors suggest to consider them as “classic” lymphomas developing in transplanted patients [36]. Interestingly, the results of an international multicentric prospective study (Phase 2) do not consider EBV status a significant factor influencing overall survival and progression terms [57].
Clinical Features
PTLD manifestations may be quite diverse. Lymphadenopathy, or limited affection of lymphoid tissue are most common. Diffuse lesions similar to fulminant septic syndrome may occur more rarely [19]. The disorder may manifest like an acute respiratory viral infection, sometimes exhibiting functional affection of a distinct organ. Many cases could be complicated by cytomegalovirus infection, or by invasive aspergillosis. In some instances, PTLD proceeds symptomless, being detectable as an occasional finding at autopsy. Any HSCT patient presenting with notable adenopathy, bulky lesions, fever, unexplained pain, weight loss, or organ dysfunction should be examined, e.g., for PTLD [32]. Mortality with PTLD reaches 40-70% after solid organ transplantation. Early mortality from PTLD pst HSCT comprised 90% a decade ago. Overall five-year survival has increased to 40-60% by the present time, due to implementation of adoptive cell therapy [11]. Most lethal outcomes are associated with disease progression. Other 40% of deaths are attributed to infections and therapeutic toxicity. Unfavorable prognosis is associated with older age of the patient, advanced disease stages, bad somatic status, CNS affection, as well as increased LDH levels and ypoalbuminaemia.An International Prognostic Index (IPI) may be used as a predictor in PTLD patients. parameters of lesion and its response to therapy. Extreme importance of PET/CT is proven, in order to justify terms of treatment, especially for the patients with incomplete response to therapy [56].
Diagnostics The best way to manage PTLD patients is to minimize potential risk factors. E.g., the PTLD risk is sufficiently increased upon usage of anti-CD3 or ATG preparations for T cell depletion, aiming for GvHD control. Respectively, an option of B cell depletion should be considered if such approaches cannot be avoided. Testing anti-EBV antibodies in donors is an obligate requirement. A seropositive donor is a risk factor in case of seronegative recipient. Additional leucocyte reduction of RBC preparations is recommended, thus allowing to decrease risk for EBV-positive blood products [47]. CMV infection is considered to be a cofactor of PTLD development following solid organ transplantation. Therefore, CMV status of donor and recipient is also of great significance.
To assess proper diagnosis, EBV detection in blood by means of PCR technique should be used, along with studies of biopsies taken from affected tissues being performed with combined histology, immunophenotyping, immunohistochemistry, molecular techmiques, e.g., in situ hybridization of early EBV DNA (EBER), and PCR for EBV. The disorder should be clearly proven, since some treatment modes could cause severe complications in the patients. In some cases, polymorphic PTLDs is difficult to discern from infectious mononucleosis or odgkin’s disease which may manifest with similar disorders [12]. Cell infiltrate in pathological samples consists of lymphocytes, histiocytes and plasmocytes. The latters comprise transformed B blasts expressing CD20 and CD30, bieng CD15-negative. Monomorphic PTLD comply with histological criteria of lymphoma, mostly, B phenotype (especially, B cell lymphoma, diffuse large cell lymphoma, plasmoblastic lymphoma). However, T cell variants are also described (e.g., hepatolienal T cell lymphoma), and combined-type lymphomas. Hodgkin’s lymphoma after HSCT occurs sporadically, with Hodgkin and Reed-Sternberg cells being an obligate component of cellular substrate containing plasmocytes, eosinophils and histiocytes. The marker cells exhibit high CD30 and CD15 expression with absence of CD20 and weak PAX5 expression [58]. In Hodgkin’s-like PTLD, they are more aggressively presented, being in most cases associated with unfavorable prognosis [28, 48, 46]. These four categories are sometimes hardly discernable, due to cross-presentation of different cellular subsets. Lesions at different sites may exhibit distinct pathohistological pattern. Therefore, correlation with clinical and visualization data should be used to make the diagnosis more correct.
Clonality studies help to confirm the diagnosis. I.e., monomorphic PTLD usually exhibits clonal immunoglobulins or TCR rearrangements, respectively, in B and T cell populations. Due to immune suppression, the B cell PTLDs often express oligoclonal reactive T cell populations detectable by PCR for distinct T cell receptors. They could not be considered classical T cell lymphomas despite their lymphoma pattern revealed by histological criteria. For PTLD staging, they use computer tomography (CT) of chest, abdomen and pelvis minor areas, as well serum LDH determination.
To conduct early monitoring of EBV burden before clinical symptoms of the disorder, quantitative PCR of viral DNA from blood serum is performed. However, it does not substitute requirements for local biopsies to perform adequate diagnostics.
Positron emission tomography with fluorodeoxyglucose (F-FDG-PET/CT) is a golden standard, aiming to assess parameters of lesion and its response to therapy. Extreme importance of PET/CT is proven, in order to justify terms of treatment, especially for the patients with incomplete response to therapy [56].
Prophylaxis
The best way to manage PTLD patients is to minimize potential risk factors. E.g., the PTLD risk is sufficiently increased upon usage of anti-CD3 or ATG preparations for T cell depletion, aiming for GvHD control. Respectively, an option of B cell depletion should be considered if such approaches cannot be avoided. Testing anti-EBV antibodies in donors is an obligate requirement. A seropositive donor is a risk factor in case of seronegative recipient. Additional leucocyte reduction of RBC preparations is recommended, thus allowing to decrease risk for EBV-positive blood products [47]. CMV infection is considered to be a cofactor of PTLD development following solid organ transplantation. Therefore, CMV status of donor and recipient is also of great significance.
Rapid T cell reconstitution is a favorable factor. E.g., incidence of EBV viremia, and, accordigly, PTLD risk in ATG-treated HSCТ patients proved to be suffificiently lower at T cell levels
of >50/mcL by D+30 [44]. Rituximab (an anti-CD20 monoclonal antibody) could be used as prophylaxis [61] and preventive treatment of PTLD. E.g., a weekly qPCR EBV monitoring at the City of Hope Clinics (USA) is performed since D+21 after HSCT [33]. In case if EBV levels exceed 1000 copies/mL, the patient is administered a single Rituximab dose. In case of EBV per-
sistence for 6 other weeks, three Rituximab infusions are preformed in addition. Acyclovir or Gancyclovir usage was also of some interest. Gancyclovir is active in vitro against EBV, however, it may cause a sufficient myelosuppression [31]. The data on its clinical efficiency in PTLD prevention are controversial. Early studies of EBV-cytotoxic T cell infusions have shown their efficiency for viral load reduction, and those may be used to prevent and treat PTLD [49, 10, 21].
Certainly, B cell depletion of hematopoietic grafts (by means of Rituximab or CD19+ cell depletion) remains the most effective tool for PTLD prevention. Treatment Special guidelines for PTLD treatment were designed on the basis of WHO classification [26]. Type 1 PTLD, or early polyclonal disturbances, including reactive lymphoplasmocytic hyperplasia or infectious monucleosis-like syndromes, do not usually require any interventions, being self-limited. However, reduction of immunosuppressive therapy (IST) is recommended in such cases. Type 2 of the polyclonal PTLD usually needs immunosuppression reduction with variable clinical response. Type 3 (lymphoma) is a subject to treatment in case of reduced immunosuppression and chemotherapy applied. Type 4 PTLD requires aggressive therapeutic approach.
Efficiency of reduced immunosuppression in PTLD is described as early as in 1984 [54]. This approach works both in EBV-associated PTLD patients, and in EBV-negative conditions. Absence of clinical response is predicted by LDH increase >2.5-fold over normal values, organ dysfunction, multiple organ failure. However, development or aggravation of acute GvHD could occur due to IST reduction, thus sufficiently worsenig prognosis of the disorder.
Rituximab proved to be an effective preparation in PTLD [3, 41, 15]. It is considered to be a “golden standard” for treatment of CD20+ PTLD including mono- and polymorphic lesions. When transplanting solid organs, full clinical response to Rituximab monotherapy was registered in 53-86% patients [41, 15]. EBV positivity is a predictor of clinical response. The authors recommend reduced immunosuppression and Rituximab admonistration for the patients with
EBV-positive PTLD, whereas polychemotherapy (PChT) is reserved for EBV negative, or Rituximab-nonresponding cases. CHOP and ProMACE-CytaBOM are used as chemotherapy regimens for PTLD, like as in non-Hodgkin’s lymphoma. This treatment mode remains problematic, due to high risk of severe infections and increased mortality levels.
Despite the Rituximab efficiency, this drug is inefficient in a group of the PTLD patients, whereas PChT application is limited by it’s adverse reactions.
Efficiency of cytotoxic EBV-specific T cells was studied in PTLD patients, however, without distinct results [49, 23]. Infusions of native donor lymphocytes may promote restoration of B cell immunity and increase clinical response rates in PTLD to 60-90% [4]. However, only 41% of these patients achieved stable remission. HSCT from EBV-seronegative donors and umbilical blood cells are of limited use in this condition. At the present time, HLA-compatible EBV-specific third-party donor lymphocytes are preferrable, thus suggesting T cell recognition of tumor cells, due to selective restriction of HLA alleles absent from PTLD cells. [13]. However, generation of EBV-specific cytotoxic lymphocytes needs time and expenses, thus limiting clinical usage of this approach. Some workers attempted to develop rapid cultures of EBV-cytotoxic lymphocytes, but their clinical efficiency is not yet proven. At present, donor banks which contain EBV-specific cytotoxic lymphocytes from third-party are arranged. Possible adverse effects may include systemic inflammatory response and minimal GvHD signs. These symptoms fade away upon administration of corticosteroids and Etanecerpt [43]. Cytokine-blocking therapy, e.g., with antibodies against IL-6, a B cell growth stimulant, is described in a Phase I-II multicentric study, showing 41% of clinical response in early PTLD [14, 22]. A concise therapeutic protocol is shown in Fig. 1 [11]. Diverse therapeutic approaches in PTLD are featured in Table 3 [11].
Figure 1. Proposed treatment algorithm for PTLD after HSCT [Dierickx D, Tousseyn T, Gheysens O. How I treat posttransplant lymphoproliferative disorders. Blood. 2015 Nov 12;126(20):2274-83. doi: 10.1182/blood-2015-05-615872. Epub 2015 Sep 17. PMID: 26384356].
Table 3. Treatment options for PTLD [11].
Notes: GvHD, Graft Versus Host Disease; IVIG, intravenous immunoglobulins.
Our clinical experience and discussion
We have analyzed our experience in allogeneic HSCTs performed over 1994-2011 at the Bone Marrow Transplantation Department at the Republican Pediatric Hospital (RPH) and
Institute of Children Hematology, as well as allo-HSCTs carried out within 2012-2016 at the Dmitry Rogachev National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia). From 1994 to 2011, 361 allo-HSCT were performed at the BMT Department, with 27 cases of EBV reactivation (8% of total). Among them, 9 patients showed EBV viremia followed by spontaneous resolution, whereas, in twelve cases, EBV loads required preventive therapy with Rituximab.
In six patients, EBV-associated lymphoproliferative syndrome was observed. Of those PTLD cases, three children received Rituximab treatment with clinical effect; two children required combined therapy with Rituximab and cytostatic chemotherapy. In one child, the disorder proceeded in a fulminant manner, showing no response to Rituximab. Among the group with documented EBV reactivation, eight children have been lost, including three cases of primary disease (1 case was combined with PTLD). In two patients, death was caused by chronic GvHD complicated by infections; in 1 case, lethal outcome was due to heart insufficiency in PTLD with clinical response to Rituximab. One lethal outcome occurred due to multiorgan failure underlied by EBV viremia, and only one case of EBV-associated PTLD proceeded in fulminant manner, with liver and abdominal lymph node affection, thus becoming an immediate cause of death. Clinical characteristics of all patients with EBV reactivation is presented in Table 4. The data on PTLD patients are shown in Table 5.
Table 4. Clinical features of the patients with EBV reactivation
Table 5. Characteristics of the EBV-PTLD patients
Below, we would like to report a detailed description of the most severe clinical case where all available therapeutic options were applied (Patient 3).
Clinical case description
A boy with immune thrombocytopenia diagnosed at 6 years, received corticosteroids without effect; intravenous immunoglobulins (IVIG) with minimal effect. At the age of 10 years, the disorder was complicated by anemia and leukopenia. At the RPH Department of General Hematology, the diagnosis was formulated as follows: acquired idiopathic aplastic anemia, a supersevere form. Due to absence of related compatible donor, immunosupressive therapy was performed with cyclosporine, ATG (2 rounds), without any clinical effect. Multiple transfusions were complicated by hemosiderosis.
At the age of 12 years, the child underwent allogeneic hematopoietic stem cell transplantation from a compatible unrelated donor (9/10 antigens, mismatch for a B locus) with minor ABO incombatibility, and EBV VCA IgG positivity in both donor and recipient. Conditioning regimen consisted of thoraco-abdominal irradiation at a dose of 2 Gy; Fludarabine, 150 mg/m 2 , Cyclophosphamide, 100 mg/kg; Thymoglobulin, 10 mg/kg (total doses are shown). Graft characteristics: nucleated cells, 5х10 8 /kg; CD34+ cells, 3.14х10 6 /kg. GvHD prophylaxis was performed with Tacrolimus and Mycophenolate mofetil.
Engraftment was registered at the day +22. Early posttransplant period was complicated by febrile neutropenia. Donor chimerism was developed at 2 months; blood group was changed to donor RBCs. Stage 1/2 acute GvHD was registered as skin affection, thus requiring Prednisolone administration for 1 month. In parallel, cytomegalovirus in blood was detectable, having been treated by Gancyclovir. Three months after HSCT, the patient developed persistent fever without response to antibiotics, as well as enlargement of left cervical lymph nodes. EBV viremia (2000 copies/mL) was first registered 2 weeks after these manifestations. Enhanced antibiotic therapy was without effect, the patient’s condition became worse, febrile state persisted, accompanied by weakness, asthenia, cachexia. Lymph nodes at the neck area were enlarged, forming a solid conglomerate up to 5 cm in diameter. Lymph node biopsies were performed, followed by their examination at different reference centers (RPH, Moscow; Bureau for Pathology&Anatomy, St. Petersburg). EBV was detected there by means of PCR. Histological pattern corresponded to monomorphic (Moscow), or polymorphic PTLD (St. Petersburg).
In Fig. 2, the results obtained at the Pathology Laboratory in St. Petersburg (Chief, Dr. Yu. A. Krivolapov). A lymphoid tissue fragment exhibited a pattern of lost organ structure. The tissue consisted of diffuse lymphoid cell fields with detectable small and medium-sized lymphocytes, plasmoblasts
and immunoblasts, large atypical cells with giant, sometimes deformed nuclei with large homogenous nucleoli. Nearly all cells in the field have intensively basophilic cytoplasm
(Fig. 3). Mitotic figures are observed. Numerous necrotic foci are revealed, with nuclear fragments (karyorrhexis). Upon immunohistochemical study, vast majority of proliferating cells expressed CD79a (JCB117) and MuM1(Mum1p), with lesser amounts of CD20 (L26)- positive lymphoid cells (Fig. 4). Activated lymphoid cells expressed CD30 (Ber-H2) (Fig. 5). Immunoglobulin light lambda chain-expressing lymphoid cells prevailed over kappa-positive cells in the samples of proliferating tissues (Fig. 6, 7). Large deformed immunoblasts are found there, being both kappa- and lambda-positive. Their cytoplasm showed intensive expression of latent EBV membrane LMP-1(CS1-4) protein (Fig. 8). A proliferative KiS5 antigen was expressed in nuclei of ca. 70% of lymphoid cells. Few CD3+ T cells were seen (Fig. 9), with CD8(1A5) cells being prevalent over CD4(4B12)+ lymphocytes. The proliferating tissue did not contain detectable lymphoid cells expressing CALLA CD10 (56C6), or (ALK-1). Ziel-Nilsen Acid fast stain of slices with carbol fuchsin did not show acid-resistant bacteria. Staining with antibodies for M.bovis did not show this antigen. Clinical pattern of the disease, histological structure of lymphoid tissue under study, and immune histochemistry results correspond to polymorphic post-transplant lymphoproliferative disease.
Immunosuppression was discontinued as a first-line therapeutic measure, and treatment with Rituximab was started. Following 4 injections, clinical effect was not reached. Therefore, we undertook a second-line therapy which consisted of a single-block CHOP chemotherapy, which was complicated by enteroparesis. Within first days of chemotherapy, a decrease and softening of the lymph node conglomerate was registered, then followed by the tumor stabilization, with persisting febrile state.
