Haematopoetic stem cells in MSSaturday, October 13, 2007, 10:50 - 11:10
Present status of HSCT in MSG.L. Mancardi (Genoa, I)
In the last years, intensive immunosuppression followed by autologous transplantation of hematopoietic stem cells (AHSCT) has been proposed as a possible strategy for the treatment of severe autoimmune disorders, including multiple sclerosis (MS). The rationale for AHSCT derives from the possibility to eradicate self reactive immune cells by immunosuppression followed by full immune reconstitution after the engraftment of the autologous haematopoietic stem cells. Beyond its immunosuppressive potential, AHSCT may also be beneficial for the possible "resetting" of the immune system due to a "de novo" regeneration of the T cell compartment, which could become tolerant against self-antigens, possibly for an extended period of time. From 1995 to 2007 more than 300 MS cases have been treated with AHSCT. The retrospective survey, carried out in 2006, of all the patients recorded in the database of the European Blood and Transplantation Group (EBMT) showed, with a median follow up of more than 3 years, that improvement or stabilization of neurological conditions occurred in 63% of cases. Transplant related mortality was very high (8%) in the 1995-2000 period, but subsequently dropped to 0.9% in the 2001-2006 years. The results appear to be particularly impressive in rapidly evolving severe MS cases unresponsive to conventional therapies. A phase 2 study (ASTIMS), comparing AHSCT vs Mitoxantrone with a MRI primary endpoint, is ongoing in Europe. Italy, probably for the longstanding collaborative relationship between the neurological and haematological community, is the country in Europe where the highest number of AHSCT in autoimmune disorders have been carried out. In the last nine years (1998-2007), 58 MS cases, who deteriorated in the year before transplantation of at least one point at EDSS in spite of the conventional therapy, have been transplanted using the same mobilizing (Cyclophosphamide 4gr/m2) and conditioning (BEAM -BCNU, etoposide, cytosine-arabinoside, and melphalan-) schedule. Out of these 58 cases, 21 were followed in a prospective study and the others were treated and followed by the same teams involved in the research program. The median follow up is now of 36.6 months. Out of the 58 cases, 33 were secondary progressive (SP) and 25 relapsing remitting (RR) forms. 56 cases are alive and 2 died, one for an unrelated cause and one for engraftment failure. The transplant related mortality of this series is therefore of 1.7%. Neutropenic fever was observed in the majority of cases in the days following the conditioning treatment, 13 had a sepsis and 6 a CMV reactivation Considering the 50 cases with a follow up of at least 6 months, evaluated with the EDSS scale, 22 improved (44%), 16 remained stable (32%), and 12 (24%) progressed. If the cases are however divided according to the clinical phase of the disease, in the SP form 7 improved (23%), 12 remained stable (40%), and 11 (37%) progressed, while in the RR cases 15 improved (75%), 4 remained stable (20%), and 1 (5%) deteriorated. If we consider the change of the EDSS in the 2 years following AHSCT the RR forms significantly behave better than the SP cases (p=0.011). The number of relapses, as well as the MRI enhancing activity, decreased after the procedure as compared to the year before therapy. These data clearly show that RR cases respond significantly better than SP cases to AHSCT, indicating the population of patients who have to be selected in the future for the design of prospective studies.