ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 8, number 1
03/30/2019
Volume 8, number 1
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
Short review by Prof. Tapani Ruutu opens the issue. It is dedicated to thrombotic angiopathy, a common complication of conditioning therapy in hematopoietic stem cell transplantation (HSCT). Special attention is drawn to erythrocyte schistocytosis as a marker of capillary damage, and its correct diagnostics.

Another review paper by O. V. Galibin et al. concerns natural and synthetic matrices developed for faster and effective regeneration of damaged nerves. Special attention is given to chitosan-containing polymers and biodegradable, electroconductive synthetic carriers allowing to perform regeneration-promoting procedures.

An article by A. B. Chukhlovin deals with some “old” drugs used in a number of non-oncological disorders which may be, in addition, applied for cancer therapy, mostly as a components of combined therapy.

Clinical results of hematopoietic stem cell transplantation from haploidentical donor (e.g., the patients’ parents) are presented in the paper by A. V. Beynarovich et al., addressing mostly clinical outcomes (early and late survival, relapse rates etc. based on a single-center experience.

Prognostic scales in the patients with myelodysplastic syndrome (MDS) show different efficiency, especially when treated with novel therapies. E.V.Morozova et al. compare different prognostic scales in MDS, with respect to appropriate clinical outcomes at long observation terms.

A specialized diagnostics and medical assistance are required in HSCT patients with ORL complications in HSCT patients. These issues are described by E. S. Utimisheva et al. who have focused on sinusitis, its bacterial pathogens, therapeutic effects of maxillary punctures in the patients.

Special clinical case is described by T. A. Bykova et al. who present a description of a patient with a case of familial hemophagocytic lymphohistiocytosis, a rare clinical entity which shows genetic predisposition in some instances.

An experimental study by A. V. Kuznetsov et al. provides original data about mitotic activity and contents of cell in thoracic duct lymph of rabbits, starting from newborns to young adults. Evidence for dividing cells makes it possible to apply these results to the issues of immune recovery in very young mammals including humans, thus being of potential importance in cytostatic therapy.

Editorial article

Editorial article

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

Review articles

Alternative approaches to overcome diastasis of damaged peripheral nerves. A review article

Oleg V. Galibin1, German V. Medvedev2, Pavel V. Popryadukhin3, Pavel A. Kulagin1, Alexandr A. Gusev1, Galina P. Kossyakova1, Natalia V. Mikhailova1, Veronika D. Novak1, Denis N. Solomitskiy1, Igor O. Shemiakin1, Vadim S. Gadzhiagaev1, Maksat Kh. Gurbannazarov1

Clinical studies

Application of standard and novel prognostic systems in patients with myelodys- plastic syndrome undergoing allogeneic hematopoietic stem cell transplantation

Elena V. Morozova, Maria V. Barabanshikova, Nikolai Yu. Tcvetkov, Ksenia V. Melsitova, Julia V. Rudnitskaya, Elena I. Darskaya, Sergey N. Bondarenko, Ivan S. Moiseev, Boris V. Afanasyev

Haploidentical stem cell transplantation in adults for the treatment of hematologic diseases: results of a single center (CIC725)

Anastasia V. Beynarovich, Elena V. Babenko, Ivan S. Moiseev, Olesya V. Paina, Olga V. Pirogova, Tatiana A. Rudakova, Tatyana L. Gindina, Elena I. Darskaya, Elena V. Morozova, Sergey N. Bondarenko, Ludmila S. Zubarovskaya, Boris V. Afanasyev

Incidence, diagnosis and treatment of sinusitis in children and adolescents after hematopoietic stem cell transplantation

Ekaterina S. Utimisheva1, Oleg I. Dolgov1, Olesya V. Paina1, Kirill A. Ekushov1, Alina A. Vitrischak1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1, Sergey A. Karpischenko1, Boris V. Afanasyev1

Clinical case

A clinical case of familial hemophagocytic lymphohistiocytosis

Tatiana A. Bykova, Varvara N. Ovechkina, Anna A. Osipova, Andrey V. Kozlov, Alexander L. Alyanskiy, Elena V. Semenova, Ludmila S. Zubarovskaya, Boris V. Afanasyev

Experimental studies

Mitotic activity of thoracic duct cells in rabbits correlates with age and total lymphocyte numbers

