ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 1, Number 3
12/01/2009
Volume 1, Number 3
Editor-in-Chief
Afanasyev B. V. (St. Petersburg, Russia)
Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A. R. (Hamburg, Germany)
Deputy Editor
Chukhlovin A. B. (St. Petersburg, Russia)
Fehse B. (Hamburg, Germany)
Novik A. А. (Moscow, Russia)
Managing Editor
Claudia Koltzenburg (Hamburg, Germany)
Editorial Board
Aleynikova O. (Minsk, Belarus)
Alyansky A. (St. Petersburg, Russia)
Anagnostou A. (Boston, USA)
Andreeff M. (Houston, USA)
Bacher U. (Hamburg, Germany)
Baуkov V. (St. Petersburg, Russia)
Baranov V. S. (St. Petersburg, Russia)
Barkhatov I. (St. Petersburg, Russia)
Baum C. (Hannover, Germany)
Bilko N. (Kiev, Ukraine)
Borset M. (Trondheim, Norway)
Buechner Th. (Muenster, Germany)
Bykov V. (St. Petersburg, Russia)
Dini G. (Genoa, Italy)
Drize N. (Moscow, Russia)
Egeland T. (Oslo, Norway)
Elstner E. (Berlin, Germany)
Emanuel V. (St. Petersburg, Russia)
Everaus H. (Tartu, Estonia)
Ferrara J. (Ann Arbor, USA)
Fibbe W. (Leiden, Netherlands)
Galibin O. (St. Petersburg, Russia)
Ganser A. (Hannover, Germany)
Granov D. (St. Petersburg, Russia)
Ivanov R. (Moscow, Russia)
Klimko N. (St. Petersburg, Russia)
Kolb H.-J. (Muenchen, Germany)
Konopleva M. (Houston, USA)
Koza V. (Pilsen, Czech Republic)
Kroeger N. (Hamburg, Germany)
Malikov A. (St. Petersburg, Russia)
Mikhailova N. (St. Petersburg, Russia)
Mentkevich G. (Moscow, Russia)
Nagler A. (Tel Hashomer, Israel)
Nemkov A. (St. Petersburg, Russia)
Neth R. (Hamburg, Germany)
Nevorotin A.J. (St. Petersburg, Russia)
Ostertag W. (Hamburg, Germany)
Palutke M. (Detroit, USA)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Stamm C. (Berlin, Germany)
Tetz V. (St. Petersburg, Russia)
To B. (Adelaide, Australia)
Totolian A. A. (St. Petersburg, Russia)
Uss A.L. (Minsk, Belarus)
Vilesov A. (St. Petersburg, Russia)
Westenfelder Ch. (Salt Lake City, USA)
Wisloff F. (Oslo, Norway)
Zubarovskaya L. (St. Petersburg, Russia)
Zvartau E. (St. Petersburg, Russia)
In this Issue

The third issue of CTT takes a look back at the development of experimental hematology. Alexander Maximow’s “The Lymphocyte as a stem cell common to different blood elements in embryonic development and during the post-fetal life of mammals” (1909) is a milestone in this development. The article was originally published in German in “Folia Haematologica” and is now available for the first time in Russian and English. It is a centenary remembrance of a development which was carried out by many European researchers at the beginning of the 20th century only to be forgotten for decades and then reactivated after World War II, leading to experimental and clinical bone marrow transplantation.

Alexander Friedenstein — the other giant in Russian hematology — reviews the work by Maximow 80 years later. Friedenstein’s mesenchymal stem cell research gave birth to the field of MSC-based regenerative medicine, which is coming into clinical practice today.

The other 5 articles in this issue deal with stem cell transplantation issues:
-    Factors influencing stem cell mobilization in patients with hematologic malignancies and solid tumors
-    The application of autologous high dose therapy for the treatment of secondary progressive multiple sclerosis
-    Complications like invasive mycosis in patients of allogenic hemopoietic transplantation and iron load
-    A rare glimpse at a potential syngeneic graft versus leukemia effect in CML

We thank our reviewers: Athanasius Anagnostou, Ulrike Bacher, Alexey B. Chukhlovin, Nina Drize, Larisa Fechina, Nicolaus Kröger, Claudia Lange, Heinrich Lellek, Michael Lioznov, Peter Nielsen, Sven Schippling, Carol Stocking.

