Multiple Sclerosis: Fassas A

Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, Filippi M, Hartung HP, Hertenstein B, Karussis D, Martino G, Tyndall A, van der Meché FG. · Multiple Sclerosis Centre, San Raffaele Scientific Institute, Milan, Italy. · J Neurol. · Pubmed #10896270 No free full text.

Abstract: Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.

Fassas A. · No affiliation provided · Haematologica. · Pubmed #12651258 links to  free full text

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Gold R, Jawad A, Miller DH, Henderson DC, Fassas A, Fierz W, Hartung HP. · Department of Neurology at St. Josef-Hospital, University of Bochum, Gudrunstrasse 56, D-47901 Bochum, Germany. · J Neuroimmunol. · Pubmed #17499366 No free full text.

Abstract: Natalizumab (Tysabri) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease. Immune compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued. Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.

Fassas A, Nash R. · Bone Marrow Transplantation Unit, Department of Haematology, George Papanicolaou Hospital, 57010 Exokhi, Thessaloniki, Greece. · Best Pract Res Clin Haematol. · Pubmed #15302338 No free full text.

Abstract: Autologous transplants for severe and refractory multiple sclerosis (MS) were proposed in 1997 and have been performed on about 200 selected patients worldwide. Phase I/II clinical studies have shown that high-dose immunosuppressive therapy suppresses inflammation in the CNS and may delay the progression of clinical disease. The procedure is associated with toxicity from the high-dose cytotoxic therapy and a risk of serious infections. There is a transplant-related mortality risk of 1-5%, requiring careful patient selection before transplantation. Treatment should be reserved for patients who have a significant chance of response, i.e. young patients with low disability scores but rapidly progressing disease who have inflammatory rather than neurodegenerative changes in the CNS. The long term effect of high-dose immunosuppression after transplantation on the frequency of relapse or progression of MS is unclear, but the initial concept of immune ablation by high-dose therapy and the reconstitution of normal immunity and tolerance from transplant-derived lymphocyte progenitors has given way to the concept of 'resetting' the immune system. The clinical effect of transplantation remains to be demonstrated in comparative studies.

Fassas A, Kimiskidis VK. · Department of Hematology and Bone Marrow Transplantation Unit, George Papanicolaou Hospital, 57010 Exokhi, Thessaloniki, Greece. · J Neurol Sci. · Pubmed #15261561 No free full text.

Abstract: Based on the encouraging results of transplantation in animals with experimental autoimmune encephalomyelitis (EAE), small-scale phase I/II trials of autologous hematopoietic stem cell transplantation (autoHSCT) were initiated in 1995 for the treatment of severe cases of multiple sclerosis (MS). More than 200 patients with treatment-resistant multiple sclerosis have been transplanted so far, mainly in Europe and the USA. The results of these studies appear promising in terms of impact on MRI disease parameters and, to a lesser extent, clinical stabilization or even improvement. Despite concerns raised by the morbidity and mortality noted in the initial pilot studies, a controlled, randomized, phase III trial of autoHSCT against the best currently available treatment, i.e., mitoxantrone, seems justified and is under way.

Fassas A, Kazis A. · Department of Hematology, Aristotle University Medical School, George Papanicolaou Hospital, Thessaloniki, Greece. · J Hematother Stem Cell Res. · Pubmed #14977479 No free full text.

Abstract: Multiple sclerosis is a relatively common and seriously disabling disease of autoimmune pathogenesis, for which there is currently no cure. Available therapies include immunomodulating agents and standard-dose immunosuppressants, which may be helpful but are not curative. Recently, studies in animal models have indicated that control of autoimmune disease can be obtained by high-dose immunosuppression followed by hematopoietic stem cell transplantation (rescue). Autologous transplants for severe and refractory multiple sclerosis were proposed in 1997 and have been performed ever since in selected patients and in the context of phase I/II trials. To date, more than 200 patients have been treated worldwide, and similar results were obtained in different centers: high-dose therapy suppresses inflammation in the brain to a degree superior to any other conventional therapy and seems to delay significantly clinical disease progression. There is, however, a procedure-related mortality risk of 1.5-5%, requiring careful patient selection before transplant. The treatment should be reserved for patients having high chance of response, i.e., young patients with low disability scores but rapidly progressing disease, having inflammatory rather than neurodegenerative changes in the central nervous system. The mechanism of action of transplantation is unclear. The initial concept of immune ablation by high-dose therapy and reconstitution of normal immunity from transplant-derived lymphocyte progenitors has given way to the concept of "resetting" the immune system and of bringing the disease to a lower level of activity. One could also speculate on a tissue repair effect, given the ability of human hematopoietic stem cells to migrate also into the central nervous system. The clinical effect of transplantation remains to be demonstrated in a randomized study. The Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation has launched such a trial, comparing transplantation to the currently best available therapy, i.e., mitoxantrone, and in about 5 years we should know whether transplantation offers more than the benefit of a transient immunosuppressive effect.

