ISSN 1866-8836
Клеточная терапия и трансплантация

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H. Autoimmune diseases and aplastic anemia

The severity of acquired aplastic anemia (AA) and long-term prognosis: lessons from current results of immunosuppressive treatment (IST)

Alexander D. Kulagin1,2, Igor A. Lisukov1,2, Vyacheslav I. Borisov2, Irina V. Kruchkova2, Vera V. Sergeevicheva2, Svetlana A. Sizikova2, Andrey V. Gilevich2, Vladimir S. Kozhevnikov2, Vladimir A. Kozlov2

Immunoablation followed by autologous stem cell transplantation in refractory autoimmune diseases: clinical outcomes and immune reconstitution

Igor A. Lisukov1,2, Vera V. Sergeevicheva2, Svetlana A. Sizikova2, Alexander D. Kulagin1,2, Irina V. Kruchkova2, Andrey V. Gilevich2, Alexey E. Sizikov2, Lyudmila P. Konenkova2, Elena R. Chernykh2, Vladimir S. Kozhevnikov2, Alexander A. Demin1, Vladimir A. Kozlov2

Outcomes of hematopoietic cell transplantation (SCT) and combined immunosupression (IST) patients with severe aplastic anemia (SAA) admitted with life-threatening infections

Galina A. Novichkova, Mikhail A. Maschan, Lili A. Khachatrian, Dina D. Baidildina, Olga V. Goronkova, Galina G. Solopova, Elena V. Skorobogatova, Irina P. Shipitsina, Alexey A. Maschan

Mesenchymal stem cell transplantation in patents with amyotrophic lateral sclerosis and multiple sclerosis

Miroslav M. Odinak1, Gennadiy N. Bisaga1, Andrey V. Novitsky2, Vadim V. Tirenko2, Dmitriy N. Sculyabin1, Dmitriy G. Polyntsev3, Petr V. Krugliakov3, Anna N. Bilibina3, A. Kolchenko3

Alternative method for treating acquired aplastic anemia

Yuri I. Yugov, Nina A. Fedorovskaya, Alexander S. Luchinin

H. Autoimmune diseases and aplastic anemia

The severity of acquired aplastic anemia (AA) and long-term prognosis: lessons from current results of immunosuppressive treatment (IST)

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Alexander D. Kulagin1,2, Igor A. Lisukov1,2, Vyacheslav I. Borisov2, Irina V. Kruchkova2, Vera V. Sergeevicheva2, Svetlana A. Sizikova2, Andrey V. Gilevich2, Vladimir S. Kozhevnikov2, Vladimir A. Kozlov2

1Novosibirsk State Medical University, Novosibirsk, Russia; 2Institute of Clinical Immunology SB RAMS, Novosibirsk, Russia (EBMT CIC 375)

Correspondence
Alexander D. Kulagin, Yadrintsevskaya str, 14, 630047, Novosibirsk, Russia
E-mail: kulagingem@rambler.ru

Objectives and Methods

We retrospectively analyzed the outcome of 65 patients (39 M and 26 F, median age 21) with moderate (MAA 22), severe (SAA 26) and very severe (VSAA 17) AA treated with ATG and CsA+/-Daclizumab (44) or with CsA alone (21) from October 1995 to May 2009. 

Results

Twenty-two (34%) and 25 (38%) patients achieved CR and PR, respectively (according to strict response criteria of B. Camitta, 2000). The quality of response was higher in the VSAA group (CR/PR=11/1) than in the SAA (9/10, p=0.02) and MAA (2/14, p=0.001) groups.

There were 2 early and 7 late deaths. Four patients (8.5%) relapsed and 3 responded again after re-treatment with ATG and CsA. Late events included MDS/AML (n=2), rectal cancer (n=1) and hemolytic PNH (n=5). The 5-year overall survival was 82 ± 6% without any difference between the MAA (81.6 %), SAA (82.1 %), and VSAA (82.4 %).  Surprisingly, there was a marked trend towards better failure-free survival (FFS) in more severe disease (32.6 ± 12.6%, 45.2 ± 11.8% and 68.8 ± 11.7% in MAA, SAA, and VSAA respectively), which was also observed even when the CsA group alone was excluded from analysis. 

The results of the telomere length measurement in PB cells by flow-FISH analysis in 35 patients gave a possible explanation for better quality of response and FFS in VSAA. The responders with VSAA have a less marked telomere loss than in MAA and SAA patients, probably due to lack of intrinsic stem cell defects and early intensive IST.    

Conclusions

Modern IST provides a high rate of hematological response and long-term survival in more than 80% of AA patients. Nevertheless, different treatment-failure events remain a crucial problem. The severity of AA is a controversial prognostic factor. Our data indicates that more severe AA predicts a better long-term prognosis.