Boris V. Afanasyev, Gerard Wagemaker, Axel R. Zander

Keynotes

On the keynote authors

The Maximow 1909 centenary: A reappraisal

Andrey A. Novik1, Tatyana I. Ionova1, Gary Gorodokin2, Alexander Smolyaninov3, and Boris V. Afanasyev4

A .J. Friedenstein, founder of the mesenchymal stem cell concept

Boris V. Afanasyev1, Elena Elstner2, Axel R. Zander3

Research articles

Factors influencing stem cell mobilization in patients with hematologic malignancies and solid tumors

Alexeev S., Babenko E., Estrina M., Mikhailova N., Zubarovskaya L., Afanasyev B.

Iron overload: causes, assessment methods, significance in transplantation setting and therapeutically approaches

M. Ivanova, E. Morozova, Y. Vasilieva, Y. Rudnitskaya, R. Nabiev, L. Zubarovskaya, B. Afanasyev

Invasive fungal diseases in patients after allogeneic hematopoietic stem cell transplantation

N. I. Zubarovskaya, E. V. Semenova, N. V. Stancheva, V. N. Vavilov, I. V. Kazantsev, Yu. G. Vasilieva, N. N. Klimko, B. V. Afanasyev


High dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in secondary progressive multiple sclerosis: Case report

A.A. Novik1, A.N. Kuznetsov1, V.Y. Melnichenko1, D.A. Fedorenko1, T.I. Ionova1, R.V. Kruglina1, A.V. Kartashov1, K.A. Kurbatova1,
G.I. Gorodokin2

Brief report

Syngeneic Graft-Versus-Chronic-Myeloid-Leukemia-Effect?

Sunday Ocheni1, Philippe Schafhausen2, Ulrike Bacher1, Boris Fehse1, Nicolaus Kröger1

Keynotes

On stromal-hematopoietic interrelationships: Maximov's ideas and modern models. (Lecture at Wilsede Meeting 1988, Audio)

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By Alexander J. Friedenstein

Keynotes

Stromal-hematopoietic interrelationships: Maximov's ideas and modern models

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A. Friedenstein

Republished from Modern Trends in Human Leukemia VIII (1989),
Ed. R. Neth, with kind permission by Springer Science and Business Media.

Keynotes

The original article in German. Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere

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Von Prof. Dr. A. Maximow

The original article in German.

Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere (Demonstrationsvortrag, gehalten in der außerordentlichen Sitzung der Berliner Hämatologischen Gesellschaft am 1. Juni 1909)

(NB: Despite our best efforts, we have been unable to find out who we might have to ask for permission to reproduce this article. We greatfully acknowledge some help on this issue by Springer Publishers, for any further hints please contact info@spam is badctt-journal.com, thank you.)

Keynotes

The lymphocyte as a stem cell, common to different blood elements in embryonic development and during the post-fetal life of mammals

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By Alexander A. Maximow

Lecture with a demonstration, held at a special meeting of the Berlin Hematological Society on 1 June 1909.

Translated from: Maximow A, Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere. (Demonstrationsvortrag, gehalten in der ausserordentlichen Sitzung der Berliner Hämatologischen Gesellschaft am 1. Juni 1909), Folia Haematologica, 8, 1909, 125-134.
Translated by Claudia Koltzenburg, Alexey Chukhlovin, Athanasius Anagnostou, and Carol Stocking.

Although every attempt is made to ensure precision in the translation into English of the material in these articles, we do not guarantee nor imply their absolute accuracy.

On the keynote authors

The Maximow 1909 centenary: A reappraisal

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Andrey A. Novik1, Tatyana I. Ionova1, Gary Gorodokin2, Alexander Smolyaninov3, and Boris V. Afanasyev4

1Pirogov National Medical Surgical Center, Moscow, Russia;
2New Jersey Center for Quality of Life and Health Outcome Research, NJ, USA;
3Stem Cell Bank Pokrovsky, St. Petersburg, Russia;
4Pavlov State Medical University, St. Petersburg, Russia

On the keynote authors

A .J. Friedenstein, founder of the mesenchymal stem cell concept

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Boris V. Afanasyev1, Elena Elstner2, Axel R. Zander3

1St. Petersburg Pavlov State Medical University, 197089, St. Petersburg, Lev Tolstoy street, 6/8, Russian Federation;
2Charité – Universitätsmedizin Berlin, Onkologie/Hämatologie, 10117 Berlin, Germany;
3Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence: editors@spam is badctt-journal.com

The outstanding scientists A. Maximow and A. Friedenstein consecrated their lives to the study of stem cells. A. Maximow created a theory of hematopoiesis and a concept of hematopoietic stem cells, A. Friedenstein discovered mesenchymal stem cells and the hematopoietic microenvironment. The achievement of both researchers inspired other scientists and doctors to develop hematopoietic stem cell transplantation and other methods of cellular therapy as a treatment for a variety of severe diseases.

