ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 10, Number 1
04/30/2021
Volume 10, Number 1
Editor-in-Chief
Kulagin A. D. (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)
Gale R. P. (Los Angeles, USA)
Galibin O. V. (St. Petersburg, Russia)
Hehlmann R. (Mannheim, Germany)
Hölzer D. (Frankfurt a.M., Germany)
Klimko N. N. (St. Petersburg, Russia)
Kolb H.-J. (München, Germany)
Kröger N. (Hamburg, Germany)
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

Dear CTT authors and readers,

The continuing COVID-19 pandemia presents great challenges to hemato-oncological and BMT clinics worldwide.

Like our colleagues in Western and Eastern World, we have encountered the new coronavirus infection in March 2020, thus requiring a variety of urgent epidemiological measures and early diagnostics of SARS-CoV-2-infected persons, involving our clinical staff and the patients admitted or those, who were on the waiting list. To this purpose, a countrywide training of medical staff was urgently performed, according to the temporary Guidelines from Russian Health Ministry (with later amendments), thus providing a uniform strategy to combat the epidemics in St. Petersburg and in dozens hematological clinics all over the country, and creating a basis for training of our doctors, nurses and relatives of the patients in this items.

Huge problems initially arised for our epidemiologists, clinical infectologists and laboratory staff who resolved appropriate organizational and educational tasks. Within several weeks, first native PCR kits for SARS-CoV2 were approved by the central surveillance authorities, their number then extended to >30 PCR test systems widely used by the network of clinical laboratories throughout Russia. About 2 months were sufficient to develop tests for detection of IgM and IgG antibodies against SARS-CoV-2 in recovered patients.

Hence, within several weeks, the infrastructure of oncohematological clinics and related clinical departments was adapted for diagnostics, isolation and observation of SARS-CoV-2-infected persons, as well as special prophylactic measures to prevent further spread of infection. In our specific setting, we were obliged to arrange ‘red’ (wards) for patients with COVID-19, with special regimen of their handling and care.

Аnother crucial problem was to adapt intensive care units for management of severe patients following chemotherapy and HSCT, and to expand diagnostic facilities at the University Department of Microbiology which worked at their extreme limits with PCR testing of the virus and antibody diagnostics over last year.

Isolation of immunocompromised patients at our clinics became extremely strict. The infected patients were displaced to the COVID hospital at our University, thus presenting a favorable opportunity to our transplantation clinics.

To minimize epidemiological risks, we were obliged to delay intensive treatment for infected patients with leukemias and lymphomas undergoing HSCT. At longer periods, the scheduled follow-up of the patients was required, however, distant counseling was arranged, if possible.

In the frames of post-COVID and post-transplant rehabilitation, clinical psychologists should support both patients, their relatives and clinicians employed in the “red” areas.

COVID vaccination is another unresolved issue, which should be considered. The existing vaccines are not yet studied for appropriate safety and specific protective ability in cancer patients, especially, in pediatric immunocompromised cohorts subjected to cytostatic and immunosuppressive therapies.

While making our efforts, we are much appreciated to international authorities, and leading medical journals, which shared their indispensable experience in this field, hoping for further multicentric studies on this issues. Of course, it is too soon to make some definite conclusions on COVID-19 impact on clinical course and outcomes in our patients. The effects of past COVID-19 upon overall and event-free survival require long-term follow-up, and, at least, several years are required to summarize these data with our colleages worldwide.

In any case, we invite our present and future authors to submit to Cellular Therapy and Transplantation their studies about specific aspects of COVID-19 infection in oncohematology and stem cell transplantation clinics.

Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal

Review articles

Immunoinformatics in COVID-19 Vaccine Development: The Role of HLA System

Anna Yu. Anisenkova1, Aleksander S. Golota1, Dmitry A. Vologzhanin1, Tatyana A. Kamilova1, Stanislav V. Makarenko1,2, Olga V. Shneider1, Oleg S. Glotov1,3, Yury A. Serov4, Sergey V. Mosenko1, Sergey V. Azarenko1, Konstantin V. Smanzerev1, Dmitry N. Khobotnikov1, Tatyana V. Gladisheva1, Sergey G. Shcherbak1,2

Clinical studies

Infectious complications in multiple myeloma patients undergoing autologous peripheral blood stem cell transplantation

Vitaly N. Chebotkevich, Alena V. Kuleshova, Anastasia A. Zhernyakova, Ivan I. Kostroma, Ekaterina E. Kiseleva, Elena I. Kaytandzhan, Natalia Yu. Semenova, Stanislav S. Bessmeltsev, Alexander V. Chechetkin, Sergei V. Gritsaev

Clinical and immune effects of fecal microbiota transplantation in children with acute graft-versus-host disease

Oleg V. Goloshchapov1, Evgeny A. Bakin1, Oksana V. Stanevich1, Ruslana V. Klementeva1, Alexander A. Shcherbakov1, Alexander N. Shvetsov1, Olesya V. Paina1, Polina V. Kozhokar1, Margarita V. Gorchakova1, Elena V. Babenko1, Maria A. Suvorova2, Sergey N. Bondarenko1, Maxim A. Kucher1, Alexander D. Kulagin1, Ludmila S. Zubarovskaya1, Ivan S. Moiseev1

Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamicin and hematopoietic stem cell transplantation

Nikolay N. Mamaev, Alyona I. Shakirova, Tatiana L. Gindina, Sergey N. Bondarenko, Bella I. Ayubova, Ildar M. Barkhatov, Yana V. Gudozhnikova, Valentina M. Kravtsova, Mikhail M. Kanunnikov, Olesya V. Paina, Zhemal Z. Rakhmanova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in children with atypical teratoid/rhabdoid CNS tumors

Liudmila V. Olkhova1, Olga G. Zheludkova2, Ludmila S. Zubarovskaya3, Anna Yu. Smirnova4, Yulia V. Dinikina4,5, Asmik G. Gevorgyan3, Andrey S. Levashov6, Elena V. Skorobogatova1

New therapeutic options in myelodysplastic syndrome: literature review and single-center treatment results

Elena V. Morozova, Nikolai Yu. Tsvetkov, Irina O. Turtanova, Ivan S. Moiseev

Nivolumab-based immunotherapy in relapsed/refractory B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma

Olesya G. Smykova, Kirill V. Lepik, Natalia B. Mikhailova, Elena V. Kondakova, Evgenia S. Borzenkova, Elena E. Lepik, Yuri R. Zalyalov, Lilia V. Stelmakh, Vadim V. Baykov, Ivan S. Moiseev, Alexander D. Kulagin, Boris V. Afanasyev

Experimental studies

Morphology of hybrid doxorubicin delivery systems (dextran sulfate-coated CaCO3 vaterites) in human blood plasma

Natalia N. Sudareva1,2, Olga М. Suvorova1, Natalia N. Saprykina1, Vladimir V. Tomson2, Dmitry N. Suslov3, Oleg V. Galibin2, Aleksandr D. Vilesov1,2

Review articles

Laboratory diagnostics of HSCT complications: immature platelets and RBCs

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Gina Zini

Fondazione Policlinico Universitario A, Gemelli IRCCS – Roma, Università Cattolica del Sacro Cuore, Roma, Italy


Correspondence

Professor Gina Zini, MD, PhD, Dpt. Diagnostica per immagini, Radioterapia oncologica e Ematologia, Fondazione Policlinico Universitario
A. Gemelli IRCCS – Roma, Università Cattolica del Sacro Cuore
E-mail: gina.zini@unicatt.it

