By Jai S. Perumal, MD
Assistant Professor of Neurology,
Weill Cornell Medical College

Dr. Perumal is on the speakers bureau for Biogen Idec, Teva Pharmaceuticals, Genzyme Corp., and Acorda Therapeutics.

SYNOPSIS: Interim analysis at 3 years post-treatment of a study of high-dose immunosuppression and autologous hematopoietic stem cell transplant for relapsing remitting-multiple sclerosis demonstrates sustained disease control but also shows potential risks associated with this treatment.

SOURCE: Nash RA, 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;72:159-169.

Relapsing-remitting multiple sclerosis (RRMS) is characterized by a predominantly inflammatory early phase with a transition to a largely neurodegenerative secondary progressive phase. Immunomodulating treatment works best in the relapsing phase with limited benefit in the secondary phase. At present, there are 10 FDA approved treatments for relapsing MS. Each of these has varying levels of efficacy and immunosuppressive effects and their own unique benefits/risk profile. However, despite the availability of these multiple medications, many patients remain treatment refractory. Moreover, these treatments (with perhaps the exception of alemtuzumab) need to be continued to maintain disease control, raising the issues of compliance and potential risk of side effects/adverse events associated with their continuous use. Hence, a potent short-term treatment that induces sustained long-term benefit is of immense interest in the treatment of MS. Autologous hematopoietic stem cell transplantation has been explored for MS for several years. Based on data from these early pilot trials, it appears that it can have a significant benefit in relapsing MS but not have a meaningful benefit in progressive MS. Taking into consideration these findings, the present study was designed.

High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, single-arm, 5-year study. Eligible subjects were RRMS patients between 18-60 years of age, who had expanded disability status scale (EDSS) of 3 to 5.5 at baseline, disease duration < 15 years, and at least two relapses in the preceding 18 months. Peripheral blood stem-cell mobilization was achieved with filgrastim. High-dose BEAM chemotherapy regimen included carmustine, etoposide, cytarabine, and melphalan. Oral prednisone was administered during mobilization to reduce risk of relapses and during stem cell transplantation. Clinical evaluations including EDSS, Multiple Sclerosis Impact Scale, and MS Functional Composite were performed at baseline, months 6 and 12, and annually thereafter. Between annual visits, patients were contacted by phone and, in the event of neurologic symptoms, they were brought in for an evaluation. Brain MRI was performed at screening, week 6, month 6, month 12, and annually thereafter.

Twenty-four patients received high-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HDIT/HCT). The median disease duration was 4.9 years and median EDSS was 4.5. The primary study endpoint was the time-to-treatment failure defined by death from any cause, or disease progression as evidenced by increase in EDSS, relapse, or two or more gadolinium-enhancing or new T2 lesions on brain MRI a year or more after HDIT/HCT. At 3 years, the probability of event-free survival was 78.4%. EDSS improved after HDIT/HCT with a median change of -0.5 at 3 years. One patient had a relapse during mobilization. Within 3 years, none of the patients developed gadolinium-enhancing lesions other than one patient who was non-complaint with prednisone prophylaxis during mobilization and had an MS relapse associated with gadolinium-enhancing lesions. Brain volume between baseline and month 6 was decreased but appeared to have stabilized afterward. All patients experienced a grade 3 or 4 adverse event, which is severe, life-threatening, or disabling, as defined by the National Cancer Institute Common Terminology Criteria for Adverse events. Most of these were expected hematological/gastrointestinal or infectious events and were reversible or treatable. There were two deaths. One death was due to disease progression at 2.5 years post HDIT/HCT and another was due to worsening pre-existing asthma at 3.5 years. Severe disease progression and death following hematopoietic stem-cell transplantation has been reported elsewhere as well.

COMMENTARY

This small, single-arm study demonstrates that high-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation can have sustained significant benefit in RRMS. However, it also highlights the risks associated with this treatment. The study also has limitations including a small number of patients, open-label nature, unblended evaluation, and the infrequent follow-up visits. Based on these preliminary results, it appears to be an option worth further exploration for highly active MS. However, when considering its potential role in this population, one would need to weigh its benefits vs risks against currently FDA-approved agents that would generally be considered for highly active MS, especially natalizumab and alemtuzumab. We will learn further about the long-term outcome from immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation at the completion of this study after a total of 5 years of follow-up.