Fassas A, Kimiskidis VK. · Hematology Department and BMT unit, George Papanicolaou Hospital, Thessaloniki, Greece. · Blood Rev. · Pubmed #14556778 No free full text.

Abstract: Experimental and clinical observations have indicated that high-dose immunosuppression followed by autologous stem cell transplantation (ASCT) can induce remissions in severe, refractory, autoimmune diseases including multiple sclerosis (MS), a T cell-mediated autoimmune disorder against CNS myelin components, causing severe chronic disability. Control of the disease is unsatisfactory in most of the patients, especially those with rapidly evolving relapsing-remitting course and those with chronic progressive disease. The rationale for treating autoimmune diseases with ASCT is based on the immunosuppressive and immunomodulating effects of ASCT which may shift the immunological balance towards disease quiescence, a hypothesis supported by the results of ASCT in animal models of MS and by clinical observations in MS patients transplanted for concurrent malignancies. A number of phase I-II studies of ASCT in patients with active MS, conducted worldwide since 1995, and a comprehensive analysis of 85 patients, recently reported by the European Group for Blood and Marrow Transplantation (EBMT), have shown the feasibility of the method, a prominent anti-inflammatory effect on magnetic resonance imaging (MRI) disease, and a possible clinical benefit for active and refractory cases. The impact on MRI disease parameters appears superior with ASCT than with conventional therapies but the clinical results, in terms of stabilization of disease and prevention of disability, need to be validated in prospective, controlled trials. The procedure is also associated with a transplant-related mortality risk, of about 5% in high-risk cases, i.e., in older patients, those with high disability scores, those receiving strong myeloablative conditioning regimens and those undergoing intensive in vivo or ex vivo T cell-depletion. Therefore, it could be recommended for the treatment of a chronic, non-lethal, disease like MS only if it proved superior to standard therapies. A randomized trial is now launched by the EBMT to compare ASCT to mitoxantrone, currently regarded as one of the best available treatments, in properly selected patients having high chance of response at minimal mortality risk.

Fassas A. · Department of Hematology, The George Papanicolaou Hospital, Thessaloniki, Greece. · Int J Hematol. · Pubmed #12430857 No free full text.

Abstract: Based on experimental and clinical observations, high-dose immunosuppression followed by autologous transplantation may induce remissions in severe, refractory, autoimmune disorders including multiple sclerosis, a disease which, in its progressive form, does not respond to treatment. Phase I/II studies of transplantation in MS published by individual centers as well as a comprehensive analysis of the reports to the EBMT registry have shown that transplantation may positively affect MS by stabilizing the clinical condition of the patients, by improving their disability status, and by completely abrogating the inflammatory process in the brain as evidenced in magnetic resonance imaging. Other available therapies do not appear to be so efficacious as transplantation. However, the procedure is associated with a transplant-related mortality risk of about 3 to 8%. Therefore, it cannot be recommended for the treatment of a chronic, non-lethal, disease like MS unless it proves superior to standard therapies in terms of efficacy. This can be demonstrated only in a randomized trial, which is being launched by the EBMT under the name ASTIMS. It compares the BEAM regimen plus autotransplantation to mitoxantrone, which is currently regarded as one of the best available treatments, in patients with secondary progressive or rapidly evolving relapsing/remitting multiple sclerosis.

Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, Carreras E, Graus F, Kashyap A, Openshaw H, Schipperus M, Deconinck E, Mancardi G, Marmont A, Hansz J, Rabusin M, Zuazu Nagore FJ, Besalduch J, Dentamaro T, Fouillard L, Hertenstein B, La Nasa G, Musso M, Papineschi F, Rowe JM, Saccardi R, Steck A, Kappos L, Gratwohl A, Tyndall A, Samijn J, Samign J, Anonymous00147. · George Papanicolaou General Hospital, Dpt. Hematology, 57010 Thessaloniki, Greece. · J Neurol. · Pubmed #12195460 No free full text.

Abstract: RATIONALE: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. PATIENTS: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. RESULTS: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. CONCLUSION: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, Smias C, Eleftheriadis N, Tsimourtou V. · Department of Hematology, The George Papanicolaou General Hospital, Thessaloniki, Greece. · J Clin Immunol. · Pubmed #10798604 No free full text.

