Transplant Promising as MS Therapy

Published: Jun 5, 2013

By  John Gever , Deputy Managing Editor, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

ORLANDO -- High-dose immunosuppressant therapy and autologous hematopoietic stem cell transplant (HSCT) induced durable freedom from relapses and MRI lesions in patients with multiple sclerosis, researchers reported here.

At evaluations performed 1 and 2 years after the procedure, patients showed no gadolinium-enhancing lesions on MRI scans, and only six of the 24 patients receiving the transplants experienced relapses, reported Richard A. Nash, MD, of Colorado Blood Cancer Institute in Denver, and colleagues.

In a poster presented at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, the investigators indicated that overall functional ability and quality of life were improved as well with the transplant procedure.

Immunosuppressant therapy with drugs and dosages high enough to be severely myelosuppressive, followed by HSCT, had been tested previously in patients with advanced, progressive MS, for which there is currently no broadly effective treatment. The results were disappointing, Nash and colleagues indicated, as "many patients continued to lose neurological function."

But it was unclear whether the lack of effect was because the treatment failed to suppress MS autoimmune activity or because the process of neurodegeneration had become independent of autoimmune mechanisms.

Since the latter seemed like the more likely explanation, Nash and colleagues tested a similar regimen in patients with relapsing-remitting MS, in which autoimmunity is widely believed to be the chief pathological process.

The 25 patients enrolled in the study had a median age of 38 and median duration of disease of 6.4 years. Median score on the Expanded Disability Status Scale (EDSS) was 4.5, indicating moderate disability. About 40% had gadolinium-enhancing lesions at baseline, including five patients with two or more each.

Participants first underwent stem cell mobilization with granulocyte colony-stimulating factor (along with cyclophosphamide in one patient who did not mobilize enough cells with G-GSF alone), with CD34 stem cells then collected.

Patients then received a high-dose immunosuppressant regimen similar to those used in cancer patients undergoing HSCT. Drugs included carmustine, etoposide, melphalan, and cytarabine given over a 6-day period. The collected stem cells (median 4.6 million/kg) were then reinfused.

One patient did not complete the procedure because of pulmonary embolism occurring during the mobilization phase.

In the remaining 24 patients, all but one had no gadolinium-enhancing lesions at the 6-month mark after the procedure, and no patients had such lesions after 1 and 2 years.

Mean T1 lesion volume remained unchanged through the 2-year evaluation. Mean T2 lesion volume declined by more than 0.5 mL at 6 months and by 0.9 mL at 2 years, relative to baseline.

Disability progression as well as relapses were rare through the first 2 years. About 90% were free of both clinical manifestations of MS. MRI disease activity was also seen in only two patients.

Overall event-free survival at 2 years -- taking into account both clinical and MRI disease activity -- was 82.8% (90% CI 65.0%-92.0%), the researchers indicated.

MS Functional Composite scores increased from a median of -0.21 at baseline to 0.22 after 2 years (P=0.012). Similarly, MS Impact Scale scores decreased by a median of 8.93 points from baseline at the 2-year evaluation (P=0.016).

Examination of circulating immune cells indicated that, 1 year after transplant, CD8-positive T-cell counts had returned to normal levels, whereas CD4-positive naive and memory T-cell counts remained depressed.

Nash and colleagues indicated that they planned to follow the cohort for 5 years. Preliminary data collected in this effort suggested a resumption of MRI disease activity in some patients after the 42-month mark. One patient died from MS-related causes after reaching 2 years in the study.

Serious adverse events during the HSCT procedure were common -- a total of 94 grade 4 events were recorded, although all but seven were either hematologic or gastrointestinal. Those seven events included depression, suicide attempt, hypokalemia, respiratory failure, and severely elevated alanine aminotransferase.