We then started block A (Dexamethasone+Ifosfamide+Methotrexate, 1 g/m 2 over 24 h + Cytosar + Vepeside, without Vincristine, due to recently observed neuropathy), accompanied by combined anti-infectious therapy. Despite treatment, the neck conglomerate was enlarged, along with continuous febrility. However, EBV was not more detectable in blood by means of PCR. Hence, this case of EBV-associated PTLD was considered refractory. A third block of polychemotherapy was scheduled, as follows: Gemsar, 1 g/m 2 (days 1-6); Carboplatine, 200 mg/m 2 (days 2-5); Vepesid, 150 mg/m 2 (days 2-5); Dexamethasone, 6 mg/m 2 (days 1-6), followed by subsequent transfusion of donor hematopoietic cells (boost without conditioning): on day 3 after finishing therapy, the patient received СD34+ cells at a dose of 11х10 6 / kg, and CD3+ cells at a dose of 1х10 4 /kg. Two weeks later, the fever faded away, and hematopoiesis recovered. However, the boy showed signs of GvHD: dry skin, exfoliation, hyperpigmentation, weak itching. Nevertheless, a decision was taken to continue donor lymphocyte infusions (DLI). Three weeks after first lymphocyte infusion, a second DLI was performed (CD3+ cells, 5х10 4 /kg). Febrile state did resume, but the neck lymph node conglomerate was reduced in size, and hepatosplenomegaly retained. Liver enzyme markers became increased to 400 U/L (ALT and AST); alcaline phosphatase, to 1400 U/L). Toxic hepatitis was diagnosed, and hepatotoxic drugs were withdrawn. However, the condition
of patient became worse, i.e., loss of appetite and weight, enteric symptomes occurred, along with icterus and hepatosplenomegaly (liver +8 cm, spleen +2 cm). Blood biochemistry: total bilirubin of 84 mcmol/L; ALT, 1060 U/L, AST, 2217 U/L, alcaline phosphatase, 2630 U/L. Spot/papule eruptions developed at the the skin of head, trunk, as well as mucosal leukoplakia, and intestinal syndrome considered as grade 3 GvHD, with skin, mucosae, liver, intestinal tract lesions consequent to DLI. Corticosteroid treatment was resumed, at 2 mg/kg/day. As result, eruptions were entirely reduced, like as fever, vomitimg and nausea. However, fatigue, low appetite, intestinal syndrome, signs of sinusitis, lung and intestinal infections (cytomegaloviral and adenoviral colitis). The patient received massive combined antibacterial and antiviral therapy (Cydofovir), antifungal treatment.
PTLD features were still detectable in MRI: heterogenous, thickened, soft, contrast-accumulating tissue retained in nasopharinx area, posterior nasal passages; posterior oropharynx (more at right side) looks deformed, mandibular lymph nodes were enlarged on the right. A heterogenous soft tissue mass persisted in lateral part of neck (left side, 18х9х31 mm in size), containing highly dense inclusions (microcalcinates), without proven contrast accumulation. Later on, a volumic decrease in lymphoproliferative changes was noted.
One month later, glucocorticoids were gradually tapered and fully discontinued. Rapamycin was administered as a basic immunosuppressive drug, aiming for immunotherapy, along with gamma-Interferon (2 injections). Clinical condition of the patient remained quite severe being characterized by cachexia, fever, adynamia, graft hypofunction with transfusion demands and requirements for hematopoiesis stimulation. Remarkable cholestasis was also documented (total bilirubin, 256 mcmol/L (direct,162); ALT, 147 U/L; AST, 174 U/L; alcaline phosphatase, 1224 U/L; GGTP, 1372 U/L), like as hemosiderosis (ferritin, 46545 mcg/L).
From these data, we suggested a secondary hemophagocytic syndrome underlied by EBV infection in immunocompromised patient subjected to unrelated allo-HSCT. Dexamethasone therapy was started (10 mg/m 2 No12), Vepesid
(150 mg/m 2 twice a week). Fever was stopped, and the size of liver and spleen was diminished. However, infectiuos complications still progressed, along with hypoalbuminemia and oedemas. Antibacterial and accessory treatment was further modified. E.g., grafting of CD34+ cells (10х10 6 / kg) was performed, aiming for acceleration of hematopoiesis recovery. During the therapy, small positive changes were documented as decrease of febrile rises, reduced abdominal pains. IST was continued with Rapamycin, and substitutive IVIG transfusions at higher doses were performed, biphosphonates were also administered.
MRI of laryngo-pharyngeal area 8 months after starting PTLD therapy, showed that the right oropharinx, left nasal passages, and left cervical area retain soft tissue lesions; some features of lymphoproliferative lesions in maxillar sinus are also present. By the present, EBV viremia comprised 600 copies/mL, followed by increase to 4320 copies/mL. In parallel, CMV-viremia did also elevate. Therapy with EBV-specific lymphocytes from the same donor was scheduled.
During the waiting period, due to problems with breathing and swallowing, the mass in oropharynx was removed preceded by tracheostoma mounting. Clinical state remained
very severe due to infectious complications underlied by pancytopenia and cholestasis syndromes. A month later, the tracheostome was removed. Therapy with EBV-specific do-
nor cytotoxic lymphocytes was commenced (a total of five injections weekly). The therapy was associated with diminished lymph nodes, gradual improvement of blood counts, as well as slow decrease in liver toxicity markers, EBV viremia. Immune reconstitution seemed to proceed with time.
1.5 years after HSCT, there were no additional data for active PTLD (i.e., a year and 3 months after beginning the therapy), main problems concerned hepatic dysfunction and hepatosplenomegaly, along with liver fidrosis and hemochromatosis. The patient has received a long-term therapy with Budenofalk and Exjade. Subsequently, gradual recovery of somatic status was observed, the boy underwent regular control examinations, replacement therapy with IVIG. His state stabilized 2 years after HSCT. There retaine hepatosplenomegaly, slight increase in hepatic transaminases and alcaline phosphatase. Budenofalk was continued for 3 years. Age-dependent vaccination was performed. At the present time, 10 years after allogeneic HSCT, clinical state of the adolescent is satisfactory, he is learning and keeps active life.
The above clinical description demonstrates an extremely aggressive course of some PTLD cases, thus requiring rapid and precise actions from the doctors. The pathological process developed within typical terms (3 months after HSCT), in absence of immune reconstitution, and exhibited and manifested as an infectious condition with fever and lymphadenopathy. Despite limited localization (oropharynx and cervical regions), the disorder proved to be refractory and threatened with asphyxia at certain stage of disease. Appropriate diagnostics required combined diagnostic measures with dominating histochemical results. Despite a divergent interpretation of mono- or polymorphic lesions in the given EBV-associated PTLD, clinical course and somatic status of the patient determined a vitla demand for changes and careful selection of adequate therapy. One should note professionalism of the medical team, as well as precise actions, patience and insistence of the doctor that determined favorable outcome of this case which initially presented a life-threatening situation.
Meanwhile, the first case presented in Table 5 concerns fulminant course of EBV-PTLD. A 3-year old girl with acute lymphoblastic leukemia (ALL) was subject to allo-HSCT
from HLA-compatible, EBV-positive unrelated donor with partial CD34+ graft enrichment. EBV viremia in the patient was registered at 4 months posttransplant, reaching 12,000 copies/mL. A week later, the viremia was increased to 500,000 copies/mL, accompanied by fever; liver damage as documented by growth in transaminases, rising bilirubin; enlarged abdominal lymph nodes. After two Rituximab injections, no positive effect was reached, her condition deteriorated rapidly, and the patient died due to progressing hepatic and respiratory failure. Only three weeks passed since EBV viremia was registered in the girl. Two-week therapy with Rituximab proved to be without any effect. This type of EBV-PTLD (any histology data are not available, due to lacking autopsy) showed a quite aggressive and rapid course, thus preventing alternative therapeutic options. Other PTLD cases observed (see Table 5) depict more favorable variants of the disorder, with positive response to the IST reduction and Rituximab treatment. Interestingly, the patient No.6 developed EBV-associated PTLD despite EBV-seronegativity in his donor, may be, due to endogenous infection of donor cells from recipient.
Another unusual presentation of PTLD was connected with affection of central nervous system. However, there was no opportunity to perform stereotactic brain biopsy at the time of encephalitis manifestation. Later on, a biopsy did not reveal an initial cellular substrate. However, a marked response to Rituximab, e.g., its endolumbar injections, and to Methotrexate therapy are indicative for malignant origin of primary CNS lesions in the given patient.
A study of the second cohort of patients who received allo-HSCT from 2012 to 2016 at the NCPHOI has revealed only two EBV-PTLD cases among 911 children (Table 6).
This cohort was analysed separately, because the transplants were performed mostly by a novel protocol with a CD19 depletion and inclusion of Rituximab into the conditioning regimen. Among 483 patients after HSCT with alpha/beta depletion and CD19-negative selection, as well as among 316 children who received Rituximab, no single case of PTLD was registered. However, B cell depletion was not performed in the two belowmentioned cases: the first patient was grafted with umbilical blood from unrelated donor. The second patient received bone marrow from a sibling. Therefore, their conditioning regimens were classic, with Thymoglobulin application which is considered an accessory risk factor for PTLD. Description, of these 2 cases, PTLD manifestations and their treatment are seen from Table 6.
Table 6. Characteristics of the two patients with monomorphic B cell PTLD
These two cases also refer to aggressive and malignant clinical forms of PTLD. The first case concerned a girl with acutemyeloblastic leukemia following allografting and development of refractory acute and chronic GvHD without any options of immunotherapy. The B cell monomorphic PTLD did partially respond to Rituximab treatment. More active treatment modes were impossible, due to poor somatic condition of thefemale patient.
In the boy with aplastic anemia, we have documented all stages of EBV-PTLD emergence, including progression from EBV viremia and lymphadenopathy to mucosal lesions (bleeding gastric ulceration requiring partial stomach resection, tonsillar involvement) followed by outgrowth of parapharyngeal tumor mass. We were also able to confirm histologically a transition from polymorphic PTLD to monomorphic aggressive form being similar to malignant large-cell lymphoma by B cell origin (Fig. 10). Such clinical course is rarely described in details, both for clinical and histological pattern, hencethis case seems to be original, due to concordance between evolution of modifying pathological pattern and specific treatment mode. At the stage of EBV-associated lymphoadenopathy, a standard approach with Rituximab therapy was applied, however, without effect. This monomorphic PTLD was refractory to therapy with anti-CD20 antibodies. At the next stage, the EBV-PTLD proceeded as a malignant B cell large-cell lymphoma (Fig. 11), this requiring a highdose chemotherapy. In future, standard polychemotherapy proved to be insuffisient, and clinical effect was obtained only from combined chemotherapy, immune drugs and donor lymphocyte infusion. Nivolumab and Brentuximab were used as a pioneering approach to treatment of such condition. In both children, antibodies against IL-6 were also used with proven effect, in order to ameliorate clinical symptoms.
Figure 10. Pathomorphosis of PTLD in one patient.
а. hematoxylin and eosin stain; х10, х40. Early PTLD lymph node lesion. The loss of topographic structure, focuses of necrosis, polymorphic cell infiltrate with large EBV-positive cells.
b. hematoxylin and eosin stain; х10, х40. Polymorhic PTLD, mucocutaneous ulcer of the antral stomach. The mucose of the antral stomach with ulceration and a massive transmural infiltration of lamina propria. Polymorphic cell infiltrate with numerous EBV-positive large cells, plasmacytic cells and plasmoblasts, small CD3/CD8 reactive Т-lymphocytes.
c. hematoxylin and eosin stain; х20, х40. Monomorphic B-cell PTLD, diffuse large cell B-cell lymphoma. Monomorphic large cell infiltrate with the diffuse distribution among the muscled fibers. Cells with a high mytotic activity – immunoblasts and centroblasts.
Conclusion
Hence, PTLD is a challenging pathological process which lets a lot of open questions be answered by appropriate specialists. This complication still bears a risk of high mortality, thus requiring further activities for studying pathogenesis and treatment modes for PTLD. Multicenter research and clinical studies are necessary to evaluate this clinical entity. The PTLD therapy represents an excellent clinical model for combined application of immune therapy, cellular therapy, and standard cytostatic treatment of malignancies which may be used for treatment of other neoplasias and severe viral infections.
Conflict of interest
No conflict of interests is declared.
References
1. Andreone P, Gramenzi A, Lorenzini S, Biselli M, Cursaro C, Pileri S, Bernardi M. Posttransplantation lymphoproliferative disorders. Arch Intern Med. 2003;163(17):1997-2004.
2. Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stemcell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003 ; 21(7):1352-1358.
3. Blaes AH, Peterson BA, Bartlett N, Dunn DL, Morrison VA. Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial. Cancer. 2005;104(8):1661-1667.
4. Bollard CM, Rooney CM, Heslop HE. T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat Rev Clin Oncol. 2012 Sep;9(9):510-519.
5. Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, Wagner JE. Marked increased risk of Epstein-Barr virus-related complications with the addition of
antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood. 2006;108(8):2874-2880.
6. Chen W, Huang Q, Zuppan CW, Rowsell EH, Cao JD, Weiss LM, Wang J. Complete absence of KSHV/HHV-8 in posttransplant lymphoproliferative disorders: an immuno
histochemical and molecular study of 52 cases. Am J Clin Pathol. 2009;131(5):632-9.
7. Cockfield SM. Identifying the patient at risk for posttransplant lymphoproliferative disorder. Transpl Infect Dis. 2001 ; 3(2):70-78. Review.
8. Cohen J.I. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore), 1991;70:137–160.
9. Cohen JM, Cooper N, Chakrabarti S, Thomson K, Samarasinghe S, Cubitt D, Lloyd C, Woolfrey A, Veys P, Amrolia PJ. EBV-related disease following haematopoietic stem
cell transplantation with reduced intensity conditioning. Leuk Lymphoma. 2007;48(2):256-269.
10. Comoli P, Labirio M, Basso S, Baldanti F, Grossi P, Furione M, Viganò M, Fiocchi R, Rossi G, Ginevri F, Gridelli B, Moretta A, Montagna D, Locatelli F, Gerna G, Maccario
R. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood. 2002 ; 99(7):2592-2598.
11. Dierickx D, Tousseyn T, Gheysens O. How I treat posttransplant lymphoproliferative disorders. Blood. 2015;126(20):2274-2283.
12. Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, Brepoels L, Kuypers D, Vanhaecke J, Nevens F, Verleden G, Van Damme-Lombaerts R, Renard M, Pirenne J, De Wolf-Peeters C, Verhoef G. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymphoma. 2013;54(11):2433-2440. ford DH., et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360(9331):436-442.
13. Doubrovina E, Oflaz-Sozmen B, Prockop SE, Kernan NA, Abramson S, Teruya-Feldstein J, Hedvat C, Chou JF, Heller G, Barker JN, Boulad F, Castro-Malaspina H, George D, Jakubowski A, Koehne G, Papadopoulos EB, Scaradavou A, Small TN, Khalaf R, Young JW, O’Reilly RJ. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood. 2012;119(11):2644-2656. 24. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol. 1997;14(1):8-14.
14. Durandy A. Anti-B cell and anti-cytokine therapy for the treatment of post-transplant lymphoproliferative disorder: past, present, and future. Transpl Infect Dis. 2001;3(2):104-107.
15. Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, Olthoff KM, Schuster SJ, Nasta SD, Stadtmauer EA, Tsai DE. Treatment of PTLD with rituximab or
chemotherapy. Am J Transplant. 2006;6(3):569-576.
25. Hoover R.N. Lymphoma risks in populations with altered immunity – a search for mechanism. Cancer Res 1992; 52: 5477s.
26. Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues. In: World Health Organization Classification of Tumours, vol.3, Lyon, France: IARC Press, 2001:264-269.
27. Knowles DM, Cesarman E, Chadburn A. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphopro-
liferative disorders. Blood. 1995 ;85(2) :552-565.
16. Epstein-Barr virus and lymphoproliferative disorders after transplantation. [No authors listed] Am J Transplant. 2004; 4 (Suppl 10):59-65. 28. Krishnamurthy S, Hassan A, Frater JL, Paessler ME, Kreisel FH. Pathologic and clinical features of Hodgkin lymphoma-like posttransplant lymphoproliferative disease. Int J Surg Pathol. 2010; 18(4): 278-285.
17. Frizzera G, Hanto DW, Gajl-Peczalska KJ, Rosai J, McKenna RW, Sibley RK, Holahan KP, Lindquist LL. Polymorphic diffuse B-cell hyperplasias and lymphomas in renal
transplant recipients. Cancer Res. 1981;41(11, Pt 1):4262-4279. 29. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, Gandjbakhch I, Binet JL, Raphael M. Post-
transplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16(6):2052-2059.
18. Gong JZ, Bayerl MG, Sandhaus LM, Sebastian S, Rehder CW, Routbort M, Lagoo AS, Szabolcs P, Chiu J, Comito M, Buckley PJ. Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children. Am J Surg Pathol. 2006; 30(3): 328-336. 30. Liebowitz D. Epstein-Barr virus and a cellular signaling
pathway in lymphomas from immunosuppressed patients. N Engl J Med 1998; 338: 1413–1421.
19. Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annu Rev Med. 2005; 56:29-44.
20. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59-67.
21. Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG. Epstein-Barr virus (EBV) load in bone marrow trans-
plant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood. 2000;95(3):807-814.
22. Haddad E, Paczesny S, Leblond V, Seigneurin JM, Stern M, Achkar A, Bauwens M, Delwail V, Debray D, Duvoux C, Hubert P, Hurault de Ligny B, Wijdenes J, Durandy A, Fischer A. Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial. Blood. 2001;97(6):1590-1597.
23. Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A, Dombagoda D, Britton KM, Swerdlow AJ, Crawford DH., et al. Treatment of Epstein-Barr-virus-positive
post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360(9331):436-442.
24. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol. 1997;14(1):8-14.
25. Hoover R.N. Lymphoma risks in populations with altered immunity – a search for mechanism. Cancer Res 1992; 52: 5477s.
26. Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues. In: World Health Organization Classification of Tumours, vol.3, Lyon, France: IARC Press, 2001:264-269.
27. Knowles DM, Cesarman E, Chadburn A. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphopro-
liferative disorders. Blood. 1995 ;85(2) :552-565.
28. Krishnamurthy S, Hassan A, Frater JL, Paessler ME, Kreisel FH. Pathologic and clinical features of Hodgkin lymphoma-like posttransplant lymphoproliferative disease. Int J Surg Pathol. 2010; 18(4): 278-285.
29. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, Gandjbakhch I, Binet JL, Raphael M. Posttransplant lymphoproliferative disorders not associated
with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16(6):2052-2059.
32. Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant. 2003;31(3):145-155.
33. Lowe T., S.Bhatia, G.Somlo. Second malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007; 13:1121-1134.
34. Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, Porter DL, Vonderheide RH, Bagg A, Heitjan DF, Tsai DE, Reshef R. The impact of EBV status on characteristics and outcomes of posttransplantation lymphoproliferative disorder. Am J Transplant. 2015;15(10):2665-2673.
35. Mathur A, Kamat DM, Filipovich AH, Steinbuch M, Shapiro RS. Immunoregulatory abnormalities in patients with Epstein-Barr virus-associated B cell lymphoprolifera-
tive disorders. Transplantation. 1994; 57(7):1042-1045.
36. Morscio J, Dierickx D, Ferreiro JF, Herreman A, Van Loo P, Bittoun E, Verhoef G, Matthys P, Cools J, Wlodarska I, De Wolf-Peeters C, Sagaert X, Tousseyn T. Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders. Am J Transplant. 2013;13(5):1305-1316.
37. Morscio J, Tousseyn T. Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders. World J Transplant. 2016; 6(3):505-516. kin-like post-transplant lymphoproliferative disease. Pediatr Transplant. 2008;12(4):426-431.
38. Nalesnik M.A., L. Makowka, T.E. Starzl. The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg, 1988; 25: 367–472. 49. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, Heslop HE. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood. 1998; 92(5):1549-1555.
39. Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol. 1988;133(1):173-192.
40. Nelson BP, Nalesnik MA, Bahler DW, Locker J, Fung JJ, Swerdlow SH. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol. 2000;24(3):375-385.
41. Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Váry M, Babel N, Trappe RU, Jonas S, Hummel M, Anagnostopoulos I, Dörken B, Riess HB. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. 2005;5(12):2901-2906.
42. Orazi A, Hromas RA, Neiman RS, Greiner TC, Lee CH, Rubin L, Haskins S, Heerema NA, Gharpure V, Abonour R, Srour EF, Cornetta K. Posttransplantation lymphoproliferative disorders in bone marrow transplant recipients are aggressive diseases with a high incidence of adverse histologic and immunobiologic features. Am J Clin Pathol. 1997; 107:419–429.
43. Orazi A, Hromas RA, Neiman RS, Greiner TC, Lee CH, Rubin L, Haskins S, Heerema NA, Gharpure V, Abonour R, Srour EF, Cornetta K. Systemic inflammatory response syndrome after administration of unmodified T lymphocytes. Mol Ther. 2014 ;22(6):1134-1138.
44. Patriarca F, Medeot M, Isola M, Battista ML, Sperotto A, Pipan C, Toffoletti E, Dozzo M, Michelutti A, Gregoraci G, Geromin A, Cerno M, Savignano C, Rinaldi C, Barbone F, Fanin R. Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab. Transpl Infect Dis. 2013;15(3):259-267.
45. Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients.Transplant Proc. 1969; 1:106-112.
46. Pitman SD, Huang Q, Zuppan CW, Rowsell EH, Cao JD, Berdeja JG, Weiss LM, Wang J. Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically. Am J Surg Pathol. 2006 ;30(4):470-476.
47. Qu L, Xu S, Rowe D, Triulzi D. Efficacy of Epstein-Barr virus removal by leukoreduction of red blood cells. Transfusion. 2005;45(4):591-595.
48. Rohr JC, Wagner HJ, Lauten M, Wacker HH, Jüttner E, Hanke C, Pohl M, Niemeyer CM. Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodg-kin-like post-transplant lymphoproliferative disease. Pediatr Transplant. 2008;12(4):426-431.
49. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, Heslop HE. Infusion of cytotoxic T cells for the preven-
tion and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood. 1998; 92(5):1549-1555.
50. Rowlings PA, Curtis RE, Passweg JR, Deeg HJ, Socié G, Travis LB, Kingma DW, Jaffe ES, Sobocinski KA, Horowitz MM. Increased incidence of Hodgkin’s disease
after allogeneic bone marrow transplantation. J Clin Oncol. 1999;17(10):3122-3127.
51. Shapiro RS, McClain K, Frizzera G, Gajl-Peczalska KJ, Kersey JH, Blazar BR, Arthur DC, Patton DF, Greenberg JS, Burke B, et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood. 1988;71(5):1234-1243.
52. Snyder MJ, Stenzel TT, Buckley PJ, Lagoo AS, Rizzieri DA, Gasparetto C, Vredenburgh JJ, Chao NJ, Gong JZ. Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation. Am J Surg Pathol. 2004;28(6):794-800.
53. Socié G, Curtis RE, Deeg HJ, Sobocinski KA, Filipovich AH, Travis LB, Sullivan KM, Rowlings PA, Kingma DW, Banks PM, Travis WD, Witherspoon RP, Sanders J, Jaffe
ES, Horowitz MM. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18(2):348-357.
54. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BW Jr, Hardesty RL, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984; 1(8377):583-587.
55. Styczynski J, Reusser P, Einsele H, de la Camara R, Cordonnier C, Ward KN, Ljungman P, Engelhard D. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant. 2009;43(10):757-770.
56. Takehana CS, Twist CJ, Mosci C, Quon A, Mittra E, Iagaru A. (18)F-FDG PET/CT in the management of patients with post-transplant lymphoproliferative disorder. Nucl
Med Commun. 2014;35(3):276-281.
57. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithäuser M, Zimmer-
mann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S; German PTLD Study Group; European PTLD Network. Sequential treatment with rituximab followed by CHOP
chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012;13(2):196-206.
58. Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med. 2007;131(8):1209-1218.
59. Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O, Winiarski J, Ljungman P, Remberger M, Mattsson J. Risk factors for Epstein-Barr virus-related posttransplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99(2):346-352.
60. Wagner HJ, Cheng YC, Huls MH, Gee AP, Kuehnle I, Krance RA, Brenner MK, Rooney CM, Heslop HE. Prompt versus preemptive intervention for EBV lymphoproliferative disease. Blood. 2004;103(10):3979-3981.
61. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE, Jakubowski A. Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transplant.
2006;37(6):539-546.
62. Zallio F, Primon V, Tamiazzo S, Pini M, Baraldi A, Corsetti MT, Gotta F, Bertassello C, Salvi F, Rocchetti A, Levis A. Epstein-Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation. Clin Transplant. 2013;27(4):E491-497.
Ирина П. Шипицына1, Елена И. Гутовская1, Дина Д. Байдильдина1, Ирина И. Калинина1, Ульяна Н. Петрова1,
Андрей Б. Абросимов1, Светлана Н. Козловская1, Михаил А. Масчан1, Дмитрий М. Коновалов1,
Дмитрий С. Абрамов1, Галина В. Терещенко1, Александр Г. Румянцев1, Елена В. Самочатова1,
Галина А. Новичкова1, Алексей А. Масчан1
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Ключевые слова
Аллогенная трансплантация гемопоэтических стволовых клеток, посттрансплантационное лимфопролиферативное заболевание." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["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) "18117" ["VALUE"]=> string(36) "10.18620/ctt-1866-8836-2017-6-2-8-25" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(36) "10.18620/ctt-1866-8836-2017-6-2-8-25" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_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) "37" ["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) "18118" ["VALUE"]=> array(2) { ["TEXT"]=> string(941) "Yulia V. Skvortsova<sup>1</sup>, Dmitrij N. Balashov<sup>1</sup>, Larisa N. Shelikhova<sup>1</sup>, Elena V. Skorobogatova<sup>2</sup>, Yurij A. Krivolapov<sup>3</sup>,<br> Irina P. Shipitsina<sup>1</sup>, Elena I. Gutovskaya<sup>1</sup>, Dina D. Bajdildina<sup>1</sup>, Irina I. Kalinina<sup>1</sup>, Ulyana N. Petrova<sup>1</sup>, Andrej B. Abrosimov<sup>1</sup>,<br> Svetlana N. Kozlovskaya<sup>1</sup>, Michael A. Maschan<sup>1</sup>, Dmitrij M. Konovalov<sup>1</sup>, Dmitrij S. Abramov<sup>1</sup>, Galina V. Tereshenko<sup>1</sup>,<br> Alexander G. Rumyantsev<sup>1</sup>, Elena V. Samochatova<sup>1</sup>, Galina A. Novichkova<sup>1</sup>, Alexej A. Maschan<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(683) "Yulia V. Skvortsova1, Dmitrij N. Balashov1, Larisa N. Shelikhova1, Elena V. Skorobogatova2, Yurij A. Krivolapov3,Irina P. Shipitsina1, Elena I. Gutovskaya1, Dina D. Bajdildina1, Irina I. Kalinina1, Ulyana N. Petrova1, Andrej B. Abrosimov1,
Svetlana N. Kozlovskaya1, Michael A. Maschan1, Dmitrij M. Konovalov1, Dmitrij S. Abramov1, Galina V. Tereshenko1,
Alexander G. Rumyantsev1, Elena V. Samochatova1, Galina A. Novichkova1, Alexej A. Maschan1" ["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) "18119" ["VALUE"]=> array(2) { ["TEXT"]=> string(530) "<sup>1</sup> National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev;<br> Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia<br> <sup>2</sup> Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia<br> <sup>3</sup> State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», 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(476) "1 National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev;
Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia
2 Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia
3 State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», 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) "18120" ["VALUE"]=> array(2) { ["TEXT"]=> string(941) "Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology. <h3>Keywords</h3> Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder.<br> <br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(917) "Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology.
Keywords
Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder." 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Alexander G. Rumyantsev1, Elena V. Samochatova1, Galina A. Novichkova1, Alexej A. Maschan1" } ["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) "18120" ["VALUE"]=> array(2) { ["TEXT"]=> string(941) "Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology. <h3>Keywords</h3> Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder.<br> <br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(917) "Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology.
Keywords
Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder." ["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(917) "Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology.
Keywords
Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder." } ["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) "18117" ["VALUE"]=> string(36) "10.18620/ctt-1866-8836-2017-6-2-8-25" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(36) "10.18620/ctt-1866-8836-2017-6-2-8-25" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(36) "10.18620/ctt-1866-8836-2017-6-2-8-25" } ["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) "18121" ["VALUE"]=> string(162) "Posttransplant lymphoproliferative disorder in children after allogeneic hematopoietic stem cell transplantation: a single-center experience and literature review" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(162) "Posttransplant lymphoproliferative disorder in children after allogeneic hematopoietic stem cell transplantation: a single-center experience and literature review" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(162) "Posttransplant lymphoproliferative disorder in children after allogeneic hematopoietic stem cell transplantation: a single-center experience and literature review" } ["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) "18119" ["VALUE"]=> array(2) { ["TEXT"]=> string(530) "<sup>1</sup> National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev;<br> Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia<br> <sup>2</sup> Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia<br> <sup>3</sup> State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», 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(476) "1 National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev;
Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia
2 Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia
3 State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», 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(476) "1 National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev;
Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia
2 Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia
3 State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», St. Petersburg, Russia" } ["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) "18114" ["VALUE"]=> array(2) { ["TEXT"]=> string(1270) "Юлия В. Скворцова<sup>1</sup>, Дмитрий Н. Балашов<sup>1</sup>, Лариса Н. Шелихова<sup>1</sup>, Елена В. Скоробогатова<sup>2</sup>, Юрий А. Kриволапов<sup>3</sup>,<br> Ирина П. Шипицына<sup>1</sup>, Елена И. Гутовская<sup>1</sup>, Дина Д. Байдильдина<sup>1</sup>, Ирина И. Калинина<sup>1</sup>, Ульяна Н. Петрова<sup>1</sup>,<br> Андрей Б. Абросимов<sup>1</sup>, Светлана Н. Козловская<sup>1</sup>, Михаил А. Масчан<sup>1</sup>, Дмитрий М. Коновалов<sup>1</sup>,<br> Дмитрий С. Абрамов<sup>1</sup>, Галина В. Терещенко<sup>1</sup>, Александр Г. Румянцев<sup>1</sup>, Елена В. Самочатова<sup>1</sup>,<br> Галина А. Новичкова<sup>1</sup>, Алексей А. Масчан<sup>1</sup><br> <br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(994) "Юлия В. Скворцова1, Дмитрий Н. Балашов1, Лариса Н. Шелихова1, Елена В. Скоробогатова2, Юрий А. Kриволапов3,
Ирина П. Шипицына1, Елена И. Гутовская1, Дина Д. Байдильдина1, Ирина И. Калинина1, Ульяна Н. Петрова1,
Андрей Б. Абросимов1, Светлана Н. Козловская1, Михаил А. Масчан1, Дмитрий М. Коновалов1,
Дмитрий С. Абрамов1, Галина В. Терещенко1, Александр Г. Румянцев1, Елена В. Самочатова1,
Галина А. Новичкова1, Алексей А. Масчан1
" ["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(994) "Юлия В. Скворцова1, Дмитрий Н. Балашов1, Лариса Н. Шелихова1, Елена В. Скоробогатова2, Юрий А. Kриволапов3,
Ирина П. Шипицына1, Елена И. Гутовская1, Дина Д. Байдильдина1, Ирина И. Калинина1, Ульяна Н. Петрова1,
Андрей Б. Абросимов1, Светлана Н. Козловская1, Михаил А. Масчан1, Дмитрий М. Коновалов1,
Дмитрий С. Абрамов1, Галина В. Терещенко1, Александр Г. Румянцев1, Елена В. Самочатова1,
Галина А. Новичкова1, Алексей А. Масчан1
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Пусковым механизмом, как правило, служит первичная инфекция, вызванная Эпштейн-Барр вирусом, или реактивация вируса в иммунокомпрометированном организме. В зависимости от вида ПТЛПЗ и динамики его развития данная патология может быть фатальной для пациента. В данной статье описаны: клинико-морфологическая классификация, факторы риска, клинические особенности, диагностика и лечение ПТЛПЗ, а также приведен клинический опыт диагностики и лечения данного осложнения на базе отделений ТГСК РДКБ и ННПЦ ДГОИ.<br> <h3>Ключевые слова</h3> Аллогенная трансплантация гемопоэтических стволовых клеток, посттрансплантационное лимфопролиферативное заболевание." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1678) "Среди различных осложнений аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) одним из самых тяжелых является пострансплантационное лимфопролиферативное заболевание (ПТЛПЗ), проявляющееся неконтролируемой пролиферацией лимфоидной ткани. Пусковым механизмом, как правило, служит первичная инфекция, вызванная Эпштейн-Барр вирусом, или реактивация вируса в иммунокомпрометированном организме. В зависимости от вида ПТЛПЗ и динамики его развития данная патология может быть фатальной для пациента. В данной статье описаны: клинико-морфологическая классификация, факторы риска, клинические особенности, диагностика и лечение ПТЛПЗ, а также приведен клинический опыт диагностики и лечения данного осложнения на базе отделений ТГСК РДКБ и ННПЦ ДГОИ.
