More Support for Stem Cell Therapy in Multiple Sclerosis

Megan Brooks

January 21, 2015

Nonmyeloablative hematopoietic stem cell transplantation (HSCT) can reduce disability and improve quality of life in patients with relapsing-remitting multiple sclerosis (RRMS), a new study suggests.

The new report focuses on a series of patients treated at a single center and followed for an average of 2.5 years.

HSCT is "clinically significantly impacting on our patients lives. All of our patients believe in this treatment; they are our biggest advocates," Richard K. Burt, MD, from Northwestern University Feinberg School of Medicine in Chicago, Illinois, noted an interview with Medscape Medical News.

"If you look at all the pharmacologic drug therapy, they're all approved on slowing progression or MRI lesion number or number of relapses. They're not approved for reversing disability. And no pharmacologic drug has ever improved quality of life but HSCT has done both," Dr Burt said.

In an article published January 20 in JAMA, Dr Burt and colleagues report clinical outcomes for 118 patients with RRMS and 27 with secondary progressive MS who underwent autologous HSCT using a nonmyeloablative conditioning regimen consisting of cyclophosphamide and either thymocyte globulin or alemtuzumab.

The investigators first reported on 21 of these patients in Lancet Neurology in 2009, reported at that time by Medscape Medical News.

Rebooting the Immune System

"Relapsing-remitting disease is an immune-mediated process," Dr Burt noted. "With this regimen, we knock the immune system down and stop the inflammation, and the stem cells regenerate the immune system in a noninflammatory environment — and when that happens you get recurrence of tolerance."

The primary outcome was reversal or progression of disability, as measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater. The researchers report that the EDSS scores 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).

Disability significantly improved (decrease in EDSS score of 1.0 point or more) in 41 patients (50%; 95% confidence interval [CI], 39% - 61%) at 2 years and in 23 patients (64%; 95% CI, 46% - 79%) at 4 years.

In contrast, in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I trial, which involved treatment-naive patients, and CARE-MS II trial, which enrolled patients previously treated with β interferon or glatiramer acetate, alemtuzumab only marginally reduced the risk for sustained accumulation of disability by 0.14 and 0.17 points on the EDSS, respectively, Dr Burt and colleagues point out in their article.

Their patients also experienced significant improvement in all secondary outcomes, notably the following:

  • Neurologic Rating Scale scores improved 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).

  • Median Multiple Sclerosis Functional Composite scores were 0.38 (IQR, –0.01 to 0.64) at 2 years (P < .001) and 0.45 (IQR, 0.04 to 0.60) at 4 years (P = .02).

  • Quality-of-life total scores on the Short-Form 36 improved from a mean of 46 (95% CI, 43 - 49) before transplant to 64 (95% CI, 61 - 68) at a median follow-up of 2 years after transplant (n = 132) (P < .001).

  • T2 lesion volume fell from median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) before HSCT 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).

One and Done

"Every parameter we looked all showed the same thing, marked and significant improvement," Dr Burt told Medscape Medical News. "And unlike standard therapy where you just keep treating forever or until they are failing it or have toxicity from it, this is a one-time treatment and they are off all therapy after it."

The Kaplan-Meier estimated relapse-free survival rates were 89% at 2 years and 80% at 4 years; progression-free survival rates were 92% and 87%, respectively, and disease activity-free survival rates were 80% and 68%, respectively.

But patient selection is important, the investigators note. In a post hoc analysis, the EDSS score did not improve in patients with secondary progressive MS or in those with disease duration longer than 10 years.

In the current case series, there were no treatment-related mortality and no early or late infectious cases of fungal, Pneumocystis jiroveci, cytomegalovirus, Epstein-Barr virus, or JC virus infection, the investigators report. Four patients developed late reactivation of dermatomal zoster, which was treated with oral acyclovir.

Posttransplant immune dysfunction (idiopathic thrombocytopenic purpura, hypothyroidism, and hyperthyroidism) occurred and was significantly more common with alemtuzumab (22.7%) than with antithymocyte globulin (6.9%).

Overall, said Dr Burt, HSCT has been "well tolerated in our patients. It's important to understand that this is nonmyeloablative, low-intensity stem cell therapy specifically designed for the immune system. These are not cancer regimens. The problem is that when people hear transplant, they think all transplants are the same and they are not all the same."

He said a randomized trial is in progress to confirm these observations.

Questions Remain

The author of an editorial published with the study says it is "noteworthy" that the 2-year disease-free survival rate in this study was nearly identical (82.8%) to that reported in the HALT-MS prospective study of 25 patients with relapsing-remitting MS.

"The disease-free survival rates with HSCT are also impressive compared with historical data from trials of other high-intensity regimens used for MS, such as natalizumab and alemtuzumab," writes Stephen L. Hauser, MD, Department of Neurology, University of California, San Francisco.

Dr Hauser says this study, coupled with other available evidence, allows several conclusions to be made with "reasonable confidence."

First, autologous HSCT does not appear to be effective for established progressive forms of MS and, "absent new data, additional trials of these protocols are probably not indicated for patients with progressive MS."

Second, immunosuppressive regimens that include HSCT appear to be effective against relapsing-remitting MS, at least over several years of observation.

"However, it is by no means clear that the beneficial effects result from the infusion of stem cells rather than from the conditioning regimen. Given the availability of highly effective FDA [Food and Drug Administration]-approved therapies against relapsing-remitting MS, it would seem reasonable to use these proven monotherapies in the clinical setting before considering complex HSCT regimens. Studies that delineate the role of HSCT specifically in improving outcomes relative to conditioning regimens alone are needed before this therapy should be deployed outside of the clinical research setting."

Dr Hauser says it's also important to remember that MS is a chronic disease that typically presents in young adults and that disability may take many years or decades to develop.

"To understand the role of any therapy for MS, and especially an intensive regimen with uncertain long-term risk, very long follow-up periods are required to meaningfully assess if the disease has indeed been rebooted over the long-term, and also to increase confidence that these therapies have not caused undue harm," he notes.

Financial support for the study was provided by the Danhakl family, the Cumming Foundation, the Zakat Foundation, the McNamara Purcell Foundation, and Morgan Stanley and Company. Dr Burt has disclosed no relevant financial relationships. A complete list of author disclosures appears with the original article. Dr Hauser reported serving on scientific advisory boards for Symbiotix, Annexon, and Bionure.

JAMA. 2015;313:251-253, 275-284. Abstract Editorial

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