Paper: Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

BMT Tandem "Scientific" Meeting

Ballroom I-J (Salt Palace Convention Center)

Richard Nash, MD , Fred Hutchinson Cancer Research Center, Seattle, WA

George J. Hutton, MD , Neurology, Baylor College

Michael Racke, MD , Ohio State University

Uday Popat, MD , UT MD Anderson Cancer Center, Houston, TX

Steven M Devine, MD , Division of Hematology, The Ohio State University, Columbus, OH

George Georges, MD , Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, WA

Linda Griffith, MD, PhD , Dait, Niaid, Nih, Bethesda, MD

Paolo A. Muraro, MD, PhD , Experimental Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom

Harry Openshaw, MD , City of Hope

Peter Sayre, MD , University of California San Francisco

Olaf Stuve , University of Texas Southwestern

Douglas Arnold, MD , McGill University

Meagan Spychala, DrPH , Rho Federal Systems Division, Inc

Noha Lim, PhD , Immune Tolerance Network

Sachin Malhotra, PhD , Immune Tolerance Network

Deborah Phippard, PhD , Immune Tolerance Network

Annette Wundes, MD , University of Washington

George H Kraft, MD , University of Washington

James D Bowen, MD , University of Washington

A phase II clinical trial of high-dose immunochemotherapy (HDIT; BEAM/antithymocyte globulin) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to assess if sustained remission could be induced. Eligibility required an EDSS of 3.0 (moderate disability, fully ambulatory) to 5.5 (severe disability, ambulatory only 100 meters without aids) and >2 relapses on treatment in previous 18 months. Treatment-failure was defined as a composite endpoint of 1) mortality 2) relapse 3) new MRI lesions or 4) disability increase >0.5 EDSS points. Adverse events (AE) were recorded according to NCI-CTCAE v3.0.

25 patients at a median age of 38(27-53) years were treated with G-CSF to mobilize the autograft; prednisone was given at the same time to prevent MS flares. The autograft was CD34-selected (Baxter, Isolex). One patient withdrew after mobilization secondary to HIT/pulmonary embolus. 24 patients had HDIT/HCT according to protocol. Median follow-up was 131 (52, 282) weeks. After initially stabilizing, one patient died from progressive loss of neurological function at 32 months. No patient had delayed recovery of blood counts. In the 1^st year after HDIT, there were 42 grade 3 and 6 grade 4 non-hematopoietic AE. Grade 4 AE included: one suicide attempt (with 3 grade 4 AE); hyperuricemia; hypokalemia; and elevated ALT. In the 2^nd year, there were 13 grade 3 and 1 grade 4 non-hematopoietic AE. The 1-year and 2-year probabilities of event-free survival (i.e. without treatment-failure) were 95.8% (90% CI: 80.2%-99.2%) and 82.8% (90% CI: 65.0%-92.0%), respectively. Progression-free and relapse-free survival at 1 year were 100% (90% CI: 100%-100%) and 95.8% (90% CI: 80.2%-99.2%) and at 2 years were 91.7% (90% CI: 75.7%-97.3%) and 91.7% (90% CI: 75.7%-97.3%), respectively. The probability of freedom from disease activity detected by brain MRI was 95.8% (90% CI: 80.2%-99.2%) at both year 1 and 2. In comparison, a randomized clinical trial of placebo vs natalizumab (Havrdova E et al, Lancet Neurology, 2009) showed that 7% and 37% of RRMS patients were free of disease activity (i.e. progression, relapse and MRI) at 2 years, respectively.

T2-weighted MRI scans measure disease burden from MS. T2 lesion volume was significantly reduced by 6 months and was sustained at 2 years (Table 1). T1 lesion volume was increased at 1 year. There was a significant loss of brain volume at 6 months but stabilized thereafter.

By flow cytometry, memory CD4 and CD8 T cells (CD45RO+) were not completely eliminated from the blood after in vivo depletion from HDIT. The numbers of CD4 naïve and memory T cells were not recovered at 1 year. CD4 and CD8 recent thymic emigrants (CD45RA+, CD31+) were increased at 1 year compared to the nadir at 1 month but did not completely recover.

HDIT/HCT for highly active RRMS resulted in profound immunosuppression and induced a high rate of sustained remissions at 2 years.

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36 Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)