Hemopoietic Stem Cells Safe, May Reverse Neurologic Disability in RRMS

Susan Jeffrey

January 30, 2009

January 30, 2009 — Results of a phase 1/2 trial of autologous nonmyeloablative hemopoietic stem-cell transplantation show that the technique appears safe and is associated with stabilization and, in some cases, even reversal of neurologic disability in patients with relapsing-remitting multiple sclerosis (RRMS).

"This is the first study that has shown with an intervention or therapy that it's not just stabilization of disease but actual reversal of disability that has occurred," lead author Richard K. Burt, MD, from Northwestern University Feinberg School of Medicine, in Chicago, Illinois, told Medscape Neurology & Neurosurgery.

The caveat is that this was a phase 1/2 trial, he added, and the results of a phase 3 randomized trial will be required to confirm their findings. A phase 3 trial with participating centers in Canada, Brazil, and their own institution is already under way.

Their report is published online January 30 in Lancet Neurology.

"Resetting" the Immune System

Autologous hemopoietic stem-cell transplantation for MS was first done by Fassas and colleagues in 1997 and has now been used in many countries, the authors write. However, they note, it has previously been used mostly in secondary progressive MS, where it was not associated with improvements in disability, although stabilization of disease has been reported.

"The rationale behind autologous hemopoietic stem-cell transplantation in MS is to reset the immune system; that is, to produce new and self-tolerant lymphocytes from the hemopoietic stem-cell (immune stem-cell) transplant after chemotherapy-induced elimination of self-reactive or autoreactive lymphocytes," they write.

The process produces intense immune suppression, they note. Peripheral blood stem cells are first mobilized, using 2 g/m2 of cyclophosphamide followed by 10 µg/kg subcutaneous filgrastim, and then collected using apheresis after neutrophil recovery.

After 3 weeks, a conditioning regimen of 200 mg/kg of cyclophosphamide and 20 mg of alemtuzumab was given to remove self-reactive lymphocytes in 17 of the 21 patients included in this study. However, after the Food and Drug Administration reported that alemtuzumab was associated with the occurrence of immune thrombocytopenic purpura in some patients with MS, they switched alemtuzumab for 6 mg/kg of rabbit antithymocyte globulin given over 5 days in the final 4 patients.

At 36 hours after completion of the cyclophosphamide, the hemopoietic stem cells that had been collected were reinfused. Engraftment occurred on a median of day 9 after the infusion (range, 8 – 11 days), and patients were released on a mean of day 11 (range, 8 – 13 days)

A total of 21 RRMS patients were included in this study, 11 women and 10 men who had not responded to at least 6 months of interferon-beta therapy; despite treatment, eligible patients had 2 corticosteroid-treated relapses within the previous 12 months. Unlike previous trials of this strategy, patients were young, with an average age of 33 years (range, 20 – 53 years) and did not have severe disability. Primary outcomes of this phase 1/2 study were progression-free survival and reversal of neurological disability at 3 years after transplantation.

The researchers report that at an average follow-up of 3 years, 17 of the 21 patients (81%) had improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS).

After a mean of 37 months, progression-free survival was 100%, with all patients free from progression on the EDSS score, and 16 were free of relapses. Five patients (24%) relapsed but achieved remission with further immunosuppression.

In addition, statistically significant improvements were seen in neurological disability as measured by the EDSS score, neurological rating scale score, paced auditory serial addition test, and 25-foot walk, as well as in quality of life, measured using the SF-36 questionnaire.

Treatment was well tolerated, they note. One patient had diarrhea due to Clostridium difficile, and 2 patients had dermatomal zoster at 20 and 22 months after the procedure. Of the 17 patients who had received alemtuzumab, 2 developed late immune thrombocytopenic purpura that remitted to standard therapy.

The key, I think, is patient selection.

"Autologous nonmyeloablative hemopoietic stem-cell transplantation for patients with relapsing-remitting MS with active inflammatory disease and frequent exacerbations is a feasible procedure that not only seems to prevent neurological progression but also appears to reverse neurological disability," they conclude.

"The current Multiple Sclerosis International Stem Cell Transplant (MIST) trial is investigating patients with relapsing-remitting MS who have not responded to interferon therapy and are randomly assigned to autologous nonmyeloablative hemopoietic stem-cell transplantation or continued standard therapy."

"The key, I think, is patient selection," Dr. Burt said. "This won't work if you do it in progressive MS. You have to do it while it's still an inflammatory disease, not a neurodegenerative disease, which progressive MS is."

Clear Results

In an accompanying commentary, Gianluigi Mancardi, MD, from the San Martino Hospital, University of Genova, in Italy, points out that "the possibility for improvement after autologous hemopoietic stem-cell transplantation has been reported in other studies, although not as clearly as in the results of Burt and colleagues."

The toxicity of the conditioning regimen was "modest, if not negligible," Dr. Mancardi notes; however, relapses among the 5 patients after 6 to 16 months suggests that nonmyeloablative conditioning regimens may not be sufficient to eradicate inflammatory activity in the long term, he writes.

"The study by Burt and colleagues is, however, the first report of a prospective single-center trial that has used such a regimen in patients with MS, and the results imply that this is a valuable alternative to the transplant conditioning therapies used so far," Dr. Mancardi writes. More research is needed, he adds, to identify which conditioning regimen — either the so-called BEAM regimen of carmustine, etoposide, cytarabine, and melphalan, or cyclophosphamide and antithymocyte globulin — has the best efficacy and safety equipoise.

"Only a large, prospective, randomized study with a clinical end point and of patients who are unresponsive to the approved treatment but are still in the early phase of the disease will definitely resolve the question of the clinical efficacy of autologous hemopoietic stem-cell transplantation in patients with severe forms of MS," he concludes.

The study was funded by the division of immunotherapy at Northwestern University. Dr. Burt and colleagues report that they have no conflicts of interest. Dr. Mancardi reports that he has received honoraria for lecturing, travel expenses to attend meetings, and financial support for research from Bayer Schering, Biogen Idec, Sanofi-Aventis, and Merck Serono Pharmaceuticals.

Lancet Neurol. 2009; Published online January 29, 2009.

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