Ключевые слова
Аллогенная трансплантация гемопоэтических стволовых клеток, посттрансплантационное лимфопролиферативное заболевание." ["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(1678) "Среди различных осложнений аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) одним из самых тяжелых является пострансплантационное лимфопролиферативное заболевание (ПТЛПЗ), проявляющееся неконтролируемой пролиферацией лимфоидной ткани. Пусковым механизмом, как правило, служит первичная инфекция, вызванная Эпштейн-Барр вирусом, или реактивация вируса в иммунокомпрометированном организме. В зависимости от вида ПТЛПЗ и динамики его развития данная патология может быть фатальной для пациента. В данной статье описаны: клинико-морфологическая классификация, факторы риска, клинические особенности, диагностика и лечение ПТЛПЗ, а также приведен клинический опыт диагностики и лечения данного осложнения на базе отделений ТГСК РДКБ и ННПЦ ДГОИ.Ключевые слова
Аллогенная трансплантация гемопоэтических стволовых клеток, посттрансплантационное лимфопролиферативное заболевание." } ["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) "18115" ["VALUE"]=> array(2) { ["TEXT"]=> string(301) "<sup>1</sup> ФГБУ ННПЦ ДГОИ им. Дм. Рогачева МЗ РФ<br> <sup>2</sup> ФГБУ РДКБ МЗ РФ<br> <sup>3</sup> ГУЗ «Ленинградское областное патологоанатомическое бюро»" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(253) "1 ФГБУ ННПЦ ДГОИ им. Дм. Рогачева МЗ РФ2 ФГБУ РДКБ МЗ РФ
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Introduction
Over last decade, a fundamentally new treatment approach has been developed for chronic myeloid leukemia (CML) patients based on tyrosine kinase inhibition (TKI) concept. I.e., imatinib proved to be a targeted drug which acts directly on the chimeric BCR-ABL protein, thus interfering intracellular signaling cascade leading to abnormal cell growth in CML [9]. The TKI therapy allowed sufficient life prolongation of CML patients, decreased progression rates and improved quality of life [9, 15, 16, 28, 32, 38]. The 2 nd generation of the TKI’s (dasatinib, nilotinib, and bosutinib) have shown their efficiency in case of Imatinib resistance or intolerance.Despite such impressive results, around one-quarter of the patients do not achieve optimal response to imatinib, or loose therapeutic effect with time. CML resistance to imatinib is more common at advanced disease stages, rather than in chronic phase (CP) [9].
Insufficient response to imatinib treatment may caused by two mechanisms, i.e., BCR-ABL-dependent, or BCR-ABL-independent. The latter include, e.g., additional chromosomal aberrations, activation of BCR-ABL-independent signal pathways, excessive imatinib binding to blood transport proteins, or increased expression of MDR proteins [17]. Among BCR-ABL-dependent resistance, BCR-ABL mutations, as well as additional copies of the BCR-ABL chimeric gene should be mentioned [11, 19].
Point mutations of the BCR-ABL kinase domain are revealed in 30-45% of resistant patients, thus being a prevailing factor of imatinib therapy failure, more often detectable in patients with secondary resistance, and at the advanced stages of disease [14, 18, 24, 35]. Emergence of point mutations is connected with increased kinase activity of the BCR-ABL protein. New BCR-ABL mutations occur on basis of genomic instability determined by different mechanisms, e.g., effects of reactive oxygen species which induce oxidative stress to genetic material [33]. Among the BCR-ABL kinase domain (KD) mutations, the T315I mutation should be especially mentioned since it causes insensitivity of leukemic cells to both imatinib and 2 nd generation of TKIs (TKI2) [35, 3, 30, 33, 34, 37].
A treonine-to-isoleucine substitution at the position 315 of the functional kinase domain disturbs spatial binding of the functional ABL domain, thus causing loss of TKI-binding hydrogen bonds. Except of spatial obstacles, the T315I mutation is associated with lacking self-inhibitory regulatory mechanisms. This mutation is the only marker causing full resistance to imatinib, as well as other second-generation TKIs (nilotinib, dasatinib, bosutinib). This mutation is found at a rate of 12 to 20% among all KD mutations of BCR-ABL gene.
It is shown that the disease prognosis in T315I-positive CML is sufficiently worse than in cases with optimal response to TKI therapy. As shown by various authors, the overall survival (OS) and progression-free survival (PFS) among patients with T315I mutation is lower than in patients with optimal response to TKI, or patients with resistance to TKI in case of absence of T315I mutation [25]. The CML patients with T315I mutation have the median of PFS only 11.5 months and median for OS as 22.4 months since mutation emergence [26]. Bad prognosis and resistance to TKIs in such cases boosted development of novel drugs. Ponatinib is the only known TKI which showed clinical efficiency in T315I-positive CML patients. So far, however, this drug is not registered in Russian Federation.
Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is a real, available and recommended choice for the patients with T315I. There are several studies showing allo-HSCT efficiency in these patients. Velev et al. have reported some results of allo-HSCT from matched unrelated donors, or umbilical blood cells to 8 CML patients with T315I mutation. Five patients are alive, including three cases of complete molecular response (CMR), one, with complete cytogenetic response (CGR), and one, with hematological level of response (HR), with the median of observation time as 13 months[39].
According to Nicolini et al., a two-year OS in 64 patients with T315I mutation after allo-HSCT proved to be 59%, 67%, 30% и 25%, respectively, for chronic phase, acceleration phase (AP), blast crisis (BK), and Ph+ acute lymphoblastic leukemia in the allo-HSCT group., respectively, with the median observation time as 26 months. Most transplants were performed from fully matched unrelated donors and fully matched related donors [23].
The same group has published combined data from the Phase II PACE study and EBMT Register comparing ponatinib and allo-HSCT results. A total of 184 CML and Ph+ ALL patients with T315I mutation, at >18 years and older at any phase of disease, were included into the study. OS rates were sufficiently higher in the patients in CP receiving ponatinib, similar in AP for the both groups, and sufficiently increased in the patients with Ph+ BC [22].
A group of Chinese workers has published data on 22 allo-HSCTs, most of them (n=16) were performed from haploidentical related donors. The two-year relapse-free survival after allo-HSCT comprised 80%, 73%, an 0%, respectively, for CP, AP, and BC phase. The median time of follow-up was 17.3 months, 14 patients survived, including 13 with complete molecular response and 1 with extramedullary relapse. Hence, allo-HSCT from haploidentical related donor seems to be a therapeutic option for CML patients harboring T315I mutation. Generally, allo-HSCT from either type of transplant may provide long-term survival, without signs of minimal residual disease [41].
Moreover, in view of sufficient number of high-risk relapse CML patients, a role of early posttransplant TKI prophylaxis is considered. A number of appropriate studies was performed, including those of TKI2. For instance, Zeidner et al., using post-transplant TKI to prevent relapse have shown higher cumulative CMR rates and lower incidence of mortality [42]. Interestingly, TKI application is associated with lower incidence of extended chronic GVHD, probably, due to influence of TKI on platelet-derived growth factor receptor. Optimal dosage of TKI’s and duration of treatment are also under studies [1].
In case of inability to perform allo-HSCT, one may use Interferon–α (IFN) since its efficiency is shown in patients with
BCR-ABL T315I as well [8]. Major molecular response (MMR), and even CMR were registered in some patients with this mutation treated by means of combined therapy with TKI and IFN [4, 12, 13].
Hence, the aim of present study was to evaluate our results concerning different treatment modalities in CML patients with T315I mutation of BCR-ABL oncogene.
Patients and methods
A retrospective study was performed for 53 CML clinical cases with detectable Т315I mutation in BCR-ABL gene.Sixteen patients underwent allo-HSCT (repeated allo-HSCT was carried out in two cases). Thirty seven patients received only pharmacological therapy. To perform the study, we analyzed medical histories and outpatient cards of 16 CML patients who underwent allo-HSCT at the clinics of the R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation (RICOHT) at the First St. Petersburg State Medical University. Clinical data about patients who underwent pharmacological therapy only have been presented by The National Research Center for Hematology (n=17); Russian Research Institute of Hematology and Transfusiology (n=4), regional centers for hematology: Samara (n=2); Vologda (n=1), Orel (n=1), Penza (n=3), Chelyabinsk (n=1), Rostov (n=1), Bryansk (n=1), Murmansk (n=1), Stavropol (n=2), Volgograd (n=2), Astrakhan (n=1).The main clinical characteristics of the patients are presented in Table 1. In total, 53 patients were enrolled into the study, at a median age of 42 (13 to 75) years at diagnosis, or 47 (1576) years since the Т315I mutation was registered. Median time passed from starting therapy to revealing the mutation was 3.6 (0.4-10.6) years. The time period from detection of the Т315I marker to allo-HSCT was 236 (32 to 2189) days.
Table 1. Clinical characteristics of CML patients with Bcr/Abl Т315I mutation
Allo-HSCT and its outcomes. Four CML patients were in CP1 by the time of transplant. Seven patients were in CP2 phase (all the cases returned to CP after acceleration phase).
The acceleration phase of CML was established in 5 cases, and 2 patients were in blast crisis before HSCT. HLA-identical siblings were HSC donors in 7 cases, whereas unrelated HLA-matched do nors have been used for eleven transplants. 69% patients (n=11) received >2 TKI rounds before allo-HSCT.
A mean time from primary diagnosis to allo-HSCT was 39 (14-139) months; from the time of evolving mutation to allo-HSCT, 10 (2-38) months. EBMT score was as follows: 3-4 points, for 12 cases; 5 to 7 points, in 4 patients. Reduced-intensity conditioning regimens were used in 13 cases (81%). Mean observation time for the surviving patients comprised 48 (8-79) months. Seven patients of 16 are now alive. By the moment of allo-HSCT, 2 patients were in CP1; 4, in CP2; 1, in acceleration phase. All these patients are in deep molecular response, i.e., 3 patients, in 1 st response, and in 4 cases, the CMR was achieved after prophylactic TKI treatment. Causes of death in allo-HSCT group are as follows: progression of the disease in 3 cases; complications due to HSCT (primary non-engraftment; veno-occlusive disease of liver, sepsis). Overall survival (OS) for the transplanted patients proved to be 37% at 1 year, with a median observation time of 5 months (Fig. 1).
Drug therapy was performed in 37 cases (21 received TKI as monotherapy or in combination with other drugs, 16 were treated with hydroxyurea, α-interferon or chemotherapy). At present, mеdian observation time of the surviving patients is 81 months (53-250). Of the patients treated with chemotherapy, 18 patients of 37 remain alive. Six patients are in CP≥1, nine patients are in hematological remission. Overall 5-year survival of the CML patients with Т315I mutation constituted 42%, and 8-year survival was 31.6% (Fig. 2).
Statistical evaluation. Methods of descriptive stastistics involved calculation of mediane values and minimal/maximal ranges. Survival analysis was performed according to
Kaplan-Meier. Intergroup comparisons were carried out by means of a log-rank criterion. Regression analysis of survival was performed with a Cox model of proportional intensities. Multivariate regression analysis included the following factors and co-variates: age at the time of diagnosis, gender, disease phase at the beginning of therapy, stage of the disease at detection of the Т315I mutation, subsequent treatment mode (with/without allo-HSCT); time until the mutation has been detected. OS evaluation was performed from the date of mutation diagnosis (for entire group), and from the date of allo-HSCT (for the patients subjected to allo-HSCT) Analysis of progression-free and event-free survival was not performed. Lethality of all the patients could be interpreted as CML-associated (leukemia-caused death), or due to allo-HSCT complications (in HSCT patients). The differences were considered statistically significant by p ≤ 0.05. Deep molecular response meant BCR-ABL levels of <0.01% by IS, including negative results of PCR with ABL copies more than 10000.
Results
Comparative survival analysis for different disease phases showed that all the patients in blast crisis died during 1 st year after the mutation was been detected, with median survival of 1.3 months. Five-year and 8-year OS among patients in CP/AP constituted 46.6% and 35%, respectively (Fig. 3).According to the results of comparative analysis for the groups of allo-HSCT and drug therapy, (all disease phases included), the five-year OS comprise 42% for the both groups (р=0.7). The overall survival median in HSCT group was 2 years, and in the drug therapy group, 2.6 years (Fig. 4). Similar analysis performed for the patients beyond blast crisis by the moment of mutation evolved has yielded similar results, i.e., 5-year OS was 47% in both groups (2.1 years for allo-HSCT group compared to 2.8 years among patients receiving drug therapy).
Our study has revealed an interesting fact, i.e., OS parameters in the group after detection of T315I mutations (N=37) did not sufficiently differ between the subgroups with drug therapy with or without TKI. For the patient group which was not treated with TKI (N=14), and for the group who received TKI (including those with combined therapy, N=23), 5-year OS comprised, respectively, 46.7% and 42.1% (р=0.53). The median of overall survival after TKI-free therapy was 1 year, compared to 2.8 years in TKI-treated group (Fig. 5).
Multivariate analysis of multiple effects upon OS has shown that the only independent significant factor was the disease phase, i.e., blast crisis by the moment of mutation detection.
A total of five patients were at the BC phase by detection of the mutation. Two of them underwent HSCT, all the patients deceased (Table 2).
Table 2. Multifactorial analysis: effects of certain factors on the overall survival at the time of Т315I detection
Discussion
According to recommendations of the European LeukemiaNet (ELN, 2011), testing for BCR-ABL mutations by means of direct sequencing is obligatory in case of treatment failure. This analysis aims to deciffer nucleotide sequence of the kinase domain in cDNA product. The method includes RNA extraction from patients’ blood, reverse transcription getting complementary DNA (cDNA), amplification of the BCR/ABL kinase gene segment, followed by its sequencing [2]. This method allows to determine all the spectrum of the kinase domain mutations with a sensitivity of 15-20%.To detect a transcript bearing T315I mutation, as well for quantitative evaluation of the mutant/wild-type clone ratio, the AC PCR is used. This approach is highly sensitive, thus allowing to find minor subclones which are undetectable by direct desequencing. АС PCR enables dynamic studies of the mutant clone, e.g., for evaluation or prediction of the treatment efficiency [41]. A minimal presence of the BCR-ABL T315I clone (≥10-5 against GUS) could be an unfavorable sign for achievement of major molecular response in imatyinib-resistant patients receiving TKI2 (nilotinib or dasatinib) [20].
Another sensitive technique for the diagnostics of mutations is a novel method of deep sequencing (ultra-deep sequencing, UDS), which allows to detect mutant subclones at a range of 1 to 15% in the cell populations which may be of clinical significance for resistance diagnostics but cannot be detected by means of direct sequencing [36].
Despite ELN recommendations on direct sequencing method as an optimal approach to searching BCR/ABL mutations, more precise techniques seem to be available in the nearest future, due to discovery and clinical studies of novel, highly efficient drugs. Allo-HSCT is known to be an effective mode to treat T315I-positive CML.
Therefore, let us briefly discuss the prospectives of drug therapy and future therapeutic approaches to this category of the patients. E.g., ponatinib (AP24534, IclusigTM) provided a new approach to therapy of CML positive for BCR-ABL T315I . This TKI inhibits several kinase targets, being active in cases of T315I mutation and multiple mutations in the BCR-ABL kinase domain. This compound does not form hydrogen links with T315 in the kinase domain of BCR-ABL, due to incorporation of vinyl and ethyl bonds into the inhibitor nucleotides, thus it does not prevent its spatial binding to the protein [29].
The data on 2-year observations concerning efficiency and safety of ponatinib at a dose of 45 mg/day were published in 2013 as a 2 nd phase of PACE clinical study. The study included 449 patients. Among them 227 patients with CP CML were under study being resistant/intolerable to previous therapy with TKI, including patients with T315I mutation. In this subgroup of pre-treated patients with failure of several lines of therapy, 58% patients received >3 TKI at preceding treatment rounds. Mean total terms of the previous comprised 6 (0.3 to 28) years. According to the data from 2-year observation, 46% of the patients still remained in the PACE study, of them 60% CML patients were in chronic phase. The rates of PFS and OS in the CP patients made 80% (a median of 27 months), and 94% (median, 12 mo); PFS and OS in patients with blast crisis comprised 18% (a median of 4 mo), and 30% (a median of 7 mo.). Among CML group, most patients with CP retained the response until 12 months, i.e., 91%, 91% and 75% of the patients presented with, respectively, MCyR, complete cytogenetic response, or MMR [16]. Moreover, the studies report on increased cumulative frequency of serious arterial thrombotic complications associated with ponatinib treatment [5, 27].
Omacetaxin/Homoharringtonin (Synribo®) was another drug approved by FDA (USA Food and Drug Administration) for CML cases resistant to ≥2 TKIs. According to the II phase clinical trials in patients with T315I mutation and failure of TKI therapy, 48 of 62 patients in CP (77%) have achieved complete hematological response, whereas 10 (16%) achieved complete cytogenetic response[6].
Among experimental compounds acceptable for T315I-positive CML therapy, one may suggest PF-114 which now undergoes 1 st phase of clinical trials. The drug is a TKI which is targeted for BCR-ABL. Efficiency of this molecule is in vitro shown using resistant mutant cell lines (Y253F, E255K, T315I, F317L). A range of suppressible tyrosine kinases (27 species with PF-114, as compared to 80 with ponatinib) reflects its higher selectivity thus reducing probability of potential in vivo adverse effects [21]. The most discussed and prospective ABL001 compound which is also under Phase 1 of clilnical trials. Early proofs are presented for its clinical efficiency towards mutations causing TKI resistance (V299L,
F317L, Y253H). Allosteric BCR-ABL1 inhibition represents another promising therapeutic approach to therapy of CML patients [31].
