ISSN 1866-8836
Клеточная терапия и трансплантация

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Regular articles

Prognostic significance of vascular endothelial growth factor and circulating endothelial cells for early and late outcomes of allogeneic hematopoietic stem cell transplantation

Ivan S. Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol,
Vladimir N. Vavilov, Boris V. Afanasyev

Comparative effects of intramyocardial autotransplantation of different bone marrow cells upon outcomes of experimental myocardial infarction in rabbits

Vladimir V. Davydenko1, Andrey A. Matyukov1, Timur D. Vlasov1, Natalya V. Tsupkina2, Anatoly N. Yalfimov3,
Georgy P. Pinaev2, Khalida K. Amineva1

Saint-Petersburg experience of allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and human immunodeficiency virus

Boris V. Afanasyev1, Marina Popova1, Sergey Bondarenko1, Ilya Zyuzgin2, Elena Babenko1, Aleksander Alyanskiy1, Susanne Morsch3, Jan van Lunzen4, Boris Fehse5, Axel R. Zander 5, Ludmila S. Zubarovskaya1

Chemotherapy in the elderly – How intense should treatment be?

Axel R. Zander1, René J. Hornung2, Hans-Peter Lipp3

Regular articles

Prognostic significance of vascular endothelial growth factor and circulating endothelial cells for early and late outcomes of allogeneic hematopoietic stem cell transplantation

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Ivan S. Moiseev, Sergej V. Lapin, Elena A. Surkova, Margarita Y. Lerner, Elena V. Babenko, Alexandra A. Sipol,
Vladimir N. Vavilov, Boris V. Afanasyev

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

Summery

A number of studies evaluated predictive value of endothelial damage markers on outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT), but they were rarely measured in combination and with long follow up. In this study we evaluated predictive value of vascular endothelial growth factor (VEGF) and circulating endothelial cells (CEC) on early and late non-relapse mortality (NRM). Given the known negative prognostic impact of VEGF expression in hematologic malignancies undergoing chemotherapy, the second goal was to access impact of VEGF level on relapse incidence after alloHSCT. Level of VEGF was analyzed in 91 consecutive patients before the start of conditioning, on day 0 and on the day of engraftment. CEC were measured in 55 consecutive patients from the same study group at the same time points. Both VEGF and CEC were predicted early, but not late NRM. High level of VEGF on day 0 in multivariate analysis was associated with increased 1-year NRM (55% vs 22%, HR 3.15, 95%CI 1.34-7.40, p=0.009), while high level of CEC before conditioning was associated with increased 1-year NRM in univariate (69% vs 20%, p=0.001), but not multivariate analysis (95%CI 0.84-5.76, p=0.102). High VEGF A level before conditioning was associated with increased 1-year relapse rate (55% vs 22%, p=0.001, HR 3.15, 95%CI 1.34-7.40), but had no impact on late relapses and 3-year overall survival (50% vs 42% respectively, p=0.60), as a large proportion of patients were successfully salvaged after relapse. CEC were not a significant prognostic factor for relapse (p=0.09). No correlation was found between VEGF and CEC at any time point (p>0.05), indicating that they may represent different aspects of endothelial dysfunction. In conclusion, VEGF and CEC are valuable biomarkers to predict early NRM, and VEGF is also a predictive factor of early relapse after alloHSCT.

Regular articles

Comparative effects of intramyocardial autotransplantation of different bone marrow cells upon outcomes of experimental myocardial infarction in rabbits

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Vladimir V. Davydenko1, Andrey A. Matyukov1, Timur D. Vlasov1, Natalya V. Tsupkina2, Anatoly N. Yalfimov3,
Georgy P. Pinaev2, Khalida K. Amineva1

