Volume 6, number 2

Change template to: announce

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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

Table 1.png

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).

Figure 1-2.png

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).

Figure 3-5.png

Table 2. Multifactorial analysis: effects of certain factors on the overall survival at the time of Т315I detection

Table 2.png

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

Introduction

Patients and methods

Table 1.png

Figure 1-2.png

Results

Figure 3-5.png

Table 2. Multifactorial analysis: effects of certain factors on the overall survival at the time of Т315I detection

Table 2.png

Discussion

Conclusion

Conflicts of interest

No conflict of interest is declared.

Funding sources

The study did not have any sponsor support.

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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.
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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. <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). <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. Ключевые слова Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность. 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array(2) { ["TEXT"]=> string(593) "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" ["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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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

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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. <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). <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. Ключевые слова Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность. " ["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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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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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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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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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" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(331) "

" } ["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) "18132" ["VALUE"]=> array(2) { ["TEXT"]=> string(3332) "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. <h3>MATERIALS AND METHODS </h3> 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. <h3>RESULTS </h3> 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). <h3>CONCLUSION </h3> 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) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3194) "

MATERIALS AND METHODS

RESULTS

CONCLUSION

MATERIALS AND METHODS

RESULTS

CONCLUSION

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) "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" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(461) "

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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. <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). <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. Ключевые слова Хронический миелоидный лейкоз, мутация T315I, аллогенная трансплантация гемопоэтических стволовых клеток, лекарственная резистентность. " ["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

ЗАКЛЮЧЕНИЕ

МАТЕРИАЛЫ И МЕТОДЫ

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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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]

Table 1.png

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]

Table 2.png

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.png

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].

Table 3.png

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 4.png

Table 5. Characteristics of the EBV-PTLD patients

Table 5.png

Table 5-1.png

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

Figure 2-3.png

Figure 4-5.png

Figure 6-7.png

Figure 8-9.png

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

Table 6.png

Table 6-1.png

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.png

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.

Figure 11.png

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.

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25.    Hoover R.N. Lymphoma risks in populations with altered immunity – a search for mechanism. Cancer Res 1992; 52: 5477s.
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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.

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" ["~DETAIL_TEXT"]=> string(62113) "

Introduction

Classification

Table 1. PTLD categories according to WHO Classification of Tumours [26]

Table 1.png

Notes: WHO, World Health Organization; PTLD, posttransplant lymphoproliferative disease; NHL, non-Hodgkin’s lymphomas.

Etiology and Pathogenesis

Table 2. EBV-associated PTLD and viral programs [37]

Table 2.png

Risk factors

Clinical Features

Prophylaxis

Figure 1.png

Table 3. Treatment options for PTLD [11].

Table 3.png

Notes: GvHD, Graft Versus Host Disease; IVIG, intravenous immunoglobulins.

Our clinical experience and discussion

Table 4. Clinical features of the patients with EBV reactivation

Table 4.png

Table 5. Characteristics of the EBV-PTLD patients

Table 5.png

Table 5-1.png

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

Figure 2-3.png

Figure 4-5.png

Figure 6-7.png

Figure 8-9.png

Table 6. Characteristics of the two patients with monomorphic B cell PTLD

Table 6.png

Table 6-1.png

Figure 10.png

Figure 10. Pathomorphosis of PTLD in one patient.

Figure 11.png

Conclusion

Conflict of interest

No conflict of interests is declared.

References

24. Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol. 1997;14(1):8-14.

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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) "" ["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

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² ФГБУ РДКБ МЗ РФ
³ ГУЗ «Ленинградское областное патологоанатомическое бюро»" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18116" ["VALUE"]=> array(2) { ["TEXT"]=> string(1696) "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. <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" } } ["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. 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) "" ["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) "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) "" ["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. " ["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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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) "" ["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,
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Svetlana N. Kozlovskaya¹, Michael A. Maschan¹, Dmitrij M. Konovalov¹, Dmitrij S. Abramov¹, Galina V. Tereshenko¹,
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Keywords

Allogeneic hematopoietic stem cell transplantation, posttransplant lymphoproliferative disorder.

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Ministry of Healthcare of Russia, 1, Samory Mashela Str., Moscow, 117997, 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
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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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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. <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." } ["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) "1 ФГБУ ННПЦ ДГОИ им. Дм. Рогачева МЗ РФ 2 ФГБУ РДКБ МЗ РФ 3 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 РФ
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Introduction

Common complications, relapse rates and clinical outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT) settings are primarily dependent on donor/recipient differences in HLA system. Highly complex polymorphic patterns of HLA genes at chromosome 6 are historically in focus of HSCT studies being carefully tested (Franca et al., 2015). In addition, gene variants of the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins may be also associated with overall survival, graft rejection or acute graft-versus-host disease (Mullighan, Petersdorf, 2006). This list includes a series of well-known cytokines as TNF-α, IL1-β, IL-2, -6, 10 and their receptors on target cell populations. Numerous polymorphisms were revealed in the genes encoding specific proteins (cytokines, chemokines and their receptors on target cells) active in immunity. The genes encoding foreign antigen-binding receptors (NOD2, TLR) and cell contact proteins may also exhibit functional polymorphisms.

Another class of non-MHC genes affecting HCT outcome is illustrated by the recent study by McCarroll et al (2009) showing that deletion of the entire UGT2B17 gene determining a numer of HLA gene alleles can result in an alloimmune response associated with aGvHD. This multi-center study (1345 patients) initially examined six common deletions (UGT2B17, UGT2B28, GSTT1, GSTM1, LCE3C and OR51A2) in a phase I discovery study using 414 HLA MRD transplants. The association of the UGT2B17 deletion with acute GVHD was validated in two additional cohorts of, resp., 336 and 595 HLA-identical sibling transplants. Risk of acute GVHD proved to be greater (OR=2.5) when donor and recipient were mismatched for homozygous deletion of UGT2B17.

Moreover, the KIR genetic region encodes variant receptors on NK cells, this cluster contains up to 15 genes, whose alleles can be identified by a variety of PCR methods. Acceptable genotyping must include typing for the known activating (2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1) and inhibitory KIR genes (2DL1, 2DL2, 2DL3, 2DL5, 3DL1), in addition to the framework genes (3DL3, 2DL4, 3DL2). Now the KIR genes are subject to an in-depth biological association studies (Petersdorf et al., 2013).

In addition, a number of genes (mostly enzymes, and molecule transporters) control pharmacological effects of specific medications used for cytostatic chemotherapy and HSCT, e.g., during conditioning phase, and post-transplant (alkylating drugs, immunosuppressor agents, antibacterial antibiotics etc.). Common polymorphisms of these genes may alter biotransformation or drug transfer across cell membrane in liver (upon oral administration), other organs, or blood cell precursors, thus determining actual pharmacokinetics and individual dose effects of these drugs (Franca et al., 2015).

Some clinically relevant gene variants are located in gene promoter or other regulatory regions of the gene. Such high or low-producing alleles (indel mutations) simply change specific mRNA production levels, without altering specific protein structure. Meanwhile, nucleotide substitution in coding region of the gene may cause gain or loss of specific protein function (e.g., enzyme activity). Mutational shift of reading frame in coding region may cause loss of gene function or deficient production of intact protein in the cell.

Hence, minimal nucleotide differences in numerous functional genes may cause sufficient deviations of cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.

Hence, even single functional gene polymorphisms may significantly influence the donor-recipient interplay and cause distinct risks for HSCT outcomes. Therefore, the aim of our comparative review was to summarize effects of some functional gene alleles of donor and recipient upon drug toxicity, incidence and severity of aGvHD and other tissue-specific complications post-transplant.

Cytotoxic drug pharmacokinetics and GvHD depend on recipient genes

Conditioning treatment with cytostatic drugs causes profound damage of mucosal epithelium (oral and intestinal mucositis), vascular endothelium (veno-occlusive hepatic disease), urothelium (hemorrhagic cystitis). Incidence and severity of these early complications, in particular, aGVHD, seem to depend on genetically altered transmembrane transport or biotransformation transformation (activation or conjugation) of busulfan, cyclophosphamide, and other cytotoxic drugs. A number of studies concerning genetic associations between pharmacokinetic parameters and GVHD occurrence were discussed by Franca et al. (2015). The workers reviewed several studies in pediatric transplantation and concluded that only few gene variants detected in HSC recipients could affect drug pharmacokinetics, e.g., ABCB1(pGp) gene for in vivo MTx concentrations; CYP3A upon CsA and Tacrolimus pharmacokinetics in plasma, whereas GST-A1, GST-P were associated with changed kinetics of oral Busulfan. Among a number of pharmacogenes, only genetic tests for CYP3A seemed to be recommended for wide clinical application in the patients undergoing chemotherapy. However, lowand high-producing variants of numerous genes and, especially, gene constellations may be determined pre-transplant, in order to adjust individual dosage of cytotoxic drugs and immune suppressors.

Our search in literature performed for different HSCT settings has also shown a clear dependence between drug transporter gene variants of a well-known methylene tetrahydrofolate reductase (MTHFR) polymorphism, and clinical GVHD post-transplant (Table 1). These modifying effects depended, mainly, on gene variants in recipients, except of an SLC19A1 gene variant (a folate transporter) in donor cells. Interestingly, Murphy et al. (2012) have shown a correlation between high-producer 677CC MTHFR in donor and GvHD severity. Meanwhile, SNPs of dihydrofolate reductase (DHFR) and solute carrier (SLC19A1) genes (both related to folate metabolism) in donors were associated with reduced risk of aGvHD, as shown by Laverdière et al. (2015). Hence, one may suggest that folate synthesis and its pharmacokinetics may depend on both recipient and donor gene variants.

Table 1. Reported effects of pharmacologically relevant gene variants upon aGVHD incidence

Table 1.png

Laverdière et al. (2015), when studying 420 recipient-donor pairs, have performed deep DNA sequencing of 20 candidate genes related to MTx and CsA metabolism and GvHD occurrence. Of them, only few genetic variants were significantly associated with acute GvHD risk. In particular, the risk was associated with genetic variations in recipients related to pharmacodynamic pathways of methotrexate and cyclosporine A, including methylenetetrahydrofolate reductase (MTHFR) rs2274976 and rs3737967, and 5-aminoimidazole-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase (ATIC, rs17514110) proved to be risk alleles (see Table 1). Similarly, donor SNPs in NFATC2 (molecular target of cyclosporine A) increased risk of worse prognosis. Meanwhile, single nucleotide polymorphisms of dihydrofolate reductase (DHFR) and solute carrier (SLC19A1) genes of donors (both related to folate metabolism) were associated with reduced risk of aGvHD.

Different types of clinical outcomes and appropriate pharmacogene correlations were also studied by Rocha et al. (2015). In 107 donor-recipient pairs, the authors studied allelic frequencies of the following genes: P450 cytochrome (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene (MDR gene), methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The endpoints, along with acute GvHD, were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), transplantation-related mortality (TRM) and survival. Most effects of pharmacologically relevant recipient gene CYP2B6 (cyclophosphamide metabolic modification) were connected with acute therapy effects (oral mucositis, hemorrhagic cystitis). Recipient VDR TaqI showed correlations with TRM and overall survival. SNPs in estrogen receptor genes may also modify response to steroid hormone therapy. A study by Middleton (2003) has shown that an estrogen receptor alpha SNP (PvuII-XbaI) in recipient may affect both GvHD incidence and survival rates. All these association studies on SNPs and HSCT outcomes should be, however, reproduced in further works, oriented for search for appropriate candidate genes.

Despite certain evidence of associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, diagnostic genotyping in order to calculate optimal initial dose for the patient is uncommon in clinical practice, probably due to absence of proof that clinical outcome is really improved when such genotyping was performed for the drug dosage. To the present time, clinical recommendations in relation to pharmacogenetic biomarkers exist only for CYP3A5 testing, in order to determine initial tacrolimus dose in patients (Pikard et al., 2016).

Effects of donor gene SNPs upon immune response in acute GvHD:

Acute GVHD is primarily caused by alloreactive donor lymphocytes which expand and migrate to the target tissues, mainly, skin and intestinal epithelium. aGVHD is an allo-aggressive inflammatory process triggered and regulated by multiple cytokines, and chemokines produced both by the host and donor cells. These gene variants may express highand low-producing activity thus modifying clinical course of aGVHD. These interactions are far from clearness, and are subject to many gene association studies.

Most factors studied in connection with GVHD risk are produced by innate immune cells (macrophages, neutrophils, natural killers etc.). To search effects of donor and recipient gene variants upon GVHD, we performed a selection of appropriate genetic associations in available literature (PubMed, keywords: GVHD, gene polymorphism). Included were the studies with positive associations found, where both recipients and their donors were genotyped. We asked whether donor, or host hyperactive genes (or both) are associated with aGvHD as the most life-threatening immune complication of allo-HSCT. The results are summarized in Table 2.

Table 2. Distinct effects of recipient and donor gene variants upon aGVHD

Table 2.png

Table 2-1.png

Table 2-3.png

Table 2-4.png

One may conclude from these data that functional gene polymorphisms of immune factors/receptors associated with incidence/severity of GvHD are most commonly by donor origin. Recipient gene alleles are connected with aGVHD in few association studies. Therefore, donor cells seem mostly determine genetic background in clinical aGVHD.

A similar gene association data with GvHD reported by 2012 were statistically evaluated by Chien et al. (2012). Their own results obtained by Affymetrix arrays (genome-wide sequencing) of 1298 allogeneic transplants (both donor and patient samples) were tested to confirm previously reported candidate genes predisposing for GvHD. Of 40 previously reported candidate SNPs, 6 were successfully genotyped by the authors, and 10 other traits were added (imputed) and passed statistical criteria, thus getting association data from >40 studies on different polymorphic candidate genes able to influence aGvHD incidence.

To assess relative importance of candidate genes, the authors (Chien et al., 2012) used an algorithm involving minimal allele frequency (MAF) and Hardy-Weinberg equilibrium parameters, in order to assess reliability and contribution of the given allele to GvHD occurrence. Among the tested alleles, they have selected IL-10 promoter alleles (IL10 SNPs rs1800871 and rs1800872); IL-6 promoter variant rs1800795; IL2 allele (rs2069762); rs3087243 in CTLA4, rs4364254 in HPSE, and rs1801131 in MTHFR genes. In general, the tested gene set largely corresponds to the list of informative genes revealed in our analysis (see Table 2). As a result, the rs1800795 SNP in IL6 donor genotype was associated with sufficiently increased risk for grade III-IV aGVHD following HSCT.

Surprisingly, Chien et al. (2012) have revealed very low replication rate for the candidate gene SNPs, i.e., only 7%. Such low replication rates are encountered in early genetic literature and may result from non-standardized techniques of SNP detection, or application of formal statistical criteria.

Another class of non-MHC genes affecting HCT outcome is illustrated by the recent study by McCarroll et al. (2009) showing that deletion of the entire UGT2B17 gene determining a numer of HLA gene alleles can result in an alloimmune response associated with aGvHD. This multi-center study (1345 patients) initially examined six common deletions (UGT2B17, UGT2B28, GSTT1, GSTM1, LCE3C and OR51A2) in a phase I discovery study using 414 HLA MRD transplants. The association of the UGT2B17 deletion with acute GVHD was validated in two additional cohorts of, resp., 336 and 595 HLA-identical sibling transplants. Risk of acute GVHD proved to be greater (OR=2.5) when donor and recipient were mismatched for homozygous deletion of UGT2B17.

Thrombosis risk and gene polymorphism

In the world literature some early data were published regarding probable risk of thrombotic complications post-HSCT (McDonald GB et al., 1993).

Later on, a single-center study by Tunisian authors concerned incidence of central venous catheter (CVC)-related thrombosis in HSCT recipients (Abdelkefi et al., 2005). The laboratory prothrombotic markers included factor V Leiden, the prothrombin gene Gly20210A mutation, plasma antithrombin levels, and protein C and S activity. A total of 171 patients were included. Of them five (2.9%) and three (1.7%) patients had evidence of protein C and protein S deficiency, respectively. Only one patient had an antithrombin deficiency (0.6%). In total, 10 patients (5.8%) were heterozygous for the factor V Leiden mutation, and one patient had heterozygous prothrombin G20210A mutation (0.6%). Thrombosis was diagnosed in four out of 20 patients (20%) with a inherited prothrombotic abnormality compared to nine of 151 patients (6%) who did not have a thrombophilic marker (relative risk 3.3 CI 95% 1.1-9.9). These results provided a marginal evidence of inherited prothrombotic abnormalities contributing to CVC-related thrombosis in HSCT group.

Over last 2 decades, studying posttransplant effects of functional thrombophylic variants have not yielded some distinct results. E.g., a work by Azik et al. (2015) concerned patients possible correlations between venous thromboembolism (VTE) in 92 pediatric allo-HSCT patients within 100 days post-transplant. The studied prothrombotic risk factors included factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein(a), plasma antithrombin III, protein C, and protein S levels in all patients pre-transplant. Eight patients (9%) proved to be heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A polymorphism. VTE was diagnosed in 5 patients (5.4%); a prothrombotic risk variant been found in 3 of them. In summary, no significant relationship between VTE and inherited prothrombotic risk factors. Hence, an inherited prothrombotic risk for VTE after HSCT is low, but should be considered.

Effects upon survival rates

General effects of different-level gene polymorphisms upon transplant-related mortality (TRM) were recently performed by Sucheston-Campbell et al. (2015). Of course, better matching for HLA combined with supportive care and infection prophylaxis have improved survival over the past two decades. Hovewer, numerous SNP variants may lead to differential gene transcription, translation, and protein structure. These changes have the potential to modify immune responses or side effects of chemotherapy and/or radiation, and thus, survival outcomes in HCT patients.

Of those, genetic associations of NOD2/CARD15 with survival after HCT draw special attention. However, the first encouraging results was not confirmed in next studies. E.g., the largest NOD2/CARD15 study to date, 567 donor-recipient pairs both HLA matched and mismatched with primary diagnoses including hematologic malignancies, non-hematologic malignancies, and nonmalignant diseases, found only a borderline association (p=0.049) of a recipient SNP with increased TRM and conflicting results in the non-malignant patient groups (Kreyenberg, 2011). Some effect upon patients survival was revealed, and weak statistical correlation was found exclusively for recipient-side (SNP13) associated with increased pTRM (<0.01).

As referred in abovementioned review by Sucheston-Campbell et al. (2015), many works concerned candidate genes have been tested for informative SNP associatiated with transplant-related mortality(TRM) and overall survival (OS), checking SNPs in oxidative genes (GSTM1, UGT2B17), cytokine and chemokine genes, their receptors in both donors and recipients. Numerous studies beared on receptor-mediated immune recognition (FCGR3A, CTLA4 ), and NOD2/CARD15, like as VDR, MTHFR etc. So far, the candidate gene studies are at phase of association studies, without current clinical applications, due to their limited reproducibility.

Discussion

Since several decades, recipient/donor HLA matching was a sine qua non condition for optimal HSCT. Transplantation of cord blood cells and HSC from haploidentical donors has changed this paradigm. By opposite, minor differences in HLA patterns are now regarded as a sufficient factor of graft-versus-leukemia effect in the patient. Moreover, HLA allelic loss (segmental chromosome 6 deletions) in leukemia clones is considered a factor of erroneous HLA typing, immune escape of tumor cells and higher relapse risk after
HSCT (Taborelli et al., 2006; Dubois et al., 2012).

Moreover, a number of other functional gene variants may affect survival and risk of complications following in HSCT patients and are grouped as follows:
1. Most by recipient origin: drug metabolism-controlling genes (pharmacogenes) influencing biotransformation, time-dose kinetics and effects of cytotoxic drugs used in conditioning therapy are mostly genes expressed mostly in recipient liver, spleen and and target cells (both normal and malignant)
2. Mostly donor cell genes: cytokine genes encoding interleukins and some key inflammation regulators – mostly donor genes
3. Both recipient and donor origin: receptor and contact protein genes which encode innate receptors recognizing bacterial antigens and contacts proteins.

Key role of activated cytokine network in aGvHD genesis is widely recognized. The cytokine response seems to be switched by severe damage to normal tissues caused by conditioning therapy. At this time point, the relatively resistant innate immune cells, such as monocyte/macrophages, produce a series of inflammatory cytokines, i.e., IL-1, IL-4, IL-6, IL-12, IFNγ, TNFα etc. The aseptic inflammation is further enhanced by antigens from exogenous microbiota invading due to loss of epithelial integrity (Fig. 1, from Ramadan, Paczesny, 2015). The authors suggest specific induction of IL-6, IL-4, and IL-12 of, respectively, Tc17/Th17, Tc2/Th2, and Tc1/Th1 lymphocyte populations. Those, together with NK cells and monocytes/macrophages, exert cytolytic effects upon target epithelial tissues causing classical acute GvHD.

We see here that the candidate genes well fit the general chain of cytokine/receptor switching in evolving inflammatory reaction underlying aGVHD.

Medical applications of these protein factors as potential therapeutic targets are confirmed by clinical trials with appropriate anticytokine monoclonal antibodies are, mostly, at Phase I/II, and their clinical significance is not yet fully assessed. Other cytokine antagonists should be tested for their efficiency to prevent aGvHD, e.g., monoclonal antibodies against gamma chains of the main cytokines. In rodent models, pharmacological blockade of TNF-a, IL-6, and C-C chemokine receptor type 5 (CCR5) is proven to prevent aGvHD development (Teshima et al., 2016).

Figure 1.png

Figure 1. Pathogenesis of acute GVHD. Pre-transplant conditioning causes tissue damage. The affected tissues and cells release DAMPs (HMGB-1), PAMPs (LPS) from gut microbiota as well as inflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) contributing to the “cytokine storm.” These are the first danger signals that activate host APCs, which activate and polarized donor T-cells toward pathogenic T-cells (TH1 and TH17 for CD4 and TC1, TC17 for CD8). Activated pathogenic T-cells infiltrate target organs (i.e., GI tract, liver, skin) and amplify local tissue destruction. The presence of regulatory T-cells (Tregs) helps to reduce GVHD severity (Ramadan, Paczesny, 2015).