Keywords

aplastic anemia, severity, ATG, cyclosporine, response, telomere, prognosis  

H. Autoimmune diseases and aplastic anemia

Immunoablation followed by autologous stem cell transplantation in refractory autoimmune diseases: clinical outcomes and immune reconstitution

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Igor A. Lisukov1,2, Vera V. Sergeevicheva2, Svetlana A. Sizikova2, Alexander D. Kulagin1,2, Irina V. Kruchkova2, Andrey V. Gilevich2, Alexey E. Sizikov2, Lyudmila P. Konenkova2, Elena R. Chernykh2, Vladimir S. Kozhevnikov2, Alexander A. Demin1, Vladimir A. Kozlov2

1Novosibirsk State Medical University, Novosibirsk, Russia; 2Institute of Clinical Immunology SB RAMS, Novosibirsk, Russia

Correspondence
Alexander D. Kulagin, Institute of Clinical Immunology SB RAMS, Yadrintsevskaya str, 14, 630047, Novosibirsk, Russia
E-mail: kulagingem@rambler.ru

High-dose immunosuppression and autologous hemopoietic stem cell transplantation (ASCT) has been proposed as an investigational therapy for patients with refractory autoimmune diseases (AD). We report the results of a single-center study of ASCT in 15 patients with refractory systemic lupus erythematosus (SLE), 7 patients with progressive multiple sclerosis (MS),
1 patient with autoimmune thrombocytopenia (ITP) relapsed after splenectomy, and 1 patient with pure red cell aplasia (PRCA) in our institution from 1998 to 2009.

Methods: Autologous HSC were collected from bone marrow (n=4) or mobilized from peripheral blood with either granulocyte colony-stimulating factor (G-CSF) (n=2) or Cy and G-CSF (n=18).

Results

Three SLE patients died due to transplant-related complications, 1 MS patient died due to t-AML 4 years after ASCT, 2 SLE and 1 PRCA patients died after 8, 7 and 2 years respectively due to relapses. At a median follow up of 54 (16–124) months 7 patients are in complete remission (4 SLE, 2 MS,
1 ITP). Three MS patients are in a stabilization phase, while 1 MS patient relapsed 5 years after ASCT. CR observed in SLE patients is accompanied by a disappearance of anti–ds DNA and ANA antibodies and an increasing number of CD4+CD45RA+ T cells, CD4+CD25+bright T cells and CD4+Foxp3+ cells. We also demonstrated the increase of CD4+ and CD8+ T cells in the S/G2M phase of the cell cycle until1 year after ASCT.

Conclusion

ASCT in refractory AD can induce stable long-term remissions; however, the majority of patients relapse. The assessment of immune reconstitution can be important to understanding the mechanisms of self-tolerance
re-establishment. International clinical trials would be required to clarify these questions. 

Keywords

immunosuppression, autologous hematopoietic stem cell transplantation, lupus erythematosus, multiple sclerosis, autoimmune thrombocytopenia

H. Autoimmune diseases and aplastic anemia

Outcomes of hematopoietic cell transplantation (SCT) and combined immunosupression (IST) patients with severe aplastic anemia (SAA) admitted with life-threatening infections

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Galina A. Novichkova, Mikhail A. Maschan, Lili A. Khachatrian, Dina D. Baidildina, Olga V. Goronkova, Galina G. Solopova, Elena V. Skorobogatova, Irina P. Shipitsina, Alexey A. Maschan

Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russia

Introduction

Infections remain a dominant cause of treatment failure in children with AA. Often severe infections present at admission are considered as contraindications to curative therapy.

Patients

Among 164 pts admitted with AA between 1998–2005, 35 (21%) had serious infections. There were 23 males and 12 females (med age 10.6 y) with SAA (2 pts) or very SAA (33 pts). Twelve pts were affected by bacterial sepsis, 9 by invasive mycoses (invasive aspergillosis (IA) 7, candidiasis 2), 4 by mixed fungal and bacterial infections, 2 had pneumonia, 6 severe stomatitis, 3 sepsis of unknown origin and 1 had cellulitis. One pt died of Gram (-) septic shock – aged 24 hours – after admission, while in the other 34 pts either SCT (5 pts) or combined IST with ATG+Cyclosporine A (29 pts) were carried out. Med interval from admission was 28 d for SCT and 10 d for IST. Intensive appropriate antimicrobial therapy was given to all patients immediately after admission.

Results

In all 5 SCT recipients complete resolution of infections (all IA) was achieved after bone marrow recovery. One pt died on day 176 from GVHD, CMV, and graft failure; the other 4 pts are alive. Of the 29 recipients of IST 14 (48%) are alive in complete (12 pts) or partial (2 pts) remission, whereas 15 died. Death occurred during the first, second, and third mo in 1, 2 and 1 pts respectively.  In 8 nonresponders to IST the main cause of death was primary infection, whereas in 7 it resolved completely and they died from secondary infections or hemorrhages. As of 09/2008, 18 (51%) of the original 35 pts are alive: the OS rate is 51%±8% and failure-free survival is 31%±7%.

Conclusion

Intensive antimicrobial therapy allows the safe performing of SCT or IST in severely infected pts with SAA. Most of them survive the early post-treatment period, while half are long term survivors.

