More Promising Data on Stem Cell Transplant for MS

Megan Brooks

February 13, 2015

Autologous hematopoietic stem cell transplant (AHSCT) proved "unequivocally" superior to mitoxantrone in reducing imaging evidence of disease activity in patients with multiple sclerosis (MS) refractory to conventional therapy in a phase 2 randomized controlled trial.

Over 4 years, patients who received AHSCT experienced 79% fewer new T2 lesions compared with patients receiving mitoxantrone. Differential treatment effects in favor of AHSCT were also seen for gadolinium-enhancing (Gd+) lesions.

The Autologous Haematopoietic Stem Cell Transplantation trial in MS (ASTIMS) study findings "strongly support phase 3 studies with primary clinical endpoints," Giovanni Mancardi, MD, from the University of Genova in Italy, and colleagues conclude.

The study was published online February 11 in Neurology.

Promoting Tolerance

The rationale for AHSCT in MS is to reset the immune system and induce a prolonged tolerance toward self-antigens.

Participants in the ASTIMS study included 21 patients with secondary progressive or relapsing-remitting MS, who had a worsening in the last year on the Expanded Disability Status Scale (EDSS) despite conventional therapy (interferon-β, glatiramer acetate, or immunosuppressive therapy), plus one or more Gd+ areas on MRI.

Nine patients were randomly allocated to intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and antithymocyte globulin) followed by AHSCT and 12 to 20 mg of mitoxantrone every month for 6 months.

The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization; secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression.

Patients in the AHSCT group developed a median of 2.5 T2 lesions (mean, 2.75; range, 0 - 8) over 4 years compared with 8 lesions (mean, 12.75; range 2 – 34) in the mitoxantrone group (rate ratio, 0.21; 95% confidence interval [CI], 0.10 - 0.48; P = .00016).

None of the patients who received AHSCT had new Gd+ lesions during follow-up, whereas 56% of patients treated with mitoxantrone had at least one Gd+ lesion.

AHSCT also significantly reduced the annualized relapse rate compared with mitoxantrone (0.19 vs 0.6; rate ratio, 0.36; 95% CI, 0.15 - 0.88; P = .026).

There was no significant between-group difference in the progression of disability; at the end of follow-up, progression occurred in 48% of patients in the mitoxantrone group and 57% in the AHSCT group (log-rank test P = .50). There was also no between-group difference in EDSS change over the study period. However, the researchers say the lack of differences in disability progression and EDSS scores is partly explained by the low power of the study to detect such differences.

The incidence and relevance of adverse events and severe adverse events were in the "expected range and similar to the data reported in the literature," they note. There were no deaths or late severe adverse events.

"More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it's very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments," Dr Mancardi said in a statement.

First RCT-Level Evidence

Paolo A. Muraro, MD, PhD, from the Division of Brain Sciences, Imperial College London, United Kingdom, author of an editorial published with the study, told Medscape Medical News the study "adds the first randomized controlled trial (RCT)-level evidence of efficacy of AHSCT above standard treatment on MRI lesions, a surrogate measure of inflammation in the brain."

Dr Muraro said AHSCT "clearly has the potential" to become standard therapy for refractory MS, "but it has proven difficult to gain adequate evidence. Unlike patented medications, this therapeutic approach did not benefit from support from the pharmaceutical industry.

"The complexities of this type of intervention and the lack of support have hindered its development. I hope that health authorities will take a keener interest in looking at whether AHSCT could complement the existing treatment options for MS by providing a therapy for people affected by highly active forms of MS, particularly those that do not respond to standard therapy," Dr Muraro said.

For now, AHSCT remains an unlicensed therapy for MS and more work is needed to define its clinical indication, Dr Muraro notes in his editorial. A phase 3 trial comparing AHSCT using a lower-intensity nonmyeloablative immunosuppressive regimen to standard drug therapy is now underway (ClinicalTrials.gov identifier: NCT00273364).

More recently, consensus was reached on the design of a phase 3 trial comparing AHSCT using an intermediate-intensity regimen against the "best available," approved, highly active therapy, including natalizumab, fingolimod, and alemtuzumab.

Dr Muraro thinks the study by Mancardi and colleagues "will raise interest and catalyze activities to move forward with the new trial."

The study was supported by the Italian Multiple Sclerosis Foundation.

Neurology. Published online February 11, 2015. Abstract Editorial

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