As seen from current studies, intestinal damage in severe GvHD forms is caused by donor T cells which attack intestinal stem cell (ISCs) niches. The antigen-presenting cells stimulated by foreign (mismatched) HLA (minor and minor ones) enhance these events by secreting IL-1, IL-6, TNF and other inflammatory cytokines. The affected mucosal layers allow bacterial dysbiosis and invasion of intestinal microflora, thus enhancing acute inflammatory reactions (Teshima et al., 2016).

Among T cell modulators, CTLA-4 and PD-1 are now intensively studied as a possible target for immune checkpoint inhibitors (e.c., ipilimumab). The CTLA-4 (CD152) is expressed both on CD4 and CD8 T cells, being, e.g., an inhibitor of autoreactive T cell populations (Buchbinder, Desai, 2016). Therefore, its functional alleles were studied by several groups for their GVHD risk (see table 2). In most studies, the recipient CTLA-4 alleles, hence, surviving lymphoid cells (may be, in thymus – Buchbinder), seem to increase AGVHD risk.

The immune stimulation from intestinal microbiota is mediated by the s.c. pattern-recognizing receptors known as TLR4 and NOD receptors in mammals (Heidegger et al., 2014). Therefore, their genetic variants may also play a significant role in GvHD modification, as seen from some studies (see Table 1).

From these literature data concerning a number of polymorphic functional genes we readily see that, in most cases, aG-VHD is associated with donor functional polymorphisms, as seen from Table 2. molecules (ICAM1, PECAM and SELL) in 425 recipient-donor pairs subjected to allogeneic HSCT, aiming to assess their effects upon clinical outcomes (TRM, GVHD). The rs5498 in the ICAM1 in both recipients and donors associated with a lower risk of Transplant-related mortality, however, without effect upon GVHD rates and severity.

Chemokines attracting distinct cell polulations to the inflammation site, could be also functionally polymorphic. A study by Bogunia-Kubik (2015) concerned CXCL12 (SDF-1) gene polymorphism (rs1801157) in 323 patients/donors with evaluation of total toxicity, aGVHD, and viral reactivation. Presence of the CXCL12-3’ A gene variant was associated with lower grade of aGVHD, thus suggesting altered migration of hematopoietic cells to the target organs.

Moreover, migration of alloreactive cells in extracellular matrix depends on local activity of collagen-degrading enzymes (matrix metalloproteinases, MMP’s). Interestingly, in our previous studies in 111 recipient/donor pairs we have found that the more transcriptionally active allele an MMP-1 gene (-1607 2G) harbored by donor HSC is associated with more frequent aGVHD in allo-HSCT patients whereas more active MMP-1 allele in recipient reduces aGvHD frequency (Chukhlovin et al., 2003). Severe GvHD (grade II-IV) was not detected with donors negative for MMP1 2G, whereas being rather common when donors carried a 2G allele of MMP1 (0/16 versus 13/44, p=0.014), as seen in Fig. 2.

Biological significance of donor-associated gene factors may be interpreted in terms of their cell sources and specific effects on target immune cell populations. E.g., interferon-gamma is ubiquitously produced by activated T lymphocytes, NK cells, macrophages, epithelial cells. E.g., IL-1beta is known to be synthesized by monocytes, macrophages, neutrophils, whereas proinflammatory IL-6 is produced by monocytes, macrophages and T cells. IL23 is again secreted by monocytes and dendritic cells, like as anti-inflammatory, immunosuppressive cytokine IL10 synthesized by monocytes, T4+ and B cells. Hence, most cytokines informative for gene polymorphism and associated with aGVHD, are produced by monocytes/macrophages. The donor monocytes are renewed from the GM-CFUs within 1 st month posttransplant and settle in different tissues, transforming to macrophages in addition to residual recipient macrophages. Therefore, both recipient and donor gene variants may function early after transplant thus determining their effects on certain cytokine synthesis and GVHD development. At later terms, however, donor macrophage populations seem to prevail among resident macrophages, due to natural replacement processes. The dynamics of this process is worth of further studies.

Contact and attraction molecules

Cell adhesion and attraction molecules may be also involved into pathogenesis of posttransplant complications. E.g., Thyagarajan et al. (2013) has tested SNPs of some contact molecules (ICAM1, PECAM and SELL) in 425 recipient-donor pairs subjected to allogeneic HSCT, aiming to assess their effects upon clinical outcomes (TRM, GVHD). The rs5498 in the ICAM1 in both recipients and donors associated with a lower risk of Transplant-related mortality, however, without effect upon GVHD rates and severity.

Chemokines attracting distinct cell polulations to the inflammation site, could be also functionally polymorphic. A study by Bogunia-Kubik (2015) concerned CXCL12 (SDF-1) gene polymorphism (rs1801157) in 323 patients/donors with evaluation of total toxicity, aGVHD, and viral reactivation. Presence of the CXCL12-3’ A gene variant was associated with lower grade of aGVHD, thus suggesting altered migration of hematopoietic cells to the target organs.

Moreover, migration of alloreactive cells in extracellular matrix depends on local activity of collagen-degrading enzymes (matrix metalloproteinases, MMP’s). Interestingly, in our previous studies in 111 recipient/donor pairs we have found that the more transcriptionally active allele an MMP-1 gene (-1607 2G) harbored by donor HSC is associated with more frequent aGVHD in allo-HSCT patients whereas more active MMP-1 allele in recipient reduces aGvHD frequency (Chukhlovin et al., 2003). Severe GvHD (grade II-IV) was not detected with donors negative for MMP1 2G, whereas being rather common when donors carried a 2G allele of MMP1 (0/16 versus 13/44, p=0.014), as seen in Fig. 2.

Figure 2.png

Figure 2. Increased incidence of acute GvHD in allogeneic hematopoietic transplants from donors carrying a hyperproducing MMP1 2G allele (Chukhlovin et al., 2003).

Some gene variants participating acting at cell and tissue barriers may alter basic tissue functions. For instance, one may suggest prothrombotic effects of PAI1-1 4G variant in veno-occlusive disease post HSCT, or MMP1 2G polymorphism to higher ECM permeability and easier migration of alloreactive donor lymphocytes to the target epithelium, etc. (Fig. 3).

Figure 3.png

Figure 3. Suggested biological effects of donor hyperactive gene variants leading to major HSCT complications.

Hence, one may suggest that active functional alleles of non-HLA genes, if present in donor cells, seem to dominate and may play a sufficient role in alloaggressive effects of donor cytotoxic T cells, thus causing severe aGVHD forms.

From Fig. 4, one may see that the local host cells (APCs) are releasing proinflammatory cytokines (TNF, IL-1, IL-6), being stimulated by damage products from cytotoxic treatment. Special affection is inflicted to intestinal wall. Death of intestinal epithelium brings about higher permeability to microbes and microbial toxins which are recognized by the
NOD2 and toll-like receptors (TLRs) on the resident APCs . Their role in other complications (veno-occlusive disease, severe mucositis needs further studies.

Figure 4.png

Figure 4. Schematic overview of gut bacteria-mediated initiation of acute graft-versus-host disease (Heidegger et al., 2014).

During the toxic conditioning regimen with total-body irradiation and/or chemotherapy, the destruction of intestinal epithelial cells leads to the loss of the epithelial barrier function. Similar effects occur at skin and other epithelial borders. Activated host and/or donor antigen-presenting cells prime allo-reactive donor T cells, which promote acute GVHD (Heidegger et al., 2014).

Most of these cytokine genes are showing informative associations showing a role of donor cells in GVHD. We cannot, of course, perform an additional donor selection for these gene variants. However, we may consider numerous non-HLA gene polymorphisms as risk factors, first of all, for AGVHD, and modify the scheduled GVHD prophylaxis regimens.

Appropriate multiplex prediction models are now developed and gradually tested, in order to personalize post-transplant preventive treatment. For example, multiple findings on donorand recipient functional gene variants allowed of designing certain informative SNP panels for donors and recipients (Kim et al., 2012). The authors tested a group of recipients’ SNPs of IL2, IL6R, FAS, EDN1, TGFB1, and NFKBIA, and donor polymorphisms of NOS1, IL1B, TGFB2, NOD2/CARD15, TNFRII, IL1R1, and FCGR2A. This selection was based on a previous big study in a total of 259 SNPs in 53 genes in 394 pairs of donors and recipients. The resulting computed risk models provided predictive stratification of the patients into low-risk (Q1), moderate-risk (Q2, Q3), and high-risk (Q4) groups with regard of OS, RFS, nonrelapse mortality (P=0.0043), and acute GVHD (P<0.0001).

Conclusion

Extensive studies are needed in order to specify distinct candidate genes for prediction of adverse pharmacological effects of cytostatic drugs in hematopoietic stem cell transplantation, covering large donor and recipient populations of various ethnicities, patient age, and different modes of hematopoietic stem cell transplants.

Modifying effects of functional gene polymorphisms, e.g., those influencing production of cytokines, adhesion and recognition molecules, are associated with incidence and severity of aGVHD. Less is known about associations of gene polymorphisms with other HSCT complications (mucositis, VOD etc.).

We have revealed some predominance in donor SNPs of immune-controlling genes associated with acute graft-versushost disease, as seen from the results of several comparative studies. This should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL-7R, MMP-1 et al.). By contrary, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.

Knowledge on the functional gene variants in donor may be applied for planning distinct schemes of cellular immune therapy, e.g., haploidentical HSCT, donor lymphocyte infusions, other cases of suggested graft-versus leukemia (lymphoma) effect.

Conflict of interest

No conflict of interests is declared.

References

Introduction

Table 1.png

Effects of donor gene SNPs upon immune response in acute GvHD:

Table 2.png

Table 2-1.png

Table 2-3.png

Table 2-4.png

Discussion

Figure 1.png

Contact and attraction molecules

Figure 2.png

Figure 3.png

Figure 4.png

Conclusion

Conflict of interest

No conflict of interests is declared.

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" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(82) "risk-immunnykh-oslozhneniy-allotransplantatsii-gemopoeticheskikh-stvolovykh-kletok" ["~CODE"]=> string(82) "risk-immunnykh-oslozhneniy-allotransplantatsii-gemopoeticheskikh-stvolovykh-kletok" ["EXTERNAL_ID"]=> string(4) "1350" ["~EXTERNAL_ID"]=> string(4) "1350" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(300) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(408) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхожденияBeyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(4711) "Эта обзорная статья касается генетической предрасположенности к ряду тяжелых иммунных осложнений при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), которые зависят в основном от различий донора и реципиента по набору системы HLA и так называемым минорным факторам совместимости, например – определенным аллелям HLA-G и другим белкам иммунной системы (TNF-α, IL1-β, IL-2, -6, 10) и их рецепторам, что связано с общей выживаемостью, возможным отторжением трансплантата или острой реакцией «трансплантат против хозяина» (оРТПХ). Кроме того, ТГСК является сложной процедурой с применением множества цитотоксических агентов, применяемых при кондиционирующей терапии, а также иммуносупрессивных препаратов, используемых после ТГСК. Минимальные различия в нуклеотидных последовательностях ряда функционально активных генов могут вызвать значительные различия в уровнях повреждения клеток и их восстановления после ТГСК. Эти полиморфные аллели могут повысить или снизить биологическое действие различных энзимов, рецепторов, молекул-транспортеров, факторов транскрипции ДНК и т.д. Поэтому конкретные полиморфные генные аллели, проявляющие высокую или низкую активность, могут быть ассоциированы с основными осложнениями ТГСК и выживаемостью реципиентов. Имеющиеся данные о многочисленных эффектах полиморфизмов не-HLA-генов в парах «донор-реципиент» позволил нам сделать следующие выводы: 1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии; 2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК. Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лимфоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-клеток, несущих более активные аллели ряда генов (например, IL-6, IL-7R, MMP-1 и др.). Напротив, эти белки могут быть мишенью соответствующих таргетных препаратов с целью предотвращения тяжелых форм оРТПХ. Ключевые слова Трансплантация гемопоэтических клеток, исходы, функциональные полиморфизмы генов, иммунные осложнения, фармакокинетика." 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функциональных не-HLA аллелей донорского происхождения" ["SECTION_META_DESCRIPTION"]=> string(300) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения" ["SECTION_PICTURE_FILE_ALT"]=> string(300) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения" ["SECTION_PICTURE_FILE_TITLE"]=> string(300) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "pomimo-hla-sistemy-risk-immunnykh-oslozhneniy-allotransplantatsii-gemopoeticheskikh-stvolovykh-kleto" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(300) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(300) "Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "pomimo-hla-sistemy-risk-immunnykh-oslozhneniy-allotransplantatsii-gemopoeticheskikh-stvolovykh-kleto" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "pomimo-hla-sistemy-risk-immunnykh-oslozhneniy-allotransplantatsii-gemopoeticheskikh-stvolovykh-kleto" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "pomimo-hla-sistemy-risk-immunnykh-oslozhneniy-allotransplantatsii-gemopoeticheskikh-stvolovykh-kleto" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(2) "70" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые 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["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["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) "18140" ["VALUE"]=> array(2) { ["TEXT"]=> string(35) "Алексей Б. Чухловин" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(35) "Алексей Б. Чухловин" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["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) "18141" ["VALUE"]=> array(2) { ["TEXT"]=> string(340) "НИИ детской онкологии, гематологии трансплантологии им. Р. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(340) "НИИ детской онкологии, гематологии трансплантологии им. Р. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18142" ["VALUE"]=> array(2) { ["TEXT"]=> string(4711) "Эта обзорная статья касается генетической предрасположенности к ряду тяжелых иммунных осложнений при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), которые зависят в основном от различий донора и реципиента по набору системы HLA и так называемым минорным факторам совместимости, например – определенным аллелям HLA-G и другим белкам иммунной системы (TNF-α, IL1-β, IL-2, -6, 10) и их рецепторам, что связано с общей выживаемостью, возможным отторжением трансплантата или острой реакцией «трансплантат против хозяина» (оРТПХ). Кроме того, ТГСК является сложной процедурой с применением множества цитотоксических агентов, применяемых при кондиционирующей терапии, а также иммуносупрессивных препаратов, используемых после ТГСК. Минимальные различия в нуклеотидных последовательностях ряда функционально активных генов могут вызвать значительные различия в уровнях повреждения клеток и их восстановления после ТГСК. Эти полиморфные аллели могут повысить или снизить биологическое действие различных энзимов, рецепторов, молекул-транспортеров, факторов транскрипции ДНК и т.д. Поэтому конкретные полиморфные генные аллели, проявляющие высокую или низкую активность, могут быть ассоциированы с основными осложнениями ТГСК и выживаемостью реципиентов. Имеющиеся данные о многочисленных эффектах полиморфизмов не-HLA-генов в парах «донор-реципиент» позволил нам сделать следующие выводы: 1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии; 2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК. Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лимфоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-клеток, несущих более активные аллели ряда генов (например, IL-6, IL-7R, MMP-1 и др.). Напротив, эти белки могут быть мишенью соответствующих таргетных препаратов с целью предотвращения тяжелых форм оРТПХ. Ключевые слова Трансплантация гемопоэтических клеток, исходы, функциональные полиморфизмы генов, иммунные осложнения, фармакокинетика." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4651) "Эта обзорная статья касается генетической предрасположенности к ряду тяжелых иммунных осложнений при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), которые зависят в основном от различий донора и реципиента по набору системы HLA и так называемым минорным факторам совместимости, например – определенным аллелям HLA-G и другим белкам иммунной системы (TNF-α, IL1-β, IL-2, -6, 10) и их рецепторам, что связано с общей выживаемостью, возможным отторжением трансплантата или острой реакцией «трансплантат против хозяина» (оРТПХ). Кроме того, ТГСК является сложной процедурой с применением множества цитотоксических агентов, применяемых при кондиционирующей терапии, а также иммуносупрессивных препаратов, используемых после ТГСК. Минимальные различия в нуклеотидных последовательностях ряда функционально активных генов могут вызвать значительные различия в уровнях повреждения клеток и их восстановления после ТГСК. Эти полиморфные аллели могут повысить или снизить биологическое действие различных энзимов, рецепторов, молекул-транспортеров, факторов транскрипции ДНК и т.д. Поэтому конкретные полиморфные генные аллели, проявляющие высокую или низкую активность, могут быть ассоциированы с основными осложнениями ТГСК и выживаемостью реципиентов. Имеющиеся данные о многочисленных эффектах полиморфизмов не-HLA-генов в парах «донор-реципиент» позволил нам сделать следующие выводы:
1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии;
2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК.

Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лимфоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-клеток, несущих более активные аллели ряда генов (например, IL-6, IL-7R, MMP-1 и др.). Напротив, эти белки могут быть мишенью соответствующих таргетных препаратов с целью предотвращения тяжелых форм оРТПХ.

Ключевые слова

Трансплантация гемопоэтических клеток, исходы, функциональные полиморфизмы генов, иммунные осложнения, фармакокинетика." ["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) "18143" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-36-51" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-36-51" ["~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) "18144" ["VALUE"]=> array(2) { ["TEXT"]=> string(20) "Alexey B. Chukhlovin" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(20) "Alexey B. Chukhlovin" ["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) "18145" ["VALUE"]=> array(2) { ["TEXT"]=> string(465) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The St. Petersburg State I. Pavlov Medical University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(435) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial
Research Institute of Children Oncology, Hematology and
Transplantation, The St. Petersburg State I. Pavlov Medical
University, L. Tolstoy St. 6-8, 197022, 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) "18146" ["VALUE"]=> array(2) { ["TEXT"]=> string(2379) "This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins (TNF-α, IL1-β, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients. Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us to make the following conclusions: 1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system; 2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles. This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD. Keywords Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2307) "This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins (TNF-α, IL1-β, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.

Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us to make the following conclusions:
1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system;
2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles.

This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.

Keywords

Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics." 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Chukhlovin" } ["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) "18146" ["VALUE"]=> array(2) { ["TEXT"]=> string(2379) "This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins (TNF-α, IL1-β, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients. Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us to make the following conclusions: 1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system; 2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles. This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD. Keywords Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2307) "This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins (TNF-α, IL1-β, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.

Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us to make the following conclusions:
1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system;
2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles.

This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.

Keywords

Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics." ["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(2307) "This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins (TNF-α, IL1-β, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.

Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us to make the following conclusions:
1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system;
2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles.

This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.

Keywords

Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics." } ["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) "18143" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-36-51" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-36-51" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-36-51" } ["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) "18147" ["VALUE"]=> string(108) "Beyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(108) "Beyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(108) "Beyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications" } ["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) "18145" ["VALUE"]=> array(2) { ["TEXT"]=> string(465) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The St. Petersburg State I. Pavlov Medical University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(435) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial
Research Institute of Children Oncology, Hematology and
Transplantation, The St. Petersburg State I. Pavlov Medical
University, L. Tolstoy St. 6-8, 197022, 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(435) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial
Research Institute of Children Oncology, Hematology and
Transplantation, The St. Petersburg State I. Pavlov Medical
University, L. 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например – определенным аллелям HLA-G и другим белкам иммунной системы (TNF-α, IL1-β, IL-2, -6, 10) и их рецепторам, что связано с общей выживаемостью, возможным отторжением трансплантата или острой реакцией «трансплантат против хозяина» (оРТПХ). Кроме того, ТГСК является сложной процедурой с применением множества цитотоксических агентов, применяемых при кондиционирующей терапии, а также иммуносупрессивных препаратов, используемых после ТГСК. Минимальные различия в нуклеотидных последовательностях ряда функционально активных генов могут вызвать значительные различия в уровнях повреждения клеток и их восстановления после ТГСК. Эти полиморфные аллели могут повысить или снизить биологическое действие различных энзимов, рецепторов, молекул-транспортеров, факторов транскрипции ДНК и т.д. Поэтому конкретные полиморфные генные аллели, проявляющие высокую или низкую активность, могут быть ассоциированы с основными осложнениями ТГСК и выживаемостью реципиентов. Имеющиеся данные о многочисленных эффектах полиморфизмов не-HLA-генов в парах «донор-реципиент» позволил нам сделать следующие выводы: 1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии; 2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК. Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лимфоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-клеток, несущих более активные аллели ряда генов (например, IL-6, IL-7R, MMP-1 и др.). Напротив, эти белки могут быть мишенью соответствующих таргетных препаратов с целью предотвращения тяжелых форм оРТПХ. Ключевые слова Трансплантация гемопоэтических клеток, исходы, функциональные полиморфизмы генов, иммунные осложнения, фармакокинетика." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4651) "Эта обзорная статья касается генетической предрасположенности к ряду тяжелых иммунных осложнений при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), которые зависят в основном от различий донора и реципиента по набору системы HLA и так называемым минорным факторам совместимости, например – определенным аллелям HLA-G и другим белкам иммунной системы (TNF-α, IL1-β, IL-2, -6, 10) и их рецепторам, что связано с общей выживаемостью, возможным отторжением трансплантата или острой реакцией «трансплантат против хозяина» (оРТПХ). Кроме того, ТГСК является сложной процедурой с применением множества цитотоксических агентов, применяемых при кондиционирующей терапии, а также иммуносупрессивных препаратов, используемых после ТГСК. Минимальные различия в нуклеотидных последовательностях ряда функционально активных генов могут вызвать значительные различия в уровнях повреждения клеток и их восстановления после ТГСК. Эти полиморфные аллели могут повысить или снизить биологическое действие различных энзимов, рецепторов, молекул-транспортеров, факторов транскрипции ДНК и т.д. Поэтому конкретные полиморфные генные аллели, проявляющие высокую или низкую активность, могут быть ассоциированы с основными осложнениями ТГСК и выживаемостью реципиентов. Имеющиеся данные о многочисленных эффектах полиморфизмов не-HLA-генов в парах «донор-реципиент» позволил нам сделать следующие выводы:
1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии;
2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК.

Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лимфоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-клеток, несущих более активные аллели ряда генов (например, IL-6, IL-7R, MMP-1 и др.). Напротив, эти белки могут быть мишенью соответствующих таргетных препаратов с целью предотвращения тяжелых форм оРТПХ.

Ключевые слова

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1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии;
2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК.

Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лимфоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-клеток, несущих более активные аллели ряда генов (например, IL-6, IL-7R, MMP-1 и др.). Напротив, эти белки могут быть мишенью соответствующих таргетных препаратов с целью предотвращения тяжелых форм оРТПХ.