Conclusion
Targeted therapy in CML sufficiently increases life expectance of the patients, causing marked malignancy reduction to undetectable levels of molecular response. So far, however, the issues of resistance remain unresolved despite TKI2 introduction. Development of clones bearing T315I mutation in resistant CML changes prognosis for the given cohort of patients since it makes impossible a target effect upon leukemia cells. This problem required improvement of novel molecular diagnostics, as well as development of new molecules efficient in BCR-ABL T315I –positive patients.Currently, T315I positivity is an absolute indication for allogeneic bone marrow transplantation. Along with HLAmatched related or unrelated donors, related haploidentical donors may be also considered. Achievement of deep molecular remission is an evident advantage of allo-HSCT in these cases.
Our results suggest that pharmacological treatment is acceptable, if T315I mutation is revealed at chronic phase of the disease. However, there is no evidence that imatinib or TKI2 continuation will lead to the mutant clone selection, increased BCR-ABL T315I expression and further progression of the disease. Treatment of CML blast crisis seems to be ineffective, using both pharmacological therapy, and allo-HSCT approaches. Hence, therapeutic choice after the T315I detection should be based on risk factors, with CML stage being of major importance.
We need long-range observations of large patient cohorts using highly sensitive T315I detection techniques, in order to study its biological characteristics (role for CML progression, proliferative activity etc.) and to develop optimal therapeutic strategy.
Introduction of novel effective approaches to clinical practice will allow to reduce the number of patients with TKI resistance and to improve general therapeutic effect.
Conflicts of interest
No conflict of interest is declared.Funding sources
The study did not have any sponsor support.References
1. Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21 st century. Blood. 2015;125(21):3230-3235.2. Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002 ;99(9):3472-3475.
3. Corbin AS, Buchdunger E, Pascal F, Druker BJ. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem 2002; 277:32214–32219.
4. Cornelison AM, Welch MA, Koller C, Jabbour E. Dasatinib combined with Interferon-alfa induces a complete cytogenetic response and major molecular response in a patient with chronic myelogenous leukemia harboring the T315I BCR-ABL1 mutation. Clin Lymphoma Myeloma Leuk. 2011 Jun;11 Suppl 1:S111-3.
5. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M,
Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New Engl J Med. 2013;369:1783-1796.
6. Cortes, J.H. Lipton, D. Rea, R. Digumarti, C. Chuah, N. Nanda et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase
CML with T315I mutation. Blood 2012;120: 2573–2580.
7. Cortes JE, Kim D-W, Pinilla-Ibarz J, D le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio JF, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Passerini CG, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Goldman JM, Shah NP,Kantarjian HM. Ponatinib in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 2-year follow-up of the PACE trial. Blood. 2013; 122:650.
8. de Lavallade H, Khorashad JS, Davis HP, Milojkovic D, Kaeda, JS, Goldman JM, et al. Interferon-alpha or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation. Blood. 2007;110: 2779–2780.
9. Goldman J, Melo J. Chronic myeloid leukemia advances in biology and new approaches to treatment. N Engl J Med. 2003; 349: 1451–1464.
10. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
Science. 2001; 293:876–880.
11. Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16, 2190–2196.
12. Ilander M, Koskenvesa P, Hernesniemi S, Lion T, Porkka K, Mustjoki S. Induction of sustained deep molecular response in a patient with chronic-phase T315I-mutated chronic myeloid leukemia with interferon-α monotherapy. Leuk Lymphoma. 2014; 55(4):934-937.
13. Itonaga H, Tsushima H, Hata T, Matsuo E, Imanishi D, Imaizumi Y, Kawaguchi Y, Fukushima T, Doi Y, Mori S, Kamihira S, Tomonaga M, Miyazaki Y. Successful treatment of a chronicphase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa. Int J Hematol. 2012; 95:209–213.
14. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, Zhou X, Luthra R, Garcia-Manero G, Giles F, Rios MB, Verstovsek S, Cortes J. Frequency and clinical signifi-
cance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia (2006) 20, 1767–1773.
15. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O’Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N.Engl. J. Med. 2002; 346: 645–652.
16. Kantarjian HM, Cortes JE, O’Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Jeha S, Rios MB, Letvak L, Bochinski K, Arlinghaus R, Talpaz M. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogeno us leukemia: high incidence of early complete and major cytogenetic responses. Blood 2003; 101: 97–100.
17. Kantarjian HM, Talpaz M, Giles F, O’Brien S, Cortes J. New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance, Mechanisms of resistance to imatinib in chronic myeloid leukaemia Ann Intern Med. 2006;145(12):913-923.
18. Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008; 26 (29) 4806-13.
19. Kutsev S.I., Mordanov S.V. Amplification of the BCR-ABL gene in patients with chronic myeloid leukemia, refractory to imatinib. Oncohematology 2009; 3: 23-26.(In Russian).
20. Lange T, Ernst T, Gruber FX, Maier J, Cross M, Müller M, Niederwieser D, Hochhaus A, Pfirrmann M. The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia. Haematologica. 2013 May; 98(5): 714–717.
21. Mian AA, Rafiei A, Metodieva A, Haberbosch I, Zeifman A, Titov I, Stroylov V, Stroganov O, Novikov F, Chilov G, Ottmann OG, Ruthardt M. PF-114, a novel selective pan-BCR/ABL inhibitor targets the T315I and suppress models of advanced Ph+ ALL. Blood. 2013; 122: 21 3907
22. Nicolini FE, Basak GW, Kim D-W, Olavarria E, Pinilla-Ibarz J, Apperley JF, Hughes TP, Niederwieser D, Mauro MJ, Chuah C, Hochhaus A, Martinelli G, DerSarkissian M, Kageleiry A, Yang M, Huang H, McGarry LJ, Kantarjian HM, Cortes JE. The impact of ponatinib versus allogeneic stem cell transplant (SCT) on outcomes in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the T315I mutation, Abstract 480,57th Annual Meeting ASH, 2015
23. Nicolini FE, Basak GW, Soverini S, Martinelli G, Mauro MJ, Müller MC, Hochhaus A, Chuah C, Dufva IH, Rege-Cambrin G, Saglio G, Michallet M, Labussière H, Morisset S, Hayette S, Etienne G, Olavarria E, Zhou W, Peter S, Apperley JF, Cortes J. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood. 2011; 118 (20): 5697-5700.
24. Nicolini FE, Corm S, Lê QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M, Facon T, Mahon FX, Cayuela JM, Rousselot P, Michallet M, Preudhomme C,
Guilhot F, Roche-Lestienne C. Mutation status of 89 imatinib mesylate resistant chronic myelogenous leukemia patients and clinical outcome. A retrospective analysis from the french intergroup of CML (Fi(phi)-LMC group). 2006, Leukemia 20:1061–1066.
25. Nicolini FE, Corm S, Lê QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M, Facon T, Mahon FX, Cayuela JM, Rousselot P, Michallet M, Preudhomme C, Guilhot F, Roche-Lestienne C. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006;20(6):1061-1066.
26. Nicolini FE, Mauro MJ, Martinelli G, Kim DW, Soverini S, Müller MC, Hochhaus A, Cortes J, Chuah C, Dufva IH, Apperley JF, Yagasaki F, Pearson JD, Peter S, Sanz Rodriguez
C, Preudhomme C, Giles F, Goldman JM, Zhou W. Epidemiologic study on survival of chronic myeloid leukemia and Ph( + ) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation . Blood 2009; 114: 5271 – 5278.
27. O’Brien S, Radich JP, Abboud CN, Akhtari M, Altman JK, Berman E, Curtin P, DeAngelo DJ, Deininger M, Devine S, Fathi AT, Gotlib J, Jagasia M, Kropf P, Moore JO, Pallera A, Reddy VV, Shah NP, Smith BD, Snyder DS, Wetzler M, Gregory K, Sundar H. Chronic myelogenous leukemia, version 1.2015. J Natl Compr Canc Netw. 2014;12(11):1590-1610.
28. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J,
Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348: 994–1004.
29. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning
Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a Pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009; 16(5): 401–412.
30. O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, Druker BJ. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS- 354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005; 65: 4500–4505.
31. Ottmann OG, Alimena G, DeAngelo DJ, Goh Y-T, Heinrich MC, Hochhaus A, Hughes TP, Mahon F-X, Mauro MJ, Minami H, Nguyen MH, Rea D, Steegmann JL, Chatterjee A, Iyer V, Martinez N, Vanasse GJ, Dong-Wook K. ABL001, a potent, allosteric inhibitor of BCR-ABL, exhibits safety and promising single- agent activity in a phase I study of patients with CML with failure of prior TKI therapy. Abstract 138, 57 th Annual Meeting ASH, 2015.
32. Peggs K, Mackinnon S. Imatinib mesylate – the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med. 2003; 348: 1048–1050.
33. Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T, Greenfield EA, Salgia R, Griffin JD. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem. 2000; 275(32): 24273–24278.
34. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase
inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125. P, Binotto G, Giannini B, Kohlmann A, Haferlach T, Roller A, Rosti G, Cavo M, Baccarani M, Martinelli G. Unraveling the complexity of tyrosine kinase inhibitor–resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood, 2013; 122(9): 1634-1648.
37. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alberti D, Pane F, Saglio G, Baccarani M. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J. Clin. Oncol. 2005; 23: 4100–4109.
38. Turkina A.G., Khoroshko N.D., Druzhkova G.A., Zingerman В.V., Zakharova E.S., Chelysheva E. Yu., Vinogradova O. Yu., Domracheva E.V., Zakharova A.V., Kovaleva L.G., Kolosheinova T.I., Kolosova L. Yu., Zkuravleva V.S., Tikhonova L. Yu. Therapeutic efficacy of Imatinib Mesilate (Gliveс) in chronic phase of myeloid leukemia.Ter Arkhiv 2003; 75(8):
62-67. (In Russian).
39. Velev N, Cortes J, Champlin R, Jones D, Rondon G, Giralt S, Borthakur G, Kantarjian HM, De Lima M. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer. 2010;116:3631-3637.
40. Wongboonma W, Thongnoppakhun W, Auewarakul CU. A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients. J Hematol Oncol. 2011 Feb 8;4:7. doi: 10.1186/1756-8722-4-7.
41. Xu LP, Xu ZL, Zhang XH, Chen H, Chen YH, Han W, Chen Y, Wang FR, Wang JZ, Wang Y, Yan CH, Mo XD, Liu KY, Huang XJ. Allogeneic stem cell transplantation for patients with T315I BCR-ABL mutated chronic myeloid leukemia. Biol Blood Marrow Transplant. 2016;22(6):1080-1086.
42. Zeidner JF, Zahurak M, Rosner GL, Gocke CD, Jones RJ, Smith D. The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation: Can tyrosine kinase inhibitors replace donor lymphocyte infusions. Leuk Lymphoma. 2015; 56(1): 128–134.
35. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, Iacobucci I, Amabile M, Abruzzese E, Orlandi E, Radaelli F, Ciccone F, Tiribelli M, di Lorenzo R, Caracciolo C, Izzo B, Pane F, Saglio G, Baccarani M, Martinelli G. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12:7374-7379.
36. Soverini S, De Benedittis C, Machova Polakova K, Brouckova A, Horner D, Iacono M, Castagnetti F, Gugliotta G, Palandri F, Papayannidis C, Iacobucci I, Venturi C, Bochicchio MT, Klamova H, Cattina F, Russo D, Bresciani P, Binotto G, Giannini B, Kohlmann A, Haferlach T, Roller A, Rosti G, Cavo M, Baccarani M, Martinelli G. Unraveling the complexity of tyrosine kinase inhibitor–resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood, 2013; 122(9): 1634-1648.
37. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alberti D, Pane F, Saglio G, Baccarani M. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J. Clin. Oncol. 2005; 23: 4100–4109.
38. Turkina A.G., Khoroshko N.D., Druzhkova G.A., Zingerman В.V., Zakharova E.S., Chelysheva E. Yu., Vinogradova O. Yu., Domracheva E.V., Zakharova A.V., Kovaleva L.G., Kolosheinova T.I., Kolosova L. Yu., Zkuravleva V.S., Tikhonova L. Yu. Therapeutic efficacy of Imatinib Mesilate (Gliveс) in chronic phase of myeloid leukemia.Ter Arkhiv 2003; 75(8):
62-67. (In Russian).
39. Velev N, Cortes J, Champlin R, Jones D, Rondon G, Giralt S, Borthakur G, Kantarjian HM, De Lima M. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer. 2010;116:3631-3637.
40. Wongboonma W, Thongnoppakhun W, Auewarakul CU. A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients. J Hematol Oncol. 2011 Feb 8;4:7. doi: 10.1186/1756-8722-4-7.
41. Xu LP, Xu ZL, Zhang XH, Chen H, Chen YH, Han W, Chen Y, Wang FR, Wang JZ, Wang Y, Yan CH, Mo XD, Liu KY, Huang XJ. Allogeneic stem cell transplantation for patients with T315I BCR-ABL mutated chronic myeloid leukemia. Biol Blood Marrow Transplant. 2016;22(6):1080-1086.
42. Zeidner JF, Zahurak M, Rosner GL, Gocke CD, Jones RJ, Smith D. The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation: Can tyrosine kinase inhibitors replace donor lymphocyte infusions. Leuk Lymphoma. 2015; 56(1): 128–134.
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Introduction
Over last decade, a fundamentally new treatment approach has been developed for chronic myeloid leukemia (CML) patients based on tyrosine kinase inhibition (TKI) concept. I.e., imatinib proved to be a targeted drug which acts directly on the chimeric BCR-ABL protein, thus interfering intracellular signaling cascade leading to abnormal cell growth in CML [9]. The TKI therapy allowed sufficient life prolongation of CML patients, decreased progression rates and improved quality of life [9, 15, 16, 28, 32, 38]. The 2 nd generation of the TKI’s (dasatinib, nilotinib, and bosutinib) have shown their efficiency in case of Imatinib resistance or intolerance.Despite such impressive results, around one-quarter of the patients do not achieve optimal response to imatinib, or loose therapeutic effect with time. CML resistance to imatinib is more common at advanced disease stages, rather than in chronic phase (CP) [9].
Insufficient response to imatinib treatment may caused by two mechanisms, i.e., BCR-ABL-dependent, or BCR-ABL-independent. The latter include, e.g., additional chromosomal aberrations, activation of BCR-ABL-independent signal pathways, excessive imatinib binding to blood transport proteins, or increased expression of MDR proteins [17]. Among BCR-ABL-dependent resistance, BCR-ABL mutations, as well as additional copies of the BCR-ABL chimeric gene should be mentioned [11, 19].
Point mutations of the BCR-ABL kinase domain are revealed in 30-45% of resistant patients, thus being a prevailing factor of imatinib therapy failure, more often detectable in patients with secondary resistance, and at the advanced stages of disease [14, 18, 24, 35]. Emergence of point mutations is connected with increased kinase activity of the BCR-ABL protein. New BCR-ABL mutations occur on basis of genomic instability determined by different mechanisms, e.g., effects of reactive oxygen species which induce oxidative stress to genetic material [33]. Among the BCR-ABL kinase domain (KD) mutations, the T315I mutation should be especially mentioned since it causes insensitivity of leukemic cells to both imatinib and 2 nd generation of TKIs (TKI2) [35, 3, 30, 33, 34, 37].
A treonine-to-isoleucine substitution at the position 315 of the functional kinase domain disturbs spatial binding of the functional ABL domain, thus causing loss of TKI-binding hydrogen bonds. Except of spatial obstacles, the T315I mutation is associated with lacking self-inhibitory regulatory mechanisms. This mutation is the only marker causing full resistance to imatinib, as well as other second-generation TKIs (nilotinib, dasatinib, bosutinib). This mutation is found at a rate of 12 to 20% among all KD mutations of BCR-ABL gene.
It is shown that the disease prognosis in T315I-positive CML is sufficiently worse than in cases with optimal response to TKI therapy. As shown by various authors, the overall survival (OS) and progression-free survival (PFS) among patients with T315I mutation is lower than in patients with optimal response to TKI, or patients with resistance to TKI in case of absence of T315I mutation [25]. The CML patients with T315I mutation have the median of PFS only 11.5 months and median for OS as 22.4 months since mutation emergence [26]. Bad prognosis and resistance to TKIs in such cases boosted development of novel drugs. Ponatinib is the only known TKI which showed clinical efficiency in T315I-positive CML patients. So far, however, this drug is not registered in Russian Federation.
Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is a real, available and recommended choice for the patients with T315I. There are several studies showing allo-HSCT efficiency in these patients. Velev et al. have reported some results of allo-HSCT from matched unrelated donors, or umbilical blood cells to 8 CML patients with T315I mutation. Five patients are alive, including three cases of complete molecular response (CMR), one, with complete cytogenetic response (CGR), and one, with hematological level of response (HR), with the median of observation time as 13 months[39].
According to Nicolini et al., a two-year OS in 64 patients with T315I mutation after allo-HSCT proved to be 59%, 67%, 30% и 25%, respectively, for chronic phase, acceleration phase (AP), blast crisis (BK), and Ph+ acute lymphoblastic leukemia in the allo-HSCT group., respectively, with the median observation time as 26 months. Most transplants were performed from fully matched unrelated donors and fully matched related donors [23].
The same group has published combined data from the Phase II PACE study and EBMT Register comparing ponatinib and allo-HSCT results. A total of 184 CML and Ph+ ALL patients with T315I mutation, at >18 years and older at any phase of disease, were included into the study. OS rates were sufficiently higher in the patients in CP receiving ponatinib, similar in AP for the both groups, and sufficiently increased in the patients with Ph+ BC [22].
A group of Chinese workers has published data on 22 allo-HSCTs, most of them (n=16) were performed from haploidentical related donors. The two-year relapse-free survival after allo-HSCT comprised 80%, 73%, an 0%, respectively, for CP, AP, and BC phase. The median time of follow-up was 17.3 months, 14 patients survived, including 13 with complete molecular response and 1 with extramedullary relapse. Hence, allo-HSCT from haploidentical related donor seems to be a therapeutic option for CML patients harboring T315I mutation. Generally, allo-HSCT from either type of transplant may provide long-term survival, without signs of minimal residual disease [41].
Moreover, in view of sufficient number of high-risk relapse CML patients, a role of early posttransplant TKI prophylaxis is considered. A number of appropriate studies was performed, including those of TKI2. For instance, Zeidner et al., using post-transplant TKI to prevent relapse have shown higher cumulative CMR rates and lower incidence of mortality [42]. Interestingly, TKI application is associated with lower incidence of extended chronic GVHD, probably, due to influence of TKI on platelet-derived growth factor receptor. Optimal dosage of TKI’s and duration of treatment are also under studies [1].
In case of inability to perform allo-HSCT, one may use Interferon–α (IFN) since its efficiency is shown in patients with
BCR-ABL T315I as well [8]. Major molecular response (MMR), and even CMR were registered in some patients with this mutation treated by means of combined therapy with TKI and IFN [4, 12, 13].
Hence, the aim of present study was to evaluate our results concerning different treatment modalities in CML patients with T315I mutation of BCR-ABL oncogene.
Patients and methods
A retrospective study was performed for 53 CML clinical cases with detectable Т315I mutation in BCR-ABL gene.Sixteen patients underwent allo-HSCT (repeated allo-HSCT was carried out in two cases). Thirty seven patients received only pharmacological therapy. To perform the study, we analyzed medical histories and outpatient cards of 16 CML patients who underwent allo-HSCT at the clinics of the R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation (RICOHT) at the First St. Petersburg State Medical University. Clinical data about patients who underwent pharmacological therapy only have been presented by The National Research Center for Hematology (n=17); Russian Research Institute of Hematology and Transfusiology (n=4), regional centers for hematology: Samara (n=2); Vologda (n=1), Orel (n=1), Penza (n=3), Chelyabinsk (n=1), Rostov (n=1), Bryansk (n=1), Murmansk (n=1), Stavropol (n=2), Volgograd (n=2), Astrakhan (n=1).The main clinical characteristics of the patients are presented in Table 1. In total, 53 patients were enrolled into the study, at a median age of 42 (13 to 75) years at diagnosis, or 47 (1576) years since the Т315I mutation was registered. Median time passed from starting therapy to revealing the mutation was 3.6 (0.4-10.6) years. The time period from detection of the Т315I marker to allo-HSCT was 236 (32 to 2189) days.
Table 1. Clinical characteristics of CML patients with Bcr/Abl Т315I mutation
Allo-HSCT and its outcomes. Four CML patients were in CP1 by the time of transplant. Seven patients were in CP2 phase (all the cases returned to CP after acceleration phase).
The acceleration phase of CML was established in 5 cases, and 2 patients were in blast crisis before HSCT. HLA-identical siblings were HSC donors in 7 cases, whereas unrelated HLA-matched do nors have been used for eleven transplants. 69% patients (n=11) received >2 TKI rounds before allo-HSCT.
A mean time from primary diagnosis to allo-HSCT was 39 (14-139) months; from the time of evolving mutation to allo-HSCT, 10 (2-38) months. EBMT score was as follows: 3-4 points, for 12 cases; 5 to 7 points, in 4 patients. Reduced-intensity conditioning regimens were used in 13 cases (81%). Mean observation time for the surviving patients comprised 48 (8-79) months. Seven patients of 16 are now alive. By the moment of allo-HSCT, 2 patients were in CP1; 4, in CP2; 1, in acceleration phase. All these patients are in deep molecular response, i.e., 3 patients, in 1 st response, and in 4 cases, the CMR was achieved after prophylactic TKI treatment. Causes of death in allo-HSCT group are as follows: progression of the disease in 3 cases; complications due to HSCT (primary non-engraftment; veno-occlusive disease of liver, sepsis). Overall survival (OS) for the transplanted patients proved to be 37% at 1 year, with a median observation time of 5 months (Fig. 1).
Drug therapy was performed in 37 cases (21 received TKI as monotherapy or in combination with other drugs, 16 were treated with hydroxyurea, α-interferon or chemotherapy). At present, mеdian observation time of the surviving patients is 81 months (53-250). Of the patients treated with chemotherapy, 18 patients of 37 remain alive. Six patients are in CP≥1, nine patients are in hematological remission. Overall 5-year survival of the CML patients with Т315I mutation constituted 42%, and 8-year survival was 31.6% (Fig. 2).
Statistical evaluation. Methods of descriptive stastistics involved calculation of mediane values and minimal/maximal ranges. Survival analysis was performed according to
Kaplan-Meier. Intergroup comparisons were carried out by means of a log-rank criterion. Regression analysis of survival was performed with a Cox model of proportional intensities. Multivariate regression analysis included the following factors and co-variates: age at the time of diagnosis, gender, disease phase at the beginning of therapy, stage of the disease at detection of the Т315I mutation, subsequent treatment mode (with/without allo-HSCT); time until the mutation has been detected. OS evaluation was performed from the date of mutation diagnosis (for entire group), and from the date of allo-HSCT (for the patients subjected to allo-HSCT) Analysis of progression-free and event-free survival was not performed. Lethality of all the patients could be interpreted as CML-associated (leukemia-caused death), or due to allo-HSCT complications (in HSCT patients). The differences were considered statistically significant by p ≤ 0.05. Deep molecular response meant BCR-ABL levels of <0.01% by IS, including negative results of PCR with ABL copies more than 10000.
Results
Comparative survival analysis for different disease phases showed that all the patients in blast crisis died during 1 st year after the mutation was been detected, with median survival of 1.3 months. Five-year and 8-year OS among patients in CP/AP constituted 46.6% and 35%, respectively (Fig. 3).According to the results of comparative analysis for the groups of allo-HSCT and drug therapy, (all disease phases included), the five-year OS comprise 42% for the both groups (р=0.7). The overall survival median in HSCT group was 2 years, and in the drug therapy group, 2.6 years (Fig. 4). Similar analysis performed for the patients beyond blast crisis by the moment of mutation evolved has yielded similar results, i.e., 5-year OS was 47% in both groups (2.1 years for allo-HSCT group compared to 2.8 years among patients receiving drug therapy).
Our study has revealed an interesting fact, i.e., OS parameters in the group after detection of T315I mutations (N=37) did not sufficiently differ between the subgroups with drug therapy with or without TKI. For the patient group which was not treated with TKI (N=14), and for the group who received TKI (including those with combined therapy, N=23), 5-year OS comprised, respectively, 46.7% and 42.1% (р=0.53). The median of overall survival after TKI-free therapy was 1 year, compared to 2.8 years in TKI-treated group (Fig. 5).
Multivariate analysis of multiple effects upon OS has shown that the only independent significant factor was the disease phase, i.e., blast crisis by the moment of mutation detection.
A total of five patients were at the BC phase by detection of the mutation. Two of them underwent HSCT, all the patients deceased (Table 2).
Table 2. Multifactorial analysis: effects of certain factors on the overall survival at the time of Т315I detection
Discussion
According to recommendations of the European LeukemiaNet (ELN, 2011), testing for BCR-ABL mutations by means of direct sequencing is obligatory in case of treatment failure. This analysis aims to deciffer nucleotide sequence of the kinase domain in cDNA product. The method includes RNA extraction from patients’ blood, reverse transcription getting complementary DNA (cDNA), amplification of the BCR/ABL kinase gene segment, followed by its sequencing [2]. This method allows to determine all the spectrum of the kinase domain mutations with a sensitivity of 15-20%.To detect a transcript bearing T315I mutation, as well for quantitative evaluation of the mutant/wild-type clone ratio, the AC PCR is used. This approach is highly sensitive, thus allowing to find minor subclones which are undetectable by direct desequencing. АС PCR enables dynamic studies of the mutant clone, e.g., for evaluation or prediction of the treatment efficiency [41]. A minimal presence of the BCR-ABL T315I clone (≥10-5 against GUS) could be an unfavorable sign for achievement of major molecular response in imatyinib-resistant patients receiving TKI2 (nilotinib or dasatinib) [20].
Another sensitive technique for the diagnostics of mutations is a novel method of deep sequencing (ultra-deep sequencing, UDS), which allows to detect mutant subclones at a range of 1 to 15% in the cell populations which may be of clinical significance for resistance diagnostics but cannot be detected by means of direct sequencing [36].
Despite ELN recommendations on direct sequencing method as an optimal approach to searching BCR/ABL mutations, more precise techniques seem to be available in the nearest future, due to discovery and clinical studies of novel, highly efficient drugs. Allo-HSCT is known to be an effective mode to treat T315I-positive CML.
Therefore, let us briefly discuss the prospectives of drug therapy and future therapeutic approaches to this category of the patients. E.g., ponatinib (AP24534, IclusigTM) provided a new approach to therapy of CML positive for BCR-ABL T315I . This TKI inhibits several kinase targets, being active in cases of T315I mutation and multiple mutations in the BCR-ABL kinase domain. This compound does not form hydrogen links with T315 in the kinase domain of BCR-ABL, due to incorporation of vinyl and ethyl bonds into the inhibitor nucleotides, thus it does not prevent its spatial binding to the protein [29].
The data on 2-year observations concerning efficiency and safety of ponatinib at a dose of 45 mg/day were published in 2013 as a 2 nd phase of PACE clinical study. The study included 449 patients. Among them 227 patients with CP CML were under study being resistant/intolerable to previous therapy with TKI, including patients with T315I mutation. In this subgroup of pre-treated patients with failure of several lines of therapy, 58% patients received >3 TKI at preceding treatment rounds. Mean total terms of the previous comprised 6 (0.3 to 28) years. According to the data from 2-year observation, 46% of the patients still remained in the PACE study, of them 60% CML patients were in chronic phase. The rates of PFS and OS in the CP patients made 80% (a median of 27 months), and 94% (median, 12 mo); PFS and OS in patients with blast crisis comprised 18% (a median of 4 mo), and 30% (a median of 7 mo.). Among CML group, most patients with CP retained the response until 12 months, i.e., 91%, 91% and 75% of the patients presented with, respectively, MCyR, complete cytogenetic response, or MMR [16]. Moreover, the studies report on increased cumulative frequency of serious arterial thrombotic complications associated with ponatinib treatment [5, 27].
Omacetaxin/Homoharringtonin (Synribo®) was another drug approved by FDA (USA Food and Drug Administration) for CML cases resistant to ≥2 TKIs. According to the II phase clinical trials in patients with T315I mutation and failure of TKI therapy, 48 of 62 patients in CP (77%) have achieved complete hematological response, whereas 10 (16%) achieved complete cytogenetic response[6].
Among experimental compounds acceptable for T315I-positive CML therapy, one may suggest PF-114 which now undergoes 1 st phase of clinical trials. The drug is a TKI which is targeted for BCR-ABL. Efficiency of this molecule is in vitro shown using resistant mutant cell lines (Y253F, E255K, T315I, F317L). A range of suppressible tyrosine kinases (27 species with PF-114, as compared to 80 with ponatinib) reflects its higher selectivity thus reducing probability of potential in vivo adverse effects [21]. The most discussed and prospective ABL001 compound which is also under Phase 1 of clilnical trials. Early proofs are presented for its clinical efficiency towards mutations causing TKI resistance (V299L,
F317L, Y253H). Allosteric BCR-ABL1 inhibition represents another promising therapeutic approach to therapy of CML patients [31].
Conclusion
Targeted therapy in CML sufficiently increases life expectance of the patients, causing marked malignancy reduction to undetectable levels of molecular response. So far, however, the issues of resistance remain unresolved despite TKI2 introduction. Development of clones bearing T315I mutation in resistant CML changes prognosis for the given cohort of patients since it makes impossible a target effect upon leukemia cells. This problem required improvement of novel molecular diagnostics, as well as development of new molecules efficient in BCR-ABL T315I –positive patients.Currently, T315I positivity is an absolute indication for allogeneic bone marrow transplantation. Along with HLAmatched related or unrelated donors, related haploidentical donors may be also considered. Achievement of deep molecular remission is an evident advantage of allo-HSCT in these cases.
Our results suggest that pharmacological treatment is acceptable, if T315I mutation is revealed at chronic phase of the disease. However, there is no evidence that imatinib or TKI2 continuation will lead to the mutant clone selection, increased BCR-ABL T315I expression and further progression of the disease. Treatment of CML blast crisis seems to be ineffective, using both pharmacological therapy, and allo-HSCT approaches. Hence, therapeutic choice after the T315I detection should be based on risk factors, with CML stage being of major importance.
We need long-range observations of large patient cohorts using highly sensitive T315I detection techniques, in order to study its biological characteristics (role for CML progression, proliferative activity etc.) and to develop optimal therapeutic strategy.
Introduction of novel effective approaches to clinical practice will allow to reduce the number of patients with TKI resistance and to improve general therapeutic effect.
Conflicts of interest
No conflict of interest is declared.Funding sources
The study did not have any sponsor support.References
1. Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21 st century. Blood. 2015;125(21):3230-3235.2. Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002 ;99(9):3472-3475.
3. Corbin AS, Buchdunger E, Pascal F, Druker BJ. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem 2002; 277:32214–32219.
4. Cornelison AM, Welch MA, Koller C, Jabbour E. Dasatinib combined with Interferon-alfa induces a complete cytogenetic response and major molecular response in a patient with chronic myelogenous leukemia harboring the T315I BCR-ABL1 mutation. Clin Lymphoma Myeloma Leuk. 2011 Jun;11 Suppl 1:S111-3.
5. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M,
Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New Engl J Med. 2013;369:1783-1796.
6. Cortes, J.H. Lipton, D. Rea, R. Digumarti, C. Chuah, N. Nanda et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase
CML with T315I mutation. Blood 2012;120: 2573–2580.
7. Cortes JE, Kim D-W, Pinilla-Ibarz J, D le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio JF, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Passerini CG, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Goldman JM, Shah NP,Kantarjian HM. Ponatinib in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 2-year follow-up of the PACE trial. Blood. 2013; 122:650.
8. de Lavallade H, Khorashad JS, Davis HP, Milojkovic D, Kaeda, JS, Goldman JM, et al. Interferon-alpha or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation. Blood. 2007;110: 2779–2780.
9. Goldman J, Melo J. Chronic myeloid leukemia advances in biology and new approaches to treatment. N Engl J Med. 2003; 349: 1451–1464.
10. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
Science. 2001; 293:876–880.
11. Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16, 2190–2196.
12. Ilander M, Koskenvesa P, Hernesniemi S, Lion T, Porkka K, Mustjoki S. Induction of sustained deep molecular response in a patient with chronic-phase T315I-mutated chronic myeloid leukemia with interferon-α monotherapy. Leuk Lymphoma. 2014; 55(4):934-937.
13. Itonaga H, Tsushima H, Hata T, Matsuo E, Imanishi D, Imaizumi Y, Kawaguchi Y, Fukushima T, Doi Y, Mori S, Kamihira S, Tomonaga M, Miyazaki Y. Successful treatment of a chronicphase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa. Int J Hematol. 2012; 95:209–213.
14. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, Zhou X, Luthra R, Garcia-Manero G, Giles F, Rios MB, Verstovsek S, Cortes J. Frequency and clinical signifi-
cance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia (2006) 20, 1767–1773.
15. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O’Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N.Engl. J. Med. 2002; 346: 645–652.
16. Kantarjian HM, Cortes JE, O’Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Jeha S, Rios MB, Letvak L, Bochinski K, Arlinghaus R, Talpaz M. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogeno us leukemia: high incidence of early complete and major cytogenetic responses. Blood 2003; 101: 97–100.