Alexander V. Kuznetsov1, Ildar R. Fakhradiyev2, Ydyrys A. Almabayev3, Aigul Y. Almabayeva4

Editorial article

Editorial article

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

Dear CTT authors and readers,
Over last several years, dramatic improvement has been achieved in treatment of some malignancies in adults, and, especially, in children by means of novel agents and technologies, i.e., bi-specific T-cell engager antibodies (BITE), conjugated monoclonal antibodies, CAR-T cells, and immune checkpoint inhibitors. The above-mentioned drugs may be combined with allogeneic hematopoietic stem cell transplantation (allo-HCT), thus creating a reliable basis for sequential successful therapy.
The largest progress was attained with lymphoproliferative disorders, e.g., in patients with R/R Hodgkin lymphoma, due to introduction of Brentuximab Vedotin (BV), conjugated antibody. The immune checkpoint inhibitors have also shown high short-term efficiency, but unfortunately, the progression-free survival in these cases remains relatively low. However, combination of these drugs with subsequent allo- HCT has promising efficacy in terms of progression-free survival.
In R/R patients with acute lymphoblastic leukemia, some drugs like Blinatumomab, a BITE antibody, or conjugated antibody Inotuzumab, have yielded high response rates, being especially efficient in the patients with detectable minimal residual disease (MRD). It is still unclear what strategy should be used for MRD-negative patients and do they require further consolidation.
Novel trends in immune therapy of malignant disorders are associated with development of CAR-T cell-based therapeutic tools which may provide a more targeted effects upon specific neoantigens of the given tumor type. There are only several limited studies of CAR-T application in adults and pediatric patients. The efficiency of CAR-T cell treatment in solid tumors is yet to be established, but sufficient progress is recently observed in this area.
Transplantation aspects of pediatric malignancies treatment are also often spotlighted in Cellular Therapy and Transplantation. When compared with high treatment efficiency in acute lymphoblastic leukemia, pediatric tumors, like medulloblastoma, Ewing sarcoma and others are less sensitive to immunotherapy approaches due to different mutation burden and expression of neoantigens. These molecular mar-kers, as well as microsatellite instability could be of value when assessing the clinical risk groups. Elucidation of the optimal immunotherapy with or without transplantation in pediatric solid tumors is one of crucial agendas in pediatric oncology.
In conclusion, we are expecting from our readers original and review articles for our Journal on pediatric oncology/hematology from our potential authors from different clinics, aiming to optimize the response rate with lesser toxicity to normal tissues by using novel approaches, especially, immune therapy of pediatric malignancies, as well as the use of stem cell transplantation in nonmalignant disorders.

Review articles

Recent developments in transplant-associated thrombotic microangiopathy

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Tapani Ruutu

Clinical Research Institute, Helsinki University Hospital

Transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively common complication of hematopoietic stem cell transplantation. The pathophysiology is complex, the central feature is endothelial injury. The role of complement activation in the pathophysiology has been increasingly recognized. The diagnostic procedures and interpretations vary considerably between centers, and aims at standardizing the criteria of this complication are important especially for study purposes. The therapy is improving, particularly due to the introduction of complement inhibitors. However, the indications and policy of administration of these drugs are not well established and need further study.

Keywords

Hemopoietic stem cell transplantation, thrombotic microangiopathy, diagnostic techniques, standardization, therapy, complement inhibitors.

Review articles

Drug repurposing in leukemia treatment and hematopoietic stem cell transplantation

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Alexey B. Chukhlovin

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

Over last decade, a number of studies has concerned possible implications of “old” medical drugs, as additional tools for cancer treatment. The main reasons for extension of drug indications are as follows: (1) limited efficiency or high costs of targeted oncogene protein inhibitors or specific monoclonal antibodies for therapy; (2) new molecular targets were revealed for some drugs traditionally used to other therapeutic purposes; and (3) sufficient decline of development costs for the new therapies performed by the “old” drugs. The list of such repurposed drugs now includes dozens of medications commonly used for treatment of cardiovascular diseases, diabetes mellitus, epilepsia, different inflammatory disorders. The present review deals, mainly, repurposing of anti-infectious drugs, including those used in prevention and management of infectious complications occurring in cytostatic therapy of leukemia and lymphomas, e.g., tetracyclines, erythromycin derivatives, as well as fluoroquinolones, antiviral compounds etc.
The antitumor effects were of these candidates for repurposing were demonstrated upon screening of their cytostatic effects in leukemic and other cancer cell lines. Some studies were performed in experimental tumor-bearing animals. Only few clinical trials were carried out in patients with leukemias and lymphomas following hematopoietic stem cell transplantation (HSCT), which showed some positive effects of antibacterial drugs in terms of graft-versus-host disease (GvHD) prevention, or prolonged survival of the patients. Controlled clinical trials of common anti-infectious drugs are required for this repurposing.