Ключевые слова

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Introduction

A number of well-known specialists in oncohematology from MD Anderson Cancer Center Forum (Houston, Texas) have attended St. Petersburg for a joint conference with
Russian hematooncologists from St. Petersburg, Moscow and many Russian regions. This conference proceeded at the Azimuth Hotel and was quite useful for practical doctors who got acquaintance with some new treatment approaches to chemotherapy, hematopoietic stem cell transplantation and immunotherapy in leukemias and lymphomas.

Lymphomas and chronic lymphocytic leukemia

After opening words from Organising Committee, Prof. Irina V. Poddubnaya has presented a review Significance of minimal residual disease in follicular lymphoma and CLL. She presented some epidemiological data about growing incidence of lymphomas and chronic lymphocytic leukemia (CLL) based on Russian and international data. Over last time, application of new drugs caused increased overall survival (OS) in follicular lymphoma (FL) and multiple myeloma (MM). New prognostic markers, e.g., ALK expression allowed distinguish more or less favorable cases of certain lymphomas. Main attention was paid to minimal residual disease (MRD) and its prognostic significance in FL and CLL. In CLL, adequate MRD predictors may be quantitatively assessed by means of flow cytometry (CD5, CD19, CD20, CD79b), as well as IGHV mutation detectable by PCR technique. These markers are taken as standards. Clear correlations are shown between MRD absence and OS as well as progression-free survival (PFS). Proper timing of MRD testing, as well as number of preceding therapy cycles are important. BEN001NORMA study data and other trials are presented, showing efficiency of MRD testing. The issues of CLL and lymphoma treatment are also discussed, especially with new drugs (Brentuximab, Ibrutinib etc.). Combined treatment options may also increase response rates. Recent data show superior effects of obinutuzumab over rituximab in combination with chemotherapyu of FL. In CLL, a combined treatment with bendamustine and Venetoclax is also effective. Optional allo-HSCT may be considered in CLL progression.

Doctors M. Keating and J. Burger (Houston, USA) have presented quite comprehensive lectures about current views on CLL diagnostics, including some recently discovered molecular predictive markers determining prognosis of CLL therapy, as well as novel schedules for of CLL treatment. Special attention was paid to modern drugs, both immune checkpoint inhibitors, apoptosis inhibitors, monoclonal; antibodies, and specific inhibitors of signaling pathways in tumor cells.

A lecture by Dr. Pei Lin The 2016 WHO classification of lymphoma, an update concerned molecular and phenotypic markers of different lymphomas. The lecturer presented a subgroup of “double-hit” malignancies with MIC rearrangements and BCL2 translocations as a sufficient pathogenetic factor in high-grade B cell lymphomas, thus presenting a molecular basis for improvement of current lymphoma classifications, along with other molecular markers adopted for stratifying lymphomas, especially their aggressive clinical forms.

Dr. Peter Johnson, in his lecture Progress in Hodgkin lymphoma at ICML 2017, has summarized the latest progress in Hodgkin’s lymphoma (HL) prognostic markers (baseline PET, cell-free DNA) and treatment, new therapies, and new biology (reprogramming the R-S cells). Early-stage disease is treated by ABVD protocol controlled by PET, followed by repeated ABVD + involved-field radiotherapy. In current studies, Rituximab is used upfront, or (in cases of PET-negative status), before radiotherapy. Total Metabolic Tumor Volume (TMTV) is compared to EORTC classification as interim quantitative PET prognostic parameters; appropriate trials are underway. Total Lesion Glycolysis (TLG) indexes are also used in UK trials, showing high efficiency. MTV & TLG 2.5 have been associated with increased 3 yr HL events and inferior PFS. Response adapted therapy using FDG-PET provides an opportunity to personalize the approach to therapy, to achieve a best balance between efficacy and toxicity. Results of a phase II study of Brentuximab vedotin (BV) using a response adapted design for 1 st line treatment of HL showed dose-dependence of adverse effects (neuropathy, haematological etc.). In summary, BV has good single agent response rates. However, it is not a sufficient treatment in advanced disease. Consolidation with high dose therapy is effective.

Meanwhile, Nivolumab demonstrated frequent and durable responses, irrespective of depth of response, BV treatment history, and refractoriness to prior therapies. Combination of BV with nivolumab appears safe and demonstrated a high objective response rate. Restoration of B cell programs may offer new types of therapy. Patient’s age (>50 years) remains a major risk factor. A gene expression-based model combined with FDG-PET imaging to predict treatment response in advanced HL was tested in the RATHL study. Changes in tumor-specific cell-free DNA (cfDNA) could complement iPET in HL treatment prognosis.

Dr. Franco Cavalli (Bellinzona, Switzerland) has summarized his views on current treatment and classification of indolent lymphomas discussed at the International Conference on Malignant Lymphomas (ICML, Lugano, 2016). Despite sufficient success in involved-field radiotherapy (IFRT), a risk of relapses is still high, with common adverse factors at diagnosis, bulky disease etc. Favorable results of CVP treatment (6 cycles) versus R-CVP after IFRT for low-grade follicular lymphoma (TROG study) are shown. Watchful waiting may be a rational strategy in some cases. Rituximab maintenance therapy after R-CHOP, or R-FCM proved to be an effective live-prolonging treatment (progression-free survival) for, at least, 3 years (PRIMA trial, 2011). In PET-controlled studies (PET state after induction), the PFS values were 65% at 4 years as compared to 24% in PET(+) cases.

Several new inhibitory drugs (Idelalisib, Ibrutinib, Copalizib) have shown good immediate clinical response (57-72%) in indolent lymphomas. A concept of «no chemotherapy» strategies in treating follicular lymphomas was developed in SAKK-Nordic 35/10 Trial with Lenalidomide + Rituximab vs. Rituximab alone, or “RELEVANCE” Trial (Rituximab + Lenalidomide vs any chemotherapy) Lenalidomide + Rituximab Vs. RCHOP or CVP or R-Bendamustine. A special attention is given to Marginal Zone B-Cell Lymphomas (MZL, according to WHO classification). E.g., staging of MALT Lymphoma should be based on pooled PET/CT detection approach. Lymphomas with t(11;18) and those with lymph node involvement are unlikely to regress after H.pylori eradication thus composing a special risk group. Rituximab-Chlorambucil protocols are effective in MZL. Strategy for Waldenstrom macroglobulinemia (WM) is also discussed. WM chemotherapy could be initiated in cases of clinical symptoms, considering Rituximab, or chlorambucil, or, currently, with Ibrutinib.

Acute myeloid leukemia

A special session was dedicated to treatment of refractory/ resistant acute myeloid leukemia. Professor Hakop Kantarjian (Houston, USA) in his lecture How I treat AML. has shared his unique long-term experience in AML treatment, beginning with standard chemotherapy protocols, and followed with combination therapy supported by some novel targeted drugs aimed to inhibit distinct kinases and control points of leukemia cells. Specific traits of AML treatment in elderly patients was shown in a report by M. Ohanian Standard chemotherapy in young and elderly AML. Distinct pathogenetic features of acute myeloid leukemia in aging organism cause big problems with its treatment efficiency. Moreover, dose intensity of chemotherapy in this age group is also limited, due to different comorbidities, thus decreasing survival rates.

A report by Dr. Sergey Konoplev Detection of minimal residual disease in AML and ALL by flow cytometry immunophenotypic studies was devoted to practical laboratory aspects of MRD diagnostics in acute leukemias. High importance should be given to optimal workflow and reproducibility of immunophenotyping and immunohistochemical studies.
The results of flow cytometry and molecular biology assays of MRD detection should be compared for each individual clinical situation. Some newly proposed marker mutations seem to be of pathogenetic significance could be valuable not only as predictive markers, but for MRD detection as well.

Professor Valery G. Savchenko (Moscow, Russia) presented an extensive report 25 years of AML randomized trials in Russia, summarizing data on consequent multicentric clinical
AML trials are performed over last decades which showed sufficient increase in survival for the cohorts at younger ages, without sufficient success for older patients (>65 years), independent on chemotherapy dose intensity. Five Russian trials on AML therapy were performed between 1992 and 2014 (n=1427 cases). In recent AML study, mean age of patients was 59 years. Upon induction treatment based on 7+3 regimen plus maintenance therapy, the main factors were determined, i.e., age, cytogenetics, WBC counts, LDH activity.

Pregnancy is a sufficient risk factor in AML treatment, with respect to OS and PFS. Meanwhile, AML is a major indication for allogeneic HSCT. Posttransplant complications could be prevented by special treatment, e.g., acute GVHD could be effectively prevented by posttransplant cyclophosphamide. To prevent possible graft failure, mesenchymal stem cells could be injected intraosseally, thus creating local microenvironment.

Novel targeted agents could present future options for AML treatment, including specific antibodies, FLT3-inhibitors, IDH-inhibitors, BCL2-inhibitors, hypomethylating drugs and immunotherapeutic tools (CAR T-cells, immune checkpoint inhibitors). Cytogenetic risk factors (with favorable, intermediate and adverse prognosis) should be taken into account when planning specific induction and consolidation therapy. European LeukemiaNet recommendations should be taken into account when considering intensive chemotherapy. Maintenance therapy proved to increase RFS in elder patients with unfavorable karyotype.

Immunotherapy

Dr. A. Bedikian (Houston, USA) has presented some modern biological concepts that the immune system can eliminate cancer cells in vivo. Modern imunotherapeutic strategies include: cytokines, (interferon, interleukin-2); cancer vaccines, oncolytic viruses, (T-vec), adoptive transfer of ex vivo activated T and NK cells, antibodies or other proteins that co-stimulate cells or block the immune checkpoint pathways. Adoptive T cell therapy, especially with CART-cells is studied for treatment of solid and, currently, hematologic cancers. The field of cancer immunotherapy has recently got a significant recognition, due to approval of immune check point inhibitors (ipilimumab, nivolumab, pembrolizumab) for treatment of melanoma by 2014. Ipilimumab (anti-CT-LA-4) showed a significant efficiency in melanoma, however, with some autoimmune adverse effects. PD-1 inhibitors (Nivolumab, Pembrolizumab) proved to be effective in some solid tumors and Hodgkin’s disease. Targeting immune checkpoints with monoclonal antibodies also showed some improvement in overall survival, either as single-agent therapy or combined treatment.

A keynote lecture Immune therapy approaches in AML/MDS was presented by Doctor Naval Daver spoke about special biological and clinical characteristics of AML/MDS, especially, in aged subjects. To increase efficiency of treatment in this cohort, one may discuss both conventional chemotherapy and its potential combinations with newly introduced targeted agents. Individual prognosis in these cases may be based on molecular expression panels, thus requiring novel maintenance strategies. Novel pharmaceutical agents may provide more frequent and longer responses such as Decitabine which is currently used in AML/MDS. Moreover, as number of other targeted therapies are at different stages of clinical trials, FLT3-inhbitors and IDH-inhibitors), monoclonal antibodies to CD33 and CD123, novel cytotoxic agents including CPX-351, Bcl2-inhibitors etc. Clinical trials of combination therapy with novel hypomethylating agents have shown an increased clinical response, when compared to single-agent demethylation treatment. In particular, combined application of FLT3-inhibitors, hypomethylating drugs and standard cytotoxic chemotherapy with cytarabine, idarubicin etc. may improve the response rate and durability of the response. Clinical trials in immune therapy are now oriented for checkpoint based combinations, AML-specific vaccines, and CART-cells to AML antigens.

Another special report by Dr. Daver was dedicated to Modern Strategies in the Treatment of Myelofibrosis including polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET). Appropriate targeted treatment in myeloproliferative neoplasias is based on phenotypic driver mutations activating the JAK-STAT pathway. A number of other mutations (SRSF3, TET, AXCL1 etc.) are common in PMF. Some data from Phase 3 COMFORT-I and –II studies with Ruxolitinib in myelofibrosis are presented in the report showing some favorable effect of Ruxolitinib, with respect to overall survival and peripheral blood parameters.

Appropriate combination therapy schedules are proposed for the myelofibrosis patients. Some data on Sotatercept (ACE-011), a novel soluble receptor fusion protein, are also proposed.
A session Translational investigations in hematology was mostly devoted to research and laboratory aspects of leukemias. Doctor C. Bueso-Ramos (Houston, USA) held a lecture on Laboratory diagnostics in modern oncohematology being a comprehensive presentation for practical doctors, introducing them to modern laboratory diagnostics in oncohematology. Recent improvements in laboratory testing allow to perform timely diagnostics of MDS & AML, their providing better subtyping based, e.g., on mutation profiles, detection of novel genetic & epigenetic drivers of neoplasia, prediction of clinical prognosis and response to therapy? Classical hematological diagnostic based on morphology and histochemistry is accomplished by modern molecular genetics methods. Multidimensional model for tumor classification is proposed, with regard to morphogenetic analysis, genetic progression, searching new molecular targets for etiological therapy. A workflow for bone marrow specimens and trephine biopsies is described. The 2016 Revision of WHO Classification for AML was presented, with new genetic subtypes introduced. A new type (cup-like nuclei) acute myeloid leukemia associated with FLT3 internal tandem duplication and NPM1 mutation is described. The issues of laboratory diagnostics of myelodysplastic syndromes (MDS) and their relations to AML and other disorders are discussed, along with new cytogemetic classification. Hypomethylating therapy is proven to be effective in MDS, especially, if combined with PD-1 inhibitors. A role of TP53 and other common mutations revealed by SNP panels of MDS cells is discussed. A novel approach based on plasma miR-NA profiles may also help to discern distinct cytogenetic types. An integrated, “just in time”, case assessment in AML & MDS is required, in order to discover a novel fusion genes and other oncogenic mutations.

Professor Michael Andreeff (Houston, USA) has spoken on a quite intriguing topic Leukemia cell – stromal interactions, reviewing a number of facts confirming microenvironment-induced chemoresistance of AML cells. E.g., mesenchymal stem cells (MSCs) support AML growth while changing their gene expression. Therefore, MSC signaling factors could be targeted for inhibition of leukemia growth.

SDF1/CXCR4 expression correlates with decreased chemosensitivity of leukemic cells. Targeting SDF/CXCR4 is proposed for leukemic stem cells (LSCs) detachment, mobilization and apoptosis. Preclinical studies of CXCR4 inihibition or knockout were performed. Inhibition of CXCR4 or hsa-let7a miRNA overexpression lead to enhanced Ara-Cinduced apoptosis in vitro and in vivo. The patients with resistant AML and Flt mutation were treated by targeted drugs (especially Sorafenib, an Flt-3 inhibitor), in combination with Plerixafor and G-CSF. Preferential mobilization of leukemic cells was observed in this group. Silencing HIF1α may also reduce AML, as shown in murine models. In summary, stromal cells may protect leukemic stem cells from chemotherapy and TKI-induced apoptosis. Endosteal and perivascular niche are favorable for LSC growth. E.g., MSC cause resistance of leukemic cells by BCL-2 inhibition of osteoblasts.

Moreover, AML cells are able to promote osteogenic differentiation, thus increasing leukemia growth support. A sufficient discussion concerned cellular immune therapy in leukemias and lymphomas. Dr. S. Neelapu (Houston, USA) held a lecture CAR T cell therapy for lymphomas which contained some general data about technologies of generating CAR-T cells, their potential applications for treatment of different cancers, performed trials for their safety. Some adverse effects, including neurological complications, are sometimes associated with infusions of CAR T cells, and the ways of management are proposed for such situations.

Alexander V. Karabelskij and Andrey Yu. Zaritskey (St.Petersburg, Russia) have presented a report on Complex approach in CAR-T platform development and improvement.
The authors reported a variety of chimeric antigen receptors (CARs) which could be applied for tumor cell recognition and cytotoxic treatment. In accordance to modern requirements for generation and expansion of virally-modified CART-cells, a laboratory complex for cell production is presented which is served by the Russian BioCad team, and equipped by GLP standards. The ongoing research concerns preparation of CD19-targeted CAR-T for therapy. In vitro augmentation of CAR cassette is currently attempted. Other oncotargets (HER2, MUC1 etc.) are also in scope. Searching for perspective applications for CAR-T therapy includes its combined usage with PD-1 inhibitors which showed its safety in Phase I clinical trials with solid tumors. Strategies for novel «off-the-shelf» CAR-T therapy products are developed. The ongoing problems are: rational optimization of CAR expression in T cells; standardization of the vector core bioprocess; extensive scaling of CAR-T cells expansion procedure.

Acute lymphoblastic leukemia

Dr. E. Jabbour (Houston, USA) in a lecture How I treat ALL presented novel results of current studies in ALL treatment, especially, in adult patients, in particular, combined treatment with a wide range of novel drugs. Dr. Marina Konopleva presented a novel view on high-risk group of Ph-like B cell leukemias, where different JAK mutations (leading to CRLF2 overexpression), gene fusions (ABL1, ABL2, JAK2, EPOR, PDGFRB), or other gene mutations (IL7R, FLT3, RAS). Frontline therapy may be based on hyper-CVAD, augmented BFM protocols. High CRFL2 expression + JAK2 mutation is associated with adverse prognosis. The Ph-like ALLs may be treatable by appropriate kinase inhibitors (dasatinib, ruxolitinib), as well as blinatumomab and other methods of immunotherapy. Diagnostics of Ph-like B-ALL requires application of flow cytometry, cytogenetics and molecular biology methods.

Dr. Elena Parovichnikova (Moscow, Russia) has summarized in her lecture Modern ALL treatment in adults some new tendencies associated with cytogenetic and molecular stratification of the ALL patients, planning a risk-based therapy including novel antibodies and tyrosine kinase inhibitors.

Professor Аlexander I. Karachunskiy (Moscow, Russia) presented his long-term studies on clinical protocols in a lecture ALL treatment optimization: Moscow-Berlin strategy, describing evolution and amendments of pediatric Moscow-Berlin protocol over last 20 years, and limits for its successful application in high-risk groups of ALL children. Role of L-asparaginase in prevention of relapses, other drugs added to the MBP may improve overall and relapse-free survival of pediatric ALL patients.

Multiple myeloma

A lecture Modern strategies in myeloma treatment presented by Professor Thierry Facon (Lille, France). Clonal evolution of combined myeloma may proceed after therapy with Melphalan and Lenalidomide; conventional treatment is, generally, followed by autologous SCT. Permanent evolution of multiple myeloma treatment is accompanied by new therapeutic targets and novel classes of drugs proposed. Along with well-known proteasome and HDAC inhibitors, some new monoclonal antibodies and immune checkpoint inhibitors are under trial over 2016-2017, like as some cellular vaccines and CAR-T cell systems are developed now, first of all, to treat relapsing/refractory myeloma cases. Somewhat higher OS rates were found in relapsing myeloma cases when accomplishing standard schedules with novel drugs (Carfilzomib, Ixazomib, Elotuzumumab, Daratumumab) at >2-year observations. Such combined (3-drug) regimens are usually more active when compared to 2 drug regimens, but several questions remain: is a triplet required for all patients; is the most active triplet the best for all patients? Moreover, the issue of cost is becoming more relevant with the current treatment regimens, due to high costs of modern therapy.

Prof. Larisa P. Mendeleeva (Moscow, Russia) reported current experience of Auto-SCT in dialysis-depended myeloma at the Federal Hematological Research Center (Moscow), especially in myeloma patients with renal failure due to myeloma cast nephropathy which may cause altered pharmacokinetics of Melphalan and other therapeutic agents. Current study was based on results of 485 auto-HSCTs in 359 patients induced with conventional protocols, with HSC harvest followed by Melphalan conditioning and auto-HSCT with subsequent maintenance with Bortezomib, or Lenalidomide. In patients resistant to these agents, Pomalidomide-based therapy cycles are effective: complete response was registered in 88% of the cases. Special problems arised with patients on hemodialysis. A possibility of canceling hemodialysis after auto-HSCT in such myeloma patients was rather low (up to 16%). Therefore, allogeneic kidney graft transplantation is a possible alternative to hemodialysis in MM patients with end-stage chronic kidney disease.

Professor Stanislav S. Bessmeltsev (St. Petersburg, Russia) presented a lecture Modern strategies in myeloma relapse treatment containing clinical data from the St.Petersburg
Institute of Hematology and Transfusiology. Multiple myeloma (MM) evolves from indolent clonal disorder to active relapse which is followed by progression and/or refractory state. This course of MM requires either conventional therapy, or, in refractory cases, combined treatment with Bortezomib-, or Lenalidomide-based regimen with Dexamethasone, as a recently proposed option. Sufficiently longer OS and progression-free survival values after 2 or more relapses are shown following autoor allogeneic HSCT combined with novel drugs Carfilzomib, Daratumumab, Ixazomib, and Elotuzumab added to standard maintenance therapy. E.g., some data from ASPIRE and ENDEAVOR studies are presented. Carfilzomib (a KRd variant) was shown to prolong progression-free survival in any tested treatment schedule. In a TOURMALINE-MM1 study, some effect of Ixazomib upon OS and PFS was registered in frames of conventional maintenance therapy, as well as Pomalidomide administration in Lenalidomide and Bortezomib-resistant patients. The favorable effect depends on the cytogenetic risk group in MM patients.

Special lectures

Professor Boris V. Afanasyev, Director, R. Gorbacheva Research Institute of Children Oncology (St. Petersburg, Russia) presented a lecture: “The place and efficacy of allo-HSCT in relapse/refractory (r/r) classical Hodgkin lymphoma: anti-CD30 and PD-1 inhibitors as the bridges for improvement of outcome”. The lecture was focused on the modern treatment concepts of most unfavorable variants of classical Hodgkin lymphoma based on different types of immunotherapy (monoclonal antibodies, immune check-point inhibitors, allogeneic HSCT). Firstly, in order to improve the results of therapy, it is necessary to introduce risk-adapted protocols of the 1 st line therapy (ABVD or BEACOPP) using PET/CT scanning control. In advanced stage, new drugs significantly improve the results of therapy. Brentuximab vedotin (BV) was reported to show positive results from Phase 3 ECHELON-1 Trial in frontline advanced Hodgkin Lymphoma (HL): 2-y OS was 82.1% vs 77.2% comparing with BV+AVD vs ABVD (p=0.035). An AETHERA study showed about 20%-gain in 3-year survival for HD patients at high risk of relapse treated with BV after auto-HSCT. However, about 50% of patients exhibit resistance to 2 nd line chemotherapy. Allo-HSCT as a treatment option provides sufficient increase of PFS in HD due to “graft versus lymphoma” effect, especially in reduced-intensity conditioning regimens (RIC) (Sureda, 2008). The outcome of haplo-HSCT in Hodgkin lymphoma seems to be better than matched related SCT (Bacigalupo, 2015). PET(+) or (-) status at allo-HSCT is also of prognostic value (Moscovits, 2016).