HSCT is a potentially life-saving procedure, associated with complications requiring increased vigilance and monitoring. In the immediate follow-up of patients, the blood count provides precise quantitative indications upon the post-transplant course, allowing to follow haematopoietic recovery, evaluating hemoglobin values, and the numbers of platelets and white blood cells. At the present time, useful and cheap automated hematology parameters are available, in order to improve both management and follow-up of HSC transplanted patients, that are the immature reticulocyte fraction (IRF), immature platelet fraction/reticulated platelets (IPF) and red blood cell (RBC) fragments. In the presence of post-transplant recovery of erythropoiesis and thrombocytopoiesis, IRF and IPF increase in the peripheral blood correlates in real time with haematopoietic recovery. Another useful parameter in the follow-up of these patients is the number of red blood cell fragments (FRC) which can correlate with presence of shistocytes. Availability of this parameter allows to intercept in routine practice the samples that could contain schistocytes: immediate evaluation of the peripheral blood smear will confirm or not the diagnostic suspicion.

Keywords

Automated blood analysis, immature reticulocytes fraction, immature platelets fraction, red blood cell fragments, hematopoietic cell transplantation, complications.

Review articles

Immunoinformatics in COVID-19 Vaccine Development: The Role of HLA System

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Anna Yu. Anisenkova1, Aleksander S. Golota1, Dmitry A. Vologzhanin1, Tatyana A. Kamilova1, Stanislav V. Makarenko1,2, Olga V. Shneider1, Oleg S. Glotov1,3, Yury A. Serov4, Sergey V. Mosenko1, Sergey V. Azarenko1, Konstantin V. Smanzerev1, Dmitry N. Khobotnikov1, Tatyana V. Gladisheva1, Sergey G. Shcherbak1,2

1 St. Petersburg City Hospital №40, St. Petersburg, Russia
2 St. Petersburg State University School of Medicine, St. Petersburg, Russia
3 D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russia
4 Pavlov University, St.Petersburg, Russia


Correspondence
Dr. Aleksander S. Golota, Ph.D., Head, Clinical Research Branch for Medical Rehabilitation, City Hospital №40, Borisova St. 9B, Sestrorezk, St.Petersburg, Russia
E-mail: golotaa@yahoo.com

Individual genetic variation may help to explain different immune responses to a coronavirus SARS-CoV-2 across a population. The in silico computer simulation methodology provides the experimental community with a more complete list of SARS-CoV-2 immunogenic peptides presented by the antigens of the HLA system. This review considers an array of computationally predicted immunogenic peptides from SARS-CoV-2 for in vitro functional validation and potential vaccine developments. Several independent studies conducted with different approaches showed a high degree of confidence and reproducibility of the results. Computer-assisted prediction is instrumental for a quick and cost-effective solution to prevent the spread and ultimately eliminate the infection.

Most efforts to develop vaccines and drugs against SARS-CoV-2 target the spike glycoprotein (protein S), the major inducer of neutralizing antibodies. Several candidates have been shown to be effective in in vitro studies and have progressed to randomized trials in animals or humans against COVID-19 infection. This article highlights current advances in the development of subunit vaccines to combat COVID-19 that are reducing the time and costs of vaccine development.

Keywords

Coronavirus, SARS-CoV-2, COVID-19, immunogenic peptides, antigen, HLA, vaccine, epitope, computational prediction, computer simulation in silico, immunoinformatics.

Clinical studies

Infectious complications in multiple myeloma patients undergoing autologous peripheral blood stem cell transplantation

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Vitaly N. Chebotkevich, Alena V. Kuleshova, Anastasia A. Zhernyakova, Ivan I. Kostroma, Ekaterina E. Kiseleva, Elena I. Kaytandzhan, Natalia Yu. Semenova, Stanislav S. Bessmeltsev, Alexander V. Chechetkin, Sergei V. Gritsaev

Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence
Prof. Vitaly N. Chebotkevich, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St. 16, 191024, St. Petersburg, Russia
Phone: +7 (906) 267 0266
E-mail: vitnikcheb@mail.ru