Abstract: Based on the good results of experimental transplantation in animal models of multiple sclerosis and of other autoimmune diseases, we have treated 24 patients suffering from chronic progressive multiple sclerosis with high-dose chemotherapy (BEAM regimen) followed by autologous blood stem cell rescue and antithymocyte globulin. Blood stem cells were mobilised with cyclophosphamide at 4g/m2 and G- (or GM-) CSF. In 9 cases, additional CD34+ cell-selection of the graft was performed. Here we update previously published results of this novel treatment, mainly with regard to clinical efficacy, as the median follow-up time has reached 40 months (range, 21-51). Infections were the principal toxicity early after the procedure, with death of a patient from aspergillosis 65 days post stem cell infusion. No serious late events occurred apart from a case of autoimmune thyroiditis that developed 11 months after transplant in a patient who had received a CD34+ cell-depleted graft. Mild and transient neurotoxicity was observed in 10 patients (42%), most probably associated with fever and infections. Eighteen patients (18/23; 78%) responded to the treatment, i.e., they were improved or stabilized, while five patients progressed, of which 4 had primary progressive disease. Of those improved or stabilised (18), 9 patients have maintained stable condition whereas 9 developed relapses or they slowly resumed progression, although their disability scores have not gotten worse than they were before transplantation. The probability of progression-free survival (compared to entry status) at 3 years is 92% for patients with secondary progressive disease and 39% for the primary progressive type. CD34+ cell-selection did not seem to yield better results except for a delay in progression or in relapse after transplantation. These results appear better than those achieved by any other treatment of progressive multiple sclerosis, including beta-interferon, but they need to be confirmed by other open or controlled studies in view of the well-known difficulty of judging objectively the effect of a treatment in patients with this disease.

Kimiskidis V, Sakellari I, Tsimourtou V, Kapina V, Papagiannopoulos S, Kazis D, Vlaikidis N, Anagnostopoulos A, Fassas A. · Department of Neurology III, Aristotle University of Thessaloniki, George Papanikolaou Hospital, Thessaloniki, 570 10 Greece. · Mult Scler. · Pubmed #17942513 No free full text.

Abstract: Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. We report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response. It is concluded that intensive immunosuppression followed by autologous stem cell transplantation is a viable therapeutic option in patients with malignant MS unresponsive to conventional forms of treatment.

Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, Havrdova E, Carreras E, Saiz A, Löwenberg B, te Boekhorst PA, Gualandio F, Openshaw H, Longo G, Pagliai F, Massacesi L, Deconink E, Ouyang J, Nagore FJ, Besalduch J, Lisukov IA, Bonini A, Merelli E, Slavino S, Gratwohl A, Passweg J, Tyndall A, Steck AJ, Andolina M, Capobianco M, Martin JL, Lugaresi A, Meucci G, Sáez RA, Clark RE, Fernandez MN, Fouillard L, Herstenstein B, Koza V, Cocco E, Baurmann H, Mancardi GL, Anonymous00211. · BMT Unit Department of Hematology, Ospedale di Careggi, Florence, Italy. · Mult Scler. · Pubmed #17263012 No free full text.

Abstract: Over the last decade, hematopoietic stem cells transplantation (HSCT) has been increasingly used in the treatment of severe progressive autoimmune diseases. We report a retrospective survey of 183 multiple sclerosis (MS) patients, recorded in the database of the European Blood and Marrow Transplantation Group (EBMT). Transplant data were available from 178 patients who received an autologous graft. Overall, transplant related mortality (TRM) was 5.3% and was restricted to the period 1995-2000, with no further TRM reported since then. Busulphan-based regimens were significantly associated with TRM. Clinical status at the time of transplant and transplant techniques showed some correlations with toxicity. No toxic deaths were reported among the 53 patients treated with the BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan)/antithymocyte globulin (ATG) regimen without graft manipulation, irrespective of their clinical condition at the time of the transplant. Improvement or stabilization of neurological conditions occurred in 63% of patients at a median follow-up of 41.7 months, and was not associated with the intensity of the conditioning regimen. In this large series, HSCT was shown as a promising procedure to slow down progression in a subset of patients affected by severe, progressive MS; the safety and feasibility of the procedure can be significantly improved by appropriate patient selection and choice of transplant regimen.

Papadaki HA, Tsagournisakis M, Mastorodemos V, Pontikoglou C, Damianaki A, Pyrovolaki K, Stamatopoulos K, Fassas A, Plaitakis A, Eliopoulos GD. · Department of Hematology of the University of Crete School of Medicine, Crete, Greece. · Bone Marrow Transplant. · Pubmed #16205726 No free full text.