A single center experience of R. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation in therapy of r/r Hodgkin lymphoma revealed the following results: BV therapy is quite efficient in HL causing CR in 35% of cases. Two to four BV courses are optimal for better response, however, accompanied by some adverse effects (neutropenia, neuropathy etc.). Several factors contributed to improved outcome after allo-HSCT in these patients: BV as a “bridge” for improving the disease status at the moment of allo-HSCT, RIC including Fludarabine/Bendamustine, and posttransplant Cyclophosphamide for prophylaxis GVHD. These three factors allowed increase of a 2-year OS to 74%. Current studies are also performed with PD-1 inhibitors (Pembrolizumab and Nivolumab). Overall response rate (ORR) was 69% after Nivolumab in resistant HL patients. A phenomenon of pseudoprogression and its role in diagnostics is discussed. Current Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) in HL is presented. Both BV and Nivolumab proved to be quite efficient in HL relapses after allo-HSCT. Immune therapy in R/R HL after 1st HSCT may include several options (donor lymphocyte infusions, BV, check-point inhibitors, second allo-HSCT).

Specific surgical issues of oncohematology were raised in a communication Surgical Diseases and Complications in Patients with Hematologic Malignancies by Dr. A. Artinyan, a surgeon, specialized in treatment of surgical leukemia complications. To his experience, most common surgical emergencies may evolve due to enteritis or colitis in the course of intensive chemotherapy, or resulting from severe GvHD. Some clinical examples of treating purulent conditions in immunocompromised patients were described in this report, thus arguing for a permanent dedicated surgeon at hemato-oncological clinics.

Myeloid neoplasia

A special session on chronic myeloid neoplasias was opened by Professor Hacop Kantarjian (Houston, USA) with a lecture How I treat CML. H. Kantarjian, a leading expert of MD
Anderson Cancer Center, has presented modern strategies of CML therapy evolving since 2000 to the present time by means of tyrosine kinase inhibitors (TKI) which drastically improved long-term survival in CML (from<10% to >90%). Therapeutic effect in acceleration phase and blast crisis still remains low, due to drug resistance at later stages. Blast excess and basophilia, as well as clonal anomalies (iso17/17p, 3q26.2 rearrangement etc.) are among adverse prognostic factors. In summary, current strategy in CML therapy is: frontline, Imatinib 400 mg daily; Dasatinib 100 mg daily; Nilotinib 300 mg BID, or Bosutinib 400 mg daily. Second/ third line includes Nilotinib, Dasatinib, Bosutinib, Ponatinib, Omacetaxine, and allogeneic SCT is considered. Other therapies may include Decitabine, Pegasys, Hydrea, Cytarabine, combined treatment with TKIs. A big IRIS study revealed similar survival with Imatinib vs Interferon+AraC in CML over 10 years. Results of ENEST study (Imatinib vs Nilotinib) are presented. In 2017, standard treatment includes Imatinib for low-risk Sokal and older pts (≥ 65-70 yrs); 2 nd generation TKIs (2G-TKIs) for higher-risk Sokal until complete clinical remission, then back to Imatinib; 2G-TKIs may be used for younger pts (< 50 yrs) in whom Rx DC is important. Meanwhile, benefits and drawbacks of the 1Gand and 2GTKIs including long-term toxicities were discussed. From financial viewpoint, a strong justification is required to use 2 nd TKIs as frontline CML treatment (versus generic imatinib) or lower prices of second TKIs. Patients with CML should be on daily TKIs, whether in complete remission or even if 100% Ph-positive, in the course of CML-CP or in transformation, except for “molecular cure” conditions. In cases of AP/BP progression or TKI failure (drug resistance mutations), HSCT is strongly indicated. In summary, Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib, Omacetaxine present an excellent therapy for CML; clinical/hematological complete remission (CGCR) is endpoint of Rx improving survival; early response (3-6 mos) is predictive for favorable course; The aim terms for PCR<10% by 6 mo, and for CGCR, by 12+ months are only indications to change the therapy; deeper molecular responses (MMR) improve EFS; however, they do not impact transformation or survival.

A lecture Treatment-free remissions in CML by the President of European Leukemia Net (ELN), Professor Rüdiger Hehlmann (Heidelberg University, Germany) tried to answer these questions as follows: (1) Discontinuation of tyrosine kinase inhibitors (TKIs) after long-term therapy in CML can be safe if you do it right; (2) The risk is connected with BCR-ABL which causes genetic damage and promotes progression of the disorder. Previous Imatinib trial showed that 10-year survival was 82%, with 70–80% deep molecular responses (MR 4 , MR 4.5 ) after 10 years and more patients dying of non-CML comorbidities; thus far, high risk of relapse remained after Imatinib discontinuation. Thus life-long treatment is recommended. However, life-long TKI treatment may be accompanied by a reduction of quality of life as a consequence of mild to moderate TKI side effects. Economic consequences of life-long treatment may be also considerable. However, due to general availability of generic Imatinib, the economic burden of life-long treatment is much reduced. Moreover, TKI discontinuation is followed in about 30% by a syndrome of skeletal pain resembling polymyalgia rheumatic. The main biological issue is that BCR-ABL persists in genomic DNA even in stable molecular remission, thus being a course of potential relapse (ISAV study). The effects of TKI discontinuation after >3 years of TKI therapy (EU-RO-SKI study) were discussed. Molecular relapse-free survival was 56% at 1 year of observation. Longer duration of Imatinib therapy (optimal ≥ 5.8 years) and longer molecular remission prior to cessation correlates to a higher probability of relapse-free survival. Thus, in favorable cases (20-40% of patients with low Sokal scores, chronic phase, typical BCR-ABL transcript) Imatinib (TKI) can be stopped safely after prolonged therapy and long-term MR 4 molecular remission. However, frequent and regular standardized PCR monitoring is essential, due to sufficient risk of relapse.

Irina N. Subortseva (Moscow, Russia), Elsa Lomaia (St. Petersburg, Russia) reported their joined study Interferon-alfa in MPNs treatment concerning treatment of myeloproliferative neoplasms (MPN) by α-Interferon. This drug (rIFNα-2b) was used in MPN patients since late 80’s. A number of studies showed hematological and clinical response in 80%, however, causing toxic effects in 1⁄4 of the group. Pegylated IFNs showed less toxicity, thus prompting current study of comparative efficacy and safety of Cepeginterferon alfa-2b, interferon alpha-2b, and hydroxycarbamide in patients with essential thrombocytopenia and polycytemia vera (n=63). JAK2 mutation was revealed in most cases. Treatment with Cepeginterferon alfa-2b caused hematological response in 78% of cases and drop in JAK2 burden, as well as improved quality of life. In summary, Cepeginterferon alfa-2b therapy in patients with MPNs is characterized by high efficacy in achieving clinical and hematological responses, and acceptable safety profile without any significant differences for these parameters with hydroxycarbamide, or α-rINF.

Stem cell transplantation

A special session on stem cell transplantation started with a lecture by Dr. I. Khouri (Houston, USA) Modern strategies in stem cell transplantation. Dr. Khouri focused his presentation on modern treatment of non-Hodgkin’s lymphomas and AML by means of allo-HSCT while mentioning age of patient, performance status and early progression as main factors predicting better clinical effect. Allo-HSCT with nonmyeloablative conditioning by Fludarabine, Rituximab, MTx (Сy) is proposed for relapsing B cell lymphoma, with longterm survival of >80%. When treating AML by allo-HSCT, minimal residual disease pre-transplant is a high risk factor for OS and RFS. Among new therapies, immunotoxic drugs (e.g., Zevalin, Tiuxetan) may be successfully used in refractory lymphomas. Rituximab may be applied together with Bendamustine and Fludarabine as pre-transplant conditioning in relapsing lymphomas. Haploidentical SCT proved to be, at least, of similar efficiency when compared to unrelated SCT, if performed with posttransplant Cyclophosphamide prophylaxis of GvHD. Brentuximab Vedotin provides better PFS rates in maintenance therapy of Hodgkin disease.

Dr. Leslie Lehmann from Dana Farber Cancer Institute (Boston, USA), in her Transplant in pediatric leukemia patients specified three challenges in ALL treatment (decreased intensity of therapy; decreased long and short-term toxicity; perfect risk-stratification). HSCT may be effective in 1 st and further clinical remissions, dependent on absence of active disease pre-transplant. Early relapse or late relapse with 2 nd induction failure are relative indications for allo-HSCT in ALL. Primary risk factors include age of the child, leukocyte number at presentation, pre-treatment degree. Disease-dependent risk factors include ALL phenotype, cytogenetic findings, extramedullary relapse sites. Conditioning regimen should take these factors into account. Majority of survivors of pediatric HSCT are similar to age-matched controls: different from age-matched controls stature, bone health, gonadal function and reproductive health. Ongoing chronic GVHD is a biggest predictor of poor outcome. Novel therapeutic approaches, e.g., cytokine therapy, vaccine therapy, anti-PD-1 inhibitors are promising, especially, in lymphomas. CAR-T anti-CD19+ cell therapy may be applied at any stage before or after HSCT, being effective also in extramedullary lesions (e.g., brain involvement). In summary, modern view includes diminished indications for standard HSCT in childhood ALL. This procedure has to be used in terms of more precise risk stratification; targeted therapy, and better tolerated intense therapy.

Dr. Dmitry Motorin has shared clinical experience of the Almazov Medical Center (St. Petersburg) in haploidentical hematopoietic stem cell transplantation (haplo-SCT). This
HSCT type is highly demanded, due to donor availability, lower costs as compared to HSCT from matched unrelated donors. Moreover, progression-free survival (PFS) in AML treatment strongly depends on duration of complete remission and molecular genetic risk group. Over last five years, a shift towards haplo-HSCT from haploidentical family donors is observed at the Almazov Center when managing acceleration phase, or blast crisis in CML, myelodysplastic syndrome/AML, and in ALL cases (male donors were preferred). Nonmyeloablative conditioning (Flu-Cy-Mel) was used in 75% of cases. GVHD prophylaxis included posttransplant Cy plus Cyclosporin A plus Mycophenolic acid. Engraftment terms, early outcomes and complications of haplo-HSCT corresponded to other alloHSCT types. OS values after allo-HSCT in CML depended on completeness of cytogenetic remission, and phase of disease at transplant. Haplo-HSCT seems to cause early decrease in activity of CML. Longer terms of observation after haplo-HSCT in AML showed a 2-year OS of >40%. Early complications (infections, GvHD et al.) occurred at certain rates. Posttransplant Azacytidine prophylaxis in AML MRD-free patients improves progression-free survival.

Mikhail Maschan, L. Shelikhova (Moscow, Russia) presented their data on haplo-SCT in pediatric leukemia patients in Russia. Dr. Shelikhova from Dmitriy Rogachev Federal
Center for Pediatric Hematology, Oncology and Immunology (Moscow) has performed allo-HSCT in 280 childhood ALL and AML patients (haplo-HSCT, in 151 cases), up to half of them performed in first remission. The grafts in 75% of cases were subject to TCR αβ,CD19 depletion which provides elimination of GVHD effectors and Epstein-Barr virus reservoire, while saving potential GVL effectors in the graft. The 3-year EFS was 59%, and transplant-related mortality was maintained at 8-11%. Acute and chronic GvHD incidence, and general relapse rates were similar for matched unrelated and haploidentical HSCTs. Meanwhile, incidence of acute GvHD after ATGAM injections proved to be twice higher than after Thymoglobulin usage. A 3-year event-free survival in AML (from complete remission state) was higher after haplo-HSCT (86%) than following unrelated matched HSCT (55%). Hence, in both AML and ALL settings, haplo-HSCT should be preferred to MUD.

In a report by Tatyana Bykova, Alexander D. Kulagin (St. Petersburg, Russia) Allo-HSCT for aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH)/AA. Dr. T. Bykova reported current data from Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation concerning allo-HSCT in aplastic anemia (AA), AA/
PNH/, and AA/MDS/AML (a total of 90 cases) including 8 haplo-HSCT. Most common conditioning was FLU/CY(Bu)/ATG or ALEM. Secondary graft failure at 2 years was recorded in 18% of transplanted patients. Severe acute GvHD occurred in 5% of cases, whereas chronic GvHD was more common upon grafting with peripheral blood stem cells. Overall survival was much higher after HSCT from matched siblings. Eculizumab as anti-hemolytic treatment was used in 16 cases as bridging therapy in AA/PNH before HSCT. Engraftment was reached at a mean of 20 days correlating with decrease in PNH clone extent. Secondary graft failure was revealed in 9% of cases. Severe GvHD was no detected, disease-free survival was 84% at 2 years. In conclusion, allogeneic BMT proved to be a standard curative option for severe AA; bone marrow is a preferred source of stem cells. Eculizumab bridging for HSCT is preferrable for hemolytic PNH/SAA therapy.

Ivan S. Moiseev (St. Petersburg, Russia) told about Novel approaches in the prophylaxis and treatment of GVHD after AlloHSCT. He has followed evolution of aGVHD prophylaxis n allo-HSCT, from Cyclosporin A+Methotrexate to Tacrolimus and MMF implementation. Haploidentical HSCT proved to be a favorable option to avoid severe aGvHD. In this respect, a trial of aGvHD prophylaxis with posttransplant cyclophosphamide (PTCy) was started at the R. Gorbacheva Research Institute of Children Oncology (trial No.NCT02294552). When comparing injections of horse ATG with PTCy prevention, the latter regimen was associated with lower incidence of acute and chronic GvHD, thus transplating in lower survival probability. Early event-free survival proved to be higher with single-agent PTCy than in CNI/MMF/MTx regimen. An NCT02627573 trial started in 2015, been designed as a randomized trial of GVHD prophylaxis with PTCy vs. Thymoglobulin in unrelated SCT with chronic myeloproliferative neoplasms and myelodysplatic syndrome. Extracorporeal cytopheresis and anticytokine therapy were compared for chronic GvHD therapy, the study is in progress.

Conflict of interest

No conflict of interests is declared.

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Introduction

Lymphomas and chronic lymphocytic leukemia

Acute myeloid leukemia

Immunotherapy

Acute lymphoblastic leukemia

Multiple myeloma

Special lectures

Myeloid neoplasia

Stem cell transplantation

Conflict of interest

No conflict of interests is declared.

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Моторин¹" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["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) "18154" ["VALUE"]=> array(2) { ["TEXT"]=> string(629) "1 Национальный медицинский исследовательский центр имени В. А. Алмазова, Санкт-Петербург, Россия 2 Научно-исследовательский институт детской онкологии, гематологии и трансплантологии им. Р. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(599) "¹ Национальный медицинский исследовательский центр имени В. А. Алмазова, Санкт-Петербург, Россия
² Научно-исследовательский институт детской онкологии, гематологии и трансплантологии им. Р. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18155" ["VALUE"]=> array(2) { ["TEXT"]=> string(2601) "Совместная конференция клиницистов медицинского Центра M.D. Anderson (Хьюстон, Техас, США) и специалистов ведущих российских гематологических центров состоялась в Санкт-Петербурге 30 июня – 1 июля 2017 г. Ряд отдельных заседаний был посвящен текущим проблемам диагностики и патогенетической молекулярной классификации в гематоонкологии, в том числе – при хроническом лимфолейкозе, острых лейкозах, апластических анемиях (AA), миелодиспластическом синдроме (МДС), злокачественных лимфомах. Протоколы стандартного лечения, а также клиническая эффективность новых таргетных препаратов и комбинированные терапевтические подходы подвергались рассмотрению с акцентом на лечение болезни Ходжкина, хронического лимфолейкоза, хронического миелоидного лейкоза и миеломной болезни. Были также представлены современные разработки в лекарственном лечении острых лейкозов, особенно – острого миелобластного лейкоза. Проводилось рассмотрение и обсуждение эффективности трансплантации гемопоэтических стволовых клеток в качестве излечивающей терапии при некоторых формах лейкозов и лимфом, а также возможности иммунотерапии опухолей (например, CAR-T клетками) и соответствующие технологии. Ключевые слова Российско-американская конференция, лейкозы, лимфомы, патогенез, классификация, лечение, таргетные препараты, аллогенная трансплантация гемопоэтических стволовых клеток." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2553) "Совместная конференция клиницистов медицинского Центра M.D. Anderson (Хьюстон, Техас, США) и специалистов ведущих российских гематологических центров состоялась в Санкт-Петербурге 30 июня – 1 июля 2017 г. Ряд отдельных заседаний был посвящен текущим проблемам диагностики и патогенетической молекулярной классификации в гематоонкологии, в том числе – при хроническом лимфолейкозе, острых лейкозах, апластических анемиях (AA), миелодиспластическом синдроме (МДС), злокачественных лимфомах. Протоколы стандартного лечения, а также клиническая эффективность новых таргетных препаратов и комбинированные терапевтические подходы подвергались рассмотрению с акцентом на лечение болезни Ходжкина, хронического лимфолейкоза, хронического миелоидного лейкоза и миеломной болезни.

Были также представлены современные разработки в лекарственном лечении острых лейкозов, особенно – острого миелобластного лейкоза. Проводилось рассмотрение и обсуждение эффективности трансплантации гемопоэтических стволовых клеток в качестве излечивающей терапии при некоторых формах лейкозов и лимфом, а также возможности иммунотерапии опухолей (например, CAR-T клетками) и соответствующие технологии.

Ключевые слова

Российско-американская конференция, лейкозы, лимфомы, патогенез, классификация, лечение, таргетные препараты, аллогенная трансплантация гемопоэтических стволовых клеток." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["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) "18156" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-52-59" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-52-59" ["~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) "18157" ["VALUE"]=> array(2) { ["TEXT"]=> string(131) "Andrey Yu. Zaritskey1, Boris V. Afanasyev2, Dmitry V. Motorin1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(95) "Andrey Yu. Zaritskey¹, Boris V. Afanasyev², Dmitry V. Motorin¹" ["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) "18158" ["VALUE"]=> array(2) { ["TEXT"]=> string(317) "1 Federal Almazov North-West Medical Research Centre, St. Petersburg, Russia. 2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(287) "¹ Federal Almazov North-West Medical Research Centre, St. Petersburg, Russia.
² R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["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) "18159" ["VALUE"]=> array(2) { ["TEXT"]=> string(1287) "A joint conference of clinicians from M.D. Anderson Medical Center (Houston, Texas, USA) and specialists from leading Russian hematological centers took place in St. Petersburg on June 30-July 1, 2017. A series of special sessions was dedicated to current issues of diagnostics and pathogenetic molecular classification in hemato-oncology, including chronic lymphocytic leukemia (CLL), acute leukemias (AL), aplastic anemias (AA), myelodysplastic syndrome (MDS), malignant lymphomas. Standard treatment schedules, as well as clinical effects of newly developed targeted drugs and combined therapeutic approaches were analyzed, with a focus on Hodgkin’s disease, chronic lymphocytic and myeloid leukemias and multiple myeloma. Recent developments in AL treatment, especially, in acute myeloblastic leukemia, were also presented. Current position of hematopoietic stem cell transplantation as a curative treatment in some leukemia/lymphoma settings, opportunities for tumor immunotherapy (e.g., CAR-T cells) and appropriate technologies were also discussed. Keywords USA-Russian conference, leukemia, lymphoma, pathogenesis, classification, treatment, targeted drugs, allogeneic hematopoietic stem cell transplantation." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1251) "A joint conference of clinicians from M.D. Anderson Medical Center (Houston, Texas, USA) and specialists from leading Russian hematological centers took place in St. Petersburg on June 30-July 1, 2017. A series of special sessions was dedicated to current issues of diagnostics and pathogenetic molecular classification in hemato-oncology, including chronic lymphocytic leukemia (CLL), acute leukemias (AL), aplastic anemias (AA), myelodysplastic syndrome (MDS), malignant lymphomas. Standard treatment schedules, as well as clinical effects of newly developed targeted drugs and combined therapeutic approaches were analyzed, with a focus on Hodgkin’s disease, chronic lymphocytic and myeloid leukemias and multiple myeloma. Recent developments in AL treatment, especially, in acute myeloblastic leukemia, were also presented. Current position of hematopoietic stem cell transplantation as a curative treatment in some leukemia/lymphoma settings, opportunities for tumor immunotherapy (e.g., CAR-T cells) and appropriate technologies were also discussed.

Keywords

USA-Russian conference, leukemia, lymphoma, pathogenesis, classification, treatment, targeted drugs, allogeneic hematopoietic stem cell transplantation." 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A series of special sessions was dedicated to current issues of diagnostics and pathogenetic molecular classification in hemato-oncology, including chronic lymphocytic leukemia (CLL), acute leukemias (AL), aplastic anemias (AA), myelodysplastic syndrome (MDS), malignant lymphomas. Standard treatment schedules, as well as clinical effects of newly developed targeted drugs and combined therapeutic approaches were analyzed, with a focus on Hodgkin’s disease, chronic lymphocytic and myeloid leukemias and multiple myeloma. Recent developments in AL treatment, especially, in acute myeloblastic leukemia, were also presented. Current position of hematopoietic stem cell transplantation as a curative treatment in some leukemia/lymphoma settings, opportunities for tumor immunotherapy (e.g., CAR-T cells) and appropriate technologies were also discussed. Keywords USA-Russian conference, leukemia, lymphoma, pathogenesis, classification, treatment, targeted drugs, allogeneic hematopoietic stem cell transplantation." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1251) "A joint conference of clinicians from M.D. Anderson Medical Center (Houston, Texas, USA) and specialists from leading Russian hematological centers took place in St. Petersburg on June 30-July 1, 2017. A series of special sessions was dedicated to current issues of diagnostics and pathogenetic molecular classification in hemato-oncology, including chronic lymphocytic leukemia (CLL), acute leukemias (AL), aplastic anemias (AA), myelodysplastic syndrome (MDS), malignant lymphomas. Standard treatment schedules, as well as clinical effects of newly developed targeted drugs and combined therapeutic approaches were analyzed, with a focus on Hodgkin’s disease, chronic lymphocytic and myeloid leukemias and multiple myeloma. Recent developments in AL treatment, especially, in acute myeloblastic leukemia, were also presented. Current position of hematopoietic stem cell transplantation as a curative treatment in some leukemia/lymphoma settings, opportunities for tumor immunotherapy (e.g., CAR-T cells) and appropriate technologies were also discussed.

