ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 6, Number 1
03/31/2017 08:23:00 am
Volume 6, 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)

The Journal founders:
University Medical Center Hamburg-Eppendorf (Germany);
St. Petersburg I. Pavlov State Medical University (Russia), and Foundation for Development of Bone Marrow Transplantation (St. Petersburg, Russia)

CTT Journal Archive:
http://cttjournal.com/archive.html
In this Issue
Alexey B. Chukhlovin

The ongoing CTT issue concerns different topics of transplantology. A special editorial article written by Boris V. Afanasyev is dedicated to 70-year anniversary of Professor Alexander G. Roumiantsev, an outstanding Russian specialist in pediatric hematology. Under clinical articles, a study by Dr. Tatiana L. Gindina concerns adverse prediction value of complex leukemia cell karyotype. Number of such abnormalities per karyotype, such as stage of disease, proved to be independent prognostic factors in a mixed cohort of Ph+ patients with acute lymphoblastic leukemia at the moment of HSCT. The article combines different additional chromosomal aberrations in acute leukemia and describes them in details.

The next article by Maxim A. Kucher and colleagues presents and substantiates a popular theory on close ties between intestinal microbiota and clinical risks after hematopoietic stem cell transplantation. This hypothesis was inspired by distinct correlations between intestinal dysbiosis and clinical episodes of chronic inflammatory bowel diseases. Assessment of microflora biodiversity and prevalence of distinct bacterial species post-HSCT could be an important tool to assess microbial activation as a factor, e.g., of graft-versushost-disease. The authors present their initial data on fetal microflora transplantation in complicated HSCT cases, aiming to prevent or treat severe aGVHD.

A clinical report by Vadim M. Kemaikin et al. from Astana (Kazakh Republic) shares his experience of bone marrow transplant service at the basis of Astana Center for Urgent Medicine. Six years of development transformed a modest auto-BMT unit to a modern Department for different types of HSCT, including haploidentical grafting with rather good outcomes in the patients. Paroxysmal nocturnal hemoglobinuria (PNH), a clonal blood system membranopathy, is among conditions potentially treatable by BMT. To improve prognosis and quality of life in such patients and other conditions with PNH clone, one may use Eculizumab, a monoclonal antibody against complement component since its infusion may block intravascular complement-mediated RBC hemolysis. In her report, Galina A. Dudina has described an instructive case of PNH in an old patient with MDS, who was successfully treated with Eculizumab, since HSCT approach is not valid at old age, with a number of severe comorbidities.

Under experimental studies we would like to recommend a review by Marina O.Popova and colleagues who discuss potential clinical uses of gene editing for treatment of genetic disorders. The authors concern methodology of the in vitro targeted editing procedure using lentiviral vectors. Next, they delineate a spectrum of inherited monogenic disease which are under clinical trials for gene therapy which contains, e.g., such well-known disorders as primary immune deficiencies, beta-thalassemia etc.

The last short communication reflects a viewpoint by Kristina Khodova, an expert for immunogenetics and development of gene therapy, upon business outlooks of the gene therapy. The author reviews a variety of different approaches to gene therapy, appropriate patent stories, current and prospective investments into the studies.

Editorial

Alexander G. Roumiantsev – Anniversary (70 years)
Professor Boris V. Afanasyev, Editor-in Chief “Cellular Therapy and Transplantation”, Director of R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg

Clinical articles

Experimental studies

Clinical implementation of genome editing for correction of human diseases
Marina O. Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, Boris V. Afanasyev

Short communications

Case report

Results of allogeneic hematopoietic stem cell transplantation in a mixed cohort of patients with Ph-positive acute lympho-blastic leukemia
Tatiana L. Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, Ludmila S. Zubarovskaya, Boris V. Afanasyev
Astana experience: Department of Oncohematology and Bone Marrow Transplantation, National Research Center of Oncology and Transplantation
Vadim M. Kemaikin, Anastasiya A. Olifirovich, Alexandr V. Kolesnev, Anatoliy V. Nemerovchenko, Ruzal F. Vildanova, Olga V. Gainutdinova, Adiya A. Tusipova, Ayauzhan E. Esimbekova, Aliya K. Baimursina, Ayzat S. Suleimenova, Olga O. Lesechko, Gulnaz D. Ansatbaeva, Mariya S. Alimbetova

