Alemtuzumab (ALE) Improves Disability after Switch from Other Disease Modifying Therapies in a High Disability Treatment-Refractory Relapsing MS Cohort

Background: Treatment-refractory MS (TRMS), e.g. recurrent relapses and worsening disability on therapy, remains challenging. Nihilism and bias against therapy of “secondary progressive” MS, worsening gait or poor Expanded Disability Status Scale (EDSS) scores may become obsolete with evidence of treatment benefit. ALE, an FDA-approved, humanized anti-CD52, cytotoxic monoclonal IgG, produces selective and transient lymphopenia and subsequent immune reconstitution. ALE achieves superior EDSS outcomes over high dose interferon-beta-1a in relapsing MS. An early phase I ALE study suggested stability in patients with progressive features, and our prior retrospective reports support long-term EDSS improvement in TRMS. Given risk-benefit ratio, ALE may also be appropriate for higher disability, active patients differing from the strictly relapsing lower disability, short disease duration, profile of phase II/III clinical trials.

Objectives: Report outcome measures EDSS and MS Severity Scale (MSSS) changes following ALE by prior therapy and follow up duration.

Methods: Phase I prospective analysis of EDSS and MSSS change following ALE. Inclusion criteria: prior immunotherapy failure, and relapse within two years, regardless of apparent progressive features.  60 ALE-treated TRMS subjects followed prospectively. Groups were stratified by (i) median lunar months follow up (MFU) duration: long-term (LT) 82 MFU (27-104, n=30) or short-term (ST) 10 MFU (6-25, n=30), and (ii) therapies immediately before and within the prior 2 year epoch before ALE: interferon-beta or glatiramer acetate (IFNGA), fingolimod (FTY), and natalizumab (NAT).

Results: The LT cohort had median baseline EDSS 5.5 (2.0-7.5) and MSSS 6.7 (1.7-9.6). The ST cohort had median baseline EDSS 5.0 (2.5-7.0) and MSSS 6.3 (1.3-9.9). Following ALE, mean EDSS change LT was -1.0 (-4.0 to +2.0) and ST -0.4 (-4.5 to +1.5). Mean MSSS change LT was  -2.34  (-6.84 to +0.89) and ST -0.54 (-2.82 to +1.16). For combined cohorts, EDSS changes from therapy immediately prior to ALE: IFNGA -0.9 (n=26, 82 MFU), FTY -0.4 (n=14, 12 MFU), NAT -0.5 (n=11, 49 MFU). EDSS change for therapies within prior 2 years to ALE:  IFNGA -0.8 (n=34, 61 MFU),  FTY -0.4 (n=14, 12 MFU), NAT -0.2 (n=29, 13 MFU).  A subset cohort of previously NAT-treated received FTY immediately prior to ALE with change of EDSS -0.4 (n=10, 12 MFU). 

Conclusions: ALE provides immunotherapeutic rescue for most TRMS patients, with group-wise EDSS and MSSS improvement, notwithstanding other recent, effective, and even aggressive, prior therapies. Improvement in ST likely becomes more prominent in our cohort with LT follow up. This improvement favors treatment of high disability TRMS. Our cohort benchmarks expected outcomes following ALE for TRMS after standard immunotherapy. Evidence supports ongoing LT sustained disability improvement after more than 5-8 years, regardless of prior immunotherapy.