Multiple myeloma (MM) accounts for approximately 10% of blood malignancies and 1% of all cancers in general. The concept of high-dose chemotherapy followed by transplantation of autologous hematopoietic stem cells (ASCT) remains the standard for treating newly diagnosed multiple myeloma in young and in selected, fit, elderly patients. Infectious complications represent important cause of morbidity and mortality in MM patients. Bloodstream infections remain the most severe bacterial complication in recipients of hematopoietic stem cell transplantation, whereas herpesviruses, especially, cytomegalovirus (CMV), dominate among viral complications. We analyzed data on 38 patients with MM who underwent ASCT from January 2018 to February 2020. Reactivation of cytomegalovirus (CMV) was revealed in 5 cases (13.2%), and Epstein-Barr virus (EBV), in 3 patients (7.9%). Pneumonia was diagnosed in one case (2.6%). Bacterial bloodstream infections were detected in 3 patients (7.9%). The bloodstream infections were stratified in accordance with the Sepsis-3 criteria, thus enabling us to identify patients with unfavorable prognosis who developed sepsis and/or septic shock. Infectious complications were observed over the period of 60 days after ASCT. Meanwhile, CMV and EBV reactivation and bloodstream bacterial infections did not affect overall survival rate.

Conclusion

Our results demonstrate that bacterial complications and viral (CMV and EBV) reactivation aggravate the course of primary disease in MM patients over the post-transplant period. The methods of infection control in clinical practice (genotyping of multidrug-resistant strains, and antimicrobial control protocols) should improve the treatment strategies in patients with MM following ASCT. Keywords Autologous hematopoietic stem cells transplantation, bacterial and viral infectious complications, sepsis, septic shock.

Keywords

Autologous hematopoietic stem cells transplantation, bacterial and viral infectious complications, sepsis, septic shock.

Clinical studies

Clinical and immune effects of fecal microbiota transplantation in children with acute graft-versus-host disease

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Oleg V. Goloshchapov1, Evgeny A. Bakin1, Oksana V. Stanevich1, Ruslana V. Klementeva1, Alexander A. Shcherbakov1, Alexander N. Shvetsov1, Olesya V. Paina1, Polina V. Kozhokar1, Margarita V. Gorchakova1, Elena V. Babenko1, Maria A. Suvorova2, Sergey N. Bondarenko1, Maxim A. Kucher1, Alexander D. Kulagin1, Ludmila S. Zubarovskaya1, Ivan S. Moiseev1

1 Pavlov University, St. Petersburg, Russia
2 Explana Research Laboratory, St. Petersbug, Russia


Correspondence
Oleg V. Goloshchapov, ICU Department, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
Phone: +7 (921) 979 2913
E-mail: golocht@yandex.ru

Over last years, an important role of altered gut microbiota and its potential correction was suggested for pediatric cancer and autoimmune disorders. The data from last decade highlight sufficient influence of the main classes of gut bacteria (Firmicutes and Bacteroides) upon development of immune response in oncological disorders and autoagressive conditions, as well as role of their imbalance and its correction using fecal microbiota transplantation (FMT) approach. Our previous studies have shown a pronounced clinical effect of FMT, mostly, in adult patients with severe acute graft-versus-host disease (GVHD). The aim of this article was to present our own experience of FMT in children with intestinal form of GVHD resistant to conventional treatment.

Materials and methods

A prospective single-center study included 7 patients aged from 3 to 10 years with severe intestinal GVHD developed after allogeneic hematopoietic stem cell transplantation. Clinical effects of FMT were evaluated by conventional scales during 120 days after the procedure. Time-dependent changes of fecal microbiota were assayed, mainly, by the multiplex polymerase chain reaction (PCR) test-system.

Results

We present our own experience of FMT in 7 children with intestinal GVHD and antibiotic-resistant colitis. Complete or partial response to the GVHD treatment was achieved in 6 cases (86%) by 120 days, in absence of serious adverse events following FMT. Since day +8 after TFM, increased amounts of B. fragilis gr., Faecalibacterium prausnitzii and E. coli were registered in fecal microbiota (р< 0.048, р< 0.001, and р<0.048, respectively), in absence of differences for Bifidobacterium spp and Lactobacillus spp.