Editorial

Alexander G. Roumiantsev – Anniversary (70 years)

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Professor Boris V. Afanasyev, Editor-in Chief “Cellular Therapy and Transplantation”, Director of R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg

This year we are celebrating the 70th Anniversary of Prof.Dr.Med. Alexander G. Roumiantsev, one of the most outstanding scientists, a hematologist-pediatrician of Russia, a person of the highest professional qualities and humanity. His achievements in the area are well known not only in Russia, but also worldwide. He is the President of National Association of Pediatric Oncologists and Hematologists, Chief Pediatrician of the Moscow Health Care Department, General Director of D.Rogacheva National Scientific and Practical Center of Pediatric Hematology and Oncology. A. G. Roumiantsev headed The Chair of Oncology, Hematology and Radiation Therapy at the Pediatric Faculty of N. Pirogov Russian National Research Medical University for many years.

Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. Pirogov Russian National Research Medical University). Over these years, А. G. Roumiantsev approved himself a highly qualified specialist in pediatrics, hematology/immunology, a skilled scientist and university professor. A gifted teacher who authored and co-authored several basic educational programs in children diseases, polyclinic pediatrics, pediatric hematology/oncology, immunology/allergology, transfusion medicine, scientific editor of some basic textbooks and teaching media in pediatrics, pediatric hematology and immunology.

Clinical articles

A mini-review on paroxysmal nocturnal hemoglobinuria and a case of Eculizumab treatment of PNH in elderly MDS patient

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Galina A. Dudina

Moscow Clinical Research Center, Moscow Health Department, Moscow, Russian Federation

CorrespondenceDudina Galina A., PhD (Medicine), Senior Research Associate, Department of Oncohematology and Secondary Immunodeficiencies, The Moscow Clinical Research Center of Moscow Health Department, Entusiastov Ave 86, 111123, Moscow, Russian Federation
Phone: +7 (916) 650 8577
E-mail: dudina_gal@mail.ru

Paroxysmal nocturnal hemoglobinuria (PNH) is a systemic, acquired clonal hematological disorder which results from loss of complement-inhibiting proteins (CD55 and CD 59) from the blood cell surface. Therefore, such patients develop chronic complement-mediated intravascular hemolysis, with thromboses manifesting as most severe clinical complications. Recommendations of International PNH groups discern certain risk groups based on detection of a pathological cell clone, including patients with myelodysplastic syndrome (MDS). Here we describe detection of a clinically sound PNH clone in an elderly patient with MDS, as well as positive results of patho-genetic treatment with Eculizumab.

Keywords

Paroxismal nocturnal hemoglobinuria, myelodysplastic syndrome, diagnostics, Eculizumab

Experimental studies

Clinical implementation of genome editing for correction of human diseases

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Marina O. Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, Boris V. Afanasyev

Raisa Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First St. Petersburg Pavlov State Medical University, St. Petersburg, Russia
Dr. Marina O. Popova, PhD, R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First Pavlov State Medical University of St. Petersburg, Russia, 12 Roentgen St., 197022, St. Petersburg, Russia
Phone: +7 (812) 233-29-25 (office), +7 (911) 711-39-77 (mobile) E-mail: marina.popova.spb@gmail.com
Genome editing is a breakthrough technology which consists of the process of precise modifications introduction into the genome of any organism. This scientific breakthrough provides a powerful tool for the errors correction in the nucleotide sequence of DNA. The development of the genome editing has inverted the concept of an available target for the therapeutic correction. The opportunity of highly precise and safe entering of single- and double-stranded breaks into the human DNA followed by natural DNA repair mechanisms has changed current approaches of the gene therapy and opened up new horizons in the treatment of numerous diseases. Genome editing is being developed to treat not only monogenic diseases but also infectious diseases and cancer. In the current review, we discuss the therapeutic application of genome editing.

