melphalan and Multiple-Sclerosis

Promising results in an animal model of multiple sclerosis (MS; experimental autoimmune encephalomyelitis, EAE) have shown that immunosuppression followed by allogeneic bone marrow transplantation has the potential to significantly ameliorate the spontaneous course of the disease. Since 1995, emerging data on autologous hematopoietic stem cell transplantation (AHSCT) has supported a benefit also in patients with multiple sclerosis. To date, results on approximately 500 cases have been consecutively reported by the European Group for Blood and Marrow Transplantation (EBMT). These reports have not only proved a favourable outcome for many patients but also provided the rationale for the currently ongoing controlled trials on AHSCT in MS. At present, results from the ASTIMS study in particular, a multicenter active-controlled phase II study, are awaited. However, a number of critical issues remain unresolved. Furthermore, with upcoming new treatment compounds that to some extent act via lymphoablative properties, it remains essential to better select those patients who might profit most from stem cell therapy based on a justifiable benefit-to-risk ratio. Although transplant related mortality has dropped to 1%, mortality combined with concerns about long-term safety remain critical issues in a primarily non-life-threatening disease like MS.

Topics: Animals; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Carmustine; Central Nervous System; Clinical Trials, Phase II as Topic; Controlled Clinical Trials as Topic; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Melphalan; Mitoxantrone; Multicenter Studies as Topic; Multiple Sclerosis; Podophyllotoxin; Risk Assessment; Survival Rate; Treatment Outcome

Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P=0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for all patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P=0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens.

Topics: Adult; Animals; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Graft Rejection; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Horses; Humans; Male; Melphalan; Middle Aged; Multiple Sclerosis; Quality of Life; Rabbits; Transplantation Conditioning

Topics: Adrenal Cortex Hormones; Adult; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Etoposide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphocyte Depletion; Magnetic Resonance Imaging; Melphalan; Middle Aged; Multiple Sclerosis; Patient Selection; T-Lymphocytes

High-dose immunoablative chemotherapy with autologous haematopoietic cell support might be beneficial in the treatment of intractable forms of MS. We mobilised PBPC in 11 patients with secondary progressive MS and finally eight patients were grafted after high-dose BEAM chemotherapy with either in vitro or in vivo T cell depletion. Median EDSS and SNRS scores at the time of inclusion were 6.5 (6.5-7.5) and 56 (44-65), respectively. PBPC mobilisation was safe with no serious adverse effects, and without significant aggravation of disability. One patient improved significantly (by 1.0 point on EDSS) after the mobilisation. Two mobilisation failures were observed. No life-threatening events occurred during the transplantation. All grafted patients, except one, at least stabilised their disability status. One patient improved significantly (by 1.5 points on EDSS), two patients improved slightly (by 0.5 points on EDSS), one patient worsened by 1.0 point on the EDSS in 10 months. Improvement occurred with a delay of 2-4 months. Median EDSS and SNRS of grafted patients at the last follow up were 6.5 (5.5-8.5) and 64 (39-73), respectively with median follow-up of 8.5 months. Further follow-up is needed to determine the disease course after complete immune reconstitution. Bone Marrow Transplantation (2000) 25, 525-531.

Topics: Adolescent; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Carmustine; CD4-CD8 Ratio; Cytarabine; Etoposide; Female; Fever; Follow-Up Studies; Graft Survival; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infections; Leukapheresis; Lymphocyte Subsets; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Multiple Sclerosis; Neutropenia; Prognosis; Severity of Illness Index

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Multiple Sclerosis; Prednisone; Vincristine

The triggers for the development of multiple sclerosis (MS) have not been fully understood to date. One hypothesis proposes a viral etiology. Interestingly, viral proteins from human endogenous retroviruses (HERVs) may play a role in the pathogenesis of MS. Allelic variants of the HERV-K18 env gene represent a genetic risk factor for MS, and the envelope protein is considered to be an Epstein-Barr virus-trans-activated superantigen. To further specify a possible role for HERV-K18 in MS, the present study examined the immunogenicity of the purified surface unit (SU). HERV-K18(SU) induced envelope-specific plasma IgG in immunized mice and triggered proliferation of T cells isolated from these mice. It did not trigger phenotypic changes in a mouse model of experimental autoimmune encephalomyelitis. Further studies are needed to investigate the underlying mechanisms of HERV-K18 interaction with immune system regulators in more detail.