17. Kantarjian HM, Talpaz M, Giles F, O’Brien S, Cortes J. New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance, Mechanisms of resistance to imatinib in chronic myeloid leukaemia Ann Intern Med. 2006;145(12):913-923.
18. Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008; 26 (29) 4806-13.
19. Kutsev S.I., Mordanov S.V. Amplification of the BCR-ABL gene in patients with chronic myeloid leukemia, refractory to imatinib. Oncohematology 2009; 3: 23-26.(In Russian).
20. Lange T, Ernst T, Gruber FX, Maier J, Cross M, Müller M, Niederwieser D, Hochhaus A, Pfirrmann M. The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia. Haematologica. 2013 May; 98(5): 714–717.
21. Mian AA, Rafiei A, Metodieva A, Haberbosch I, Zeifman A, Titov I, Stroylov V, Stroganov O, Novikov F, Chilov G, Ottmann OG, Ruthardt M. PF-114, a novel selective pan-BCR/ABL inhibitor targets the T315I and suppress models of advanced Ph+ ALL. Blood. 2013; 122: 21 3907
22. Nicolini FE, Basak GW, Kim D-W, Olavarria E, Pinilla-Ibarz J, Apperley JF, Hughes TP, Niederwieser D, Mauro MJ, Chuah C, Hochhaus A, Martinelli G, DerSarkissian M, Kageleiry A, Yang M, Huang H, McGarry LJ, Kantarjian HM, Cortes JE. The impact of ponatinib versus allogeneic stem cell transplant (SCT) on outcomes in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the T315I mutation, Abstract 480,57th Annual Meeting ASH, 2015
23. Nicolini FE, Basak GW, Soverini S, Martinelli G, Mauro MJ, Müller MC, Hochhaus A, Chuah C, Dufva IH, Rege-Cambrin G, Saglio G, Michallet M, Labussière H, Morisset S, Hayette S, Etienne G, Olavarria E, Zhou W, Peter S, Apperley JF, Cortes J. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood. 2011; 118 (20): 5697-5700.
24. Nicolini FE, Corm S, Lê QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M, Facon T, Mahon FX, Cayuela JM, Rousselot P, Michallet M, Preudhomme C,
Guilhot F, Roche-Lestienne C. Mutation status of 89 imatinib mesylate resistant chronic myelogenous leukemia patients and clinical outcome. A retrospective analysis from the french intergroup of CML (Fi(phi)-LMC group). 2006, Leukemia 20:1061–1066.
25. Nicolini FE, Corm S, Lê QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M, Facon T, Mahon FX, Cayuela JM, Rousselot P, Michallet M, Preudhomme C, Guilhot F, Roche-Lestienne C. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006;20(6):1061-1066.
26. Nicolini FE, Mauro MJ, Martinelli G, Kim DW, Soverini S, Müller MC, Hochhaus A, Cortes J, Chuah C, Dufva IH, Apperley JF, Yagasaki F, Pearson JD, Peter S, Sanz Rodriguez
C, Preudhomme C, Giles F, Goldman JM, Zhou W. Epidemiologic study on survival of chronic myeloid leukemia and Ph( + ) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation . Blood 2009; 114: 5271 – 5278.
27. O’Brien S, Radich JP, Abboud CN, Akhtari M, Altman JK, Berman E, Curtin P, DeAngelo DJ, Deininger M, Devine S, Fathi AT, Gotlib J, Jagasia M, Kropf P, Moore JO, Pallera A, Reddy VV, Shah NP, Smith BD, Snyder DS, Wetzler M, Gregory K, Sundar H. Chronic myelogenous leukemia, version 1.2015. J Natl Compr Canc Netw. 2014;12(11):1590-1610.
28. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J,
Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348: 994–1004.
29. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning
Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a Pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009; 16(5): 401–412.
30. O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, Druker BJ. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS- 354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005; 65: 4500–4505.
31. Ottmann OG, Alimena G, DeAngelo DJ, Goh Y-T, Heinrich MC, Hochhaus A, Hughes TP, Mahon F-X, Mauro MJ, Minami H, Nguyen MH, Rea D, Steegmann JL, Chatterjee A, Iyer V, Martinez N, Vanasse GJ, Dong-Wook K. ABL001, a potent, allosteric inhibitor of BCR-ABL, exhibits safety and promising single- agent activity in a phase I study of patients with CML with failure of prior TKI therapy. Abstract 138, 57 th Annual Meeting ASH, 2015.
32. Peggs K, Mackinnon S. Imatinib mesylate – the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med. 2003; 348: 1048–1050.
33. Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T, Greenfield EA, Salgia R, Griffin JD. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem. 2000; 275(32): 24273–24278.
34. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase
inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125. P, Binotto G, Giannini B, Kohlmann A, Haferlach T, Roller A, Rosti G, Cavo M, Baccarani M, Martinelli G. Unraveling the complexity of tyrosine kinase inhibitor–resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood, 2013; 122(9): 1634-1648.
37. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alberti D, Pane F, Saglio G, Baccarani M. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J. Clin. Oncol. 2005; 23: 4100–4109.
38. Turkina A.G., Khoroshko N.D., Druzhkova G.A., Zingerman В.V., Zakharova E.S., Chelysheva E. Yu., Vinogradova O. Yu., Domracheva E.V., Zakharova A.V., Kovaleva L.G., Kolosheinova T.I., Kolosova L. Yu., Zkuravleva V.S., Tikhonova L. Yu. Therapeutic efficacy of Imatinib Mesilate (Gliveс) in chronic phase of myeloid leukemia.Ter Arkhiv 2003; 75(8):
62-67. (In Russian).
39. Velev N, Cortes J, Champlin R, Jones D, Rondon G, Giralt S, Borthakur G, Kantarjian HM, De Lima M. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer. 2010;116:3631-3637.
40. Wongboonma W, Thongnoppakhun W, Auewarakul CU. A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients. J Hematol Oncol. 2011 Feb 8;4:7. doi: 10.1186/1756-8722-4-7.
41. Xu LP, Xu ZL, Zhang XH, Chen H, Chen YH, Han W, Chen Y, Wang FR, Wang JZ, Wang Y, Yan CH, Mo XD, Liu KY, Huang XJ. Allogeneic stem cell transplantation for patients with T315I BCR-ABL mutated chronic myeloid leukemia. Biol Blood Marrow Transplant. 2016;22(6):1080-1086.
42. Zeidner JF, Zahurak M, Rosner GL, Gocke CD, Jones RJ, Smith D. The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation: Can tyrosine kinase inhibitors replace donor lymphocyte infusions. Leuk Lymphoma. 2015; 56(1): 128–134.
35. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, Iacobucci I, Amabile M, Abruzzese E, Orlandi E, Radaelli F, Ciccone F, Tiribelli M, di Lorenzo R, Caracciolo C, Izzo B, Pane F, Saglio G, Baccarani M, Martinelli G. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12:7374-7379.
36. Soverini S, De Benedittis C, Machova Polakova K, Brouckova A, Horner D, Iacono M, Castagnetti F, Gugliotta G, Palandri F, Papayannidis C, Iacobucci I, Venturi C, Bochicchio MT, Klamova H, Cattina F, Russo D, Bresciani P, Binotto G, Giannini B, Kohlmann A, Haferlach T, Roller A, Rosti G, Cavo M, Baccarani M, Martinelli G. Unraveling the complexity of tyrosine kinase inhibitor–resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood, 2013; 122(9): 1634-1648.
37. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alberti D, Pane F, Saglio G, Baccarani M. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J. Clin. Oncol. 2005; 23: 4100–4109.
38. Turkina A.G., Khoroshko N.D., Druzhkova G.A., Zingerman В.V., Zakharova E.S., Chelysheva E. Yu., Vinogradova O. Yu., Domracheva E.V., Zakharova A.V., Kovaleva L.G., Kolosheinova T.I., Kolosova L. Yu., Zkuravleva V.S., Tikhonova L. Yu. Therapeutic efficacy of Imatinib Mesilate (Gliveс) in chronic phase of myeloid leukemia.Ter Arkhiv 2003; 75(8):
62-67. (In Russian).
39. Velev N, Cortes J, Champlin R, Jones D, Rondon G, Giralt S, Borthakur G, Kantarjian HM, De Lima M. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer. 2010;116:3631-3637.
40. Wongboonma W, Thongnoppakhun W, Auewarakul CU. A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients. J Hematol Oncol. 2011 Feb 8;4:7. doi: 10.1186/1756-8722-4-7.
41. Xu LP, Xu ZL, Zhang XH, Chen H, Chen YH, Han W, Chen Y, Wang FR, Wang JZ, Wang Y, Yan CH, Mo XD, Liu KY, Huang XJ. Allogeneic stem cell transplantation for patients with T315I BCR-ABL mutated chronic myeloid leukemia. Biol Blood Marrow Transplant. 2016;22(6):1080-1086.
42. Zeidner JF, Zahurak M, Rosner GL, Gocke CD, Jones RJ, Smith D. The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation: Can tyrosine kinase inhibitors replace donor lymphocyte infusions. Leuk Lymphoma. 2015; 56(1): 128–134.
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Несмотря на высокую эффективность ИТК, некоторые пациенты в ХФ и значительно большее количество пациентов в ФА и БК оказываются к нему резистентными. Наиболее важный из обсуждаемых механизмов резистентности к ИТК – возникновение точечных мутаций в киназном домене АВL-тирозинкиназы. На сегодня T315I считается единственной мутацией, вызывающей резистентность лейкозных клеток ко всем известным ИТК I и II поколения, кроме понатиниба. Целью нашей работы была оценка результатов различных методов лечения у пациентов с мутацией T315I ХМЛ.<br> <h3> МАТЕРИАЛЫ И МЕТОДЫ</h3> Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53). <br> <h3>ЗАКЛЮЧЕНИЕ</h3> Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.<br> <br> <b>Ключевые слова</b><br> Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.<br>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(193) "Клинические характеристики и исходы лечения у пациентов хроническим миелоидным лейкозом с мутацией Т315I " ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(193) "Клинические характеристики и исходы лечения у пациентов хроническим миелоидным лейкозом с мутацией Т315I " ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(193) "Клинические характеристики и исходы лечения у пациентов хроническим миелоидным лейкозом с мутацией Т315I " ["SECTION_META_TITLE"]=> string(193) "Клинические характеристики и исходы лечения у пациентов хроническим миелоидным лейкозом с мутацией Т315I " ["SECTION_META_KEYWORDS"]=> string(193) "Клинические характеристики и исходы лечения у 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Власова<sup>1</sup>, Олег А. Шухов<sup>2</sup>, Елена В. Морозова<sup>1</sup>, Мария В. Барабанщикова<sup>1</sup>, Татьяна Л. Гиндина<sup>1</sup>, Ильдар М. Бархатов<sup>1</sup>, Ирина С. Мартынкевич<sup>3</sup>, Василий А. Шуваев<sup>3</sup>, Анна Г. Туркина<sup>2</sup>, Борис В. Афанасьев<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(461) "
Юлия Ю. Власова1, Олег А. Шухов2, Елена В. Морозова1, Мария В. Барабанщикова1, Татьяна Л. Гиндина1, Ильдар М. Бархатов1, Ирина С. Мартынкевич3, Василий А. Шуваев3, Анна Г. Туркина2, Борис В. Афанасьев1
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Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, Санкт-Петербург
2 «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
3 «Российский НИИ Гематологии и Трансфузиологии», ФМБА, Санкт-Петербург
МАТЕРИАЛЫ И МЕТОДЫ
Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53).ЗАКЛЮЧЕНИЕ
Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.Ключевые слова
Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.
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Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1,
Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
1 R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg
2 National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR-ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors, except of ponatinib. The aim of our study was to evaluate the results of different treatment modalities in CML patients with T315I mutation.
MATERIALS AND METHODS
etrospective analysis of 53 BCR-ABL T315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs other 16 pts received hydroxyurea, interferonα or chemotherapy). At the time of T315I detection 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5 pts were in AP, 7 pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). Mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time from TKI treatment initiation to T315I detection.
RESULTS
The mean follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All patients in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1.3 month. 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2.8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months. All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0.53).
CONCLUSION
Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection, however, taking transplant risks into consideration.
Keywords
Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug resistance." 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Vlasova<sup>1</sup>, Elena V. Morozova<sup>1</sup>, Oleg A. Shukhov<sup>2</sup>, Maria V. Barabanshchikova<sup>1</sup>, Tatiana L. Gindina<sup>1</sup>,<br> Ildar M. Barhatov<sup>1</sup>, Irina S. Martynkevich<sup>3</sup>, Vasily A. Shuvaev<sup>3</sup>, Anna G. Turkina<sup>2</sup>, Boris V. Afanasyev<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(331) "
Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1,
Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1,
Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR-ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors, except of ponatinib. The aim of our study was to evaluate the results of different treatment modalities in CML patients with T315I mutation.
MATERIALS AND METHODS
etrospective analysis of 53 BCR-ABL T315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs other 16 pts received hydroxyurea, interferonα or chemotherapy). At the time of T315I detection 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5 pts were in AP, 7 pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). Mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time from TKI treatment initiation to T315I detection.
RESULTS
The mean follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All patients in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1.3 month. 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2.8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months. All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0.53).
CONCLUSION
Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection, however, taking transplant risks into consideration.
Keywords
Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug 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(3194) "
Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR-ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors, except of ponatinib. The aim of our study was to evaluate the results of different treatment modalities in CML patients with T315I mutation.
MATERIALS AND METHODS
etrospective analysis of 53 BCR-ABL T315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs other 16 pts received hydroxyurea, interferonα or chemotherapy). At the time of T315I detection 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5 pts were in AP, 7 pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). Mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time from TKI treatment initiation to T315I detection.
RESULTS
The mean follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All patients in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1.3 month. 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2.8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months. All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0.53).
CONCLUSION
Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection, however, taking transplant risks into consideration.
Keywords
Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug 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) "18129" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-26-35" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-26-35" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-26-35" } ["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) "18133" ["VALUE"]=> string(78) "Clinical features and outcomes in chronic myeloid leukemia with T315I mutation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(78) "Clinical features and outcomes in chronic myeloid leukemia with T315I mutation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(78) "Clinical features and outcomes in chronic myeloid leukemia with T315I mutation" } ["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) "18131" ["VALUE"]=> array(2) { ["TEXT"]=> string(521) "<p><sup>1</sup> R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg<br> <sup>2</sup> National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia<br> <sup>3</sup> Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(461) "
1 R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg
2 National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
1 R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg
2 National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
Юлия Ю. Власова1, Олег А. Шухов2, Елена В. Морозова1, Мария В. Барабанщикова1, Татьяна Л. Гиндина1, Ильдар М. Бархатов1, Ирина С. Мартынкевич3, Василий А. Шуваев3, Анна Г. Туркина2, Борис В. Афанасьев1
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Несмотря на высокую эффективность ИТК, некоторые пациенты в ХФ и значительно большее количество пациентов в ФА и БК оказываются к нему резистентными. Наиболее важный из обсуждаемых механизмов резистентности к ИТК – возникновение точечных мутаций в киназном домене АВL-тирозинкиназы. На сегодня T315I считается единственной мутацией, вызывающей резистентность лейкозных клеток ко всем известным ИТК I и II поколения, кроме понатиниба. Целью нашей работы была оценка результатов различных методов лечения у пациентов с мутацией T315I ХМЛ.<br> <h3> МАТЕРИАЛЫ И МЕТОДЫ</h3> Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53). <br> <h3>ЗАКЛЮЧЕНИЕ</h3> Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.<br> <br> <b>Ключевые слова</b><br> Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6555) "Современное лечение хронического миелоидного лейкоза (ХМЛ) основано на применении ингибиторов тирозинкиназ (ИТК). Несмотря на высокую эффективность ИТК, некоторые пациенты в ХФ и значительно большее количество пациентов в ФА и БК оказываются к нему резистентными. Наиболее важный из обсуждаемых механизмов резистентности к ИТК – возникновение точечных мутаций в киназном домене АВL-тирозинкиназы. На сегодня T315I считается единственной мутацией, вызывающей резистентность лейкозных клеток ко всем известным ИТК I и II поколения, кроме понатиниба. Целью нашей работы была оценка результатов различных методов лечения у пациентов с мутацией T315I ХМЛ.МАТЕРИАЛЫ И МЕТОДЫ
Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53).ЗАКЛЮЧЕНИЕ
Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.Ключевые слова
Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.
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МАТЕРИАЛЫ И МЕТОДЫ
Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53).ЗАКЛЮЧЕНИЕ
Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.Ключевые слова
Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.
