Stem cell transplantation results very similar to alemtuzumab

Is hematopoietic stem transplantation cheaper and more effective than alemtuzumab treatment? #MSResearch #MSBlog

"The following open-label study on non-myeloablative hematopoietic stem transplantation (aka as bone marrow stem cell transplant) is very encouraging and not too dissimilar to that found with alemtuzumab treatment in the mid to late 90s. If you use the procedure in early RRMS, when you still have reserve capacity, you better outcome with a high likelihood of becoming NEDA (no evident disease activity) and seeing an improvement in disability. Unfortunately, the results in SPMS are a familiar one (see excerpt below)." 

Excerpt from the paper: Scores on the EDSS did not improve significantly for patients with secondary progressive MS (n = 27), in those with a disease duration of longer than 10 years (n = 32), or in those with sustained peritransplant fever of greater than 38.5°C (n = 31). In the mixed-effects analysis, both the difference in duration of disease (>10 years vs ≤10 years) and type of disease (secondary-progressive MS vs relapsing-remitting MS) were associated with a significantly (P = .05) increased post-transplant EDSS score.

"These results are almost identical to alemtuzumab, which is why it is going to be very difficult to justify this procedure in the UK when alemtuzumab has a 1st-line license for active RRMS. The good news that in this study there were no deaths related to the procedure."

"This study confirms what we already know; early highly-effective treatment gives you the best option of becoming NEDA and having a confirmed improvement in your level of disability. If you wait too long then you miss out the benefits of early treatment. These results need to be put into context of end-organ damage and quality of life. I think we are entering an era when MSers will have the option of front loading risk for the maximum benefit from the more effective treatments. Delay taking on the risk of treatment for when your disease has progressed will be the real gamble; time is brain and you can't turn back the clock. In addition, all DMTs get less effective the longer you wait. I suspect all the critics of the early-effective approach will say well what about all those MSers who will turnout to have benign MS. The problem with this statement is that it is very difficult to call benign MS upfront; if you give MS sufficient time the number of MSers who turnout to have benign MS is very small. Our treatment aim should be to increase the odds of you having benign MS. Another point is that highly-effective therapies don't have to be risky; we can de-risk them and develop new therapies that are safer. That is our challenge; how can we give highly effective therapies as early as possible with very little risk to the individual? If we can crack this nut then we will see a massive impact."

"Other questions that needs answering is whether, or not, non-myeloablative hematopoietic stem transplantation is cheaper, and safer, than alemtuzumab therapy? May be a pragmatic comparator trial comparing these two approaches needs to be done? It would be in the interests of payer to fund this study as the treatment costs of DMTs continue to soar."

Burt et al. Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis. JAMA. 2015 Jan 20;313(3):275-284.

Background & importance: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability.

Objective: To determine the association of non-myeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS.

Design, Setting, and Participants: Case series of RRMSers (n = 123) or SPMSers (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014.

Interventions: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells.

Main Outcomes and Measures: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan.

Results: Outcome analysis was available for 145 MSers with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, −0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).

Conclusions and Relevance: Among RRMSers, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

CoI: multiple

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