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Autologous haematopoietic stem cell transplantation in multiple sclerosis: a meta-analysis
M.P. Sormani1, I. Schiavetti1, A. Signori1, P.A. Muraro2, R. Saccardi3, G. Mancardi4 1Department of Healt Sciences - Section of Biostatistics, University of Genova, Genova, Italy, 2Division of Brain Sciences, Imperial College London, London, United Kingdom, 3Haematology Department, Careggi University Hospital, Firenze, 4Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova and IRCCS AOU San Martino-IST, Genova, Italy
Background: Immunoablative therapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has been investigated for the past two decades to manage severe and treatment-refractory MS.
Objective: To quantitatively summarize all the published evidence about the efficacy of aHSCT on MS progression after transplant, to estimate transplant related mortality (TRM) and overall mortality (OM), and to evaluate the effect of patients' characteristics and transplant procedures on these outcomes.
Methods: We prospectively collected all the published studies of aHSCT in MS from 1995 to 2016; we included studies assessing aHSCT on any form of MS, collecting >=5 patients, reporting data on mortality and on clinical follow-up. We carefully excluded studies that were updates of previous records. Endpoints were TRM, OM over the first and the second year after transplant, rate of progression, defined as 1 EDSS point increase (0.5 if baseline EDSS>=5.5), and No Evidence of Disease Activity (NEDA) status at 2 years. A weighted meta-regression based on a Poisson model was run, assessing whether there were study specific characteristics with a relevant effect on TRM and progression.
Results: 17 studies including 887 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 1.9% (95%CI=1.2%,3.1%), the 1-year OM was 2.3% (95%CI=0.54%,3.2%), and OM during the second year after transplant was 0.9% (95%CI=0.4%,1.8%). No TRM was observed among the 325 patients transplanted after 2008 (6 studies), vs a TRM of 3.0% (95%CI=1.9%,4.9%,
p< 0.001) among the 562 patients in the 11 older studies. Studies with a proportion of RRMS patients>=40% (median value) had a TRM=0.5% (95%CI=0.1%,2.1%), while those with a proportion of RRMS< 40% had a TRM=3.0% (95%CI=1.8%,4.9%, p< 0.001). An older age and a higher baseline EDSS were also significantly associated to a higher TRM. Pooled rate of progression was 19.2% at 2 years (95%CI=11.9%,26.5%) and 30.5% (95%CI=18%,42.9%) at 5 years. Lower 2 year progression rate was significantly associated with higher proportions of RRMS patients (p=0.008) and with more recent year of transplant (p=0.008). The pooled proportion of NEDA patients at 2 years was 77% (95%CI=70%,84%).
Conclusion: The emerging evidence of the efficacy of this therapeutic approach in aggressive MS calls for a concerted action to plan a clinical trial defining its role with evidence level acceptable by the neurological community and regulators.
M.P. Sormani1, I. Schiavetti1, A. Signori1, P.A. Muraro2, R. Saccardi3, G. Mancardi4 1Department of Healt Sciences - Section of Biostatistics, University of Genova, Genova, Italy, 2Division of Brain Sciences, Imperial College London, London, United Kingdom, 3Haematology Department, Careggi University Hospital, Firenze, 4Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova and IRCCS AOU San Martino-IST, Genova, Italy
Background: Immunoablative therapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has been investigated for the past two decades to manage severe and treatment-refractory MS.
Objective: To quantitatively summarize all the published evidence about the efficacy of aHSCT on MS progression after transplant, to estimate transplant related mortality (TRM) and overall mortality (OM), and to evaluate the effect of patients' characteristics and transplant procedures on these outcomes.
Methods: We prospectively collected all the published studies of aHSCT in MS from 1995 to 2016; we included studies assessing aHSCT on any form of MS, collecting >=5 patients, reporting data on mortality and on clinical follow-up. We carefully excluded studies that were updates of previous records. Endpoints were TRM, OM over the first and the second year after transplant, rate of progression, defined as 1 EDSS point increase (0.5 if baseline EDSS>=5.5), and No Evidence of Disease Activity (NEDA) status at 2 years. A weighted meta-regression based on a Poisson model was run, assessing whether there were study specific characteristics with a relevant effect on TRM and progression.
Results: 17 studies including 887 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 1.9% (95%CI=1.2%,3.1%), the 1-year OM was 2.3% (95%CI=0.54%,3.2%), and OM during the second year after transplant was 0.9% (95%CI=0.4%,1.8%). No TRM was observed among the 325 patients transplanted after 2008 (6 studies), vs a TRM of 3.0% (95%CI=1.9%,4.9%,
p< 0.001) among the 562 patients in the 11 older studies. Studies with a proportion of RRMS patients>=40% (median value) had a TRM=0.5% (95%CI=0.1%,2.1%), while those with a proportion of RRMS< 40% had a TRM=3.0% (95%CI=1.8%,4.9%, p< 0.001). An older age and a higher baseline EDSS were also significantly associated to a higher TRM. Pooled rate of progression was 19.2% at 2 years (95%CI=11.9%,26.5%) and 30.5% (95%CI=18%,42.9%) at 5 years. Lower 2 year progression rate was significantly associated with higher proportions of RRMS patients (p=0.008) and with more recent year of transplant (p=0.008). The pooled proportion of NEDA patients at 2 years was 77% (95%CI=70%,84%).
Conclusion: The emerging evidence of the efficacy of this therapeutic approach in aggressive MS calls for a concerted action to plan a clinical trial defining its role with evidence level acceptable by the neurological community and regulators.