Research articles

Factors influencing stem cell mobilization in patients with hematologic malignancies and solid tumors

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Alexeev S., Babenko E., Estrina M., Mikhailova N., Zubarovskaya L., Afanasyev B.

St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

Mobilized peripheral blood stem cells (PBSC) have become the main source for autologous and allogeneic hemopoietic stem cells transplantation (HSCT) following myeloablative therapy in patients with hematological malignancies or solid tumors. Classical strategies for PBSC mobilization include administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with other agents or myelosuppressive chemotherapy. PBSC mobilization and collection have been optimized in numerous clinical trials, but a proportion of patients fail to mobilize. The aim of the study was to establish the influence of diagnosis, sex, age, number of previous courses of chemotherapy, mobilization regimen, and bone marrow (BM) involvement on the outcome of peripheral blood stem cell mobilization.

Patients and methods

121 patients with hematological malignancies and solid tumors were included in the study (Hodgkin’s lymphoma (HD) (n=24), non-Hodgkin lymphomas (NHL) (n=29), multiple myeloma (MM) (n=32), acute leukemias (AL) (n=15), and solid tumors (ST) (n=21)). 100 patients (82%) were mobilized with G-CSF, and a combination of chemotherapy and G-CSF was used in 21 patients (18%). 57 patients (49%) received more than six courses of chemotherapy and 74 (51%) less than six respectively. The criterion for adequate mobilization was a score of at least 2.0 x 106 CD34+ cells/kg of body weight.

In our trial there was no correlation between PBSC yield and the patient’s diagnosis, age, or gender. BM involvement does not seem to be an independent factor, with significant adverse influence on PBSC mobilization (p=0.78). Stem cell yield was significantly higher in those patients who received fewer than six courses of chemotherapy (10.0 ± 2.2 х 106 CD34+/kg against 5.5 ± 1.7 х 106 CD34+/kg (p=0.006)). A better outcome was seen in patients mobilized with chemotherapy plus G-CSF than with G-CSF alone (8.12 ± 1.12 х 106 CD34+/kg against 6.9 ± 0.9 х 106 CD34+/kg  (p= 0.008)).

Conclusions

Diagnosis, age, sex, and bone marrow involvement does not influence the outcome of stem cell mobilization. Better stem cell yield was seen in patients who received fewer than six courses of chemotherapy, and in patients mobilized with cytokines combined with chemotherapy than cytokines alone.

Research articles

Iron overload: causes, assessment methods, significance in transplantation setting and therapeutically approaches

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M. Ivanova, E. Morozova, Y. Vasilieva, Y. Rudnitskaya, R. Nabiev, L. Zubarovskaya, B. Afanasyev

Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

Posttransfusional iron overload is a relatively common complication related to long-term treatment of various haematological diseases. Haematopoietic stem cell transplant recipients - both allogenic and autologous - often present with iron overload because of exposure to red blood cell (RBC) transfusions during the initial treatment and in the post transplant period. Despite these there are also some conditions which contribute to increased risk for iron overload.

A variety of early post transplantant complications including infections, liver function abnormalities, and hepatic sinusoidal obstruction syndrome have been connected with iron overload. The late morbidity of iron overload is primarily due to involvement of heart and liver. Iron overload has been reported to increase the risk of infections late after transplantation.

It has been suggested that all candidates for and all survivors of haematopoietic stem cell transplantation HSCT should be screened for iron overload at various time points before and after transplantation. Serum ferritin is sensitive but not specific for iron overload and is a poor predictor of body iron burden. It can be used for iron overload assessment, but it is recommended to use it together with some other parameters.

Adequate chelation therapy can reduce iron burden and complications and should be administered as soon as there are signs of iron overload.

More studies are needed to better define the natural history of iron overload and its impact on late morbidity and mortality in transplant recipients.

Research articles

Invasive fungal diseases in patients after allogeneic hematopoietic stem cell transplantation

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N. I. Zubarovskaya, E. V. Semenova, N. V. Stancheva, V. N. Vavilov, I. V. Kazantsev, Yu. G. Vasilieva, N. N. Klimko, B. V. Afanasyev


R. M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence: Natalia Zubarovskaya, Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia, Tel.: +7 (812) 499-68-19, Fax: +7 (812) 234-06-16,
E-mail: zoubarov@spam is badmail.ru

Background

The aim of the study was to determine the risk factors and incidence of invasive fungal diseases (IFD) in patients after allo-HSCT.

