ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 7, Number 2
06/04/2018 04:46:00 pm
Volume 7, Number 2
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

The ongoing CTT number begins with a review article by Dr. A. Grigoriants et al. which deals with oral problems in the patients after allogeneic hematopoietic stem cell transplantation (HSCT), expecially, short- and long-term dental disorders in children after intensive cytotoxic therapy, and inflammatory/atrophic changes of oral mucosa associated with acute and chronic graft-versus-host disease (GVHD), due to infections and autoaggressive processes.

International data show good efficiency of haploidentical HSCT when treating acute leukemias. Appropriate clinical protocols for children and adolescents using non-manipulated hematopoietic grafts, and evaluation of medium- and long-term results are reported by Dr. O. Paina et al. The authors conclude on good efficiency of haploidentical HSCT for this age group, being comparable to HLA-compatible transplantation.

Novel inhibitors of PD-1 apoptotic pathway are intensively studied, aiming for enhanced immune therapy of different malignancies. The article by Dr. K. Lepik et al. concerns application of Nivolumab in relapsed Hodgkin’s disease (HD) following allogeneic HSCT. Most patients exhibited appreciable clinical response, thus confirming efficiency of this drug in HD.

Treatment of myelodysplastic syndromes and acute myeloblastic leukemias (AML) evolving from acquired aplastic anemia are discussed in the article by Dr. I. Golubovskaya et al. which presents clinical results obtained, when treating these rare conditions with complex pathogenesis. In particular, the authors discuss early complications and overall survival following immunosuppressive therapy and allo-HSCT.

The article by Dr. E. Babenko et al. presents a comparative statistical evaluation of transplantation with cryopreserved vs freshly taken hematopoietic grafts in a heterogenous patient sample. A long-term experience has generally shown that the results of allogeneic HSCT with cryopreserved graft are comparable to native hematopoietic transplants, in terms of severe acute and chronic GVHD, overall survival, and GVHD-relapse-free survival.

Expression of leukemia-associated genes, such as EVI 1, WT 1, etc., is important both for primary diagnostics, and, especially, for the minimal residual disease (MRD) quantitation after therapy. The study by Dr. A. Shakirova et al. is focused on prognostic significance and diagnostic cut-off values for BAALC gene expression predictive for high risk of relapse in acute myeloid leukemia after allo-HSCT.

Clinical value of cytogenetics for tracing clonal evolution in myelodysplastic syndrome is well illustrated by a clinical case presented by Prof. N. Mamaev et al. The case is quite instructive to oncohematologists since it compares clinical course, cytogenetic and molecular evolution in the patient.

A good experimental study is presented by a group from Novosibirsk (Dr. D. Matvienko et al.). The authors have produced a clone of CAR cells which could be potentially applied for immunotherapy of prostate cancer.

This issue also contains a concise comment by Professor Axel R. Zander, who presents the available clinical criteria for risk prediction in AML patients that was vividly discussed in two previous CTT journals. The readership is invited to follow the entire discussion in details.

Editorial article

Editorial article
Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Therapy and Transplantation

Review articles

Stomatological problems and infectious complications after hematopoietic stem cell transplantation
Artur P. Grigoriants1, Ilya M. Rabinowitch2, Alexey B. Chukhlovin1