Keywords

severe aplastic anemia, infections, hematopoietic cell transplantation, combined immunosupression

H. Autoimmune diseases and aplastic anemia

Mesenchymal stem cell transplantation in patents with amyotrophic lateral sclerosis and multiple sclerosis

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Miroslav M. Odinak1, Gennadiy N. Bisaga1, Andrey V. Novitsky2, Vadim V. Tirenko2, Dmitriy N. Sculyabin1, Dmitriy G. Polyntsev3, Petr V. Krugliakov3, Anna N. Bilibina3, A. Kolchenko3

1Department of Neurology and 2Department of  Hematology and Clinical Immunology of the Military Medical Academy, St. Petersburg; 3Trans–technologies Ltd., St. Petersburg, Russia

Correspondence
Andrey V. Novitsky, Dept. of Neurology of the Medical Military Academy, Lesnoy prospekt 2, 194044, St. Petersburg, Russia
Phone: +7812292-33-37, Fax +7812542-88-19
E-mail: anov1@mail.ru

Background

Stem cell transplantation is suggested to be the most promising therapeutic strategy for degenerative and progressive diseases, among which the most significant are amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Human mesenchymal stem cells (MSCs) are thought to be multipotent cells that have the potential to differentiate to lineages of mesenchymal tissues including bone, muscle, neurons, and oligodendrocytes.

Materials and methods

In this study autologous MSCs were isolated from the bone marrow of 10 patients with ALS (5F, 5M, aged 40–63 ys, duration 18–57 mths, 32–20 points of ALSSS scale) and 3 patients with MS (1F, 2M, aged 30–37 ys, duration 4–14 ys, SP course (2 pts) and RR course (1 pt), EDSS 3.5–6.5). Growth kinetics, immunophenotypes, and karyotypes were evaluated during in vitro expansion. The in vitro expanded MSCs did not show any bacterial or fungal contamination, hemopoietic cell contamination, chromosomic alterations, or early cellular senescence. The patients received monthly intravenous injections of autologous MSCs in doses of 2 x 106 cells/kg for 3–20 months. No signs of abnormal cell proliferation were observed.

Results

No significant acute or late side effects were evidenced. Minor adverse events were headaches and transient hyperthermia after MSC infusion in two ALS patients, reversible after 10 hours. Four ALS patients died 3–6 mths after start of therapy due to conditions not directly related with MSC therapy: 1 pt committed suicide (had not had any positive results from therapy), 2 pts died of cardiac arrest (both had a long history of ischemic cardiac disease),
1 pt died of disease progression and of refusing mechanical ventilation. Three ALS patients show a significant (for 4–10 mths), 2 –doubtful (for 1–3 mths), and 5 lack of progression slowing.  The EDSS scores of all 3 MS patients show a decrease in 1 point despite repeated relapses every 3 mths in 1 pt.

Conclusion

Our results seem to demonstrate that MSCs represent a good chance for stem cell therapy in MS, but are considerably less preferable in ALS patients. MSC therapy was safe for the observed treatment period. 

Keywords

stem cell, cell therapy, multiple sclerosis, lateral sclerosis, transplantation

H. Autoimmune diseases and aplastic anemia

Alternative method for treating acquired aplastic anemia

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Yuri I. Yugov, Nina A. Fedorovskaya, Alexander S. Luchinin

Research Institute of Hematology and Blood Transfusion, Kirov, Russia

Acquired aplastic anemia (AA) is an autoimmune disorder which is characterized by pancytopenia and hypocellular bone marrow. Combined immunosuppressive therapy (CIT) including the use of antithymocyte globulin (ATG), cyclosporine-A (CS) and methylprednisolone (MP) is the main therapeutic method. However, responding patients will frequently have relapses, become dependent on CS, or develop a secondary clonal disease.

In 1987, researchers at our hematology clinic formulated the aim of scientific investigations in this direction. The purpose of their work was to create an alternative protocol of CIT AA that would be no less effective than existing protocols. Cyclophosphamide (CPh) was used as the main immunosupppressive drug. Moreover, splenectomies (SE), MP and cyclosporine (CS) were principally used in this scheme. Protocol was being constantly modified. The final protocol version is given below.

MP was administered intravenously at 500–250 mg on days 1–7, and after that orally at 36 mg per day with a subsequent gradual cancellation over 1.5 months. CS was administered at 5mg/kg per os daily from day 1 and continued for 12–28 weeks. SE was carried out on days 4–7 from the beginning of MP. CPh was administered intravenously at 200 mg per day. №5 started on days 4–10 after SE, then №5 every other day, then two times a week until transfusion independence was achieved. However, the general dose was not allowed to exceed 4 g.

This protocol for CIT was applied to 13 patients aged 13 to 43 years (7 males, 6 females). Nonsevere AA was diagnosed in 2 patients, severe AA in 8 and very severe AA in 3 cases. Remission was achieved in 11 patients, 2 patients died during therapy, 1 patient had a relapse, and 1 developed myelodysplasia. Of the 13 patients, 8 are alive and in complete remission.

Keywords

aplastic anemia, treatment, cyclophosphamide, splenectomy