Conclusion

Combined therapy with immunosuppressive agents and FMT procedure in the patients with intestinal GVHD resistant to standard therapy is associated with pronounced clinical responses correlating with distinct changes of intestinal microbiota, with acceptable safety profile.

Keywords

Hematopoietic stem cell transplantation, graft-versus-host disease, fecal microbiota transplantation, clinical efficiency.

Clinical studies

Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamicin and hematopoietic stem cell transplantation

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Nikolay N. Mamaev, Alyona I. Shakirova, Tatiana L. Gindina, Sergey N. Bondarenko, Bella I. Ayubova, Ildar M. Barkhatov, Yana V. Gudozhnikova, Valentina M. Kravtsova, Mikhail M. Kanunnikov, Olesya V. Paina, Zhemal Z. Rakhmanova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Professor Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamev524@gmail.com

There is evidence that relapses of acute myeloid leukemia (AML) are closely related to heterogeneous population of leukemic precursors. At least, two classes of the leukemia-initiating cells (LIC) may be discerned, according to recent experimental studies with hematopoietic cell transplants to immunodeficient mice. The main class of LICs is presented by immature precursors with CD34+CD38 immunophenotype which, in turn, are capable of selective expression of BAALC gene. The second class of LICs is presented by relatively mature precursors with more differentiated immunophenotypes. According to indirect findings, they are able of WT1 gene expression, along with blast cells. Since both BAALC and WT1 mRNAs may be quantitatively evaluated by means of standardized quantitative polymerase reaction in real time (qRT-PCR), this approach may be effective for specifying the mechanisms of relapses and resistance to therapy in AML patients. The aim of this work was to perform simultaneous dynamic evaluation of BAALC and WT1 genes expressions along with determination of blast numbers in the tested bone marrow samples in 14 AML patients treated at our Center with Gemtuzumab ozogamicin (GO, Mylotarg), which was combined with high-dose chemotherapy (ChT), followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our preliminary results are as follows: a) superior 3-year overall survival (OS) in general group of patients with normal or nearly-normal karyotypes, and FLT3-mutated AML variants as compared to those with more complex karyotypes and EVI1 gene overexpression (85.7% vs 16.7%; p=0.032); b) highly sensitive response of immature BAALC-expressing precursors to combined ChT and GO treatment; c) hypothetical participation of some mature precursors, along with blast cells, in WT1 gene expression; d) real evidence for switching hematopoietic regulation from immature BAALC-expressing precursors to more mature WT1-expressing progeny. These results suggest diagnostic utility of combined BAALC/WT1/blast counts panel for quantitative studies and assessment of distinct precursors in AML progression and emergence of relapses.

Keywords

Acute myeloid leukemia, resistance to therapy, relapses, pathogenesis, Gemtuzumab ozogamycin, BAALC expression, WT1 expression, leukemic cell precursors, qRT-PCR.

Clinical studies

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in children with atypical teratoid/rhabdoid CNS tumors

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Liudmila V. Olkhova1, Olga G. Zheludkova2, Ludmila S. Zubarovskaya3, Anna Yu. Smirnova4, Yulia V. Dinikina4,5, Asmik G. Gevorgyan3, Andrey S. Levashov6, Elena V. Skorobogatova1

1 Russian Pediatric Clinical Hospital, N. N. Pirogov Russian National Medical University, Moscow, Russia
2 St. Luke Clinical Research Center for Children, Moscow, Russia
3 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
4 V. A. Almazov National Medical Research Center, St. Petersburg, Russia
5 St. Petersburg State Pediatric Medical University, St. Petersburg, Russia
6 N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia


