After three years of follow-up, 17 of 21 patients maintained at least a one-point improvement in a standard disability scale, Richard K. Burt, M.D., of Northwestern University, and colleagues reported online in The Lancet Neurology.
All patients were progression free at last follow-up, and 16 were relapse free.
"Autologous nonmyeloabalative hematopoietic 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," the authors concluded.
However, they noted that "these results need to be confirmed in a randomized trial."
Hematopoietic stem cell transplantation has been evaluated throughout the world as therapy for MS. However, the trials typically involved patients with late secondary-progressive disease, and most had no improvement in neurologic disability, the authors said.
"Neurological deficits during the late secondary-progressive phase of MS are mostly caused by neurodegeneration from axonal atrophy, for which no immune-based therapy, including hematopoietic stem cell therapy, has been effective for reversing the deficits," they noted.
In contrast, they continued, demyelination associated with relapsing-remitting MS is mediated by immune cells. Therapy emphasizes immune modulation to ameliorate inflammatory processes that damage the central nervous system.
Standard therapies aim to delay disease progression. Dr. Burt and colleagues sought to reverse neurologic disability with hematopoietic stem cell transplantation in patients who had not reached the largely irreversible neurodegenerative phase of the disease process.
Their study involved patients whose disease had not responded to immune modulation but was still in an active inflammatory state. The patients' median age was 33, mean baseline expanded disability scale score (EDSS) was 3.1, and median disease duration before transplantation was five years.
The patients received a median infused dose of hematopoietic stem cells of 11Â·40x106 CD34+ cells per kg, mobilized with 2 g/m2 of cyclophosphamide and 10Âµg/kg/d filgrastim (Neupogen).
The conditioning regimen for the cells consisted of 200 mg/kg cyclophosphamide and either 20 mg alemtuzumab (Campath) or 6 mg/kg rabbit antithymocyte globulin.
The primary outcomes were progression-free survival and reversal of neurologic disability three years after transplantation.
Engraftment of white cells occurred a median of nine days after transplantation, and hospital length of stay averaged 11 days.
One patient developed diarrhea caused by Clostridium difficile, and two patients had dermatomal zoster. Two of 17 patients treated with alemtuzumab developed late immune thrombocytopenic purpura that resolved with standard therapy.
Five patients relapsed but achieved remission again after immunosuppressive therapy.
After a mean follow-up of 37 months, 81% of patients had improved by at least one point on the EDSS.
As determined by EDSS scores, the patients had significant improvement in neurologic disability (P<0.0001).
Significant improvement also occurred in the neurologic rating scale (P=0.0001), paced auditory serial addition test (P=0.014), 25-foot walk (P<0.0001), and quality of life (P<0.0001).
In an accompanying commentary, Gianluigi Mancardi, M.D., of the University of Genova in Italy, noted that the conditioning regimen plays a major role in the success of hematopoietic stem cell transplantation.
He noted that the regimen used by Dr. Burt and colleagues caused "modest, if not negligible" toxicity.
The fact that five patients relapsed, suggested that "nonmyeloablative conditioning regimens might not be sufficient to eradicate inflammatory activity in the long term."
Despite the relapses, Dr. Mancardi continued, "the results imply that this [conditioning regimen] is a valuable alternative to the transplant conditioning therapies used so far."
| The authors reported no competing interests.
Dr. Mancardi reported having 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.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
Lancet NeurologySource Reference: Burt RK, et al "Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study" Lancet Neurol 2009; DOI:10.1016/S1474-4422(09)70018-3.
Lancet NeurologySource Reference: Mancardi G "Further data on autologous haemopoietic stem cell transplantation in multiple sclerosis" Lancet Neurol 2009; DOI:10.1016/S1474-4422(09)70018-3.