Keywords

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Keywords

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² R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(287) "¹ Federal Almazov North-West Medical Research Centre, St. Petersburg, Russia.
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Ряд отдельных заседаний был посвящен текущим проблемам диагностики и патогенетической молекулярной классификации в гематоонкологии, в том числе – при хроническом лимфолейкозе, острых лейкозах, апластических анемиях (AA), миелодиспластическом синдроме (МДС), злокачественных лимфомах. Протоколы стандартного лечения, а также клиническая эффективность новых таргетных препаратов и комбинированные терапевтические подходы подвергались рассмотрению с акцентом на лечение болезни Ходжкина, хронического лимфолейкоза, хронического миелоидного лейкоза и миеломной болезни. Были также представлены современные разработки в лекарственном лечении острых лейкозов, особенно – острого миелобластного лейкоза. Проводилось рассмотрение и обсуждение эффективности трансплантации гемопоэтических стволовых клеток в качестве излечивающей терапии при некоторых формах лейкозов и лимфом, а также возможности иммунотерапии опухолей (например, CAR-T клетками) и соответствующие технологии. 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Ключевые слова

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Ключевые слова

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Introduction

The progress in genome editing over the last three decades has been accompanied by the development of appropriate legal regulations and ongoing discussions of their implementation into real practice.

In this article, we will focus primarily on current regulatory practice supporting development of the first clinically oriented products for treatment of disease, such as HIV, Hepatitis B and cancer. Moreover, regulations and guidance are still developing especially, in Russia and will require a permanent dialogue between regulatory agencies and scientists [14].

The logic of product development, addressing scientific questions and engagement to a regulatory dialogue, may be based on the following principles:

Unique requirements for each genome-edited cell product (GECP) require a case-by-case review, aiming to comply with current local guidelines (or discuss how they are not relevant to this product);
For most cases, there is lacking knowledge on potential clinical consequences, thus requiring cautious approaches to be taken;
Regulatory authorities should be interested in partnership with developers of genome-editing technology, thus ensuring its sooner access to patients.

Generally, genome editing therapy (ex vivo or in vivo manipulations) will determine a significant part of preclinical and clinical study program. Similarly, the type of product will impact main characteristics of manufacturing process. Usage of mock product (individual cell material from donors or patients) is acceptable since it is needed to assure quality of process development and characterization for personalized approaches, especially for ex vivo applications. This implementation strategy is very similar to evaluation of cell products.

Genome editing: variety of tools and products

Three genome editing tools are mostly used now: ZFN and TALEN systems which are at a more advanced stage, and CRISPR/Cas9 being in very early clinical development, thus providing us an opportunity to proceed with their further development and regulatory discussions [14, 16]. Moreover, type of genome editing therapy (either ex vivo, or in vivo manipulation) will generate, at least, two specific questions:

1. Should be an ex vivo genome editing therapy tested prior to reinfusion into patients, and how should it be performed?

A great deal of sterility assurances and processes (including fluorescent flow cytometry and cell sorting (FACS techniques) should be applicable for the machines used to sort each patients’ cells. This is considered to have a slightly better safety profile due to appropriate control and tests that can be conducted ex vivo to reassure quality of the cells (end product) that is returned to the patients. Fast-developing CAR-T cell products are a good example of this therapy [12].

2. Should be the applied therapy used for in vivo gene modifications?

These genome-modified cell products require more preclinical (molecular biology, in vitro)) data to understand their mechanism of action (MOA) and proliferation pathways.
Moreover, specific activity of such products cannot be stopped even after a single injection, if some self-limiting mechanism is not provided [15]. Hence, a self-inactivation activity of a viral vector driven by a switch-off mechanism could be also developed. At the same time, additional virus-shedding studies are required to test levels of target gene expression and their time frames [8]. Long term clinical safety data will be also required for evaluation of vector-driven products, most possibly, for 5 years and more (longer terms are possible, for post-market availability, expecting large benefits observed due to high demand for the product) [10, 14].

Potential off-target activity is another critical challenge for in vivo gene modifications. It’s well known that ZFN and TALEN are more site-specific and generate less regulatory concerns. CRISPR\Cas9 has more variability and causes serious challenges due to possible off-target activity especially in vivo modifications. A recent publication in Molecular Therapy [18] has reported that high levels of additional mutations in mice treated with CRISPR/Cas9 generated attention and debates on this aspect [18]. In a letter published June, 2017, the researchers reported a whole genome sequencing study which showed uncovered more than 1,600 genetic differences between the two mice treated with CRISPR/Cas9 technology, and 1 untreated control [17]. The authors concluded that CRISPR/Cas9 may be much less precise than previously expected [17]. Not surprisingly, the publications received a great deal of pushback from CRISPR companies and researchers criticizing the study, its methodology, and conclusions. In a Letter to The Editor, the authors replied that the analysis showed a “striking similarity” for single nucleotide variants (SNV) and insertions, deletions (indels) across the genome between treated mice that suggesting “either underlying genetic similarities or a mutagen that is strongly directive.” In addition, the authors compared the SNV and indels variant list against the mouse reference genome, and found the variants that were distributed in a way that a mutagen such as CRISPR “is unlikely to be causative for these observed variants.” [4]. Undoubtedly, regulatory bodies will have their say by providing feedback to requests addressing this challenge, or even by publishing guidelines for off-target evaluation.

Product characterization

The genome-modified cell description will depend on nature and purpose of the product and could fall into:
(а) Genome therapy medicinal product (GTMP) described by special EMA guidelines (10) or FDA one [7-8] or
(b) Cell product based on CAR T and other types of ex vivo genome editing therapy [6-11]

Since these treatments may be applied for treatment of rare diseases, batches manufactured according to GLP standards (Good Laboratory Practice) can be used for phase 1/2, with additional controls expected for phase 2/3 studies in a significant number of countries [6, 8, 9]. Russian regulations require GMP materials for clinical studies [1, 2]. The remaining cautions are typically expected for biological research aimed for clinical trials and commercial manufacturing. Review and discussion with Agencies (EMA, FDA etc) will help to clarify the issues and will be considered case by case.

A very important point for product characterization of non-viral in vivo delivery therapy will depend on description of physical methods (for example, electroporation and microfluidic-based technologies), nanomaterial-based methods (for example, cationic lipids and cell penetrating peptides) and self-assembled nanoparticles (more classical characterization from regulatory point of view). Viral delivery may utilize different viral vectors (for example, lentiviruses, AAVs, or adenoviruses), to pack the gene of interest, as RNA or DNA form, in order to facilitate its efficient delivery [19].

On the ex vivo side, CAR T is developing to the following directions [16]:
1. Individual patient-specific product as a quite labor-intensive process which requires conduction of a number of mock validation runs;
2. Universal or allogenic ‘off–the shelf ’ CAR T product with similar regulatory characterization methodology as for to biopharmaceuticals.

Preclinical

Detailed preclinical program will be build a case by case with clear justification of conducted studies. In general, one cannot omit all preclinical/non clinical developments due to rarity of a disease and its target. Disease-specific animal models with appropriate functional outcomes are preferred in such situations, but it is understood that sometimes only ‘off-target’ preclinical models can be used. In this case, a relevant animal with similar DNA targets and use of surrogates makers is expected to check ensure activity of the product in this animal model.

A great deal of focus is on the proof-of-concept (POC) animal studies, as these provide a reason to believe in the technology to agencies and sponsors, and this is crucial for first trial in human (FIH) but also for EMA Orphan Drug applications. For vector products expression, the studies need to be conducted with rather long follow-up time (6 months possible for FIH, 12 months or more) for phase 2/3.

Clinical

Clinical Program with phase 1/2 and one final phase 3 study are possible to consider enough to register. The studies will take a lot of time and will require staggered enrollment and dose escalation, especially in the FIH study [8, 10]. The phase 1 approach includes a classical oncology dose escalation/cohort approach of enrolling one patient at a time, for a total of 3 per dose cohort, with waiting periods of up to 20-30 days.

Prior dose to next patient in any given cohort depends on the product profile and expected time frame to observe the most serious common adverse events. This is a cautious approach given the limitations of many preclinical models [9, 14].

By the present time, there is a number of phase 1-2 studies designed in order to treat rare disease, cancer and viral disease. In vivo studies are required when developing an ‘off switch’ mechanism by introducing suicide gene into the modified cell product triggering apoptosis or molecules terminating in vivo editing [16].

Regulatory trends EMA and FDA are maintaining a product-focused, science-based regulatory policy [5, 11, 14]. Human medical products that apply gene editing to exert their therapeutic effect are regulated under the existing framework for biological products, which include gene therapy products [5-11]. “Gene editing” here refers to non-heritable situations with somatic cell gene therapy only, and not to heritable conditions (germline gene therapy). FDA’s Center for Biologics Evaluation and Research (CBER) has a well-established program and policies in place to evaluate gene therapy products in their newly formed Office of Tissues and Advanced Therapies (OTAT, formerly known as the Office of Cellular, Tissue and Gene Therapies, or OCTGT). Although different types of gene editing have potential clinical applications, currently only one type of gene editing, namely, zinc finger nuclease(ZFN)-mediated, has been announced by their sponsors as being applied in clinical trials, being underway in the United States.

Proposals for NIH-funded human gene therapy clinical trials are discussed and reviewed for scientific, clinical, and ethical issues by the NIH’s Recombinant DNA Advisory Committee (RAC). The RAC recently discussed and did not find any objections to the first clinical protocol to use CRISPR/Cas9-mediated gene editing. The potential for “off-target” effects such as insertions or deletions at unintended genetic loci are considered by experts in the field as a key concern.

Interestingly, FDA also has a longstanding collaborative relationship with the NIH office that oversees the RAC. FDA serves as a non-voting liaison on the committee, hears the discussions first-hand, and receives the written recommendations. These recommendations may be considered during our overall review of investigational new drug applications (INDs) submitted to FDA.

EMA is following similar approach having establishing a category of products termed Advanced therapy medicinal products (ATMPs) for medicines for human use that are based on genes or cells. In addition EMA established a Committee for Advanced Therapies (CAT) which plays a central role in scientific assessment of advanced therapy medicines. It provides the expertise that is needed to evaluate advanced therapy medicines. The use of a newly launched PRIME mechanism for early scientific dialogue can also be used with these therapies [5].

Three main regulations are covering the genome editing in Russia:

Federal Law #180 FZ
ex vivo and it looks CART technologies will fall under this law [1];
Federal Law #61 FZ – in vivo [2]; – Federal Law #83 FZ
broader range of transgenic products [3].

The key need is to have across laws guidance dedicated to common aspects of analytical evaluation, manufacturing, preclinical and clinical development similar to EMA or FDA.

Ethical aspects and next steps

“A triangle of considerations – extraordinary suffering, highly penetrant genotypes, and justifiable interventions – has, thus far, constrained our attempts to intervene on humans. As we loosen the boundaries of this triangle (by changing the standards for “extraordinary suffering” or “justifiable interventions”, we need new biological, cultural, and social precepts to determine which genetic interventions may be permitted or constrained, and the circumstances in which these interventions become safe or permissible” [15].

National regulations in many countries including Russia restrict or prohibit research in which human embryo is intentionally created or modified, including a heritable genetic modification [12].

Legal supervision provided by EMA, FDA and other agencies is one aspect of broader governance necessary for safe and responsible research and development of genome editing applications. Moreover, the expansive scope of intentional genomic alterations using modern genome editing technologies has triggered debate on fundamental ethical and social issues, which will continue to influence public opinion and acceptance of genome editing applications. Even as regulatory agencies implements necessary steps for effective regulation to ensure the safety of products, the role of broader, inclusive public discussion involving multiple constituencies (e.g., scientists, developers, bioethicists, and public interest and community groups) to address the larger societal considerations should not be overlooked.

Conflict of Interest

No conflict of interest are declared.

Acknowledgements

The author is grateful to colleagues for their excellent support and challenging questions during the manuscript preparation.

References

Introduction

Unique requirements for each genome-edited cell product (GECP) require a case-by-case review, aiming to comply with current local guidelines (or discuss how they are not relevant to this product);
For most cases, there is lacking knowledge on potential clinical consequences, thus requiring cautious approaches to be taken;
Regulatory authorities should be interested in partnership with developers of genome-editing technology, thus ensuring its sooner access to patients.

Genome editing: variety of tools and products

Product characterization

Preclinical

Clinical

Federal Law #180 FZ
ex vivo and it looks CART technologies will fall under this law [1];
Federal Law #61 FZ – in vivo [2]; – Federal Law #83 FZ
broader range of transgenic products [3].

The key need is to have across laws guidance dedicated to common aspects of analytical evaluation, manufacturing, preclinical and clinical development similar to EMA or FDA.

Ethical aspects and next steps

Conflict of Interest

No conflict of interest are declared.

Acknowledgements

The author is grateful to colleagues for their excellent support and challenging questions during the manuscript preparation.

References

1. Federal Law No. 61-FZ. On the Turnover of Medical Drugs. Moscow, 12.04.2010 (In Russian).
2. Federal Law No. 86-FZ On State Regulation in Gene Engineering Activities. Moscow, 05.07.1996 (In Russian)
3. Federal Law No. 180-FZ. On Biomedical Cell Products, Moscow, 23.06.2016 (In Russian).
4. Bothmer A, Maeder ML, Reyon D et al. The experimental design and data interpretation. In: Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk AG, Mahajan VB. Unexpected
mutations after CRISPR-Cas9 editing in vivo are insufficient to support the conclusions drawn by the authors. Nat Methods. 2017; 14(6):547-548. bioRxiv Jun. 21, 2017; doi: http://dx.doi.org/10.1101/153338.
5. Enhanced early dialogue to facilitate accelerated assessment of PRIority MEdicines (PRIME), EMA/CHMP/57760/2015, 25 February 2016, 1-12
6. Draft guidance for industry and Food and Drug Administration staff, Minimal manipulation of human cells, tissues, and cellular and tissue-based products., FDA , December 2014, 1-9
7. Guidance for industry. Potency test for cellular and gene therapy products. FDA; January 2011, 1-17.
8. Guidance for industry, design and analysis of shedding studies for virus or bacteria-based gene therapy and oncolytic products. FDA; July 2014:1-17.
9. Guidance for industry. Preclinical assessment of investigational cellular and gene therapy products. FDA; November 2013:1-32.
10. Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. European Medicines Agency. 2015; EMA\CAT\80183\2014: 1-42
11. Guideline on human cell-based medicinal products, European Medicines Agency. 2008; EMEA/CHMP/410869/2006: 1-25
12. Kingwell K. CAR T therapies drive into new terrain, Nature Review Drug Discovery, 2017; 16:301-304.
13. Mukherjee S, The gene. An intimate history, Scribner Publ,: N-Y; 2016: 1-592.
14. Narayanan G, Cossu G, Galli MC. Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union, Human Gene Therapy
Clinical Development. 2014, 25: 1-6.
15. Pawluk A, Amrani N, Zhang Y, Garcia B, Hidalgo-Reyes Y, Lee J, Edraki A, Shah M, Sontheimer EJ, Maxwell KL, Davidson ARl. Naturally occurring off-switches for CRIS-
PR-Cas9. Cell. 2016; 167(7): 1829-1838.e9.
16. Popova MO, Lepik KV, Sergeev VS, et al. Clinical implementation of genome editing for correction of human disease. Cell Ther Transplant. 2017; 6(1): 35-40.
17. Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk AG, Mahajan VB. Unexpected mutations after CRISPR-Cas9 editing in vivo. Nature Methods 2017:14(6): 547-548.
18. Wu WH, Tsai YT, Justus S, Lee TT, Zhang L, Lin CS, Bassuk AG, Mahajan VB, Tsang SH. CRISPR repair reveals causative mutation in preclinical model of retinitis pigmentosa.
Mol Ther. 2016; 24:1388-1394.
19. Yin H, Kauffman KJ, Anderson DG. Delivery technologies for genome editing. Nature Reviews Drug Discovery. 2017;16:387-399.

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Известно несколько классов подобных комплексов: нуклеазы типа Zinc Finger (ZFN), нуклеазы типа TALEN и недавно открытые комплексы типа CRISPR/Cas9. Эти технологии относятся к растущему списку методов персонализированной терапии и требуют особого внимания в плане развития, стандартизации производства для каждого больного, эффективных доклинических и клинических программ, касающихся основных проблем новой технологии, например – побочных («внецелевых») эффектов. Весьма важными являются также этические аспекты применения этих технологий. Ключевые слова Геномное редактирование, ZFN, TALEN, CRISPR/Cas9, юридические правила, оценка выгоды/риска." 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Известно несколько классов подобных комплексов: нуклеазы типа Zinc Finger (ZFN), нуклеазы типа TALEN и недавно открытые комплексы типа CRISPR/Cas9. Эти технологии относятся к растущему списку методов персонализированной терапии и требуют особого внимания в плане развития, стандартизации производства для каждого больного, эффективных доклинических и клинических программ, касающихся основных проблем новой технологии, например – побочных («внецелевых») эффектов. Весьма важными являются также этические аспекты применения этих технологий.

Ключевые слова

Геномное редактирование, ZFN, TALEN, CRISPR/Cas9, юридические правила, оценка выгоды/риска." ["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) "18169" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-60-63" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-2-60-63" ["~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) "18170" ["VALUE"]=> array(2) { ["TEXT"]=> string(19) "Mikhail Y. Samsonov" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(19) "Mikhail Y. Samsonov" ["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) "18171" ["VALUE"]=> array(2) { ["TEXT"]=> string(193) "JSC RPharm, Moscow, Russia Dr. Mikhail Y. Samsonov, PhD, Chief Medical Officer, JSC RPharm, Russia, 111B Leninsky prospect, 197002, Moscow, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(169) "JSC RPharm, Moscow, Russia

Dr. Mikhail Y. Samsonov, PhD, Chief Medical Officer,
JSC RPharm, Russia, 111B Leninsky prospect, 197002,
Moscow, 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) "18172" ["VALUE"]=> array(2) { ["TEXT"]=> string(1006) "Genome editing tools can be mostly used to introduce, remove, or substitute one or more specific nucleotides at a specific site in an organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, Zinc Finger Nuclease (ZFN), transcription activator-like effector nuclease (TALEN and the most recent discovery – Clustered regularly interspaced short palindromic repeats /CRISPR associated protein 9 (CRISPR/Cas9). The technology belongs to a growing list of personalized therapies and requires special attention to perform development, standardization of manufacturing for every patient, robust preclinical and clinical program addressing key challenges of the new technology, e.g. “off-target” effects. The ethical aspects of these tools are also quite critical. Keywords Genome editing, ZFN, TALEN, CRISPR-Cas9, regulatory environment, benefit\risk evaluation. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(964) "Genome editing tools can be mostly used to introduce, remove, or substitute one or more specific nucleotides at a specific site in an organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, Zinc Finger Nuclease (ZFN), transcription activator-like effector nuclease (TALEN and the most recent discovery – Clustered regularly interspaced short palindromic repeats /CRISPR associated protein 9 (CRISPR/Cas9). The technology belongs to a growing list of personalized therapies and requires special attention to perform development, standardization of manufacturing for every patient, robust preclinical and clinical program addressing key challenges of the new technology, e.g. “off-target” effects. The ethical aspects of these tools are also quite critical.

Keywords

Genome editing, ZFN, TALEN, CRISPR-Cas9, regulatory environment, benefit\risk evaluation.
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Samsonov" } ["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) "18172" ["VALUE"]=> array(2) { ["TEXT"]=> string(1006) "Genome editing tools can be mostly used to introduce, remove, or substitute one or more specific nucleotides at a specific site in an organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, Zinc Finger Nuclease (ZFN), transcription activator-like effector nuclease (TALEN and the most recent discovery – Clustered regularly interspaced short palindromic repeats /CRISPR associated protein 9 (CRISPR/Cas9). The technology belongs to a growing list of personalized therapies and requires special attention to perform development, standardization of manufacturing for every patient, robust preclinical and clinical program addressing key challenges of the new technology, e.g. “off-target” effects. The ethical aspects of these tools are also quite critical. Keywords Genome editing, ZFN, TALEN, CRISPR-Cas9, regulatory environment, benefit\risk evaluation. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(964) "Genome editing tools can be mostly used to introduce, remove, or substitute one or more specific nucleotides at a specific site in an organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, Zinc Finger Nuclease (ZFN), transcription activator-like effector nuclease (TALEN and the most recent discovery – Clustered regularly interspaced short palindromic repeats /CRISPR associated protein 9 (CRISPR/Cas9). The technology belongs to a growing list of personalized therapies and requires special attention to perform development, standardization of manufacturing for every patient, robust preclinical and clinical program addressing key challenges of the new technology, e.g. “off-target” effects. The ethical aspects of these tools are also quite critical.

Keywords

Genome editing, ZFN, TALEN, CRISPR-Cas9, regulatory environment, benefit\risk evaluation.
" ["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(964) "Genome editing tools can be mostly used to introduce, remove, or substitute one or more specific nucleotides at a specific site in an organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, Zinc Finger Nuclease (ZFN), transcription activator-like effector nuclease (TALEN and the most recent discovery – Clustered regularly interspaced short palindromic repeats /CRISPR associated protein 9 (CRISPR/Cas9). The technology belongs to a growing list of personalized therapies and requires special attention to perform development, standardization of manufacturing for every patient, robust preclinical and clinical program addressing key challenges of the new technology, e.g. “off-target” effects. The ethical aspects of these tools are also quite critical.