Topics: Animals; Endogenous Retroviruses; Epstein-Barr Virus Infections; gamma-Globulins; Herpesvirus 4, Human; Humans; Melphalan; Mice; Multiple Sclerosis

Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.. Using longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.. Total B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.. Our detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.

Topics: Antilymphocyte Serum; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Immunoglobulin Heavy Chains; Melphalan; Multiple Sclerosis

To determine the possible boundaries of high-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HDIT-autoHSCT) for autoimmune diseases (AUDs), such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS).. A long-term trial was conducted at one center to evaluate the efficiency and safety of HDIT-autoHSCT in patients with AUDs. The previous standard therapy was noted to be resistant or lowly effective. The age of 10 patients with systemic connective tissue diseases was 27.6±2.8 years; the pre-HDIT-autoHSCT disease duration was 5.9±1.3 years; the median posttransplantation follow-up was 39.3 months. The age of 49 patients with MS reached 34.9±1.33 years; the pretransplantation disease duration was 8.4±0.69 years; the median post-HDIT-autoHSCT follow-up was 42 months. The efficiency of transplantation was evaluated on the basis of clinical findings, by using scales, laboratory tests, and magnetic resonance imaging. Pretransplantation conditioning was carried out according to the protocols: a) BEAM + antilymphocyte globulin (ALG); b) fludarabine + melphalan + ALG. No fatal outcomes due to a transplant procedure were observed.. Overall 5-year survival after transplantation was 80% for systemic connective tissue diseases and 95% for MS; 5-year progression-free survival rates were 30% in the RA and SLE groups and 45% in the MS group. HDIT-autoHSCT turned out safe and reduced the activity of the process and further disease progression for a long period of time, as confirmed by regression of clinical symptoms and/or status stabilization in 9 patients with SLE or RA and in all patients with MS.. The favorable factors associated with the results of transplantation are age younger than 35 years in collagenoses with their short-term duration and moderate signs; age younger than 40 years in MS with a disease duration of less than 10 years and expanded disability status scale scores of not more than 6.5. Of importance are functional system scores, duration of first remission, and an index of disease progression in different types of MS.. Цель исследования. Определение возможных границ применения высокодозной иммуносупрессивной терапии с аутотрансплантацией стволовых кроветворных клеток (ВИСТ-аутоТСКК) при аутоиммунных заболеваниях (АИЗ): системной красной волчанке (СКВ), ревматоидном артрите (РА), рассеянном склерозе (РС). Материалы и методы. Проведено многолетнее одноцентровое исследование по оценке эффективности и безопасности применения ВИСТ-аутоТСКК у больных с АИЗ. Отмечена резистентность или низкая эффективность предшествующей стандартной терапии. Возраст 10 больных с системными заболеваниями соединительной ткани составил 27,6±2,8 года, длительность заболевания до ВИСТ-аутоТСКК - 5,9±1,3 года, медиана наблюдения после трансплантации - 39,3 мес. Возраст 49 больных РС достигал 34,9±1,33 года, длительность заболевания до трансплантации - 8,4±0,69 года, медиана наблюдения после ВИСТ-аутоТСКК 42 мес. Оценку эффективности трансплантации осуществляли на основании клинических данных с применением шкал, лабораторных методов, магнитно-резонансной томографии. Предтрансплантационное кондиционирование проводили по протоколам: а) ВЕАМ + антилимфоцитарный глобулин (АЛГ); б) флударабин + мелфалан + АЛГ. Летальных исходов, связанных с процедурой трансплантации, не отмечено. Результаты. Общая 5-летняя выживаемость от даты трансплантации при системных заболеваниях соединительной ткани составила в среднем 80%, при РС - 95%; 5-летняя выживаемость без прогрессирования в группе РА и СКВ - 30%, в группе РС - 45%. ВИСТ-аутоТСКК безопасна, снижала активность процесса и дальнейшее прогрессирование заболевания на длительный срок, что подтверждено регрессом клинических симптомов и/или стабилизацией состояния у 9 пациентов с СКВ, РА и у всех больных РС. Заключение. Благоприятными факторами, связанными с результатами трансплантации, являются при коллагенозах возраст моложе 35 лет с небольшой длительностью заболевания и умеренными признаками активности болезни; при РС возраст моложе 40 лет с длительностью заболевания менее 10 лет при показателе по расширенной шкале инвалидизации (EDSS) не более 6,5 балла. Имеют значение данные шкалы функциональных систем (FS), длительность первой ремиссии, индекс прогрессирования болезни при различных типах течения РС.