Clinical studies

Safety and efficacy of nivolumab applied at different dosage in the patients with relapsing Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation
Kirill V. Lepik, Andrey V. Kozlov, Evgeniya S. Borzenkova, Marina O. Popova, Ivan S. Moiseev, Elena I. Darskaya, Asmik G. Gevorgyan, Luibov A. Tsvetkova, Sergey N. Bondarenko, Alexander L. Alyanskiy, Elena V. Kondakova, Natalya B. Mikhailova, Boris V. Afanasyev
Ten-year experience of allogeneic haploidentical hematopoietic stem cell transplantation with non-manipulated grafts in children and adolescents with high-risk acute leukemia
Olesya V. Paina, Polina V. Kozhokar, Anastasia S. Borovkova, Anastasia S. Frolova, Kirill A. Ekushov, Tatyana A. Bykova, Zhemal Z. Rakhmanova, Mariya A. Galas, Aigul G. Khabirova, Inna V. Markova, Elena V. Semenova, Sergey N. Bondarenko, Elena V. Babenko, Tatyana L. Gindina, Alexander L. Alyanskiy, Ildar M. Barkhatov, Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev
Myelodysplastic syndrome/acute myeloid leukemia evolving from aplastic anemia: Efficacy of hematopoietic stem cell transplantation
Irina K. Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. Afanasyev
Pair-matched study of cryopreserved versus native graft in adult and pediatric recipients of allogeneic hematopoietic stem cell transplantation
Elena V. Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev
Primary myelodysplastic syndrome with two rare recurrent chromosome abnormalities [t(3q26.2;q22) and trisomy 13] associated with resistance to chemotherapy and hematopoietic stem cell transplantation
Nikolay N. Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev
Prognostic significance of BAALC overexpression in patients with AML during the posttransplant period
Alena I. Shakirova, Ildar M. Barkhatov, Anna I. Churkina, Ivan S. Moiseev, Tatiana L. Gindina, Sergey N. Bondarenko, Boris V. Afanasyev

Experimental studies

Analysis of in vitro activity of PSCA-specific CARs in the context of human NK cell line YT
Daria A. Matvienko a, b, #, Sergey V. Kulemzin a, #, Anna S. Smagina a, b, Tatyana N. Belovezhets a, b, Anton N. Chikaev a, Olga Y. Volkova a, Nikolay A. Chikaev a, Olga A. Koval b, c, Elena V. Kuligina b, c, Alexandr V. Taranin a, b, Andrey A. Gorchakov a, b

Letter to the Editor

Letter to the Editor
Axel Rolf Zander

Editorial article

Editorial article

Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Therapy and Transplantation

Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.

Review articles

Stomatological problems and infectious complications after hematopoietic stem cell transplantation

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Artur P. Grigoriants1, Ilya M. Rabinowitch2, Alexey B. Chukhlovin1

1The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
2Central Research Institute of Stomatology, Moscow, Russia

The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.

Keywords

Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.

Clinical studies

Safety and efficacy of nivolumab applied at different dosage in the patients with relapsing Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation

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Kirill V. Lepik, Andrey V. Kozlov, Evgeniya S. Borzenkova, Marina O. Popova, Ivan S. Moiseev, Elena I. Darskaya, Asmik G. Gevorgyan, Luibov A. Tsvetkova, Sergey N. Bondarenko, Alexander L. Alyanskiy, Elena V. Kondakova, Natalya B. Mikhailova, Boris V. Afanasyev

R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. P. Pavlov Medical University, Roentgen St. 12; 197022, St. Petersburg,Russia

Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.

Keywords

Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.

Clinical studies

Ten-year experience of allogeneic haploidentical hematopoietic stem cell transplantation with non-manipulated grafts in children and adolescents with high-risk acute leukemia

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Olesya V. Paina, Polina V. Kozhokar, Anastasia S. Borovkova, Anastasia S. Frolova, Kirill A. Ekushov, Tatyana A. Bykova, Zhemal Z. Rakhmanova, Mariya A. Galas, Aigul G. Khabirova, Inna V. Markova, Elena V. Semenova, Sergey N. Bondarenko, Elena V. Babenko, Tatyana L. Gindina, Alexander L. Alyanskiy, Ildar M. Barkhatov, Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev

R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State I. Pavlov Medical University; St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia

Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.

Materials and methods

106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.

Statistical analysis

SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.

Conclusion

Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.

Keywords

Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.

Clinical studies

Myelodysplastic syndrome/acute myeloid leukemia evolving from aplastic anemia: Efficacy of hematopoietic stem cell transplantation

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Irina K. Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. Afanasyev

R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia

Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.

Keywords

Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.

Clinical studies

Pair-matched study of cryopreserved versus native graft in adult and pediatric recipients of allogeneic hematopoietic stem cell transplantation

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Elena V. Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev

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

Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.