Keywords

Genome editing, hematopoietic stem cells, ZFN, TALEN, CRISPR-Cas9, hematopoietic stem cell transplantation, HSCT, HIV, inherited diseases, monogenic diseases, cancer, hematological malignancies.

Short communications

Genome Games: Market Challenges, Investment Opportunities and Patent Battles

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Kristina A. Khodova

Skolkovo Foundation, Moscow, Russia

Correspondence
Dr. Kristina A. Khodova, Skolkovo Innovation Center, Nobel Street 5, 143026, Moscow, Russia
Phone: +7 (916) 438-29-54
E-mail: kris.khodova@gmail.com

Recent improvements in targeted genome editing technologies have opened new potential therapeutic applications in different medical conditions. Despite the fact that most of these technologies are still at early implementation phase, they already demonstrate a high therapeutic potential which may change treatment methodology for many severe diseases, and exert a significant influence upon market landscape and human population in general. However, some major issues and risks remain in the field, i.e., whether appropriate products and results will meet expectations of scientists, engineers and investors, and what risks could be anticipated for the registration procedures and introduction of original products into clinical practice.

Keywords

Genome editing, investment, startups, research & development, intellectual property.

Case report

Results of allogeneic hematopoietic stem cell transplantation in a mixed cohort of patients with Ph-positive acute lympho-blastic leukemia

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Tatiana L. Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, Ludmila S. Zubarovskaya, Boris V. Afanasyev

R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology and Transplantation, The First St. Petersburg I. Pavlov State Medical University, St. Petersburg, Russia
Additional chromosomal abnormalities (ACA) are rather common in Ph+ acute lymphoblastic leukemia (ALL). However, their prognostic significance in the era of protein tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still poorly known. A recent study [1] has shown that ACA exert unfavorable effect upon HSCT results in adult patients with Ph+ALL.

Patients and methods

We have performed a retrospective analysis of treatment results for a mixed cohort of the patients with Ph+ ALL, including 19 children (aged 5 – 18 y.o.) and 46 adults (aged 19 – 57 y.o.) who received allo-HSCT at our Institute over 2008 to 2015. Among sixty-five subjects with Ph+ ALL, the results of standard cytogenetic studies were available for 53 patients.

Results

Thirty-three patients of 53 (51%) exhibited an isolated t(9;22) translocation. ACA were revealed in 20/53 patients (31%), including 13/53 (20%) subjects with 3 and more chromosome abnormalities. Chromosomes 1, 5, 7, 8, 9, 22 were most commonly affected with additional anomalies. Structural abnormalities attributable to ACA were imbalanced in 16 patients (80%), whereas only 4 patients (20%) showed balanced translocations. In a univariate analysis, significance was shown for the donor type (matched related and unrelated vs haploidentical, p=0.02), clinical stage at HSCT (1st remission vs other stages, p=0.01, for EFS only), additional chromosomal abnormalities (ACA-negative vs ACA-positive, p=0.04, for OS only), and, in particular, complex chromosomal aberrations (<3 anomalies vs ≥3 anomalies, p=0.01, for OS only). According to multivariate analysis, the number of additional chromosomal abnormalities per karyotype (HR 2.79, 95% CI 1.23-6.34; р=0.01, for OS only) and clinical stage at HSCT (HR 2.15, 95% CI 1.13-4.09; р=0.01, for EFS only) are independent prognostic factors for clinical outcomes.

Conclusion

The study has shown that complex chromosomal anomalies and the stage of disease at the moment of HSCT are independent prognostic factors in a mixed cohort of Ph+ ALL patients treated with hematopoietic stem cell transplantation.