Correspondence
Dr. Liudmila V. Olkhova, Pediatric Oncologist, Department of Bone Marrow Transplantation, Russian Pediatric Clinical Hospital, N. N. Pirogov Russian National Medical University, Leninsky Ave 117, 119571, Moscow, Russia
Phone: +7 (995) 707 5140
E-mail: rylkova87@mail.ru

Atypical teratoid rhabdoid tumor (ATRT) of central nervous system (CNS) is an aggressive malignancy with poor prognosis, predominantly observed in young children. There are no established approaches to CNS ATRT management nowadays. This retrospective study aimed to analyze the effectiveness and prognostic factors of high dose chemotherapy with autologous hematopoietic stem cell transplantation HDCT/auto-HSCT in pediatric CNS ATRT. Thirty CNS ATRT patients treated with HDCT/auto-HSCT were enrolled in the analysis. Median age was 19.5 months. There were 11 (36.6%) infants and 19 (63.4%) children older than 12 months, among them 21 (70%) boys and 9 (30%) girls. Infratentorial tumor was diagnosed in 7 patients (56.7%) and supratentorial in 13 (43.3%). All children initially received surgery with total resection (n=8, 26.7%), subtotal resection (n=9, 30%), partial resection (n=11, 36.6%) and biopsy (n=2, 6.7%). The majority of patients had M+ stage (n=16, 53.3%) and the minority had M-0 stage (n=12, 40%), while stage wasn't clarified (Mx) in 2 (6.7%) cases. After surgery everyone received treatment according to various protocols: EU-RHAB (n=12, 40%), MUV-ATRT (n=11, 36.7%), individual therapy (n=7, 23.3%). Radiotherapy (RT) was performed in 24 children (80%) after HDCT/auto-HSCT. The majority of patients (n=22, 73.3%) received intraventricular/intrathecal chemotherapy. The disease status was assessed in all cases prior to HDCT/auto-HSCT with complete response (CR) in 12 (40%), partial response (PR) in 8 (26.7%) and stabilization (S) in 10 (33.3%). Single auto-HSCT was performed in the majority of patients (n=21, 70%) and tandem transplants were carried out in 9 cases only (30%). In total, 39 transplants were performed. Peripheral blood hematopoietic stem cells (PBSC) were the transplant source in 27 children (90%), and combination of PBSC and bone marrow (BM), in 3 (10%). Five-year event-free survival (EFS) and overall survival (OS) were 44%. The majority of relapses were diagnosed during first 24 months after disease onset. These data are comparable to the most international results. Survival of CNS ATRT patients after HDCT/auto-HSCT was statistically significantly higher after total tumor resection, RT, intraventricular/intrathecal chemotherapy, and CR prior to transplantation.

Keywords

Сhildren, young age, atypical teratoid rhabdoid tumor, central nervous system, chemotherapy, high-dose, radiation therapy, clinical outcomes, survival, prognostic factors.

Clinical studies

New therapeutic options in myelodysplastic syndrome: literature review and single-center treatment results

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Elena V. Morozova, Nikolai Yu. Tsvetkov, Irina O. Turtanova, Ivan S. Moiseev

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence

Dr. Ivan S. Moiseev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (921) 796 1951
E-mail: moisiv@mail.ru

Myelodysplastic syndromes (MDS) comprise a group (continuum) of clonal hematopoietic diseases associated with high risk of transformation into acute myeloid leukemia (AML) and unfavorable prognosis. Compared to the other hematologic malignant diseases, there was only a modest improvement in survival of MDS patients over the last years. Allogeneic stem cell transplantation remains the only curative option for these patients, however, most of them are not candidates for transplantation. This review focuses on the long-term outcomes of existing therapies and novel agents that are currently tested at different stages of clinical trials. These include inhibitors of TGFβ, various kinase inhibitors, and immune checkpoint inhibitors. Administration of new therapies in the patients with different pathogenetic MDS variants is discussed.

Keywords

Myelodysplastic syndrome, treatment, checkpoint inhibitors, luspatercept, glasdegib, venetoclax, IDH inhibitors.