Keywords

Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.

Clinical studies

Primary myelodysplastic syndrome with two rare recurrent chromosome abnormalities [t(3q26.2;q22) and trisomy 13] associated with resistance to chemotherapy and hematopoietic stem cell transplantation

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Nikolay N. Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev

R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantology at the St. Petersburg State I. Pavlov Medical University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.

Keywords

Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.

Clinical studies

Prognostic significance of BAALC overexpression in patients with AML during the posttransplant period

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Alena I. Shakirova, Ildar M. Barkhatov, Anna I. Churkina, Ivan S. Moiseev, Tatiana L. Gindina, Sergey N. Bondarenko, Boris V. Afanasyev

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

Summary

Acute myeloid leukemia (AML) is a heterogenous clonal blood disease of a neoplastic origin. There are challenging issues for the intermediate-risk AML group, which is defined as non-homogeneous due to a variety of gene mutations (FLT3, NPM1, CEBPA, etc.), prediction of differential clinical course, relapse risk, and selection of adequate therapy. In this context, a search for new molecular markers with sufficient prognostic value for the relapse risk estimation in AML cases with no detectable cytogenetic abnormalities represents a high-priority task for clinical molecular oncohematology. We analyzed prognostic significance of BAALC (Brain And Acute Leukemia, Cytoplasmic) gene overexpression in 93 AML patients during the posttransplant period, in order to estimate feasibility of BAALC expression level monitoring, to predict the relapse risk, and to evaluate sensitivity and specificity of BAALC gene expression assay, to the purpose of minimal residual disease (MRD) monitoring. BAALC expression was determined by quantitative real-time polymerase chain reaction in fresh bone marrow samples. Patients were dichotomized at BAALC's individual and general cut-off into low and high expressers. We have concluded that BAALC overexpression above both individual and common cut-off levels is recognized as a prognostically significant factor for posttransplant relapse risk estimation, overall survival and relapse-free survival. A more detailed analysis of BAALC as a marker for estimation of therapeutic efficiency was performed. We have also compared its sensitivity to the reference techniques for minimal residual disease monitoring (i.e., qPCR-based detection of chimeric gene transcripts), showing inferior sensitivity of such approach to MRD detection in post-transplant period, at least, for our study group. Serial BAALC monitoring may be recommended for clinical relapse prediction during the post-transplant period in AML patients.

Keywords

Acute myeloblastic leukemia, BAALC, gene expression, clinical prognosis, minimal residual disease.

Experimental studies

Analysis of in vitro activity of PSCA-specific CARs in the context of human NK cell line YT

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Daria A. Matvienko a, b, #, Sergey V. Kulemzin a, #, Anna S. Smagina a, b, Tatyana N. Belovezhets a, b, Anton N. Chikaev a, Olga Y. Volkova a, Nikolay A. Chikaev a, Olga A. Koval b, c, Elena V. Kuligina b, c, Alexandr V. Taranin a, b, Andrey A. Gorchakov a, b

a Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia b Novosibirsk State University, Novosibirsk, Russia c Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia # equal contribution

Comprehensive structural optimization of chimeric antigen receptors (CARs) is the key to their successful performance both in vitro and in vivo. In order to compare various CAR designs in an unified format, we took advantage of a lentiviral platform, where all CAR modules can be easily shuffled and tested for functionality. This platform was used to delineate the effects of various spacer regions on the function of a PSCA-specific CAR in the context of a human NK cell line, YT. We show that three CAR designs (IgG1-, CD8a-, and spacerless) perform similarly in vitro regardless of the length of the spacer region.

Keywords

Chimeric antigen receptor (CAR), adoptive immunotherapy, prostate cancer, prostate stem cell antigen (PSCA).

Letter to the Editor

Letter to the Editor

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Axel Rolf Zander

Huntsman Cancer Institute, University of Utah, Salt Lake City

Keywords

Acute myeloblastic leukemia, hematopoietic stem cell transplantation, clinical outcomes, prediction.