Keywords

Acute lymphoblastic leukemia, Ph1-positive, allo-HSCT, additional chromosomal abnormalities.

Case report

Astana experience: Department of Oncohematology and Bone Marrow Transplantation, National Research Center of Oncology and Transplantation

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Vadim M. Kemaikin, Anastasiya A. Olifirovich, Alexandr V. Kolesnev, Anatoliy V. Nemerovchenko, Ruzal F. Vildanova, Olga V. Gainutdinova, Adiya A. Tusipova, Ayauzhan E. Esimbekova, Aliya K. Baimursina, Ayzat S. Suleimenova, Olga O. Lesechko, Gulnaz D. Ansatbaeva, Mariya S. Alimbetova

Bone Marrow Transplantation Department, National Research Center for Oncology and Transplantation, Astana, Republic of Kazakhstan
Dr. Vadim M. Kemaikin, Chief, BMT Department, National Research Centre for Oncology and Transplantation, Kerey, Zhanibek Khanov st., 3, Astana, 010000, Republic of Kazakhstan
Phone: +7 7172 70 29 41 E-mail: hematology.astana@gmail.com
The Unit of Oncohematology and Bone Marrow Transplantation (BMT) was arranged on basis of the Republican Research Center of Hospital Emergencies SC (Astana, Republic of Kazakhstan) in August 2010. Since July 2014, a Clinical Department with 69 beds was arranged, and National Research Center for Oncology and Transplantation SC was arranged. From 2010 to 2016, the modalities of hematopoietic stem cell transplantation have been advanced, from autologous BMT to allogeneic hematopoietic stem cell transplants (HSCT) from matched donors (33%), and haploidentical HSCTs (43% in 2016), a total of 186 transpants. Bone marrow was used as a source of stem cells in 71 cases (71 donors for allo-HSCT in 69 recipients), whereas peripheral stem cells were harvested in 73 cases (15 donors for 15 recipients of allo-BMT, and 58 marrow harvests for autologous BMT). In particular, our BMT clinic and Bone Marrow Donor Registry developed with invaluable support and contribution by the leading specialists from R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the St. Petersburg. This system of education and training allowed to arrange an effective HSCT structure within 3 years. This assistance was performed in order to consult severe patients, arrange optimal transplantation regimens, analyze difficult clinical cases, perform master classes and conferences.

Keywords

Hematopoietic stem cell transplantation, clinical advancements, Astana, Republic of Kazakhstan.

Case report

Fecal microbiota transplantation as a method to treat complications after hematopoietic stem cell transplantation

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Maxim A. Kucher, Oleg V. Goloschapov, Ivan S. Moiseev, Boris V. Afanasyev

R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation, The First State I. Pavlov Medical University, St. Petersburg, Russia;
Dr. Maxim A. Kucher, Head, Department of Clinical Nutrition, R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; The First State I. Pavlov Medical University, St. Petersburg, Russia, L. Tolstoy St. 6-8, 197022
Phone: 8 (812) 338 6260, +7 (921) 993 9902 E-mail: doctorkucher@yandex.ru
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method of treatment for hematological, malignant and hereditary diseases in adults and children. Despite its efficiency, HSCT is associated with several potential life-threatening complications. Mortality from bloodstream infections is the main limiting factor for HSCT. Those are caused by bacterial strains refractory to antimicrobial treatment, e.g., Clostridium difficile and Klebsiella pneumoniae, and due to immune complications, such as acute and chronic “graft versus host disease” (GvHD), which represents a conflict between donor lymphocytes and patients’ tissues. In most cases, gastrointestinal tract (GIT) is primarily damaged post-HSCT, as a result of enhanced inflammation, serious diarrhea manifesting in GvHD and intestinal infections, in particular – pseudo-membranous colitis associated with Clostridium difficile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GvHD, pseudo-membranous colitis and antibiotic-associated diarrhea post-HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications.

Keywords

Fecal microbiota transplantation, hematopoietic stem cell transplantation, antibiotic resistance.