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1 НИИ Детской Онкологии Гематологии и Трансплантологии им. Р. М. Горбачевой
Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, Санкт-Петербург
2 «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
3 «Российский НИИ Гематологии и Трансфузиологии», ФМБА, Санкт-Петербург
1 НИИ Детской Онкологии Гематологии и Трансплантологии им. Р. М. Горбачевой
Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, Санкт-Петербург
2 «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
3 «Российский НИИ Гематологии и Трансфузиологии», ФМБА, Санкт-Петербург
Сlinical studies
Irina P. Shipitsina1, Elena I. Gutovskaya1, Dina D. Bajdildina1, Irina I. Kalinina1, Ulyana N. Petrova1, Andrej B. Abrosimov1,
Svetlana N. Kozlovskaya1, Michael A. Maschan1, Dmitrij M. Konovalov1, Dmitrij S. Abramov1, Galina V. Tereshenko1,
Alexander G. Rumyantsev1, Elena V. Samochatova1, Galina A. Novichkova1, Alexej A. Maschan1
Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1,
Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
Сlinical studies
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Ирина П. Шипицына<sup>1</sup>, Елена И. Гутовская<sup>1</sup>, Дина Д. Байдильдина<sup>1</sup>, Ирина И. Калинина<sup>1</sup>, Ульяна Н. Петрова<sup>1</sup>,<br>
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[TEXT] => <sup>1</sup> ФГБУ ННПЦ ДГОИ им. Дм. Рогачева МЗ РФ<br>
<sup>2</sup> ФГБУ РДКБ МЗ РФ<br>
<sup>3</sup> ГУЗ «Ленинградское областное патологоанатомическое бюро»
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2 ФГБУ РДКБ МЗ РФ
3 ГУЗ «Ленинградское областное патологоанатомическое бюро»
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[TEXT] => Среди различных осложнений аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) одним из самых тяжелых является пострансплантационное лимфопролиферативное заболевание (ПТЛПЗ), проявляющееся неконтролируемой пролиферацией лимфоидной ткани. Пусковым механизмом, как правило, служит первичная инфекция, вызванная Эпштейн-Барр вирусом, или реактивация вируса в иммунокомпрометированном организме. В зависимости от вида ПТЛПЗ и динамики его развития данная патология может быть фатальной для пациента. В данной статье описаны: клинико-морфологическая классификация, факторы риска, клинические особенности, диагностика и лечение ПТЛПЗ, а также приведен клинический опыт диагностики и лечения данного осложнения на базе отделений ТГСК РДКБ и ННПЦ ДГОИ.<br>
<h3>Ключевые слова</h3>
Аллогенная трансплантация гемопоэтических стволовых клеток, посттрансплантационное лимфопролиферативное заболевание.
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Ключевые слова
Аллогенная трансплантация гемопоэтических стволовых клеток, посттрансплантационное лимфопролиферативное заболевание.
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[TEXT] => Yulia V. Skvortsova<sup>1</sup>, Dmitrij N. Balashov<sup>1</sup>, Larisa N. Shelikhova<sup>1</sup>, Elena V. Skorobogatova<sup>2</sup>, Yurij A. Krivolapov<sup>3</sup>,<br>
Irina P. Shipitsina<sup>1</sup>, Elena I. Gutovskaya<sup>1</sup>, Dina D. Bajdildina<sup>1</sup>, Irina I. Kalinina<sup>1</sup>, Ulyana N. Petrova<sup>1</sup>, Andrej B. Abrosimov<sup>1</sup>,<br>
Svetlana N. Kozlovskaya<sup>1</sup>, Michael A. Maschan<sup>1</sup>, Dmitrij M. Konovalov<sup>1</sup>, Dmitrij S. Abramov<sup>1</sup>, Galina V. Tereshenko<sup>1</sup>,<br>
Alexander G. Rumyantsev<sup>1</sup>, Elena V. Samochatova<sup>1</sup>, Galina A. Novichkova<sup>1</sup>, Alexej A. Maschan<sup>1</sup>
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Irina P. Shipitsina1, Elena I. Gutovskaya1, Dina D. Bajdildina1, Irina I. Kalinina1, Ulyana N. Petrova1, Andrej B. Abrosimov1,
Svetlana N. Kozlovskaya1, Michael A. Maschan1, Dmitrij M. Konovalov1, Dmitrij S. Abramov1, Galina V. Tereshenko1,
Alexander G. Rumyantsev1, Elena V. Samochatova1, Galina A. Novichkova1, Alexej A. Maschan1
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[TEXT] => <sup>1</sup> National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev;<br>
Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia<br>
<sup>2</sup> Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia<br>
<sup>3</sup> State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», St. Petersburg, Russia
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Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia
2 Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia
3 State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», St. Petersburg, Russia
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[TEXT] => Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology.
<h3>Keywords</h3>
Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder.<br>
<br>
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[TEXT] => Posttransplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Pathogenesis of this disease is associated with uncontrolled lymphoid tissue proliferation in immunocompromised recipients, most often triggered by primary Epstein-Barr virus infection, or its reactivation. This complication could be fatal, depending on the type of PTLD. This article describes clinical and morphological classification, risk factors, clinical features, diagnostic and treatment of PTLD and presents the clinical experience of the diagnostic and treatment of PTLD in patients of HSCT departments of Russian Children’s Hospital and National Scientific Center of Children’s Hematology, Oncology and Immunology.
Keywords
Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder.
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Yulia V. Skvortsova1, Dmitrij N. Balashov1, Larisa N. Shelikhova1, Elena V. Skorobogatova2, Yurij A. Krivolapov3,
Irina P. Shipitsina1, Elena I. Gutovskaya1, Dina D. Bajdildina1, Irina I. Kalinina1, Ulyana N. Petrova1, Andrej B. Abrosimov1,
Svetlana N. Kozlovskaya1, Michael A. Maschan1, Dmitrij M. Konovalov1, Dmitrij S. Abramov1, Galina V. Tereshenko1,
Alexander G. Rumyantsev1, Elena V. Samochatova1, Galina A. Novichkova1, Alexej A. Maschan1
Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, Russia
2 Russian Children Clinical Hospital ; Ministry of Healthcare of Russia, 117, Leninskiy Prospect, Moscow, 119571, Russia
3 State Institution «Leningradskoye Regional Bureau of Pathological Anatomy», St. Petersburg, Russia
Keywords
Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder.Сlinical studies
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[TEXT] => <p>Юлия Ю. Власова<sup>1</sup>, Олег А. Шухов<sup>2</sup>, Елена В. Морозова<sup>1</sup>, Мария В. Барабанщикова<sup>1</sup>, Татьяна Л. Гиндина<sup>1</sup>, Ильдар М. Бархатов<sup>1</sup>, Ирина С. Мартынкевич<sup>3</sup>, Василий А. Шуваев<sup>3</sup>, Анна Г. Туркина<sup>2</sup>, Борис В. Афанасьев<sup>1</sup></p>
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[TEXT] => <p><sup>1</sup> НИИ Детской Онкологии Гематологии и Трансплантологии им. Р. М. Горбачевой<br>
Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, Санкт-Петербург<br>
<sup>2 </sup>«Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия<br>
<sup>3</sup> «Российский НИИ Гематологии и Трансфузиологии», ФМБА, Санкт-Петербург</p>
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Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, Санкт-Петербург
2 «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
3 «Российский НИИ Гематологии и Трансфузиологии», ФМБА, Санкт-Петербург
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[TEXT] => Современное лечение хронического миелоидного лейкоза (ХМЛ) основано на применении ингибиторов тирозинкиназ (ИТК). Несмотря на высокую эффективность ИТК, некоторые пациенты в ХФ и значительно большее количество пациентов в ФА и БК оказываются к нему резистентными. Наиболее важный из обсуждаемых механизмов резистентности к ИТК – возникновение точечных мутаций в киназном домене АВL-тирозинкиназы. На сегодня T315I считается единственной мутацией, вызывающей резистентность лейкозных клеток ко всем известным ИТК I и II поколения, кроме понатиниба. Целью нашей работы была оценка результатов различных методов лечения у пациентов с мутацией T315I ХМЛ.<br>
<h3>
МАТЕРИАЛЫ И МЕТОДЫ</h3>
Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53). <br>
<h3>ЗАКЛЮЧЕНИЕ</h3>
Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.<br>
<br>
<b>Ключевые слова</b><br>
Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.<br>
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[TEXT] => Современное лечение хронического миелоидного лейкоза (ХМЛ) основано на применении ингибиторов тирозинкиназ (ИТК). Несмотря на высокую эффективность ИТК, некоторые пациенты в ХФ и значительно большее количество пациентов в ФА и БК оказываются к нему резистентными. Наиболее важный из обсуждаемых механизмов резистентности к ИТК – возникновение точечных мутаций в киназном домене АВL-тирозинкиназы. На сегодня T315I считается единственной мутацией, вызывающей резистентность лейкозных клеток ко всем известным ИТК I и II поколения, кроме понатиниба. Целью нашей работы была оценка результатов различных методов лечения у пациентов с мутацией T315I ХМЛ.
МАТЕРИАЛЫ И МЕТОДЫ
Приведены результаты ретроспективного анализа 53 BCR-ABL T315I –позитивных пациентов. 18 аллогенных трансплантаций костного мозга (алло-ТГСК) выполнены 16 пациентам, фармакологическую терапию получили 37 пациентов (21 получали ИТК в качестве монотерапии или в комбинации с другими препаратами, 16 получали гидроксикарбамид, α-интерферон или химиотерапию). К моменту алло-ТГСК 4 пациента находились в хронической фазе 1 (ХФ1); 7 – в ХФ≥2; 5 – в фазе акселерации (ФА); 2 – в бластном кризе (БК). Медиана возраста на момент выявления мутации составляла 47 лет (15-76), или 38 лет в группе алло-ТГСК. В группе алло-ТГСК в 7 случаях донорами были HLA–идентичные сиблинги, в 11 – неродственные доноры, 11 пациентов (69%) получили более 2 линий лечения ИТК до проведения алло-ТГСК. Количество баллов по шкале EBMT: 3-4 балла – 12 пациентов; 5-7 баллов – у 4 пациентов. Режим кондиционирования в 13 случаях (81%) был со сниженной интенсивностью доз. Медиана времени от выявления мутации до алло-ТГСК составила 10 месяцев (2-38). Анализ выживаемости проводили с использованием метода Каплан-Майера; сравнение в группах осуществляли с применением лог-рангового критерия. Регрессионный анализ выживаемости выполнен с применением модели пропорциональных интенсивностей Кокса. Многофакторный регрессионный анализ включал следующие факторы и ковариаты: возраст на дату диагноза, пол, фаза на начало терапии, фаза на дату выявления мутации, терапия после выявления мутации (без алло-ТГСК и с алло-ТГСК), время до выявления мутации от начала терапии. Результаты исследования: медиана времени наблюдения после выявления мутации T315I составляла 21 месяц (1-100). 5-летняя общая выживаемость (ОВ) была 42%. По данным многофакторного анализа, только фаза ХМЛ на время обнаружения мутации значительно влияла на ОВ всей группы. Всего в фазе БК на момент выявления мутации были 5 человек, 2-м из них была выполнена алло-ТГСК. Все больные умерли в течение 1-го года после индикации T315I с медианой выживаемости 1.3 месяца. 5-летняя ОВ в группе фармакологической терапии (n=37) была 42% с медианой выживаемости 2.8 года. 3-летняя ОВ в группе алло-ТГСК (n=16) – 37%, медиана выживаемости составила 5 месяцев. У всех пациентов после алло-ТГСК получен глубокий молекулярный ответ. Не обнаружено достоверных различий в группах фармакологической терапии без ИТК (N=11); и включая ИТК (N=23) по показателям 5-летней ОВ (42% и 47% соответственно, р=0,53).
ЗАКЛЮЧЕНИЕ
Появление клона с мутацией T315I у больных ХМЛ с резистентностью изменяет прогноз для данной категории пациентов, особенно в продвинутых фазах. Выявление данной мутации является основанием для переключения на понатиниб или другие экспериментальные препараты. Алло-ТГСК остается потенциальной терапевтической опцией, однако необходимо учитывать трансплантационные риски.
Ключевые слова
Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность.
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[TEXT] => <p>Julia Yu. Vlasova<sup>1</sup>, Elena V. Morozova<sup>1</sup>, Oleg A. Shukhov<sup>2</sup>, Maria V. Barabanshchikova<sup>1</sup>, Tatiana L. Gindina<sup>1</sup>,<br>
Ildar M. Barhatov<sup>1</sup>, Irina S. Martynkevich<sup>3</sup>, Vasily A. Shuvaev<sup>3</sup>, Anna G. Turkina<sup>2</sup>, Boris V. Afanasyev<sup>1</sup></p>
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[TEXT] => Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1,
Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
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[TEXT] => <p><sup>1</sup> R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg<br>
<sup>2</sup> National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia<br>
<sup>3</sup> Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia</p>
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[TEXT] => 1 R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg
2 National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
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[TEXT] => <p>Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR-ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors, except of ponatinib. The aim of our study was to evaluate the results of different treatment modalities in CML patients with T315I mutation. <br></p>
<h3>MATERIALS AND METHODS </h3>
<p>etrospective analysis of 53 BCR-ABL T315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs other 16 pts received hydroxyurea, interferonα or chemotherapy). At the time of T315I detection 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5 pts were in AP, 7 pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). Mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time from TKI treatment initiation to T315I detection. <br></p>
<h3>RESULTS </h3>
<p>The mean follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All patients in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1.3 month. 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2.8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months. All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0.53). <br></p>
<h3>CONCLUSION </h3>
<p>Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection, however, taking transplant risks into consideration. <br></p>
<br>
<b>Keywords</b> <br>
<br>
Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug resistance.
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MATERIALS AND METHODS
etrospective analysis of 53 BCR-ABL T315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs other 16 pts received hydroxyurea, interferonα or chemotherapy). At the time of T315I detection 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5 pts were in AP, 7 pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). Mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time from TKI treatment initiation to T315I detection.
RESULTS
The mean follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All patients in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1.3 month. 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2.8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months. All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0.53).
CONCLUSION
Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection, however, taking transplant risks into consideration.
Keywords
Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug resistance.
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Julia Yu. Vlasova1, Elena V. Morozova1, Oleg A. Shukhov2, Maria V. Barabanshchikova1, Tatiana L. Gindina1,
Ildar M. Barhatov1, Irina S. Martynkevich3, Vasily A. Shuvaev3, Anna G. Turkina2, Boris V. Afanasyev1
1 R. M. Gorbacheva Institute of Children Oncology, Hematology and Transplantation, department of Hematology, Transfusiology and Transplantation, I. P. Pavlov First St. Petersburg I. Pavlov State Medical University, St. Petersburg
2 National Medical Research Center for Hematology, Russian Ministry of Health, Moscow, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR-ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors, except of ponatinib. The aim of our study was to evaluate the results of different treatment modalities in CML patients with T315I mutation.
MATERIALS AND METHODS
etrospective analysis of 53 BCR-ABL T315I –positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo-HSCT) was made in 16 pts, 37 pts received only pharmacological therapy (21 pts received TKI as monotherapy or in combination with other drugs other 16 pts received hydroxyurea, interferonα or chemotherapy). At the time of T315I detection 29 (55%) pts were in CP, 19 (36%) pts had AP and 5 (9%) pts were in BC. Median (Me) age at the time of mutation detected was 47 years (15-76) (38 years in HSCT-group). In allo-HSCT group 11 (69%) pts had unrelated donors, 11 (69%) pts received more than 2 lines TKIs before HSCT, 2 (12%) pts were in BC at the time of HSCT, 5 pts were in AP, 7 pts were in CP≥2. The number of points on EBMT scale: 3-4 points – 12(75%) pts, 5-7 points – 4(25%) pts. Conditioning regimen in 13 (81%) pts had reduced intensity. Me time to HSCT after T315I detection was 10 months (1-38). Mutation analysis was performed by Sanger sequencing. Overall survival (OS) was estimated by Kaplan-Meier method with log-rank test for comparison between groups. Cox regression was used for multivariate survival analysis that included next covariates: age, phase on the time of mutation detection, performance of allo-HSCT, time from TKI treatment initiation to T315I detection.
RESULTS
The mean follow-up time after T315I detection was 21 months (1-100). 5-years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All patients in BC (n=5, 2 in HSCT group and 3 in non-HSCT group) died within first year after T315I indication wherein Me survival time was 1.3 month. 5-years OS in non-HSCT group (n=37) was 42% with Me survival time 2.8 years. 5-years OS after allo-HSCT (n=16) was 37% with Me survival time 5 months. All living patients after allo-HSCT are in deep molecular response. There was no significant difference in 5-years OS between TKI (n=21) and non-TKI (n=16) pharmacological therapy (non-HSCT) groups (42% and 47% respectively, p=0.53).
CONCLUSION
Detection of T315I mutation in TKI-resistant patients is extremely unfavorable factor for survival, especially in the advanced phase CML, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo-HSCT can be a potential option for this group of patients in case of good selection, however, taking transplant risks into consideration.
Keywords
Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug resistance.