Clinical studies

Nivolumab-based immunotherapy in relapsed/refractory B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma

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Olesya G. Smykova, Kirill V. Lepik, Natalia B. Mikhailova, Elena V. Kondakova, Evgenia S. Borzenkova, Elena E. Lepik, Yuri R. Zalyalov, Lilia V. Stelmakh, Vadim V. Baykov, Ivan S. Moiseev, Alexander D. Kulagin, Boris V. Afanasyev

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Dr. Olesya G. Smykova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, Roentgen St. 12, 197022, St. Petersburg, Russia
E-mail: olesya.gen@gmail.com

The treatment of relapsed/refractory gray zone lymphoma (r/r GZL) remains challenging. Genetic aberrations involving 9p24.1 and associated with programmed death ligand (PD-L1/L2) upregulation are important in GZL pathogenesis and immune evasion. Immune checkpoint inhibitor nivolumab (PD-1-blocking antibody) may be an attractive treatment strategy in GZL. We have retrospectively assessed efficacy and toxicity of nivolumab-based regimens in nine patients with r/r GZL. Most of the patients n=7 (78%) had primary chemoresistance and the median number of prior therapy lines was 3 (range, 2-5). At the start of nivolumab treatment disease stage III-IV was in n=6 (67%) patients and bulky disease was in n=3 (33%) patients. All nine patients had high-level of PD-L1 expression (80%-100%) on tumor cells. In this group n=4 (44%) patients received nivolumab as monotherapy, n=3 (33%) received nivolumab in combination with chemotherapy, n=1 (11%) received nivolumab in combination with BV and n=1 (11%) received nivolumab in combination with lenalidomide. The objective response rate among all treated patients was 89% with 6 cases (67%) of complete response and 2 (22%), with partial response. One patient (11%) had stabilization of the disease as best response. Median duration of response was 14 (range 5-26) months. Median follow‐up time was 25 months (range, 6-30) from the start of nivolumab-based treatment. Overall survival and progression free survival rates were 83% and 38%, respectively. This case series demonstrated that nivolumab-based regimen may be an effective treatment option for patients with r/r GZL.

Keywords

Gray-zone lymphoma, relapse, immune checkpoints inhibitors, nivolumab, hematopoietic stem cell transplantation, allogeneic, autologous.

Experimental studies

Morphology of hybrid doxorubicin delivery systems (dextran sulfate-coated CaCO3 vaterites) in human blood plasma

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Natalia N. Sudareva1,2, Olga М. Suvorova1, Natalia N. Saprykina1, Vladimir V. Tomson2, Dmitry N. Suslov3, Oleg V. Galibin2, Aleksandr D. Vilesov1,2

1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 A. M. Granov Russian Research Center of Radiology and Surgical Technologies, St. Petersburg, Russia


Correspondence
Dr. Natalya N. Sudareva, Institute of Macromolecular Compounds, Bolshoy Ave 31, Vassilievsky Island, 199004, St. Petersburg, Russia
E-mail: nnsas@mail.ru

In a number of cases, efficiency of cancer therapy may be enhanced by local administration of chemotherapeutic drugs into the tumor area. After regional injection, a drug, or appropriate delivery system is exposed to the interstitial fluid, which differs from blood plasma, mainly, in lesser protein amounts. In the present work, we studied the influence of human blood plasma upon structure and properties of hybrid drug delivery systems based on calcium carbonate (СаСО3) vaterites coated with polyelectrolyte dextran sulfate (DexS). These delivery systems included anti-cancer drug doxorubicin (DOX).

It has been shown that DexS-modified vaterites provided the prolonged release of DOX to blood plasma. SEM microphotographs revealed structural changes in hybrid delivery systems occurring in plasma and correlating with the DOX release profiles.

Keywords

Doxorubicin, drug delivery system, СаСО3, dextran sulfate, blood plasma.