Keywords

Genome editing, ZFN, TALEN, CRISPR-Cas9, regulatory environment, benefit\risk evaluation.
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Dr. Mikhail Y. Samsonov, PhD, Chief Medical Officer,
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Dr. Mikhail Y. Samsonov, PhD, Chief Medical Officer,
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Известно несколько классов подобных комплексов: нуклеазы типа Zinc Finger (ZFN), нуклеазы типа TALEN и недавно открытые комплексы типа CRISPR/Cas9. Эти технологии относятся к растущему списку методов персонализированной терапии и требуют особого внимания в плане развития, стандартизации производства для каждого больного, эффективных доклинических и клинических программ, касающихся основных проблем новой технологии, например – побочных («внецелевых») эффектов. Весьма важными являются также этические аспекты применения этих технологий. Ключевые слова Геномное редактирование, ZFN, TALEN, CRISPR/Cas9, юридические правила, оценка выгоды/риска." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1625) "Технологии редактирования генома могут быть чаще всего использованы для введения, удаления или замещения одного или нескольких нуклеотидов в определенном месте генома, и они осуществляются с применением белок-нуклеотидных комплексов.
Известно несколько классов подобных комплексов: нуклеазы типа Zinc Finger (ZFN), нуклеазы типа TALEN и недавно открытые комплексы типа CRISPR/Cas9. Эти технологии относятся к растущему списку методов персонализированной терапии и требуют особого внимания в плане развития, стандартизации производства для каждого больного, эффективных доклинических и клинических программ, касающихся основных проблем новой технологии, например – побочных («внецелевых») эффектов. Весьма важными являются также этические аспекты применения этих технологий.

Ключевые слова

Геномное редактирование, ZFN, TALEN, CRISPR/Cas9, юридические правила, оценка выгоды/риска." ["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(1625) "Технологии редактирования генома могут быть чаще всего использованы для введения, удаления или замещения одного или нескольких нуклеотидов в определенном месте генома, и они осуществляются с применением белок-нуклеотидных комплексов.
Известно несколько классов подобных комплексов: нуклеазы типа Zinc Finger (ZFN), нуклеазы типа TALEN и недавно открытые комплексы типа CRISPR/Cas9. Эти технологии относятся к растущему списку методов персонализированной терапии и требуют особого внимания в плане развития, стандартизации производства для каждого больного, эффективных доклинических и клинических программ, касающихся основных проблем новой технологии, например – побочных («внецелевых») эффектов. Весьма важными являются также этические аспекты применения этих технологий.

Ключевые слова

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Памяти профессора Йона Ван Роода" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(123) "Некролог. Памяти профессора Йона Ван РоодаObituary. In memory of Professor Jon van Rood" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(12653) "<img alt="Jon van Rood.png" src="/upload/medialibrary/551/jon-van-rood.png" title="Jon van Rood.png" width="300" height="301"> Профессор Йон ван Роод скончался 21 июля 2017 г. в Леувардене (Нидерланды). Его исследования были посвящены иммунологии и науке о трансплантации. Он был профессором университета Лейдена (Нидерланды) и был всемирно признанным основателем тканевой иммунологии и тестирования антигенов HLA в клинической трансплантологии. Йон ван Роод родился в 1926 г. в Схевенингене (Нидерланды). Он учился медицине в Лейденском университете и в 1957 г. стал главой департамента иммуногематологии и банка крови университетского госпиталя в Лейдене. После получения звания доктора в 1962 г. он 1 год стажировался в Научном институте общественного здоровья (Нью-Йорк). Затем он вернулся в Лейден, где в 1969 г. стал профессором по специальности «внутренние болезни». С 1976 г. он был директором Департамента гематологии Лейденского университетского госпиталя, был в числе основателей Лейденского института иммунологии. Профессор Йон ван Роод провел свою главную научную работу, когда открыл и классифицировал генетически обусловленную систему совместимости человеческих лейкоцитов (HLA-антигены). Это открытие было сделано как раз вовремя, из-за сложных иммунологических проблем, которые были барьером на пути прогресса клинической трансплантологии в 60-х годах прошлого века. Будучи активен в клинической трансфузиологии, Йон ван Роод предложил собирать и исследовать образцы сыворотки крови от беременных женщин. Из-за частой иммунизации фетальными антигенами, индуцируется большое разнообразие специфических анти-HLA антител, которые можно далее классифицировать и использовать для выявления совместимых пар «донор-реципиент» при трансплантации органов и тканей. Проводились обширные совместные исследования с использованием стандартизированных панелей сывороток и образцов лейкоцитов, и тестов на цитотоксичность in vitro. Позже эти биологические тесты были дополнены более специфичным ДНК-тестированием, основанным на методиках ПЦР. Такой подход позволил профессору ван Рооду и его сотрудникам открыть несколько различных типов HLA. Многочисленные данные об антигенах совместимости, по мере накопления информации, потребовали систематического анализа. Профессор ван Роод был в числе первых, кто использовал компьютерный анализ многофакторной системы тканевых антигенов. Это исследование было основополагающим в обширных исследовательских программах фундаментальной и клинической иммуногенетики, и в развитии крупной индустрии HLA-типирования. Стандартизированное типирование индивидуальных наборов генов HLA оказалось незаменимым методом подбора пациентов и доноров для трансплантаций, а также для гемотрансфузий в ряде особых клинических ситуаций. Кроме того, профессор ван Роод провел первые HLA-совместимые трансфузии тромбоцитов и разработал рутинные способы деплеции лейкоцитов для предотвращения HLA-аллоиммунизации. Изучение системы HLA потребовало обширных международных усилий, направленных на сбор экспериментальных результатов и обработку больших массивов данных. Профессор Йон ван Роод был превосходным организатором международных программ, обеспечив разнообразную поддержку при создании более 30 лабораторий по типированию тканевой совместимости по всему миру. Кроме того, типирование HLA проложило новые пути в изучении соотношений между генотипами HLA и предрасположенностью к различным заболеваниям, в особенности – аутоиммунным синдромам. Соответствующие клинико-генетические ассоциации получены для ряда HLA-генотипов, но причины такой предрасположенности еще следует выяснить в дальнейшем. В 1967 году профессор Йон ван Роод основал организацию «Евротрансплант», в 1985 г. – Европейский фонд иммуногенетики, став одним из ключевых участников этих организаций. «Евротрансплант» является известной организацией, направленной на поддержку и координацию органной трансплантации, поиска наиболее совместимых доноров для трансплантации почек и других органов. Ван Роод также основал Фонд «Евродонор» в 1970 г., предназначенный для донорства костного мозга, «Eurotissue» для задач тканевой трансплантации (1987), и, наконец, Всемирную Ассоциацию доноров костного мозга в 1994 году. Для нас наиболее важно то, что Йон ван Роод был среди главных основателей Европейской группы трансплантации костного мозга в 1974 году. За последние 40 лет она стала широко известным Европейским обществом трансплантации крови и костного мозга (ЕВМТ), которое теперь координирует многие аспекты трансплантации гемопоэтических стволовых клеток. За свои заслуги профессор Йон ван Роод был удостоен множества международных почетных наград, в том числе – званий почетного доктора, а также научных премий в знак признания его научных заслуг. В 1977 г. Йон ван Роод вместе с профессором Доссе был награжден премией Роберта Коха. Он был также удостоен премии Вольфа по медицине вместе с Дж. Снеллом и Ж. Доссе «За вклад в познание сложности системы HLA у человека и его приложений в трансплантологии и при заболеваниях», премии Ф. Х. Хайнекена по медицине в 1990 г. Профессор ван Роод ушел в отставку со своей университетской должности в 1991 г., но оставался активным исследователем и лектором. Работы профессора ван Роода характеризуются уникальным сочетанием фундаментальных медицинских исследований с большой ценностью этих исследований для клинической медицины, в частности – трансплантации органов и гемопоэтических тканей. Он основал школу иммунологов-трансплантологов, которые теперь работают в разных странах. Йона ван Роода всегда будут называть в числе основателей современной трансплантационной иммунологии. Он сделал многое для поддержки активности молодых ученых в этой области, обеспечивая им гранты на пребывание и исследования. С 2010 г., ЕВМТ учреждена ежегодная премия ван Роода за лучшие исследования в области трансплантационной. Он не ограничивался деятельностью в Америке и Западной Европе. Так, при посещении России в начале 90-х годов, он много консультировал российских иммуногематологов, чтобы организовать Национальный Регистр доноров костного мозга. За последние годы эта идея претворена в работающий единый регистр с базой в Санкт-Петербурге, работающий в кооперации с аналогичными регистрами в России и Казахстане (Москва, Киров, Челябинск, Ростов-на Дону, Екатеринбург, Самара, Казань и Астана). Будучи широко образованным и любознательным человеком, профессор Йон ван Роод любил получать новые впечатления от путешествий и поездок. Мы помним его интерес к Санкт-Петербургу и русской культуре при поездке на остров Валаам и в Кижи в 1992 г. Мы будем многие годы вспоминать Йона ван Роода, яркого интеллектуала и организатора науки, как пример для будущих поколений ученых, работающих в биологии и медицине. " ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(78) "Некролог. Памяти профессора Йона Ван Роода" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(78) "Некролог. Памяти профессора Йона Ван Роода" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(78) "Некролог. Памяти профессора Йона Ван Роода" ["SECTION_META_TITLE"]=> string(78) "Некролог. 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Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(307) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского
государственного медицинского университета им. И. П. Павлова" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "18181" ["VALUE"]=> array(2) { ["TEXT"]=> string(12653) "<img alt="Jon van Rood.png" src="/upload/medialibrary/551/jon-van-rood.png" title="Jon van Rood.png" width="300" height="301"> Профессор Йон ван Роод скончался 21 июля 2017 г. в Леувардене (Нидерланды). Его исследования были посвящены иммунологии и науке о трансплантации. Он был профессором университета Лейдена (Нидерланды) и был всемирно признанным основателем тканевой иммунологии и тестирования антигенов HLA в клинической трансплантологии. Йон ван Роод родился в 1926 г. в Схевенингене (Нидерланды). Он учился медицине в Лейденском университете и в 1957 г. стал главой департамента иммуногематологии и банка крови университетского госпиталя в Лейдене. После получения звания доктора в 1962 г. он 1 год стажировался в Научном институте общественного здоровья (Нью-Йорк). Затем он вернулся в Лейден, где в 1969 г. стал профессором по специальности «внутренние болезни». С 1976 г. он был директором Департамента гематологии Лейденского университетского госпиталя, был в числе основателей Лейденского института иммунологии. Профессор Йон ван Роод провел свою главную научную работу, когда открыл и классифицировал генетически обусловленную систему совместимости человеческих лейкоцитов (HLA-антигены). Это открытие было сделано как раз вовремя, из-за сложных иммунологических проблем, которые были барьером на пути прогресса клинической трансплантологии в 60-х годах прошлого века. Будучи активен в клинической трансфузиологии, Йон ван Роод предложил собирать и исследовать образцы сыворотки крови от беременных женщин. Из-за частой иммунизации фетальными антигенами, индуцируется большое разнообразие специфических анти-HLA антител, которые можно далее классифицировать и использовать для выявления совместимых пар «донор-реципиент» при трансплантации органов и тканей. Проводились обширные совместные исследования с использованием стандартизированных панелей сывороток и образцов лейкоцитов, и тестов на цитотоксичность in vitro. Позже эти биологические тесты были дополнены более специфичным ДНК-тестированием, основанным на методиках ПЦР. Такой подход позволил профессору ван Рооду и его сотрудникам открыть несколько различных типов HLA. Многочисленные данные об антигенах совместимости, по мере накопления информации, потребовали систематического анализа. Профессор ван Роод был в числе первых, кто использовал компьютерный анализ многофакторной системы тканевых антигенов. Это исследование было основополагающим в обширных исследовательских программах фундаментальной и клинической иммуногенетики, и в развитии крупной индустрии HLA-типирования. Стандартизированное типирование индивидуальных наборов генов HLA оказалось незаменимым методом подбора пациентов и доноров для трансплантаций, а также для гемотрансфузий в ряде особых клинических ситуаций. Кроме того, профессор ван Роод провел первые HLA-совместимые трансфузии тромбоцитов и разработал рутинные способы деплеции лейкоцитов для предотвращения HLA-аллоиммунизации. Изучение системы HLA потребовало обширных международных усилий, направленных на сбор экспериментальных результатов и обработку больших массивов данных. Профессор Йон ван Роод был превосходным организатором международных программ, обеспечив разнообразную поддержку при создании более 30 лабораторий по типированию тканевой совместимости по всему миру. Кроме того, типирование HLA проложило новые пути в изучении соотношений между генотипами HLA и предрасположенностью к различным заболеваниям, в особенности – аутоиммунным синдромам. Соответствующие клинико-генетические ассоциации получены для ряда HLA-генотипов, но причины такой предрасположенности еще следует выяснить в дальнейшем. В 1967 году профессор Йон ван Роод основал организацию «Евротрансплант», в 1985 г. – Европейский фонд иммуногенетики, став одним из ключевых участников этих организаций. «Евротрансплант» является известной организацией, направленной на поддержку и координацию органной трансплантации, поиска наиболее совместимых доноров для трансплантации почек и других органов. Ван Роод также основал Фонд «Евродонор» в 1970 г., предназначенный для донорства костного мозга, «Eurotissue» для задач тканевой трансплантации (1987), и, наконец, Всемирную Ассоциацию доноров костного мозга в 1994 году. Для нас наиболее важно то, что Йон ван Роод был среди главных основателей Европейской группы трансплантации костного мозга в 1974 году. За последние 40 лет она стала широко известным Европейским обществом трансплантации крови и костного мозга (ЕВМТ), которое теперь координирует многие аспекты трансплантации гемопоэтических стволовых клеток. За свои заслуги профессор Йон ван Роод был удостоен множества международных почетных наград, в том числе – званий почетного доктора, а также научных премий в знак признания его научных заслуг. В 1977 г. Йон ван Роод вместе с профессором Доссе был награжден премией Роберта Коха. Он был также удостоен премии Вольфа по медицине вместе с Дж. Снеллом и Ж. Доссе «За вклад в познание сложности системы HLA у человека и его приложений в трансплантологии и при заболеваниях», премии Ф. Х. Хайнекена по медицине в 1990 г. Профессор ван Роод ушел в отставку со своей университетской должности в 1991 г., но оставался активным исследователем и лектором. Работы профессора ван Роода характеризуются уникальным сочетанием фундаментальных медицинских исследований с большой ценностью этих исследований для клинической медицины, в частности – трансплантации органов и гемопоэтических тканей. Он основал школу иммунологов-трансплантологов, которые теперь работают в разных странах. Йона ван Роода всегда будут называть в числе основателей современной трансплантационной иммунологии. Он сделал многое для поддержки активности молодых ученых в этой области, обеспечивая им гранты на пребывание и исследования. С 2010 г., ЕВМТ учреждена ежегодная премия ван Роода за лучшие исследования в области трансплантационной. Он не ограничивался деятельностью в Америке и Западной Европе. Так, при посещении России в начале 90-х годов, он много консультировал российских иммуногематологов, чтобы организовать Национальный Регистр доноров костного мозга. За последние годы эта идея претворена в работающий единый регистр с базой в Санкт-Петербурге, работающий в кооперации с аналогичными регистрами в России и Казахстане (Москва, Киров, Челябинск, Ростов-на Дону, Екатеринбург, Самара, Казань и Астана). Будучи широко образованным и любознательным человеком, профессор Йон ван Роод любил получать новые впечатления от путешествий и поездок. Мы помним его интерес к Санкт-Петербургу и русской культуре при поездке на остров Валаам и в Кижи в 1992 г. Мы будем многие годы вспоминать Йона ван Роода, яркого интеллектуала и организатора науки, как пример для будущих поколений ученых, работающих в биологии и медицине. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(12411) " Jon van Rood.png

Professor Jon van Rood passed away on 21 July 2017 in Leeuwarden. His research was dedicated to immunology and transplantation science. Being a Professor at the Leiden University, he was a worldwide recognized founder of tissue immunology and HLA testing in clinical transplantation.

Johannes J. van Rood was born in 1926 in Scheveningen (The Netherlands). He studied medicine at the University of Leiden and in 1957 became the head of the Immunohematology Department and the Blood Bank of Leiden University Hospital. After achieving a Doctor’s title in 1962, he trained a year at the Immunology Department in the Public Health Research Institute (New York). Then he returned to Leiden, where he was appointed a Professor of Internal Medicine in 1969. Since 1976 he was Director of the Hematology Department, the Leiden University Hospital. He was among founders of the Leiden Institute for Immunology.

Professor Jon van Rood made his main successful research while discovering and classifying the genetically determined human leukocyte compatibility system (HLA membrane proteins). This discovery was made just in right time, because of difficult immunological problems that remained barriers to the progress of clinical transplantation in 60’s. Being active in clinical transfusion medicine, Jon van Rood suggested collection and studying blood sera samples from pregnant women.

Due to common maternal immunization by fetal antigens, a variety of specific anti-HLA antibodies are induced which have became a useful tool for detection of well-matched donor-recipient pairs in organ and tissue transplantation. Extensive collaborative studies that used standardized panels of sera and leukocyte samples using in vitro cytotoxity assays.

Later on, these test systems were largely replaced by more precise PCR-based DNA testing. Such an approach enabled Professor Jon van Rood and his co-researchers to discover several different antigens of the HLA system.

Numerous data on HLA variability, upon their accumulation, required a systematic analysis. Professor Jon van Rood pioneered in computer-assisted analysis of the multifactorial tissue antigen system. This research was seminal to extensive research programs in fundamental and clinical immunogenetics, and development of big HLA-typing industry. Standardized typing of individual HLA sets proved to be indispensable for matching patients and donors for transplants, as well as blood transfusions in some special clinical situations. Furthermore, using HLA typing, Professor Jon van Rood performed the first HLA-matched platelet transfusions and developed routine leukocyte depletion as a means to prevent HLA alloimmunization.

The studies on HLA antigens required large international efforts for collection of wast experimental results and big data analysis. Professor Jon van Rood was an excellent organizer of international programs, providing a support with launching over thirty tissue-typing laboratories worldwide.

Moreover, HLA typing has paved new ways in studying the relations between HLA genotypes and predisposition towards distinct diseases, especially, autoimmune disorders.

Appropriate clinical associations were obtained for some HLA genotypes but the reasons for such susceptibility are still to be cleared. In 1967 Professor Jon van Rood founded the Eurotransplant organization, and in 1985, the European Foundation for Immunogenetics, becoming a key member of these organizations. Eurotransplant is a well known organization, now aimed for promotion and coordinating organ transplants, search for the best possible donors for kidney and other organ transplants. He also founded the Europdonor Foundation in 1970 (for bone marrow donation), Eurotissue for tissue transplantation (1987) as well as the World Marrow Donor Association in 1994.

Jon van Rood was among key persons who founded European group for Bone Marrow Transplantation in 1974 which, over last 40 years, has evolved to the widely known European Society for Blood and Marrow Transplantation which coordinates many aspects of hematopoietic stem cell transplantation.

For his achievements, Professor Jon van Rood received a lot of international honorary awards, including several Doctor honoris causa degrees, as well as honorary prizes recognizing his scientific merits. In 1977, Jon van Rood, together with Prof. Dausset, was awarded the Robert Koch Prize. He was also awarded the Wolf Prize in Medicine, jointly with George D. Snell and Jean Dausset, “for his contribution to the understanding of the complexity of the HLA system in man and its implications in transplantation and in disease”. Dr. A. H. Heineken Prize for Medicine was awarded to Johannes van Rood in 1990. He retired from his university position in 1991 but remained active researcher and lecturer.

Professor Jon van Rood’s work was characterized by the unique way in which he combined scientific medical research with great value of these studies for practical medicine, especially transplantation of solid organs and hematopoietic tissues. He founded a school of transplantation immunologists who are now working in various countries.

Jon van Rood will be always nominated among founders of modern transplantation immunology. He did a lot to promote activity of young workers in this area by providing them with research and travel grants. Since 2010, the Jon van Rood prize was established by the European Blood and Marrow Transplant Group for best studies in the field of transplantation immunology. He did not limit his activities by America and Western Europe. When visiting Russia in early 90’s, he consulted Russian immunohematologists in order to arrange a National Bone Marrow Donor Registry. Over last years, this idea is implemented as a working united registry with a hub in St. Petersburg, cooperating with appropriate registries in Russia and Kazakhstan: (Moscow, Kirov, Chelyabinsk, Rostov on Don, Ekaterinburg, Samara, Kazan’ and Astana).

Being a widely educated and intellectually curious person, Professor Jon van Rood brought new insights and impressions from his travels and journeys. We remember his interest to St. Petersburg, Russian culture when traveling to Valaam and Kizhi in 1992.

