Medicine & Research

Updates by the Pharmacist HALT-MS Trial

By Ellen Whipple, BS, Pharm.D.

“Updates by the Pharmacist” spotlights the latest significant research on MS medications as well as pharmaceutical issues significant to MS care. No endorsement is implied.

Data shows the currently approved disease-modifying drugs decrease the number and severity of relapses in patients with relapsing-remitting multiple sclerosis, but do not entirely eliminate them. Consequently, many patients with relapsing-remitting multiple sclerosis experience relapses, disease progression, and accumulated neurological disability while receiving these medications. Three year data from the Phase II, multicenter HALT-MS trial suggested treatment with high-dose immunosuppressant therapy followed by autologous hematopoietic stem cell transplant may improve patient outcomes (beyond what the currently approved disease-modifying drugs can offer) by inducing sustained remissions.
High-dose immunosuppressant drugs: high-doses of drugs that suppress or reduce the strength of the body’s immune system 

Autologous Hematopoietic Stem Cell Transplant: stem cell transplants that utilize the patient’s own stem cells
Three-Year Findings

The purpose of the HALT-MS study was to determine the effectiveness of high-dose immunosuppressant therapy (using carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin) followed by autologous hematopoietic stem cell transplant in patients with multiple sclerosis. In the study, patients received high-dose chemotherapeutic drugs that suppressed the immune system followed by blood-forming (hematopoietic, CD34+) stem cells, which were collected individually from the patients prior to the administration of the high-dose chemotherapeutic drugs. The transplantation of the autologous hematopoietic stem cells were necessary to prevent the long and prolonged periods of low blood cell counts that occur after the administration of high-dose chemotherapy. After receiving the high-dose immunosuppressant therapy and the hematopoietic stem cell transplant, patients were not given additional disease-modifying drugs.

Twenty-five patients were enrolled in the HALT-MS study. Final result will be available after five years of treatment. Three year results were recently published for 24 patients. These results are available in the December 2014 issue of the Journal of the American Medical Association Neurology which is available online.

While this study is still ongoing, it is no longer recruiting patients.

The majority of patients were diagnosed with multiple sclerosis during the last 15 years. All patients experienced clinical relapse with loss of neurological function while receiving currently approved disease-modifying therapies in the 18 months prior to enrollment.

The primary endpoint of this study was event-free survival (survival without death or disease progression from confirmed loss of neurological function, clinical relapse, or new lesions on MRI). At three years, event-free survival was 78.4 percent. Other endpoints in the study included EDSS progression-free survival and clinical-relapse free survival. At three years, progression-free survival was 90.9 percent, and clinical-relapse free survival was 86.3 percent. In addition, EDSS scores, MS Functional Composite Scores, and MS Impact Scale quality-of-life scores were also improved.

According to the authors of the study, “Adverse events were consistent with expected toxic effects associated with high-dose immunosuppressant therapy followed by autologous hematopoietic stem cell transplant.” These toxicities included both Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 events (severe adverse events) and CTCAE Grade 4 events (life-threatening or disabling events). More specifically there were 130 CTCAE Grade 3 events and 94 CTCAE grade 4 events!
Hope or Hype?

The three-year efficacy results were very impressive, especially since high-dose immunosuppressant therapy followed by autologous hematopoietic stem cell transplant was a one-time treatment. If the four-year and five-year data are consistent with these findings, larger studies will still be needed to confirm the results. If these findings are confirmed in larger studies, high-dose immuno-suppressant therapy followed by autologous hematopoietic stem cell transplant may become a potential therapeutic option for some patients with relapsing-remitting multiple sclerosis, particularly those who have not responded to the FDA-approved therapies.

The toxicity profile of the high-dose immunosuppressant therapy is the most concerning factor. During the three years of this trial, the 24 patients experienced more than 200 CTCAE Grade 3 and 4 events. These toxicities are generally not seen with the first-line injectable disease modifying drugs. The long-term effects of the high-dose immunosuppressant therapies will also need to be considered. For example, many immunosuppressant therapies have been linked to blood cancers, specifically acute myeloid leukemia and myelodysplastic syndromes, and reactivation of latent viruses. To fully understand the long-term effects of the high-dose immuno-suppressant therapy, patients will need to be monitored for many years after the study is completed. 

So, for now, the jury is still out. Stay tuned. 

Ellen Whipple has been a medical advisor with the MSF since 2002. She is a clinical pharmacist employed as a medical affairs specialist, as well as an assistant clinical professor at the University of Georgia. She received her Doctorate of Pharmacy degree from the University of Georgia College of Pharmacy in 1994 and was later employed at the Shepherd Center and Children’s Healthcare of Atlanta. Ellen is an active member of the Georgia Society of Health System Pharmacists. She has also served on the Pharmacy Advisory Committee for the Department of Community and Health.