1FirstSt.Petersburg State I.Pavlov Medical University

2Institute of Cytology, Russian Academy of Sciences, St.Petersburg

3Russian Center of Radiology and Surgical Technologies, St.Petersburg

Summary

Over the last decade, different cell therapy options have been tested to improve treatment of myocardial infarction (MI), including cardiomyoplastics. Autologous bone marrow is a widely used source of therapeutic cell preparations, i.e., freshly isolated mononuclear cell fraction (MF), or cultured multipotent mesenchymal stromal cells (MMSC). The aim of our pilot study was to compare short- and long-term consequences of intramyocardial MF and MMSC transplantation upon clinical course and outcome of experimental MI. Materials and methods: The experiments were performed with male Chinchilla rabbits of 2.8+0.2 kg weight. MI was modelled by ligation of anterior descendent left coronary artery. Mononuclear cell fraction was obtained from the bone marrow aspirate. MMSC cell culture was grown by MF cell passages in МЕМ medium with 10% fetal calf serum. Intramyocardial injections of MF or MMSC suspensions were performed into 6 points of the infarcted area. The surviving animals were divided in four groups, each consisting of 13 rabbits: group 1 (controls), group 2 (placebo-treated), group 3 (MMSC injections), and group 4 (MF injections). Electrocardiography (ECG) and echo-cardiography were carried out in all animals before surgery, during 1 mo and 1 year after surgery. Myocardial perfusion rates were assessed with SPECT technique. IM dimensions (perfusion areas) were determined by means of staining heart sections with 2,3,5-TTC. Routine histology of myocardial sections was also performed. Vascularization rates of different myocardial areas were assessed in similar way.

Results

Intramyocardial transplantation of autologous bone marrow cells (MF and MMSC) into the area of rabbit experimental MI during the acute phase has changed natural process development and resulted in principally different morpho-functional outcomes. Ten days after coronary occlusion, all animals exhibited pronounced perfusion decrease in infarcted anterior wall of LV (p<0,05). However, the animals, treated with MMSC or MF showed less impaired perfusion rates than in control or placebo groups (p<0.05). 1.5 months after treatment, a gradual recovery of mean perfusion rates was observed in damaged myocardium in MMSC and MF-treated groups. These changes were confirmed by perfusion tomoscyntigraphy of myocardium at 1.5 and 12 months after surgery. Histological studies have shown that, after MMSC transplantation, a pattern of microfocal cardiosclerosis was observed, followed by recovery of myocardial structure, whereas MF injections were followed by development of fibrotic aneurism affecting both left and right ventricles. One year after surgical intervention, a more expressed positive effect of MMSC transplantation was observed, i.e., nearly full recovery of all functional parameters (LV ejection fraction; EDSLV, end LV diastolic size; blood flow rates in ascending aorta) at 12 months post-surgery (p<0.05), and absence of akinetic areas.

Conclusions

MMSC injections were associated with pronounced therapeutic effect, by reducing myocardium damage area. By the contrary, MF transplantation showed a negative effect, expanding myocardium damage area and impairing systolic function indices. Both MMSC and MF intramyocardial transplantation display neoangiogenesis stimulation and perfusion improvement in rabbit experimental infarction area.

Regular articles

Should Allogeneic Hematopoietic Stem Cell Transplantation be a Treatment Option for Patients with Nijmegen Breakage Syndrome? Belarusian Experience

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Olga V. Aleinikova, Alina S. Fedorova, Svetlana O. Sharapova

Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus

Summery

Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma.

Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment.

Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually.

Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated.

Conclusions: NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1st complete remission.

Regular articles

Saint-Petersburg experience of allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and human immunodeficiency virus

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Boris V. Afanasyev1, Marina Popova1, Sergey Bondarenko1, Ilya Zyuzgin2, Elena Babenko1, Aleksander Alyanskiy1, Susanne Morsch3, Jan van Lunzen4, Boris Fehse5, Axel R. Zander 5, Ludmila S. Zubarovskaya1

1Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation,

First Pavlov State Medical University of Saint-Petersburg, Russia

2Oncology, Hematology and BMT department, Petrov Research Institute of Oncology, Saint-Petersburg, Russia

3Stefan Morsch Stiftung, Birkenfeld, Germany

4Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation

First Pavlov State Medical University of Saint-Petersburg, Russia

Summery

Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including high-dose CT with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with HIV-associated lymphomas and well-controlled HIV infection on HAART has similar outcomes compared with patients without HIV infection. However, the outcome of HIV-patients after allogeneic hematopoietic stem cells transplantation (allo-HSCT) is unknown with only limited case reports and small series. Most of these patients are potentially curable from hematological malignancies by allo-HSCT. Allo-HSCT from donor with homozygote CCR5 del 32 mutation can cure from the both diseases: HIV and cancer that was demonstrated by the Berlin patient. Prevalence of this mutation is low and this way seems unacceptable in most HIV-positive patients with high-risk hematologic malignancies. Allo-HSCT from donor without CCR5 mutation with ongoing HAART has looked more promising but has failed which was reported as Boston patients. But other aspects including donor type, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, post-transplant immunoadoptive and new agent therapy in HIV-patients maintain interest to allo-HSCT as a potential cure procedure. It was not reported an allo-HSCT from donor with heterozygote CCR5 del 32 mutation. An application of HAART in post-transplant period can be used not only for HIV control also as a component of GvHD prophylaxis. We report on three HIV-infected patients with high-risk acute leukemia which have undergone an allo-HSCT and donor lymphocyte infusions (DLI) to treat post-allo-HSCT relapse in Saint-Petersburg.

