Objectives: A phase II clinical trial of high-dose immunochemotherapy (HDIT; BEAM/antithymocyte globulin) and autologous hematopoietic cell transplantation (HCT) was conducted in patients with highly active RRMS who had failed conventional therapy to assess if sustained remission could be induced.
Methods: Eligibility required an EDSS of 3.0 to 5.5 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.
Results: 25 patients at a median age of 38(27-53) years were mobilized with G-CSF only; prednisone was given at the same time to prevent MS flares. The autograft was CD34-selected. One patient withdrew after mobilization secondary to heparin-induced thrombocytopenia/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. In the 1st 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 2ndyear, 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 at 2 years, respectively.
T2 lesion volume was significantly reduced by 6 months and was sustained at 2 years. T1 lesion volume was minimally 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.
Conclusions: HDIT/HCT for highly active RRMS resulted in profound immunosuppression and induced a high rate of sustained remissions at 2 years. Patients will be followed on study for 5 years.