PracticeUpdate Neurology February 2019

EDITOR’S PICKS 6

Effect of Nonmyeloablative HSCT vs Continued Disease-Modifying Therapy on Disease Progression in Relapsing–Remitting MS JAMA: The Journal of the American Medical Association Take-home message • The authors of this small trial randomized 110 patients with relapsing–remitting mul- tiple sclerosis (MS) who had two or more relapses while receiving disease-modifying therapy (DMT) in the prior year to receive either nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus cyclophosphamide and antithymocyte globulin or DMT of higher efficacy or a different class than previously taken. After a median follow-up of 2 years, disease had progressed in 3 patients in the HSCT group and 34 patients in the DMT group. Furthermore, in the first year, disability scores improved in the HSCT group but worsened in the DMT group. • In patients with relapsing–remitting MS, nonmyeloablative HSCT appears to be more effective for slowing disease progression than DMT.

COMMENT By Erin Longbrake MD N onmyeloablative hematopoietic stem cell therapy (HSCT) has been emerging as an effective therapy for aggressive, relapsing multiple scle- rosis (MS). Several case series and a phase II clinical trial reported decreases in relapses and improvement in neuro- logic disability after HSCT, 1,2 but questions about safety and relative efficacy com- pared with standard immunomodulatory treatments remained. In this article, Burt and colleagues pro- vide initial findings for the MS International Stem cell Transplant (MIST) trial. In this open-label trial, patients with highly active, relapsing MS were randomized to either HSCT or standard immunomodulatory medications. A variety of immunomodu- lators were utilized, including natalizumab as well as injectable and oral medications. Most experts will agree that these immu- nomodulators have wide-ranging efficacy for MS, with natalizumab typically recog- nized as more efficacious. Among the 55 patients randomized to pharmacologic immunomodulation, 21 were prescribed natalizumab. HSCT was performed using autologous hematopoietic stem cells after immunoablation with pulse cyclophospha- mide and antithymocyte globulin. Patients receiving HSCT had significantly longer times to disability progression and relapse

than patients receiving standard immu- nomodulation, with a large effect size (eg, 9.7% of HSCT patients had disease progression at 5 years compared with 75.3% of patients on standard immuno- modulation). This was true even when natalizumab-treated patients were con- sidered separately in a subgroup analysis. There were no deaths, and infectious complications occurred in both treatment groups. Larger studies will be needed to assess the relative risk of HSCT compared with traditional immunomodulation. It is important to note that patients in the HSCT arm received pulse cyclo- phosphamide as immunoablation. Pulse cyclophosphamide has been long rec- ognized as an effective treatment for MS, although it is not widely used due to long-term safety concerns (eg, late malignancies). 3 Longer follow-up data will be necessary to determine whether malignancy is increased in MS patients receiving HSCT. It will also be important to compare HSCT with best-available immunotherapy, as the variable effica- cies and mechanisms of action for the immunomodulators utilized in this trial limit interpretability. A clinical trial compar- ing HSCT with alemtuzumab is recruiting (Clinicaltrials.gov NCT03477500) and will provide more definitive data about the

relative efficacy of HSCT versus other highly effective treatments. Available data suggest that HSCT is effective for relapsing, but not progressive MS, limit- ing its scope of use. HSCT also remains experimental, used at limited MS centers or in the context of clinical trials. Finally, it should be noted that HSCT is synony- mous with bone marrow transplantation and does not equate with using stem cells to replace nerves and/or myelin that have been previously destroyed by MS, a dis- tinction that is sometimes not appreciated by the public. References 1. Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 2015;313(3):275-284. 2. Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing- remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol 2015;72(2):159-169. 3. Weiner HL, Hauser SL, Hafler DA, et al. The use of cyclophosphamide in the treatment of multiple sclerosis. Ann N Y Acad Sci 1984;436(1):373-381. Dr. Longbrake is an Assistant Professor in the Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut.

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