Keywords

Antibacterial drugs, repurposing, anticancer effects, leukemia treatment, hematopoietic stem cell transplantation.

Review articles

Alternative approaches to overcome diastasis of damaged peripheral nerves. A review article

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Oleg V. Galibin1, German V. Medvedev2, Pavel V. Popryadukhin3, Pavel A. Kulagin1, Alexandr A. Gusev1, Galina P. Kossyakova1, Natalia V. Mikhailova1, Veronika D. Novak1, Denis N. Solomitskiy1, Igor O. Shemiakin1, Vadim S. Gadzhiagaev1, Maksat Kh. Gurbannazarov1

1 First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
2 Russian R. R.Wreden Research Institute of Traumatology and Orthopedy, St. Petersburg, Russia
3 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia

Damage of peripheral nerves is often accompanied by a primary or secondary diastasis (gap, spread) between the neural ends, thus complicating a standard manual nerve stitching by means of surgical threads. As based on analysis of published data, the effective techniques were proposed for surgical treatment of peripheral nerve damage accompanied by diastasis. Moreover, some limitations of autoneural plastics are clearly revealed. Therefore, overcoming of nerve diastasis following damage remains to be a strong need, especially when treating prolonged and multiple defects of nerve trunks. Usage of implants providing repair and junction of the damaged nerve seems to be an alternative option allowing end-to-end connection of the damaged nerve from its central to distal segment. Application of biocompatible and bio-degradable polymers as a neural prosthesis promotes more safe regeneration and does not require switching-off a donor nerve and its functions. Moreover, the options are improved which allow to influence rates and quality of the nerve damage repair.

Keywords

Nerve, damage, diastasis, implant, polymeric scaffolds, chitosan.

Clinical studies

Application of standard and novel prognostic systems in patients with myelodys- plastic syndrome undergoing allogeneic hematopoietic stem cell transplantation

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Elena V. Morozova, Maria V. Barabanshikova, Nikolai Yu. Tcvetkov, Ksenia V. Melsitova, Julia V. Rudnitskaya, Elena I. Darskaya, Sergey N. Bondarenko, Ivan S. Moiseev, Boris V. Afanasyev

R. Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First Pavlov St. Petersburg State Medical University, St. Petersburg, Russian Federation

Several prognostic indexes were developed to predict outcome in patients with myelodysplastic syndrome (MDS). The aim of our study was to evaluate prognostic impact of disease- and transplant-specific indexes on the results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MDS patients.

Patients and methods

A retrospective cohort of fifty-nine MDS patients (excluding secondary acute myeloid leukemia) and treated with allo-HSCT was used to evaluate the predictive value of the following prognostic indexes: IPSS, IPSS-R, WPSS, Disease Risk Index (DRI), prognostic systems developed by Kroeger et al., Armand et al., Pretransplant Assessment of Mortality Score (PAM), EBMT risk score and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI).

Results

There was a significant difference in risk estimation between indexes (p<0.001). Clinical factors significant for overall survival (OS) in the univariate and multivariate analyses were as follows: acute graft-versus-host disease (GVHD) grade I-II (HR 0.223, 95% CI 0.059-0.721, p=0.0134) and occurrence of sepsis during aplasia (HR 3.636, 95% CI 1.438-8.673, p=0.0059). Despite significant impact of CD34+ cell contents in hematopoietic graft (p=0.006) revealed in ROC analysis, only DRI remained a significant predictor of 5-year OS in the multivariate model (HR 1.857, 95% CI 1.036-3.328, p=0.037). Inferiority of other MDS-specific indexes to predict the outcome for allo-HSCT seems to be associated with adverse results in the intermediate risk group. In conclusion, we presume a need for further characterization of the intermediate risk patients when predicting the therapy outcomes.

