FitzGerald, Susan
doi: 10.1097/01.NT.0000520472.01901.8f
Features
Two new reports on autologous hematopoietic stem cell transplantation (AHSCT) for multiple sclerosis (MS) indicate that the therapy may benefit some MS patients. But whether AHSCT is viable is a matter of debate among some MS experts, who contend that the regimen could be toxic, leading to infection and death.
Two new reports on autologous hematopoietic stem cell transplantation (AHSCT) for multiple sclerosis (MS) indicate that the therapy may benefit some MS patients. But whether AHSCT is viable is a matter of debate among some MS experts, who contend that the regimen, which uses a combination of cytotoxic drugs to ablate the immune system in an attempt to reset the immunological memory could be toxic, leading to infection and death.
Experts who were not involved with the study said that newer, second generation MS drugs may be safer options, though few studies comparing the method with these drugs have been undertaken.
The first new report, published in the April 28 online edition of Neurology, provided a meta-analysis of 15 studies involving 764 MS patients who underwent AHSCT. The report found that the risk-benefit profile of the therapy makes it best suited for patients who have aggressive, relapsing-remitting MS who have not yet become highly disabled.
The second report, which provided long-term outcomes for 281 MS patients from an observational, retrospective study, found that almost half of the patients remained free from neurological progression five years after AHSCT. The study, published in the April edition of JAMA Neurology, reported that younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS [Expanded Disability Status Scale] score were factors associated with better outcomes.
Maria Pia Sormani, PhD, professor of biostatistics at the University of Genoa in Italy, and lead author of the report in Neurology, told Neurology Today that skepticism about the treatment approach is likely due to multiple factors.
MS is not a lethal disease, and this procedure is very invasive and has a non-negligible mortality risk, said Dr. Sormani, who also was a study author on the JAMA Neurology study. The lack of data from a rigorous clinical trial of AHSCT for MS has also been problematic.
To gain a clearer picture of what the current evidence shows, her team's meta-analysis pooled data from 15 studies, mostly open label, from January 1991 to July 2016. The researchers found that treatment-related mortality (TRM) declined during the period covered by the review, likely a result of improvements in transplant techniques, more clinical experience, and better patient selection, Dr. Sormani said. Overall TRM was 2.1 percent, but after 2005 it was 0.3 percent.
The meta-analysis found that the rate of disease progression in patients was 17.1 percent at two years following AHSCT and 23.3 percent at five years. The analysis also found that 83 percent of patients had no evidence of disease activity (NEDA) at two years, and 67 percent had no evidence at five years. Doing the transplant earlier, before the patient develops much disability seems advantageous, Dr. Sormani said.
The meta-analysis had the usual limitations of such reviews, she noted. The original studies were not all designed or executed in the same way, patient selection and study methodology were not uniform, and transplant techniques and protocols varied.
Even with advanced immunotherapy, such as natalizumab or alemtuzumab, only 32-39 percent maintained NEDA at two years in the phase II clinical trials, wrote Joachim Burman, MD, PhD, of Uppsala University in Sweden and Robert Fox, MD, of the Cleveland Clinic, in the editorial accompanying the paper. They agreed with the research team that the approach is more likely to benefit those with RRMS, not those with progressive forms of MS.
The report in JAMA Neurology included data on 281 patients from 25 centers who underwent AHSCT between January 1995 and December 2006. Seventy-eight percent of the patients had progressive forms of MS. The median follow-up was 6.6 years, with some patients followed for as long as 16 years
The five-year probability of progression-free survival was 46 percent and overall survival was 96 percent, the research team headed by Paolo A. Muraro, MD, a clinical reader in neuroimmunology and deputy head of the division of brain sciences at Imperial College London.
Factors associated with neurological progression after transplant were older age, progressive (versus relapsing) form of MS, more than two previous disease-modifying therapies, and higher baseline EDSS scores.
An accompanying editorial coauthored by Michael K. Racke, MD, professor of neurology and neuroscience at Ohio State University, noted that while the transplant therapy appears to favor those with RRMS with aggressive breakthrough disease, it Z
Dr. Racke told Neurology Today in an interview that he is currently planning a multicenter randomized controlled trial, which will include 55 RRMS patients in each arm. The study will compare AHSCT using what is considered a medium-intensity myelobation (BEAM) technique to best available drug treatment (whatever treatment a given patent is taking).
Dr. Racke said one question that needs to be further considered is, When is the best time to do a transplant? He said drug therapies need to be given a chance, but earlier might be better than later because once you start getting damage to the central nervous system we can't really fix that.
He said the upcoming trial will likely include cost analyses to compare the cost of long-term drug therapy to the mostly upfront costs of transplant, which is thought to be a once-and-done procedure.
Commenting on the two studies, Timothy L. Vollmer, MD, FAAN, professor of neurology at University of Colorado Health Sciences Center and co-director of the Rocky Mountain MS Clinic at Anschutz Medical Center, expressed skepticism about using AHSCT, particularly in light of effectiveness of the second-generation MS drugs that have come into use, such as natalizumab for JCV negative patients, fingolimod, dimethyl fumarate, and ocrelizumab.
Dr. Vollmer said most studies of AHSCT for MS were done before the newer drugs were available. He is concerned about both the immediate risks (infection, death) and potential long-term consequences of undergoing a toxic regimen to eradicate the immune system, noting that it could cause brain atrophy, already a concern for MS patients.
Mark S. Freedman, MD, professor of neurology at the University of Ottawa, senior scientist at The Ottawa Hospital Research Institute, and director of the Multiple Sclerosis Research Unit at The Ottawa Hospital-General Campus, is more sanguine about the procedure.
In a 2016 report in The Lancet, he and a colleague described outcomes for 24 RRMS patients who underwent transplant after failing drug therapy. Dr. Freedman said he has done about 25 more cases since the study came out. He said no patient has experienced a clinical relapse following transplant, none has evidence of new brain lesions on MRI, and none requires disease-modifying medication.
Dr. Freedman said there is a high level of interest in the procedure among MS patients, but it isn't for everyone. Patients must be carefully selected for the procedure, and undergo an aggressive chemotherapy regimen to eliminate their immune system, he said, noting that those with a high inflammatory component to their disease are ideal. Harvested stem cells undergo a special sorting technique at his center before being infused into the body to make sure that no previous disease-causing lymphocytes are accidentally included.
We're taking away immunologic memory, Dr. Freedman said. The new immune system is learning all over again what it should and shouldn't be doing.
He said that while the procedure is only done in patients who have not fared well with drug therapy, the best timing for this treatment would be as early as possible, when disability is minimal.
Probably doing it within five years from the onset of illness would give the optimal results, he said.
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Is Autologous Heamatopoietic Stem Cell Transplantation Still Viable for MS? - LWW Journals