Alicia Ault

June 06, 2016

NATIONAL HARBOR, Maryland — Most recent data from a small, phase 2 study of autologous hematopoietic cell transplantation for multiple sclerosis shows that two thirds of the patients had a sustained remission of disease 5 years after transplant.

Sixty-nine percent of patients met the primary endpoint of event-free survival.

"That's certainly much higher than any other treatment to this point," Michael K. Racke, MD, professor of neurology and neuroscience at Wexner Medical Center at The Ohio State University in Columbus, told Medscape Medical News.

Dr Racke is an investigator in the HALT-MS (High-dose Immunosuppression and Autologous Stem Cell Transplantation for Poor Prognosis Multiple Sclerosis) trial). The 5-year results were presented at two sessions here at the Consortium of Multiple Sclerosis Centers (CMSC) 2016 Annual Meeting by Richard A. Nash, MD, from the Colorado Blood Cancer Institute, and James Bowen, MD, medical director of the Multiple Sclerosis Center at the Swedish Neuroscience Institute, Seattle, Washington.

Interim 3-year results were previously reported in JAMA Neurology in February 2015.

The 5-year follow-up shows that the regimen "was highly effective for inducing sustained remissions of highly active relapsing remitting MS through the 5 years," said Dr Nash.

The regimen was highly effective for inducing sustained remissions of highly active relapsing remitting MS through the 5 years. Dr Richard A. Nash

Brain lesions detected by MRI were reduced; brain volume stabilized; and disability, measured by the Expanded Disability Status Scale (EDSS), slightly improved by an average of half a point, said Dr Bowen.

Patients also were largely functionally stable according to several measures, including the Multiple Sclerosis Functional Composite assessment, he said.

And, at the end of the 5 years, none of the patients in remission were taking maintenance therapy.

Transplant Did Not Work for All

Seven of the 24 patients with relapsing-remitting MS who received a transplant had an event that disqualified them from being considered a success. Two had an EDSS increase of 0.5 points or more, 3 had a clinical relapse, and 2 met the MRI criteria for progression of disease.

Individuals were eligible for the prospective, open-label, single-group study if they had MS for less than 15 years, an EDSS score of 3.0 to 5.5, and had two or more relapses within 18 months of the trial with an EDSS increase of 0.5 points or more, or one relapse with an EDSS increase of 1 point or greater and one separate event with gadolinium-enhancing lesions.

The goal was to find patients who had attacks severe enough to create symptoms, said Dr Bowen.

Patients also had experienced treatment failure with at least one prior therapy; interferon β-1a failed in 22 patients and glatiramer acetate failed in 18 patients. Other previous therapies included natalizumab, mitoxantrone, and interferon β-1b.

Before transplant, patients were treated with granulocyte colony-stimulating factor (G-CSF) and prednisone to mobilize CD34 cells for transplant. The cells were then selected out. All were then given the high-dose immunosuppressive regimen known as BEAM plus antithymocyte globulin, which began 6 days before transplant. BEAM includes bis-chloroethylnitrosourea, etoposide, arabinofuranosyl cytidine, and melphalan. On day 0, patients received their autograft, and post-transplant, they were given G-CSF starting on day 5 until the absolute neutrophil count was greater than 500 cells/μL. To head off engraftment syndrome and MS flare-ups, patients were started on prednisone, 0.5 mg/kg per day from day 7 to 21, and then tapered off over 2 weeks.

The regimen did lead to multiple adverse events: 399 overall, with 66 serious adverse events. Two patients attempted suicide, one had a pulmonary embolism, and another had respiratory arrest.

The 5-year relapse-free survival rate was 86.9% (90% confidence interval [CI], 68.7% - 94.5%). Ninety-one percent (90% CI, 73.7% - 97.1%) of patients had no progression of disease at the 5-year point; the 2 patients who did progress did so 2 years after transplant.

Overall, 3 patients died, giving an overall survival rate of 86%. One died of MS progression 2 years after transplant. Another patient died of anoxic encephalopathy 3 years after transplant, and another had cardiorespiratory arrest 4 years after transplant.

The probability of freedom from disease activity detected by brain MRI was 88.2% (90% CI, 67% - 96.2%). Disease burden — as measured by T2-weighted lesion volume on MRI — was significantly reduced 6 months after transplant and was sustained over the study, with a median change of –1.208 mL (P < .001). T1 lesion volume, however, increased, with a median change of 0.094 mL (P = .041). This may have been a result of T2 volume decrease, said Dr Nash.

Are Benefits Worth Risks?

Fred Lublin, MD, Saunders Family Professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, New York, asked Dr Nash, why, given the risks, transplant should be considered — and for which patients.

Dr Nash said that as a transplant surgeon, he was interested in seeing the procedure succeed, but he acknowledged the potential downsides, including the possibility of secondary malignancies. Although "the risk appears to be very small," he said, it still means that "patients have to be counseled about the risk."

Overall, in the study, "We wanted to show that patients would have to have very high degree of response to take on the risks of transplant," said Dr Nash.

But, he noted, multiple therapies had failed in the patients in the trial, and the patients were at high risk for progression. Noting the 70% remission rate in the study, he said, "If you look at other therapies, not transplant therapies, the results are not as good," said Dr Nash, citing the 38% to 48% success rate with current therapies.

"It's not for everybody," said Dr Bowen, adding that it's most appropriate for patients "with extremely aggressive disease."

With 30% of patients still having evidence of disease activity, the investigators discussed whether those individuals should be offered maintenance therapy. That has not happened. "That's an investigational question," said Dr Nash.

However, he said, "It would be difficult to demonstrate that you could improve from 70% disease-free survival to something higher."

The study was funded by the National Institute of Allergy and Infectious Diseases and conducted by the Immune Tolerance Network. Dr Nash has disclosed no relevant financial relationships. Dr Racke disclosed that he received consulting fees and grant and research support from Genentech and Novartis and research support from the National Multiple Sclerosis Society.

Consortium of Multiple Sclerosis Centers (CMSC) 2016 Annual Meeting: Abstract DX05. Presented June 2, 2016.

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