Keywords

Myelodysplastic syndrome, allogeneic hematopoietic stem cell transplantation, prognostic indexes, risk estimation.

Clinical studies

Haploidentical stem cell transplantation in adults for the treatment of hematologic diseases: results of a single center (CIC725)

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Anastasia V. Beynarovich, Elena V. Babenko, Ivan S. Moiseev, Olesya V. Paina, Olga V. Pirogova, Tatiana A. Rudakova, Tatyana L. Gindina, Elena I. Darskaya, Elena V. Morozova, Sergey N. Bondarenko, 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

Allogeneic HSCT (allo-HSCT) is potentially curative option for a wide variety of malignant and nonmalignant disorders of hematopoiesis. For patients who lack an HLA-matched sibling, HLA-haploidentical related donors (haplo-HSCT) can be considered as alternative sources of donor grafts. The benefits of haplo-HSCT include immediate donor availability for patients who are in urgent need of the transplant. Besides, an availability of a related donor makes post-transplant donor-derived cellular therapy more easily accessible. In addition, the greater HLA mismatch associated with haploidentical HSCT (haplo-HSCT) may potentiate graft-versus-tumor (GVT) effects. The aim of our study was to summarize our single-center experience of haplo-HSCT performed with non-manipulated grafts in adult patients with different malignant diseases. The study included a total of 119 patients with different hematological disorders subjected to haplo-HSCT. At the time of analysis, median follow-up was 371 days (1-2219). Most frequent diagnosis in transplanted patients was acute leukemia. 67 (56%) patients received haplo-HSCT as salvage therapy.
Overall survival with an observation term of 2 years was 40.3% for the general group. In particular, the two-year OS in patients transplanted in remissions of ALL and AML was 57% and 46% respectively as compared to 22% and 15% for the patients transplanted in adverse disease status). Two-year event-free survival (EFS) and GVHD-free/relapse-free survival (GRFS) group proved to be 35.7% and 21% respectively. The cumulative incidence of acute GVHD grade II-IV and severe aGVHD grade III-IV was 19% and 10% respectively. The cumulative incidence of chronic GVHD (cGVHD) was 16%.The cumulative incidence of relapse was 21%. The overall transplant-associated mortality was 43% in the studied group. In conclusion, our results show that unmanipulated haplo-HSCT is reasonable treatment option for adult patients with different malignant disorders of hematopoiesis. However, such problems as higher rate graft failure, increased nonrelapse mortality (NRM) and post-transplant relapses remain extremely relevant.

Keywords

Allogeneic hematopoietic stem cell transplantation, haploidentical, adult patients, overall survival, post-transplant relapse, graft-versus-host disease, graft failure, post-transplant cyclophosphamide.

Clinical studies

Incidence, diagnosis and treatment of sinusitis in children and adolescents after hematopoietic stem cell transplantation

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Ekaterina S. Utimisheva1, Oleg I. Dolgov1, Olesya V. Paina1, Kirill A. Ekushov1, Alina A. Vitrischak1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1, Sergey A. Karpischenko1, Boris V. Afanasyev1

1 Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia
2 St. Petersburg State Electrotechnical University LETI, St. Petersburg, Russia

Sinusitis after allogeneic transplantation of hematopoietic stem cells occurs in 22.2% of cases being more frequent at >100 days following allo-HSCT, than at earlier terms (p=0.006). The main risk factors for sinusitis after allogeneic stem cell transplantation were as follows: sinusitis before allo-HSCT (p <0.001), neutropenia duration for more than 10 days (p=0.054), acute (p=0.022) or chronic graft-versus-host disease (p <0.001) in the patients. The main pathogens of sinusitis revealed in allo-HSCT recipients during the study were: Gram-positive Staphylococcus epidermidis (30%), Streptococcus viridans (30%); Gram-negative Klebsiella pneumoniae (17.5%). A monoculture of bacteria predominated within 100 days posttransplant (p=0.011). Poly-etiological origin of the causative bacterial agents in sinusitis was more likely in adolescent patients, in comparison to the younger children group. The severity of changes in paranasal sinuses, as registered with computed tomography after 100 days after allo-HSCT, was more pronounced (p=0.014) than at earlier terms, thus being discordant with less common clinical signs of sinusitis (p=0.008), and milder clinical course of sinusitis assessed by a visual analogue scale (p=0.032) during this period. Punctures of maxillary sinuses combined with antimicrobial therapy proved to shorten the duration of sinusitis treatment in these patients (p=0.024).