Regular articles

Allogeneic hematopoietic stem cell transplantation and solid organ transplantation in the same patient

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Tapani Ruutu1, Christian Koenecke2 and Grzegorz W. Basak3

1Helsinki University Central Hospital, Comprehensive Cancer Center, Stem Cell Transplantation Unit, Helsinki, Finland;
2Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover, Germany;
3The Medical University of Warsaw, Department of Hematology, Oncology and Internal Diseases, Poland

Summary

The present review is largely based on two surveys on patients who have undergone both an allogeneic hematopoietic stem cell transplantation (HSCT) and a solid organ transplantation (SOT), carried out by the European Society for Blood and Marrow Transplantation (EBMT). Some additional references to the literature are included. From these sources of data it can be summarized that SOT represents a valuable treatment strategy in HSCT recipients who develop an organ failure. In stringently selected young patients, the overall and organ survivals appear to be comparable to patients undergoing SOT for other causes. Complications, such as infections and graft rejection are frequent but usually manageable. Thus, SOT offers a viable therapeutic option for selected patients with single organ failure after HSCT. Also, selected SOT recipients suffering from hematologic disorders may benefit from allogeneic SCT and experience long-term survival without loss of organ function.

Regular articles

MRD evaluation, targeted therapy and stem cell transplantation: how to combine in adult ALL

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Dieter Hoelzer

J. W. Goethe University, Frankfurt

Summery

There exist standard molecular methods of minimal residual disease (MRD) evaluation in acute lymphoblastic leukemia (ALL), in order to detect leukemic blast cells (LBC) not assessable by microscopy of bone marrow. The best time point for MRD evaluation and MRD-based treatment stratification in ALL is shown to be ca.14-16 weeks after induction/ consolidation treatment. Reduction of MRD load before SCT, as a next step of therapy, is quite desirable. E.g., induction and consolidation treatment with tyrosine kinase inhibitors (NKI) increase the molecular CR rate compared to conventional chemotherapy, as measured by the quantitative RT-PCR assays of bcr/abl fusion oncogene. Failure of treatment by molecular criteria identifies the worst ALL subgroup. Several window studies in ALL with new cytostatic drugs (TKIs or MoABs) were aimed to reduce the tumor load before SCT. Moreover, novel immunotherapeutic approaches include application of monoclonal antibodies against specific surface antigens typical to certain differentiation steps in B-lineage.

Hence, evaluation of minimal residual disease is a new parameter for treatment stratification. The conversion of MRD-positivity to MRD-negativity is also a new endpoint for studies. Targeted therapy with TKI has improved the outcome for adult Ph+ ALL patients substantially, evidently by an increased molecular remission rate, and a substantial improvement of survival after SCT. Meanwhile, maintenance with a TKI is recommended after SCT, whereby the optimal duration is so far not known. Maintenance with a TKI is recommended after SCT, whereby the optimal duration is so far not known.

Regular articles

Chemotherapy in the elderly – How intense should treatment be?

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Axel R. Zander1, René J. Hornung2, Hans-Peter Lipp3

Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany1

University Medical Centre Hamburg-Eppendorf, Hamburg, Germany2

Department of Hospital Pharmacy, University Tübingen, Tübingen, Germany3

Summary

Physiological changes and deficiencies in cognitive processes in the elderly have an influence on therapy and drug dosage compliance. The consequences of differences for the outcome of especially chemotherapies are neither well nor systematically studied. Existing studies though could actually demonstrate age-related differences in clinical pharmacokinetics. Another problem is the increased number of prescribed drugs that are often necessary when getting older (polypharmacy) and their interference with over-the-counter drugs (OTC) and complementary and alternative medicine (CAM). While they are often seen as harmless since they require no prescription or are of “natural origin”, they can contain pharmaceutical active agents. For example green tea is reported to prevent prostate cancer and pre-menopausal breast cancer and is therefore often recommended to cancer patients, but also contains Epigallocatechin gallate (EGCg) an active substance which decreases the bio-availability of the anti-cancer drugs Bortezomid or Sunitinib. Conclusion: a further and more systematic study of age-related differences in the outcome of chemotherapies in the elderly is necessary. Here especially the kidney function requires adaption of treatment regimen. Furthermore the interactions with other drugs, in particular over-the-counter and alternative medicine, need to be better understood and communicated.