Materials and patients

In our department 221 allo-HSCTs from related, unrelated and haploidentical donors were performed between October 2000 and June 2008. In the study were enrolled 131 patients younger than 21 and 90 patients older than 21 years old after allo-HSCT. In 87 (37%) patients allo-HSCT was conducted in non-remission.

Results

The incidence of IFD after allo-HSCT remains high. Depending on donor characteristics (HLA-matched related, unrelated or haploidentical donor) it is 28%, 35%, and 38% respectively. Looking at age it is 32% for patients ≤21 years, and 27% for patients >21 years. In the RIC regimen group IFD was diagnosed in 34% of younger (≤21 years) patients and 31% of older (>21 years); and for the MC group it amounted to 32% for younger (p>0.05) and 17% for elder age groups (p<0.05). Neither the rate of IFD in both age groups, the source of HSC and/or rate of post-transplant engraftment were found to independently exert influence on the incidence of IFD following allo-SCT.

In multifactor analysis was noticed correlation between HSC sources and age.

IFD incidence was 1.8-fold higher in elder relapsed patients after related allo-HSCT with RIC (p<0.05). Contrariwise, in this group the incidence of IFD was low in patients that underwent HSCT in remission and received PBSC (p<0.05). The influence of transplant type was also noticed in the younger (≤21 years) group: the probability of IFD development was much higher in relapsed patients after BM allo-HSCT with RIC (p<0.05). It was noticed that the disease stage, grade I–IV mucositis (p<0.05), and extensive cGVHD (p<0.05) were the most prominent risk factors for IFD development. When these factors are present no difference was seen in groups with different conditioning regimens and HSC sources.

In patients >21 years IFD incidence increased by inclusion of ATG in the conditioning regimen (p<0.05).

Conclusions

The main risk factors that influence the incidence of IFD after allo-HSCT in all age groups are the stage of the disease, mucositis development, and extensive form of cGVHD. After diagnosis of IFD 12-weeks OS is 50%. IFD impairs 5-years OS after allo-HSCT.

Research articles

High dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in secondary progressive multiple sclerosis: Case report

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A.A. Novik1, A.N. Kuznetsov1, V.Y. Melnichenko1, D.A. Fedorenko1, T.I. Ionova1, R.V. Kruglina1, A.V. Kartashov1, K.A. Kurbatova1,
G.I. Gorodokin2

1Pirogov National Medical Surgical Center, the Department of Hematology and Cellular Therapy and the Department of Neurology, Pirogov National Medical Surgical Center, Moscow, Russia;
2New Jersey Center for Quality of Life and Health Outcome Research, USA

During the last several years high dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-HSCT) has been established as a therapeutic option for multiple sclerosis (MS) patients. We report clinical and patient-reported outcomes of HDCT + auto-HSCT in a male patient affected by secondary progressive MS (EDSS 5.0 at base-line). Reduced BEAM conditioning regimen was used. As a result, clinical response in terms of reduction of disability and disease activity was achieved along with quality of life (QoL) treatment response and symptom treatment response. The patient was off immunosuppressive or immunomodulating therapy throughout the post-transplant period. Our findings demonstrate that HDCT+auto-HSCT might be considered as an effective treatment for MS patients with high disease activity and relatively low disability rate. Reduction of dose intensity seems to have no influence on treatment outcome. QoL and symptom measurement appears to be an effective approach to assessment of treatment outcomes in patients with MS.

Brief report

Syngeneic Graft-Versus-Chronic-Myeloid-Leukemia-Effect?

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Sunday Ocheni1, Philippe Schafhausen2, Ulrike Bacher1, Boris Fehse1, Nicolaus Kröger1

1Dept. for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany;
2Department of Oncology and Hematology, University Cancer Center Hamburg, Hamburg, Germany

Correspondence: Prof. Dr. med. Nicolaus Kröger, Dept. for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany, Tel.: +49-40-74105-5864, Fax: +49-40-74105-3795,
E-mail: nkroeger@spam is baduke.uni-hamburg.de

Fefer et al first suggested in 1979 that the Ph1-positive clone in chronic myeloid leukemia (CML) can be eradicated by chemotherapy, and that the marrow can be repopulated by stem cells from identical twins. Since then, there have been increasing reports of a graft-versus-leukemia-like effect following syngeneic stem cell transplantation (SCT) in CML. This case report describes three CML patients who achieved complete hematological, cytogenetic and molecular remission following syngeneic SCT. We suggest that syngeneic SCT should be included in the treatment decisions for CML patients with available identical twins, considering the reduced incidence of morbidity and mortality compared to allogeneic SCT.