Abstract: Bone marrow (BM) stem cell reserves and function and stromal cell hematopoiesis supporting capacity were evaluated in 15 patients with multiple sclerosis (MS) and 61 normal controls using flow cytometry, clonogenic assays, long-term BM cultures (LTBMCs) and enzyme-linked immunosorbent assays. MS patients displayed normal CD34+ cell numbers but a low frequency of colony-forming cells (CFCs) in both BM mononuclear and purified CD34+ cell fractions, compared to controls. Patients had increased proportions of activated BM CD3+/HLA-DR+ and CD3+/CD38+ T cells that correlated inversely with CFC numbers. Patient BM CD3+ T cells inhibited colony formation by normal CD34+ cells and patient CFC numbers increased significantly following immunomagnetic removal of T cells from BMMCs, suggesting that activated T cells may be involved in the defective clonogenic potential of hematopoietic progenitors. Patient BM stromal cells displayed normal hematopoiesis supporting capacity indicated by the CFC number in the nonadherent cell fraction of LTBMCs recharged with normal CD34+ cells. Culture supernatants displayed normal stromal derived factor-1 and stem cell factor/kit ligand but increased flt-3 ligand levels. These findings provide support for the use of autologous stem cell transplantation in MS patients. The low clonogenic potential of BM hematopoietic progenitors probably reflects the presence of activated T cells rather than an intrinsic defect.

Saccardi R, Tyndall A, Coghlan G, Denton C, Edan G, Emdin M, Farge D, Fassas A, Finke J, Furst D, Lassus M, Mancardi G, Miniati I, Mini E, Pagliai F, Passweg J, Pignone A, van Laar JM, Bocelli-Tyndall C, Matucci-Cerinic M. · Haematology Unit, University of Florence, Italy. · Bone Marrow Transplant. · Pubmed #15517007 No free full text.

Abstract: Autologous haematopoietic stem cell transplantation is now a feasible and effective treatment for selected patients with severe autoimmune diseases. Worldwide, over 650 patients have been transplanted in the context of phase I and II clinical trials. The results are encouraging enough to begin randomised phase III trials. However, as predicted, significant transplant-related morbidity and mortality have been observed. This is primarily due to complications related to either the stage of the disease at transplant or due to infections. The number of deaths related to cardiac toxicity is low. However, caution is required when cyclophosphamide or anthracyclines such as mitoxantrone are used in patients with a possible underlying heart damage, for example, systemic sclerosis patients. In November 2002, a meeting was held in Florence, bringing together a number of experts in various fields, including rheumatology, cardiology, neurology, pharmacology and transplantation medicine. The object of the meeting was to analyse existing data, both published or available, in the European Group for Blood and Marrow Transplantation autoimmune disease database, and to propose a safe approach to such patients. A full cardiological assessment before and during the transplant emerged as the major recommendation.

Burt RK, Fassas A, Snowden J, van Laar JM, Kozak T, Wulffraat NM, Nash RA, Dunbar CE, Arnold R, Prentice G, Bingham S, Marmont AM, McSweeney PA. · Northwestern University Medical Center, Department of Medicine, Chicago, IL 60611-2950, USA. · Bone Marrow Transplant. · Pubmed #11498738 links to  free full text

Abstract: We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of stem cell collection including methods used, cell yields, effects on disease activity, and complications in patients with autoimmune diseases. Twenty-one unprimed bone marrow harvests and 174 peripheral blood stem cell mobilizations were performed on 187 patients. Disease indications were multiple sclerosis (76 patients), rheumatoid arthritis (37 patients), scleroderma (26 patients), systemic lupus erythematosus (19 patients), juvenile chronic arthritis (13 patients), idiopathic autoimmune thrombocytopenia (8 patients), Behcet's disease (3 patients), undifferentiated vasculitis (3 patients), polychondritis (1 patient) and polymyositis (1 patient). Bone marrow harvests were used in the Peoples Republic of China and preferred worldwide for children. PBSC mobilization was the preferred technique for adult stem cell collection in America, Australia, and Europe. Methods of PBSC mobilization included G-CSF (5, 10, or 16 microg/kg/day) or cyclophosphamide (2 or 4 g/m2) with either G-CSF (5 or 10 microg/kg/day) or GM-CSF (5 microg/kg/day). Bone marrow harvests were without complications and did not affect disease activity. A combination of cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone (P < 0.001). g-csf alone was more likely to cause disease exacerbation than the combination of cyclophosphamide and g-csf (P = 0.003). Three patients died as a result of cyclophosphamide-based stem cell collection (2.6% of patients mobilized with cyclophosphamide). When corrected for patient weight and apheresis volume, progenitor cell yields tended to vary by underlying disease, prior medication history and mobilization regimen. Trends in the approaches to, and results of, progenitor cell mobilization are suggested by this survey. While cytokine-based mobilization appears less toxic, it is more likely to result in disease reactivation. Optimization with regard to cell yields and safety are likely to be disease-specific and prospective disease-specific studies of mobilization procedures appear warranted.

Kaloyannidis P, Sakellari I, Fassas A, Fragia T, Vakalopoulou S, Kartsios C, Garypidou B, Kimiskidis V, Anagnostopoulos A. · No affiliation provided · Bone Marrow Transplant. · Pubmed #15195073 No free full text.

This publication has no abstract.