As a bright intellectual and organizer of science, he will be remembered for many years as an example to follow for next generations of scientists working in biology and medicine.
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His research was dedicated to immunology and transplantation science. Being a Professor at the Leiden University, he was a worldwide recognized founder of tissue immunology and HLA testing in clinical transplantation. Johannes J. van Rood was born in 1926 in Scheveningen (The Netherlands). He studied medicine at the University of Leiden and in 1957 became the head of the Immunohematology Department and the Blood Bank of Leiden University Hospital. After achieving a Doctor’s title in 1962, he trained a year at the Immunology Department in the Public Health Research Institute (New York). Then he returned to Leiden, where he was appointed a Professor of Internal Medicine in 1969. Since 1976 he was Director of the Hematology Department, the Leiden University Hospital. He was among founders of the Leiden Institute for Immunology. Professor Jon van Rood made his main successful research while discovering and classifying the genetically determined human leukocyte compatibility system (HLA membrane proteins). This discovery was made just in right time, because of difficult immunological problems that remained barriers to the progress of clinical transplantation in 60’s. Being active in clinical transfusion medicine, Jon van Rood suggested collection and studying blood sera samples from pregnant women. Due to common maternal immunization by fetal antigens, a variety of specific anti-HLA antibodies are induced which have became a useful tool for detection of well-matched donor-recipient pairs in organ and tissue transplantation. Extensive collaborative studies that used standardized panels of sera and leukocyte samples using in vitro cytotoxity assays. Later on, these test systems were largely replaced by more precise PCR-based DNA testing. Such an approach enabled Professor Jon van Rood and his co-researchers to discover several different antigens of the HLA system. Numerous data on HLA variability, upon their accumulation, required a systematic analysis. Professor Jon van Rood pioneered in computer-assisted analysis of the multifactorial tissue antigen system. This research was seminal to extensive research programs in fundamental and clinical immunogenetics, and development of big HLA-typing industry. Standardized typing of individual HLA sets proved to be indispensable for matching patients and donors for transplants, as well as blood transfusions in some special clinical situations. Furthermore, using HLA typing, Professor Jon van Rood performed the first HLA-matched platelet transfusions and developed routine leukocyte depletion as a means to prevent HLA alloimmunization. The studies on HLA antigens required large international efforts for collection of wast experimental results and big data analysis. Professor Jon van Rood was an excellent organizer of international programs, providing a support with launching over thirty tissue-typing laboratories worldwide. Moreover, HLA typing has paved new ways in studying the relations between HLA genotypes and predisposition towards distinct diseases, especially, autoimmune disorders. Appropriate clinical associations were obtained for some HLA genotypes but the reasons for such susceptibility are still to be cleared. In 1967 Professor Jon van Rood founded the Eurotransplant organization, and in 1985, the European Foundation for Immunogenetics, becoming a key member of these organizations. Eurotransplant is a well known organization, now aimed for promotion and coordinating organ transplants, search for the best possible donors for kidney and other organ transplants. He also founded the Europdonor Foundation in 1970 (for bone marrow donation), Eurotissue for tissue transplantation (1987) as well as the World Marrow Donor Association in 1994. Jon van Rood was among key persons who founded European group for Bone Marrow Transplantation in 1974 which, over last 40 years, has evolved to the widely known European Society for Blood and Marrow Transplantation which coordinates many aspects of hematopoietic stem cell transplantation. For his achievements, Professor Jon van Rood received a lot of international honorary awards, including several Doctor honoris causa degrees, as well as honorary prizes recognizing his scientific merits. In 1977, Jon van Rood, together with Prof. Dausset, was awarded the Robert Koch Prize. He was also awarded the Wolf Prize in Medicine, jointly with George D. Snell and Jean Dausset, “for his contribution to the understanding of the complexity of the HLA system in man and its implications in transplantation and in disease”. Dr. A. H. Heineken Prize for Medicine was awarded to Johannes van Rood in 1990. He retired from his university position in 1991 but remained active researcher and lecturer. Professor Jon van Rood’s work was characterized by the unique way in which he combined scientific medical research with great value of these studies for practical medicine, especially transplantation of solid organs and hematopoietic tissues. He founded a school of transplantation immunologists who are now working in various countries. Jon van Rood will be always nominated among founders of modern transplantation immunology. He did a lot to promote activity of young workers in this area by providing them with research and travel grants. Since 2010, the Jon van Rood prize was established by the European Blood and Marrow Transplant Group for best studies in the field of transplantation immunology. He did not limit his activities by America and Western Europe. When visiting Russia in early 90’s, he consulted Russian immunohematologists in order to arrange a National Bone Marrow Donor Registry. Over last years, this idea is implemented as a working united registry with a hub in St. Petersburg, cooperating with appropriate registries in Russia and Kazakhstan: (Moscow, Kirov, Chelyabinsk, Rostov on Don, Ekaterinburg, Samara, Kazan’ and Astana). Being a widely educated and intellectually curious person, Professor Jon van Rood brought new insights and impressions from his travels and journeys. We remember his interest to St. Petersburg, Russian culture when traveling to Valaam and Kizhi in 1992. As a bright intellectual and organizer of science, he will be remembered for many years as an example to follow for next generations of scientists working in biology and medicine. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6735) " Jon van Rood.png

Professor Jon van Rood passed away on 21 July 2017 in Leeuwarden. His research was dedicated to immunology and transplantation science. Being a Professor at the Leiden University, he was a worldwide recognized founder of tissue immunology and HLA testing in clinical transplantation.

Johannes J. van Rood was born in 1926 in Scheveningen (The Netherlands). He studied medicine at the University of Leiden and in 1957 became the head of the Immunohematology Department and the Blood Bank of Leiden University Hospital. After achieving a Doctor’s title in 1962, he trained a year at the Immunology Department in the Public Health Research Institute (New York). Then he returned to Leiden, where he was appointed a Professor of Internal Medicine in 1969. Since 1976 he was Director of the Hematology Department, the Leiden University Hospital. He was among founders of the Leiden Institute for Immunology.

Professor Jon van Rood made his main successful research while discovering and classifying the genetically determined human leukocyte compatibility system (HLA membrane proteins). This discovery was made just in right time, because of difficult immunological problems that remained barriers to the progress of clinical transplantation in 60’s. Being active in clinical transfusion medicine, Jon van Rood suggested collection and studying blood sera samples from pregnant women.

Due to common maternal immunization by fetal antigens, a variety of specific anti-HLA antibodies are induced which have became a useful tool for detection of well-matched donor-recipient pairs in organ and tissue transplantation. Extensive collaborative studies that used standardized panels of sera and leukocyte samples using in vitro cytotoxity assays.

Later on, these test systems were largely replaced by more precise PCR-based DNA testing. Such an approach enabled Professor Jon van Rood and his co-researchers to discover several different antigens of the HLA system.

Numerous data on HLA variability, upon their accumulation, required a systematic analysis. Professor Jon van Rood pioneered in computer-assisted analysis of the multifactorial tissue antigen system. This research was seminal to extensive research programs in fundamental and clinical immunogenetics, and development of big HLA-typing industry. Standardized typing of individual HLA sets proved to be indispensable for matching patients and donors for transplants, as well as blood transfusions in some special clinical situations. Furthermore, using HLA typing, Professor Jon van Rood performed the first HLA-matched platelet transfusions and developed routine leukocyte depletion as a means to prevent HLA alloimmunization.

The studies on HLA antigens required large international efforts for collection of wast experimental results and big data analysis. Professor Jon van Rood was an excellent organizer of international programs, providing a support with launching over thirty tissue-typing laboratories worldwide.

Moreover, HLA typing has paved new ways in studying the relations between HLA genotypes and predisposition towards distinct diseases, especially, autoimmune disorders.

Appropriate clinical associations were obtained for some HLA genotypes but the reasons for such susceptibility are still to be cleared. In 1967 Professor Jon van Rood founded the Eurotransplant organization, and in 1985, the European Foundation for Immunogenetics, becoming a key member of these organizations. Eurotransplant is a well known organization, now aimed for promotion and coordinating organ transplants, search for the best possible donors for kidney and other organ transplants. He also founded the Europdonor Foundation in 1970 (for bone marrow donation), Eurotissue for tissue transplantation (1987) as well as the World Marrow Donor Association in 1994.

Jon van Rood was among key persons who founded European group for Bone Marrow Transplantation in 1974 which, over last 40 years, has evolved to the widely known European Society for Blood and Marrow Transplantation which coordinates many aspects of hematopoietic stem cell transplantation.

For his achievements, Professor Jon van Rood received a lot of international honorary awards, including several Doctor honoris causa degrees, as well as honorary prizes recognizing his scientific merits. In 1977, Jon van Rood, together with Prof. Dausset, was awarded the Robert Koch Prize. He was also awarded the Wolf Prize in Medicine, jointly with George D. Snell and Jean Dausset, “for his contribution to the understanding of the complexity of the HLA system in man and its implications in transplantation and in disease”. Dr. A. H. Heineken Prize for Medicine was awarded to Johannes van Rood in 1990. He retired from his university position in 1991 but remained active researcher and lecturer.

Professor Jon van Rood’s work was characterized by the unique way in which he combined scientific medical research with great value of these studies for practical medicine, especially transplantation of solid organs and hematopoietic tissues. He founded a school of transplantation immunologists who are now working in various countries.

Jon van Rood will be always nominated among founders of modern transplantation immunology. He did a lot to promote activity of young workers in this area by providing them with research and travel grants. Since 2010, the Jon van Rood prize was established by the European Blood and Marrow Transplant Group for best studies in the field of transplantation immunology. He did not limit his activities by America and Western Europe. When visiting Russia in early 90’s, he consulted Russian immunohematologists in order to arrange a National Bone Marrow Donor Registry. Over last years, this idea is implemented as a working united registry with a hub in St. Petersburg, cooperating with appropriate registries in Russia and Kazakhstan: (Moscow, Kirov, Chelyabinsk, Rostov on Don, Ekaterinburg, Samara, Kazan’ and Astana).

Being a widely educated and intellectually curious person, Professor Jon van Rood brought new insights and impressions from his travels and journeys. We remember his interest to St. Petersburg, Russian culture when traveling to Valaam and Kizhi in 1992.

As a bright intellectual and organizer of science, he will be remembered for many years as an example to follow for next generations of scientists working in biology and medicine.
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Его исследования были посвящены иммунологии и науке о трансплантации. Он был профессором университета Лейдена (Нидерланды) и был всемирно признанным основателем тканевой иммунологии и тестирования антигенов HLA в клинической трансплантологии. Йон ван Роод родился в 1926 г. в Схевенингене (Нидерланды). Он учился медицине в Лейденском университете и в 1957 г. стал главой департамента иммуногематологии и банка крови университетского госпиталя в Лейдене. После получения звания доктора в 1962 г. он 1 год стажировался в Научном институте общественного здоровья (Нью-Йорк). Затем он вернулся в Лейден, где в 1969 г. стал профессором по специальности «внутренние болезни». С 1976 г. он был директором Департамента гематологии Лейденского университетского госпиталя, был в числе основателей Лейденского института иммунологии. Профессор Йон ван Роод провел свою главную научную работу, когда открыл и классифицировал генетически обусловленную систему совместимости человеческих лейкоцитов (HLA-антигены). Это открытие было сделано как раз вовремя, из-за сложных иммунологических проблем, которые были барьером на пути прогресса клинической трансплантологии в 60-х годах прошлого века. Будучи активен в клинической трансфузиологии, Йон ван Роод предложил собирать и исследовать образцы сыворотки крови от беременных женщин. Из-за частой иммунизации фетальными антигенами, индуцируется большое разнообразие специфических анти-HLA антител, которые можно далее классифицировать и использовать для выявления совместимых пар «донор-реципиент» при трансплантации органов и тканей. Проводились обширные совместные исследования с использованием стандартизированных панелей сывороток и образцов лейкоцитов, и тестов на цитотоксичность in vitro. Позже эти биологические тесты были дополнены более специфичным ДНК-тестированием, основанным на методиках ПЦР. Такой подход позволил профессору ван Рооду и его сотрудникам открыть несколько различных типов HLA. Многочисленные данные об антигенах совместимости, по мере накопления информации, потребовали систематического анализа. Профессор ван Роод был в числе первых, кто использовал компьютерный анализ многофакторной системы тканевых антигенов. Это исследование было основополагающим в обширных исследовательских программах фундаментальной и клинической иммуногенетики, и в развитии крупной индустрии HLA-типирования. Стандартизированное типирование индивидуальных наборов генов HLA оказалось незаменимым методом подбора пациентов и доноров для трансплантаций, а также для гемотрансфузий в ряде особых клинических ситуаций. Кроме того, профессор ван Роод провел первые HLA-совместимые трансфузии тромбоцитов и разработал рутинные способы деплеции лейкоцитов для предотвращения HLA-аллоиммунизации. Изучение системы HLA потребовало обширных международных усилий, направленных на сбор экспериментальных результатов и обработку больших массивов данных. Профессор Йон ван Роод был превосходным организатором международных программ, обеспечив разнообразную поддержку при создании более 30 лабораторий по типированию тканевой совместимости по всему миру. Кроме того, типирование HLA проложило новые пути в изучении соотношений между генотипами HLA и предрасположенностью к различным заболеваниям, в особенности – аутоиммунным синдромам. Соответствующие клинико-генетические ассоциации получены для ряда HLA-генотипов, но причины такой предрасположенности еще следует выяснить в дальнейшем. В 1967 году профессор Йон ван Роод основал организацию «Евротрансплант», в 1985 г. – Европейский фонд иммуногенетики, став одним из ключевых участников этих организаций. «Евротрансплант» является известной организацией, направленной на поддержку и координацию органной трансплантации, поиска наиболее совместимых доноров для трансплантации почек и других органов. Ван Роод также основал Фонд «Евродонор» в 1970 г., предназначенный для донорства костного мозга, «Eurotissue» для задач тканевой трансплантации (1987), и, наконец, Всемирную Ассоциацию доноров костного мозга в 1994 году. Для нас наиболее важно то, что Йон ван Роод был среди главных основателей Европейской группы трансплантации костного мозга в 1974 году. За последние 40 лет она стала широко известным Европейским обществом трансплантации крови и костного мозга (ЕВМТ), которое теперь координирует многие аспекты трансплантации гемопоэтических стволовых клеток. За свои заслуги профессор Йон ван Роод был удостоен множества международных почетных наград, в том числе – званий почетного доктора, а также научных премий в знак признания его научных заслуг. В 1977 г. Йон ван Роод вместе с профессором Доссе был награжден премией Роберта Коха. Он был также удостоен премии Вольфа по медицине вместе с Дж. Снеллом и Ж. Доссе «За вклад в познание сложности системы HLA у человека и его приложений в трансплантологии и при заболеваниях», премии Ф. Х. Хайнекена по медицине в 1990 г. Профессор ван Роод ушел в отставку со своей университетской должности в 1991 г., но оставался активным исследователем и лектором. Работы профессора ван Роода характеризуются уникальным сочетанием фундаментальных медицинских исследований с большой ценностью этих исследований для клинической медицины, в частности – трансплантации органов и гемопоэтических тканей. Он основал школу иммунологов-трансплантологов, которые теперь работают в разных странах. Йона ван Роода всегда будут называть в числе основателей современной трансплантационной иммунологии. Он сделал многое для поддержки активности молодых ученых в этой области, обеспечивая им гранты на пребывание и исследования. С 2010 г., ЕВМТ учреждена ежегодная премия ван Роода за лучшие исследования в области трансплантационной. Он не ограничивался деятельностью в Америке и Западной Европе. Так, при посещении России в начале 90-х годов, он много консультировал российских иммуногематологов, чтобы организовать Национальный Регистр доноров костного мозга. За последние годы эта идея претворена в работающий единый регистр с базой в Санкт-Петербурге, работающий в кооперации с аналогичными регистрами в России и Казахстане (Москва, Киров, Челябинск, Ростов-на Дону, Екатеринбург, Самара, Казань и Астана). Будучи широко образованным и любознательным человеком, профессор Йон ван Роод любил получать новые впечатления от путешествий и поездок. Мы помним его интерес к Санкт-Петербургу и русской культуре при поездке на остров Валаам и в Кижи в 1992 г. Мы будем многие годы вспоминать Йона ван Роода, яркого интеллектуала и организатора науки, как пример для будущих поколений ученых, работающих в биологии и медицине. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(12411) " Jon van Rood.png

Профессор Йон ван Роод скончался 21 июля 2017 г. в Леувардене (Нидерланды). Его исследования были посвящены иммунологии и науке о трансплантации. Он был профессором университета Лейдена (Нидерланды) и был всемирно признанным основателем тканевой иммунологии и тестирования антигенов HLA в клинической трансплантологии.

Йон ван Роод родился в 1926 г. в Схевенингене (Нидерланды). Он учился медицине в Лейденском университете и в 1957 г. стал главой департамента иммуногематологии и банка крови университетского госпиталя в Лейдене. После получения звания доктора в 1962 г. он 1 год стажировался в Научном институте общественного здоровья (Нью-Йорк). Затем он вернулся в Лейден, где в 1969 г. стал профессором по специальности «внутренние болезни». С 1976 г. он был директором Департамента гематологии Лейденского университетского госпиталя, был в числе основателей Лейденского института иммунологии.

Профессор Йон ван Роод провел свою главную научную работу, когда открыл и классифицировал генетически обусловленную систему совместимости человеческих лейкоцитов (HLA-антигены). Это открытие было сделано как раз вовремя, из-за сложных иммунологических проблем, которые были барьером на пути прогресса клинической трансплантологии в 60-х годах прошлого века. Будучи активен в клинической трансфузиологии, Йон ван Роод предложил собирать и исследовать образцы сыворотки крови от беременных женщин.

Из-за частой иммунизации фетальными антигенами, индуцируется большое разнообразие специфических анти-HLA антител, которые можно далее классифицировать и использовать для выявления совместимых пар «донор-реципиент» при трансплантации органов и тканей. Проводились обширные совместные исследования с использованием стандартизированных панелей сывороток и образцов лейкоцитов, и тестов на цитотоксичность in vitro. Позже эти биологические тесты были дополнены более специфичным ДНК-тестированием, основанным на методиках ПЦР. Такой подход позволил профессору ван Рооду и его сотрудникам открыть несколько различных типов HLA. Многочисленные данные об антигенах совместимости, по мере накопления информации, потребовали систематического анализа.

Профессор ван Роод был в числе первых, кто использовал компьютерный анализ многофакторной системы тканевых антигенов. Это исследование было основополагающим в обширных исследовательских программах фундаментальной и клинической иммуногенетики, и в развитии крупной индустрии HLA-типирования.

Стандартизированное типирование индивидуальных наборов генов HLA оказалось незаменимым методом подбора пациентов и доноров для трансплантаций, а также для гемотрансфузий в ряде особых клинических ситуаций. Кроме того, профессор ван Роод провел первые HLA-совместимые трансфузии тромбоцитов и разработал рутинные способы деплеции лейкоцитов для предотвращения HLA-аллоиммунизации.

Изучение системы HLA потребовало обширных международных усилий, направленных на сбор экспериментальных результатов и обработку больших массивов данных. Профессор Йон ван Роод был превосходным организатором международных программ, обеспечив разнообразную поддержку при создании более 30 лабораторий по типированию тканевой совместимости по всему миру.

Кроме того, типирование HLA проложило новые пути в изучении соотношений между генотипами HLA и предрасположенностью к различным заболеваниям, в особенности – аутоиммунным синдромам. Соответствующие клинико-генетические ассоциации получены для ряда HLA-генотипов, но причины такой предрасположенности еще следует выяснить в дальнейшем.

В 1967 году профессор Йон ван Роод основал организацию «Евротрансплант», в 1985 г. – Европейский фонд иммуногенетики, став одним из ключевых участников этих организаций. «Евротрансплант» является известной организацией, направленной на поддержку и координацию органной трансплантации, поиска наиболее совместимых доноров для трансплантации почек и других органов. Ван Роод также основал Фонд «Евродонор» в 1970 г., предназначенный для донорства костного мозга, «Eurotissue» для задач тканевой трансплантации (1987), и, наконец, Всемирную Ассоциацию доноров костного мозга в 1994 году. Для нас наиболее важно то, что Йон ван Роод был среди главных основателей Европейской группы трансплантации костного мозга в 1974 году. За последние 40 лет она стала широко известным Европейским обществом трансплантации крови и костного мозга (ЕВМТ), которое теперь координирует многие аспекты трансплантации гемопоэтических стволовых клеток.

За свои заслуги профессор Йон ван Роод был удостоен множества международных почетных наград, в том числе – званий почетного доктора, а также научных премий в знак признания его научных заслуг.

В 1977 г. Йон ван Роод вместе с профессором Доссе был награжден премией Роберта Коха. Он был также удостоен премии Вольфа по медицине вместе с Дж. Снеллом и Ж. Доссе «За вклад в познание сложности системы HLA у человека и его приложений в трансплантологии и при заболеваниях», премии Ф. Х. Хайнекена по медицине в 1990 г. Профессор ван Роод ушел в отставку со своей университетской должности в 1991 г., но оставался активным исследователем и лектором.

Работы профессора ван Роода характеризуются уникальным сочетанием фундаментальных медицинских исследований с большой ценностью этих исследований для клинической медицины, в частности – трансплантации органов и гемопоэтических тканей. Он основал школу иммунологов-трансплантологов, которые теперь работают в разных странах.

Йона ван Роода всегда будут называть в числе основателей современной трансплантационной иммунологии. Он сделал многое для поддержки активности молодых ученых в этой области, обеспечивая им гранты на пребывание и исследования. С 2010 г., ЕВМТ учреждена ежегодная премия ван Роода за лучшие исследования в области трансплантационной. Он не ограничивался деятельностью в Америке и Западной Европе. Так, при посещении России в начале 90-х годов, он много консультировал российских иммуногематологов, чтобы организовать Национальный Регистр доноров костного мозга. За последние годы эта идея претворена в работающий единый регистр с базой в Санкт-Петербурге, работающий в кооперации с аналогичными регистрами в России и Казахстане (Москва, Киров, Челябинск, Ростов-на Дону, Екатеринбург, Самара, Казань и Астана).

Будучи широко образованным и любознательным человеком, профессор Йон ван Роод любил получать новые впечатления от путешествий и поездок. Мы помним его интерес к Санкт-Петербургу и русской культуре при поездке на остров Валаам и в Кижи в 1992 г.

Мы будем многие годы вспоминать Йона ван Роода, яркого интеллектуала и организатора науки, как пример для будущих поколений ученых, работающих в биологии и медицине.

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Рекомбинантные антитела (например – Брентуксимаб) также обеспечивают дополнительные направленные эффекты против злокачественных новообразований, экспресcирующих CD30. На протяжении последних лет разработан оригинальный подход к адоптивной терапии в связи с начальными испытаниями опухоль-специфических Т-клеток с генными модификациями Т-антигенов или клеток со специфическими химерными Т-клеточными рецепторами (CAR-T-клетки), которые вначале показали хорошие результаты в экспериментах и клинических исследованиях. Неопределенная длительность лечебного действия и возможные побочные эффекты могут здесь привести к существенным проблемам. Таким образом, различные способы клеточной иммунотерапии сейчас постепенно внедряются в клиническую практику онкогематологов, становясь эффективными и, возможно, менее токсичными методами лечения по сравнению с обычной химиотерапией и онкоген-специфическими препаратами, такими, как ингибиторы тирозин-киназы, блокаторы JAK2 и т.д." 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Долговременное развитие в этой области проходило от комбинированных цитотоксических протоколов индукционной терапии к трансплантации гемопоэтических стволовых клеток (ТГСК). В то же время, хорошо доказанный механизм «трансплантат против лейкоза» при ТГСК способствовал интересу к иммунотерапии злокачественных заболеваний. Индукцию специфического противоопухолевого иммунного ответа можно получить путем перенаправления адаптивной иммунной системы с ее мощными цитотоксическими эффектами против лейкозных клеток. Клеточную иммунотерапию можно комбинирвать с обычной терапией и препаратами нового класса – ингибиторами контрольных пунктов иммунитета, которые способны усиливать цитотоксический эффект трансплантата против лейкоза. Однако оптимальный выбор времени применения и доз этих терапевтических агентов следует установить в дальнейших клинических испытаниях. Рекомбинантные антитела (например – Брентуксимаб) также обеспечивают дополнительные направленные эффекты против злокачественных новообразований, экспресcирующих CD30. На протяжении последних лет разработан оригинальный подход к адоптивной терапии в связи с начальными испытаниями опухоль-специфических Т-клеток с генными модификациями Т-антигенов или клеток со специфическими химерными Т-клеточными рецепторами (CAR-T-клетки), которые вначале показали хорошие результаты в экспериментах и клинических исследованиях. Неопределенная длительность лечебного действия и возможные побочные эффекты могут здесь привести к существенным проблемам. Таким образом, различные способы клеточной иммунотерапии сейчас постепенно внедряются в клиническую практику онкогематологов, становясь эффективными и, возможно, менее токсичными методами лечения по сравнению с обычной химиотерапией и онкоген-специфическими препаратами, такими, как ингибиторы тирозин-киназы, блокаторы JAK2 и т.д." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3810) "Основные принципы лечения лейкозов путем цитотоксической химиои радиотерапии не менялись в течение трех десятилетий, достигнув своей максимальной эффективности несколько лет тому назад. Долговременное развитие в этой области проходило от комбинированных цитотоксических протоколов индукционной терапии к трансплантации гемопоэтических стволовых клеток (ТГСК). В то же время, хорошо доказанный механизм «трансплантат против лейкоза» при ТГСК способствовал интересу к иммунотерапии злокачественных заболеваний.

