ResearchSpeak: can we prevent autoimmunity post-alemtuzumab?

The PAPA Study: an attempt to prevent secondary autoimmunity post-alemtuzumab. #ResearchSpeak #MSBlog #MSResearch

"Alemtuzumab is one of the most effective licensed treatments we have for relapsing MS. The majority of people with MS (pwMS) only require two courses of alemtuzumab to go into long-term, and possibly life-long remission (cure). The main long-term side effect of alemtuzumab treatment is secondary autoimmunity; the study below indicates that the accumulative incidence of  secondary autoimmunity is just shy of 50% (higher than we previously thought)."

"Secondary autoimmunity may also occur in pwMS treated with BMT/HSCT, but is generally not seen with other induction therapies that have been used to treat MS, i.e. cyclophosphamide, mitoxantrone and cladribine. The risk of secondary autoimmunity, and the monitoring requirements (monthly blood and urine tests) that are bundled with the use of alemtuzumab, are the main reason for its slow adoption as a DMT in MS and may yet prove to be its achilles heel when safer high-efficacy therapies are licensed."

"We hypothesise that the secondary autoimmunity that occurs with alemtuzumab in pwMS is due to the repopulation kinetics of the peripheral T and B cell pools; the B-cell pool repopulates rapidly with and overshoot above normal. The latter does not occur with cladribine and we have therefore hypothesised that it is the repopulation of the peripheral B-cell compartment in the absence of regulatory T cells that is responsible for the high incidence of secondary autoimmunity. We have therefore proposed a study whereby we give alemtuzumab-treated pwMS a low dose of rituximab, after each cycle of alemtuzumab, to blunt and delay the recovery of the peripheral B-cell compartment until regulatory T-cells are back to control autoimmune T & B-cells. This is a high-risk trial, but if it works it would change the risk:benefit profile of alemtuzumab and make it more appealing to many more pwMS and possibly their neurologists. What do you think? Would you volunteer to participate in this study if you had already decided to be treated with alemtuzumab? Our preliminary power calculations suggest we will need 30 pwMS in each arm."

"We have proposed an adaptive design study so that sequential arms could be added to test other strategies, by using the same control arm. This is a novel way of maximising the potential of the study design."

Epub: Willis et al. Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort. Mult Scler. 2015 Oct 29. pii: 1352458515614092.

BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve.

OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab.

METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review.

RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity.

CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.

CoI: multiple

Labels: , , ,