High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS

Abstract

Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT).

Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE).

Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of -0.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study.

Conclusion: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years.

Clinicaltrialsgov identifier: NCT00288626.

Classification of evidence: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT.

Figure 1. Patient-level pretransplant characteristics and outcomes

Patient-level pretransplant characteristics and study outcomes are presented for the 24 transplanted participants. Time is measured in months relative to day 0, the day of graft infusion. The eligibility window is defined as the period of time beginning 18 months prior to the screening visit. At screening, the number of relapses, as defined in the protocol, that occurred during the eligibility window were identified retrospectively and documented in the clinical database, for the purpose of determining eligibility. The period of screening to transplant is defined as the time from determination of protocol eligibility until day 0. To obtain a more complete understanding of the events that occurred during the time from screening to day 0, we retrospectively investigated reports of multiple sclerosis (MS) attack, to determine if the participant had met the protocol definition of relapse, or if the event was a less severe MS worsening event. MS worsening is a new neurologic sign or symptom that does not meet criteria for relapse, and was documented only during the period from screening to day 0. Patients 2, 6, 14, 15, 19, and 22 experienced an Expanded Disability Status Scale (EDSS) increase of at least 0.5 during the period of screening to transplant. Study completion for some participants occurred beyond the 28-day visit window for the year 5 visit, due to scheduling difficulties. The participant flow diagram is presented as figure e-1 in the current publication. A total of 18 participants completed the year 4 assessment and 17 participants completed the year 5 assessment. MS disease activity is reduced for participants posttransplant as compared to prior to treatment. DMT = disease-modifying therapy.

Figure 2. Neurologic outcomes: Composite primary endpoint and components

Kaplan-Meier plots of the probability an event will not occur were calculated. The number of participants at risk is presented at each time point along the x axis. Short vertical bars on the curves indicate censored data. Participants who withdrew early were censored at the date of last follow-up. (A) Event-free survival (without death or disease activity from any one of: loss of neurologic function, relapse, or new lesions on MRI). (B) Summary of all primary endpoint and subsequent events by participant with type and time of event since transplant. Primary endpoint events are bolded and starred. (C) Progression-free survival (increased Expanded Disability Status Scale [EDSS] greater than 0.5 from baseline). (D) Relapse-free survival. (E) MRI activity-free survival (presence of 2 or more independent multiple sclerosis lesions indicated on MRI). Note that the MRI event that occurred at 11.9 months was not a primary endpoint event, but rather an event that occurred subsequently after the participant met primary endpoint via clinical relapse at 5.1 months. (F) Overall survival. For each of the 3 deaths, the participant had previously met primary endpoint. In the analysis of the individual components comprising event-free survival (C–F), follow-up for any component was not censored by earlier events (see text).

Figure 3. Clinical outcomes

(A) Expanded Disability Status Scale (EDSS). (B) Multiple Sclerosis Functional Composite (MSFC). (C) MSFC component: 3-second Paced Auditory Serial Addition test (PASAT-3). (D) MSFC component: 9-Hole Peg Test. Average of trials from the dominant and nondominant hands. (E) MSFC component: Timed 25-Foot Walk Test. (F) Quality of life: 29-Item Multiple Sclerosis Impact Scale (MSIS-29). The p values from a Wilcoxon signed-rank test are presented at each postbaseline visit along the x-axis assessing the change from baseline. The p value in the MSFC components in panels C through E assesses a change in the component Z score from baseline. The median component Z scores can be found in table e-3.

Figure 4. MRI studies

(A) New gadolinium-enhancing (GD+) lesions occurring after transplant. The GD + lesions as seen at years 3 and 4 are 2 different GD+ lesions observed in the same participant, and thus this individual met primary endpoint. (B) New T2 lesions since previous visit. The new T2 lesions seen at year 4 are in one individual, who met primary endpoint. (C) T2 lesion volume (mL) change from baseline. There was a decrease in T2 lesion volume at year 5 (p < 0.001). (D) T1 lesion volume (mL) change from baseline. There was an increase in T1 lesion volume at year 5 (p = 0.015). (E) Percentage of change in brain volume from screening. At year 5, brain volume was significantly decreased compared to baseline (p < 0.001); however, there was stabilization in brain volume from year 3 to 5 (p = 0.311) after transplant.