Topics: Adult; Age Factors; Antilymphocyte Serum; Arthritis, Rheumatoid; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Melphalan; Multiple Sclerosis; Patient Acuity; Retrospective Studies; Transplantation, Autologous; Treatment Outcome; Vidarabine

There are multiple sclerosis patients who suffer from an aggressive course of the disease with severe relapses and rapid accumulation of disability despite adequate treatment. In such cases high-dose immunoablation with autologous haematopoietic stem cell transplantation (ASCT) may be considered. Our objective was to report our experience with 26 multiple sclerosis patients treated with ASCT within the years 1998-2008. Twenty-six patients (Expanded Disability Status Scale 2.5-7.5 (median 6.0), multiple sclerosis duration 2-19 years (median 7)) with aggressive multiple sclerosis underwent autologous haematopoietic stem cell transplantation. Stem cells were mobilized by high-dose cyclophosphamide and granulocyte colony-stimulating factor, BEAM (carmustine, etoposide, cytarabine, melphalan) was used for immunoablation. Patients were evaluated at baseline and every six months post ASCT for adverse events and clinical outcome. Follow-up period was 11-132 months (median 66). Progression-free survival was calculated using the Kaplan- Meier method. At 3 and 6 years of follow-up 70.8% and 29.2% of patients respectively were free of progression. Patients with relapsing multiple sclerosis course, disease duration <5 years and age <35 years had a more favourable outcome. There was no death within 100 days after ASCT. We conclude that ASCT represents a viable and effective treatment option for aggressive multiple sclerosis.

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Kaplan-Meier Estimate; Male; Melphalan; Multiple Sclerosis; Treatment Outcome

We describe the results of a clinical trial to evaluate the feasibility and toxicity of autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with progressive multiple sclerosis (MS). Fifteen patients (all patients with secondary progressive MS) were enrolled. The median expanded disability status scale (EDSS) score at baseline was 6.0 (range, 4.5-7.5). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. In 9 patients, CD34+ cell selection was performed with a CliniMACS cell selection system, and 6 patients accepted infusion of unmodified peripheral blood stem cells. The modified BEAM (carmustine, teniposide, cytarabine, and melphalan) was the sole conditioning regimen used. The adverse effects included infections, mucositis, transient hepatotoxicity, and diarrhea. Three patients had flares of neurologic deterioration during mobilization, 8 patients had the same manifestation during transplantation, and 2 patients had similar flares within 3 months of transplantation. Six patients experienced continuous neurologic improvement after transplantation, 5 patients experienced neurologic progression, and 4 patients had stabilization of their disease. The confirmed progression-free rate was 63.8% at 49 months. The results of lymphocyte purging were no better than for no purging. Auto-HSCT proved to be safe and beneficial for some MS patients. Further studies are needed to establish the merit of this procedure for MS patients.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Diarrhea; Disease-Free Survival; Female; Hematopoietic Stem Cell Mobilization; Humans; Liver Diseases; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Mucositis; Multiple Sclerosis; Peripheral Blood Stem Cell Transplantation; Podophyllotoxin; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non-primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.

Topics: Adult; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Middle Aged; Multiple Sclerosis; Peripheral Blood Stem Cell Transplantation; Podophyllotoxin; Quality of Life; Radiography; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Topics: Humans; Melphalan; Multiple Sclerosis