High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS)

Abstract

IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.OBJECTIVE To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation forRelapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34 + selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURESThe primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes:(1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

Autologous hematopoietic cell transplantation in multiple sclerosis

“…One study has looked at the efficacy of AHCT in patients with RRMS who have continued to have relapses while treated with disease-modifying therapies, including natalizumab [23]. This study showed that at 3 years, the event-free survival in patients treated with AHCT was 78.4%, which is higher than that reported in the AFFIRM study for natalizumab.…”

“…AHCT does lead to the suppression of production of certain types of T-cell [22,23], but the balance between regulatory and pro-inflammatory lymphocytes is re-set in favor of regulatory cells [24].…”

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

“…Over the last decade, multiple efforts have been made to optimize the cell source, patient selection, and the safety and tolerability of stem cell-based therapies [74]. In a recent phase II trial, high-dose immunosuppressive therapy and autologous hematopoietic cell transplantation without maintenance therapy was found to be effective for inducing sustained remission of active RRMS at 3 years [78]. While autologous hematopoietic stem cell transplantation is based on utilizing hematopoietic cells to repopulate the immune system following high-dose immunosuppression, infusion of mesenchymal cells or autologous unfractionated bone marrow is not preceded by immunosuppression.…”

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

“…Summarizing the cited protocols, with domination of BEAM and Cy (200 mg/kg), both ±ATG/ alemtuzumab make an impression that in case of MS, lower intensity protocols demonstrate lower, up to 0%, mortality rate, while OS and progression-free survival are similar; in resent studies, they range from 65 to 100%, far better than the results of conventional MS therapies [77][78][79][80][81]. Our limited experience demonstrates 71% of progression-free survival after nonmyeloablative transplantations performed in Hadassah-HUJI Medical Center (14 patients, 1998-2016, 12 after autologous and 2 after allogeneic transplantation; S. Savin, R. Or, M. Shapira and I. Resnick; unpublished data).…”