Keywords

Sinusitis, children, hematopoietic stem cell transplantation.

Clinical case

A clinical case of familial hemophagocytic lymphohistiocytosis

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Tatiana A. Bykova, Varvara N. Ovechkina, Anna A. Osipova, Andrey V. Kozlov, Alexander L. Alyanskiy, Elena V. Semenova, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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

Familial hemophagocytic lymphohistiocytosis (hemophagocytic syndrome) is a rare hereditary disease, characterized by dysregulation of the immune response, leading to the proliferation and activation of histiocytes, phagocytosis of peripheral blood cells. Timely diagnostics, specific combined immunosuppressive therapy and chemotherapy followed by allo-HSCT significantly increase the chances for a favorable outcome. We are presenting a case of family hemophagocytic lymphohistiocytosis associated with UNC13D mutation which was found in three siblings who exhibited quite different course of the disease and clinical prognosis.

Keywords

Familial hemophagocytic lymphohistiocytosis, hemophagocytic syndrome, hematopoietic stem cell transplantation.

Experimental studies

Mitotic activity of thoracic duct cells in rabbits correlates with age and total lymphocyte numbers

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Alexander V. Kuznetsov1, Ildar R. Fakhradiyev2, Ydyrys A. Almabayev3, Aigul Y. Almabayeva4

1 Department of Human Anatomy, Novosibirsk State Medical University, Russia
2 Laboratory of Experimental Medicine, Kazakh National Medical University, Republic of Kazakhstan
3 Department of Clinical Anatomy, Kazakh National Medical University, Republic of Kazakhstan
4 Department of Human Anatomy with O.S. Medical University Astana, Republic of Kazakhstan

The aim of this study was to assess correlations between rabbit mitotic thoracic duct (TD) cells, rabbit’s age, and TD lymphocytes. The experiments were carried out in 27 intact male Chinchilla rabbits weighing 120-2.500 g (at the age of 1.5 weeks to 36 weeks). TD lymph specimens were drawn from the cisterna chyli of anaesthetised rabbits. The numbers of mitotic cells from TD per 100 cells, and absolute numbers of TD lymphocytes were counted in the Giemsa-stained cell smears by means of routine light microscope methods, and routine hemocytometric counts. We have performed statistical evaluation of the data by Microsoft Office Excel 2007 software. Correlations between the TD mitotic cell ratio, lymphocyte numbers, and animal age was estimated by Pearson’s criteria. The mitotic cell number in TD lymph decreased from the age of 1.5 weeks (infant animals) to 36 weeks (young adult rabbits). Maximal mitotic activity was found in rabbits at 1.5 week of age (23.0 ± 0.14, P=0.02) in comparison with appropriate indexes in rabbits at 4.5 and 13.5 weeks of age (11.0 ± 0.14*, P<0.05 and 6.3 ± 0.08**, P<0.001 respectively). In contrast to mitotic cell amounts, the absolute TD lymphocyte numbers were increased in older rabbits. The minimal TD; lymphocyte number in the 1.5-week old rabbits aged was 2.8 ± 0.03, being significantly different (P=0.04) against the lymphocyte numbers in rabbits aged 36 week (5.9 ± 0.05, P=0.03). Hence, strong negative correlations were found between the TD mitotic activity and age, mitotic cells and total TD lymphocyte numbers, as well as positive correlation between the TD lymphocytes and age (respectively, R2=0.7, R2=0.96 and R2=0.8) in immature rabbits (age from 1.5 weeks to 36 weeks). To our knowledge, these interrelations for TD lymph cells in the very young animals were detected for the first time. We conclude that the age-related correlation between mitotic activity and total lymphocyte amounts in TD allows presume optimal combinations of cytokines and other bioactive factors that regulate mitotic activity of thoracic duct cells with advancing age.

Keywords

Thoracic lymphatic duct, cell population, mitotic activity, age-dependent changes.