Индукцию специфического противоопухолевого иммунного ответа можно получить путем перенаправления адаптивной иммунной системы с ее мощными цитотоксическими эффектами против лейкозных клеток. Клеточную иммунотерапию можно комбинирвать с обычной терапией и препаратами нового класса – ингибиторами контрольных пунктов иммунитета, которые способны усиливать цитотоксический эффект трансплантата против лейкоза. Однако оптимальный выбор времени применения и доз этих терапевтических агентов следует установить в дальнейших клинических испытаниях. Рекомбинантные антитела (например – Брентуксимаб) также обеспечивают дополнительные направленные эффекты против злокачественных новообразований, экспресcирующих CD30.

На протяжении последних лет разработан оригинальный подход к адоптивной терапии в связи с начальными испытаниями опухоль-специфических Т-клеток с генными модификациями Т-антигенов или клеток со специфическими химерными Т-клеточными рецепторами (CAR-T-клетки), которые вначале показали хорошие результаты в экспериментах и клинических исследованиях. Неопределенная длительность лечебного действия и возможные побочные эффекты могут здесь привести к существенным проблемам.

Таким образом, различные способы клеточной иммунотерапии сейчас постепенно внедряются в клиническую практику онкогематологов, становясь эффективными и, возможно, менее токсичными методами лечения по сравнению с обычной химиотерапией и онкоген-специфическими препаратами, такими, как ингибиторы тирозин-киназы, блокаторы JAK2 и т.д." 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The long-term evolution in this field has proceeded from combined cytotoxic induction protocols to hematopoietic stem cell transplantation (HSCT). Meanwhile, a well-proven graft-versus-leukemia mechanism of HSCT promoted interest to immunotherapy of malignant disorders. Induction of specific anti-tumour immune response may be obtained through re-direction of adaptive immune system with potent cytotoxic effects against leukemic cells. Cellular immunotherapy may be combined with conventional therapy and novel class of drugs, checkpoint inhibitors potentially enhancing the antileukemic effect. However, optimal timing and dosage for these therapeutic agents should be established in future trials. Recombinant antibodies (e.g., Brentuximab) also provide additional targeted effects against CD30+ malignancies. Over last year, an original approach to adoptive therapy is developed due to initial trials on tumor-specific T cells with introduced TCR or CAR (CAR-T cells) which initially provided good results in experiments and clinical settings. Duration of therapeutic action and probable adverse effects may present sufficient issues on this way. Hence, different modes of cellular immunotherapy are now gradually being implicated into clinical practice of oncohematology, being an effective and, probably, less toxic treatment as compared with conventional chemotherapy and oncogene-targeted drugs, such as tyrosine kinase inhibitors, JAK2 blockers etc." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1665) "Basic principles of leukemia treatment with cytotoxic chemo/radiotherapy have not change over last 30 years, reaching their maximal efficiency several years ago. The long-term evolution in this field has proceeded from combined cytotoxic induction protocols to hematopoietic stem cell transplantation (HSCT). Meanwhile, a well-proven graft-versus-leukemia mechanism of HSCT promoted interest to immunotherapy of malignant disorders.

Induction of specific anti-tumour immune response may be obtained through re-direction of adaptive immune system with potent cytotoxic effects against leukemic cells. Cellular immunotherapy may be combined with conventional therapy and novel class of drugs, checkpoint inhibitors potentially enhancing the antileukemic effect. However, optimal timing and dosage for these therapeutic agents should be established in future trials. Recombinant antibodies (e.g., Brentuximab) also provide additional targeted effects against CD30+ malignancies.

Over last year, an original approach to adoptive therapy is developed due to initial trials on tumor-specific T cells with introduced TCR or CAR (CAR-T cells) which initially provided good results in experiments and clinical settings. Duration of therapeutic action and probable adverse effects may present sufficient issues on this way.

Hence, different modes of cellular immunotherapy are now gradually being implicated into clinical practice of oncohematology, being an effective and, probably, less toxic treatment as compared with conventional chemotherapy and oncogene-targeted drugs, such as tyrosine kinase inhibitors,
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The long-term evolution in this field has proceeded from combined cytotoxic induction protocols to hematopoietic stem cell transplantation (HSCT). Meanwhile, a well-proven graft-versus-leukemia mechanism of HSCT promoted interest to immunotherapy of malignant disorders. Induction of specific anti-tumour immune response may be obtained through re-direction of adaptive immune system with potent cytotoxic effects against leukemic cells. Cellular immunotherapy may be combined with conventional therapy and novel class of drugs, checkpoint inhibitors potentially enhancing the antileukemic effect. However, optimal timing and dosage for these therapeutic agents should be established in future trials. Recombinant antibodies (e.g., Brentuximab) also provide additional targeted effects against CD30+ malignancies. Over last year, an original approach to adoptive therapy is developed due to initial trials on tumor-specific T cells with introduced TCR or CAR (CAR-T cells) which initially provided good results in experiments and clinical settings. Duration of therapeutic action and probable adverse effects may present sufficient issues on this way. Hence, different modes of cellular immunotherapy are now gradually being implicated into clinical practice of oncohematology, being an effective and, probably, less toxic treatment as compared with conventional chemotherapy and oncogene-targeted drugs, such as tyrosine kinase inhibitors, JAK2 blockers etc." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1665) "Basic principles of leukemia treatment with cytotoxic chemo/radiotherapy have not change over last 30 years, reaching their maximal efficiency several years ago. The long-term evolution in this field has proceeded from combined cytotoxic induction protocols to hematopoietic stem cell transplantation (HSCT). Meanwhile, a well-proven graft-versus-leukemia mechanism of HSCT promoted interest to immunotherapy of malignant disorders.

Induction of specific anti-tumour immune response may be obtained through re-direction of adaptive immune system with potent cytotoxic effects against leukemic cells. Cellular immunotherapy may be combined with conventional therapy and novel class of drugs, checkpoint inhibitors potentially enhancing the antileukemic effect. However, optimal timing and dosage for these therapeutic agents should be established in future trials. Recombinant antibodies (e.g., Brentuximab) also provide additional targeted effects against CD30+ malignancies.

Over last year, an original approach to adoptive therapy is developed due to initial trials on tumor-specific T cells with introduced TCR or CAR (CAR-T cells) which initially provided good results in experiments and clinical settings. Duration of therapeutic action and probable adverse effects may present sufficient issues on this way.

Hence, different modes of cellular immunotherapy are now gradually being implicated into clinical practice of oncohematology, being an effective and, probably, less toxic treatment as compared with conventional chemotherapy and oncogene-targeted drugs, such as tyrosine kinase inhibitors,
JAK2 blockers etc." ["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(1665) "Basic principles of leukemia treatment with cytotoxic chemo/radiotherapy have not change over last 30 years, reaching their maximal efficiency several years ago. The long-term evolution in this field has proceeded from combined cytotoxic induction protocols to hematopoietic stem cell transplantation (HSCT). Meanwhile, a well-proven graft-versus-leukemia mechanism of HSCT promoted interest to immunotherapy of malignant disorders.

Induction of specific anti-tumour immune response may be obtained through re-direction of adaptive immune system with potent cytotoxic effects against leukemic cells. Cellular immunotherapy may be combined with conventional therapy and novel class of drugs, checkpoint inhibitors potentially enhancing the antileukemic effect. However, optimal timing and dosage for these therapeutic agents should be established in future trials. Recombinant antibodies (e.g., Brentuximab) also provide additional targeted effects against CD30+ malignancies.

Over last year, an original approach to adoptive therapy is developed due to initial trials on tumor-specific T cells with introduced TCR or CAR (CAR-T cells) which initially provided good results in experiments and clinical settings. Duration of therapeutic action and probable adverse effects may present sufficient issues on this way.

Hence, different modes of cellular immunotherapy are now gradually being implicated into clinical practice of oncohematology, being an effective and, probably, less toxic treatment as compared with conventional chemotherapy and oncogene-targeted drugs, such as tyrosine kinase inhibitors,
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Долговременное развитие в этой области проходило от комбинированных цитотоксических протоколов индукционной терапии к трансплантации гемопоэтических стволовых клеток (ТГСК). В то же время, хорошо доказанный механизм «трансплантат против лейкоза» при ТГСК способствовал интересу к иммунотерапии злокачественных заболеваний. Индукцию специфического противоопухолевого иммунного ответа можно получить путем перенаправления адаптивной иммунной системы с ее мощными цитотоксическими эффектами против лейкозных клеток. Клеточную иммунотерапию можно комбинирвать с обычной терапией и препаратами нового класса – ингибиторами контрольных пунктов иммунитета, которые способны усиливать цитотоксический эффект трансплантата против лейкоза. Однако оптимальный выбор времени применения и доз этих терапевтических агентов следует установить в дальнейших клинических испытаниях. Рекомбинантные антитела (например – Брентуксимаб) также обеспечивают дополнительные направленные эффекты против злокачественных новообразований, экспресcирующих CD30. На протяжении последних лет разработан оригинальный подход к адоптивной терапии в связи с начальными испытаниями опухоль-специфических Т-клеток с генными модификациями Т-антигенов или клеток со специфическими химерными Т-клеточными рецепторами (CAR-T-клетки), которые вначале показали хорошие результаты в экспериментах и клинических исследованиях. Неопределенная длительность лечебного действия и возможные побочные эффекты могут здесь привести к существенным проблемам. Таким образом, различные способы клеточной иммунотерапии сейчас постепенно внедряются в клиническую практику онкогематологов, становясь эффективными и, возможно, менее токсичными методами лечения по сравнению с обычной химиотерапией и онкоген-специфическими препаратами, такими, как ингибиторы тирозин-киназы, блокаторы JAK2 и т.д." 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Индукцию специфического противоопухолевого иммунного ответа можно получить путем перенаправления адаптивной иммунной системы с ее мощными цитотоксическими эффектами против лейкозных клеток. Клеточную иммунотерапию можно комбинирвать с обычной терапией и препаратами нового класса – ингибиторами контрольных пунктов иммунитета, которые способны усиливать цитотоксический эффект трансплантата против лейкоза. Однако оптимальный выбор времени применения и доз этих терапевтических агентов следует установить в дальнейших клинических испытаниях. Рекомбинантные антитела (например – Брентуксимаб) также обеспечивают дополнительные направленные эффекты против злокачественных новообразований, экспресcирующих CD30.

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Индукцию специфического противоопухолевого иммунного ответа можно получить путем перенаправления адаптивной иммунной системы с ее мощными цитотоксическими эффектами против лейкозных клеток. Клеточную иммунотерапию можно комбинирвать с обычной терапией и препаратами нового класса – ингибиторами контрольных пунктов иммунитета, которые способны усиливать цитотоксический эффект трансплантата против лейкоза. Однако оптимальный выбор времени применения и доз этих терапевтических агентов следует установить в дальнейших клинических испытаниях. Рекомбинантные антитела (например – Брентуксимаб) также обеспечивают дополнительные направленные эффекты против злокачественных новообразований, экспресcирующих CD30.

На протяжении последних лет разработан оригинальный подход к адоптивной терапии в связи с начальными испытаниями опухоль-специфических Т-клеток с генными модификациями Т-антигенов или клеток со специфическими химерными Т-клеточными рецепторами (CAR-T-клетки), которые вначале показали хорошие результаты в экспериментах и клинических исследованиях. Неопределенная длительность лечебного действия и возможные побочные эффекты могут здесь привести к существенным проблемам.

Таким образом, различные способы клеточной иммунотерапии сейчас постепенно внедряются в клиническую практику онкогематологов, становясь эффективными и, возможно, менее токсичными методами лечения по сравнению с обычной химиотерапией и онкоген-специфическими препаратами, такими, как ингибиторы тирозин-киназы, блокаторы JAK2 и т.д." } } } }

Volume 6, Number 2
07/31/2017 04:17:00 pm

Editor-in-Chief
Afanasyev B. V. (St. Petersburg, Russia)

Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A.R. (Hamburg, Germany)

Deputy Editor
Fehse B. (Hamburg, Germany)

Managing Editor
Chukhlovin A. B. (St. Petersburg, Russia)

Editorial Board
Aleynikova O. V. (Minsk, Belarus)
Borset M. (Trondheim, Norway)
Chechetkin A. V. (St. Petersburg, Russia)
Fibbe W. (Leiden, Netherlands)
Galibin O. V. (St. Petersburg, Russia)
Hölzer D. (Frankfurt a.M., Germany)
Klimko N. N. (St. Petersburg, Russia)
Kolb H.-J. (München, Germany)
Kröger N. (Hamburg, Germany)
Kulagin A. D. (St. Petersburg, Russia)
Lange C. (Hamburg, Germany)
Mamaev N. N. (St. Petersburg, Russia)
Mikhailova N. B. (St. Petersburg, Russia)
Moiseev I. S. (St. Petersburg, Russia)
Nagler A. (Tel-Aviv, Israel)
Nemkov A. S. (St. Petersburg, Russia)
Paramonov I. V. (Kirov, Russia)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Uss A. L. (Minsk, Belarus)
Zubarovskaya L. S., (St. Petersburg, Russia)

In this Issue

Under clinical studies, a group of pediatric oncologists (Yulia V. Skvortsova et al.) from D. Rogachev Memorial Center of Pediatric Hematology, Oncology and Immunology (Mos- cow) present a large review with sufficient clinical data on posttransplant lymphoproliferative disease (PTLD) which may develop after solid organ transplantations and alloge- neic hematopoietic stem cell transplantations (allo-HSCT), being a specific posttransplant complication in immuno- suppressed patients. Its origin is, most probably, viral (Ep- stein-Barr virus), but cytostatic treatment depends on its clinical and morphological features. The authors describe PTLD in a skilled manner, being both comprehensive and valuable to clinicians.

Another clinical article by Julia Yu. Vlasova et al. (St. Peters- burg-Moscow) deals with a special genetic variant of chronic myeloid leukemia (CML) which, due to T315I mutation in BCR/ABL gene, does not respond to the best available tar- geted treatment, i.e., Imatinib and some other tyrosine ki- nase inhibitors which are effective in majority of CML cases without such a mutation. The authors describe strategies of treatment for such cases including Ponatinib treatment, or allo-HSCT which can be a potential option for selected pa- tients.

A review by A. B. Chukhlovin describes some genes which may predispose for common immune complications in allo-HSCT, in order to demonstrate that a number of non- HLA genes may influence immune complications (e.g., acute GvHD) and total survival of the patients following allogeneic HSCT. Interestingly, many of these gene variants are encod- ed by donor genome, thus showing some value for genotyp- ing of HSCT donors to predict risk of immune disorders post-HSCT.

We could not also miss such an important event as a joint meeting of leading hematologists from M.D.Anderson Med- ical Center (Houston, Texas, USA) and Russian hemato-on- cologists devoted to diagnostics and treatment of myelo- and lymphoproliferative disorders. Emerging issues of molecular diagnostics and clinical trials of novel targeted drugs were presented and discussed.

Continuing discussion about novel legislation and regu- lations in the field of gene editing and its possible clinical introduction, we publish a short opinion on the matter by Mikhail Samsonov, a Moscow expert in R&D of novel medi- cal drugs. We would be glad to get alternative views concern- ing gene editing, gene therapy and, especially, new approach- es to cellular therapy in oncology.

Сlinical studies

Clinical features and outcomes in chronic myeloid leukemia with T315I mutation

Posttransplant lymphoproliferative disorder in children after allogeneic hematopoietic stem cell transplantation: a single-center experience and literature review

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

Experimental studies

Beyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications

Alexey B. Chukhlovin

Conferences

A report on International Conference “Modern Treatment Strategies and Horizons in Hematology and Oncology” (June 30-July 1, 2017)

Andrey Yu. Zaritskey¹, Boris V. Afanasyev², Dmitry V. Motorin¹

Short communications

Genome editing: development and regulatory challenges

Mikhail Y. Samsonov

Obituary

Obituary. In memory of Professor Jon van Rood

Professor Boris V. Afanasyev

Editorial

Editorial article

Professor Boris V. Afanasyev, The CTT Editor-in-Chief

Сlinical studies

Clinical features and outcomes in chronic myeloid leukemia with T315I mutation

Download PDF version

MATERIALS AND METHODS

RESULTS

CONCLUSION

Keywords

Chronic myeloid leukemia, T315I mutation, allogeneic transplantation of hematopoietic cells, drug resistance.

Сlinical studies

Posttransplant lymphoproliferative disorder in children after allogeneic hematopoietic stem cell transplantation: a single-center experience and literature review

Download PDF version

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

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.

Experimental studies

Beyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications

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Alexey B. Chukhlovin

R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial
Research Institute of Children Oncology, Hematology and
Transplantation, The St. Petersburg State I. Pavlov Medical
University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins (TNF-α, IL1-β, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.

Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us to make the following conclusions:
1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system;
2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles.

This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.

Keywords

Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics.

Conferences

A report on International Conference “Modern Treatment Strategies and Horizons in Hematology and Oncology” (June 30-July 1, 2017)

Download PDF version

Andrey Yu. Zaritskey¹, Boris V. Afanasyev², Dmitry V. Motorin¹

¹ Federal Almazov North-West Medical Research Centre, St. Petersburg, Russia.
² R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

A joint conference of clinicians from M.D. Anderson Medical Center (Houston, Texas, USA) and specialists from leading Russian hematological centers took place in St. Petersburg on June 30-July 1, 2017. A series of special sessions was dedicated to current issues of diagnostics and pathogenetic molecular classification in hemato-oncology, including chronic lymphocytic leukemia (CLL), acute leukemias (AL), aplastic anemias (AA), myelodysplastic syndrome (MDS), malignant lymphomas. Standard treatment schedules, as well as clinical effects of newly developed targeted drugs and combined therapeutic approaches were analyzed, with a focus on Hodgkin’s disease, chronic lymphocytic and myeloid leukemias and multiple myeloma. Recent developments in AL treatment, especially, in acute myeloblastic leukemia, were also presented. Current position of hematopoietic stem cell transplantation as a curative treatment in some leukemia/lymphoma settings, opportunities for tumor immunotherapy (e.g., CAR-T cells) and appropriate technologies were also discussed.

Keywords

USA-Russian conference, leukemia, lymphoma, pathogenesis, classification, treatment, targeted drugs, allogeneic hematopoietic stem cell transplantation.

Short communications

Genome editing: development and regulatory challenges

Download PDF version

Mikhail Y. Samsonov

JSC RPharm, Moscow, Russia

Dr. Mikhail Y. Samsonov, PhD, Chief Medical Officer,
JSC RPharm, Russia, 111B Leninsky prospect, 197002,
Moscow, Russia

Genome editing tools can be mostly used to introduce, remove, or substitute one or more specific nucleotides at a specific site in an organism’s genome, and is achieved with the use of protein-nucleotide complexes. Several classes of these complexes exist, Zinc Finger Nuclease (ZFN), transcription activator-like effector nuclease (TALEN and the most recent discovery – Clustered regularly interspaced short palindromic repeats /CRISPR associated protein 9 (CRISPR/Cas9). The technology belongs to a growing list of personalized therapies and requires special attention to perform development, standardization of manufacturing for every patient, robust preclinical and clinical program addressing key challenges of the new technology, e.g. “off-target” effects. The ethical aspects of these tools are also quite critical.

Keywords

Genome editing, ZFN, TALEN, CRISPR-Cas9, regulatory environment, benefit\risk evaluation.

Obituary

Obituary. In memory of Professor Jon van Rood

Download PDF version

Professor Boris V. Afanasyev

Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation at the First State
I. Pavlov Medical University

Editorial

Editorial article

Professor Boris V. Afanasyev, The CTT Editor-in-Chief

Basic principles of leukemia treatment with cytotoxic chemo/radiotherapy have not change over last 30 years, reaching their maximal efficiency several years ago. The long-term evolution in this field has proceeded from combined cytotoxic induction protocols to hematopoietic stem cell transplantation (HSCT). Meanwhile, a well-proven graft-versus-leukemia mechanism of HSCT promoted interest to immunotherapy of malignant disorders.

Induction of specific anti-tumour immune response may be obtained through re-direction of adaptive immune system with potent cytotoxic effects against leukemic cells. Cellular immunotherapy may be combined with conventional therapy and novel class of drugs, checkpoint inhibitors potentially enhancing the antileukemic effect. However, optimal timing and dosage for these therapeutic agents should be established in future trials. Recombinant antibodies (e.g., Brentuximab) also provide additional targeted effects against CD30+ malignancies.

Over last year, an original approach to adoptive therapy is developed due to initial trials on tumor-specific T cells with introduced TCR or CAR (CAR-T cells) which initially provided good results in experiments and clinical settings. Duration of therapeutic action and probable adverse effects may present sufficient issues on this way.

Hence, different modes of cellular immunotherapy are now gradually being implicated into clinical practice of oncohematology, being an effective and, probably, less toxic treatment as compared with conventional chemotherapy and oncogene-targeted drugs, such as tyrosine kinase inhibitors,
JAK2 blockers etc.