Immunoablative therapy followed or not by autologous hematopoietic stem cell transplant has been investigated for 20 years in a scenario where there are no approved medications that effectively prevent, reverse, or stabilize secondary progressive, primary progressive, or some patients with very aggressive RR multiple sclerosis who do not respond to conventional DMT. The hypothesis is that intense immunosuppression causes an immune reset, with a better control of disease related cells. A PubMed search retrieved 140 articles published between 1995 and 2016; 122 were excluded. A final set of 15 studies of aH stem cell transplantation for the treatment of MS was analyzed, including 764 transplanted patients, contributing information on 2,680 patient-years.
It is difficult to compare outcomes of autologous transplants with clinical trials of drugs for MS, because the population has much more aggressive or advanced forms/stages of MS. So, a rate of progression of 17% after 2 years from transplant is generally higher than in treated arms of trials in RRMS or the 13% in patients treated with alemtuzumab, but it was 20% in patients treated with interferon [IFN]–b-1a in the Comparison of Alemtuzumab and Rebif trial. But it is much lower than in trials in SPMS, when after 2 years it was around 45% in patients treated with IFN-b-1a or placebo.
The largest contribution to disease activity events in transplanted patients comes from disability progression, rather than relapses or MRI activity, similar to what is typically observed in patients with RRMS treated with DMTIn their study, Atkins et al detected a disappearance of relapse and MRI activity after aH stem cell transplant up to 6 years after the procedure. This observation is confirmed by the very high proportion of NEDA patients over time that was estimated by pooling the studies reporting this information during follow-up: patients with NEDA were 83% after 2 years and 67% after 5 years, proportions much higher than those reported for all the most efficacious drugs in published clinical trials. This reinforces the recently reported results comparing the proportion of NEDA in 2 aH stem cell transplantation studies with that achieved by all the other drugs. The risk of TRM is the other side of the coin and it represents one of the reasons why the neurologic community is reluctant to consider this therapy, perceiving this risk as unacceptably high. In this meta-analysis, the TRM, defined according to the hematologists’ definition as mortality within 100 days from transplant, was 2.1%, and there was no additional mortality during the first year after transplant. In the aH stem cell transplant setting, a clinically relevant hematopoietic and immunologic recovery is generally completed within the first 6 months and therefore no adverse events are expected beyond this timeframe, as opposite to the allogeneic setting, where chronic graft-versus-host disease may result in adverse events also in the intermediate or long term.
However, this overall rate of death must be looked at more carefully; in fact, subgroup analysis shows that TRM is close to zero in studies including patients who were younger, with RRMS rather than SPMS, with a lower baseline EDSS, and performed in more recent years, suggesting that patient selection and transplant care may significantly influence mortality. Moreover, in the last update of the EBMT Registry, just 1 death was recorded out of 232 procedures in patients with MS reported to the EBMT Registry after 2012 (Dr. Saccardi, personal communication, 2016).
Maria Pia Sormani et al (full text abstracted by Dr Paulo R M de Bittencourt on 3.05.2017)
Published in Neurology April 28, 2017 as 10.1212/WNL.0000000000003987