AHSCT more effective than alemtuzumab

A

This says what I think we know, but there is a trial ready to go to put this question to bed. The people taking HSCT were more active thand the alemtuzumab treated group and in terms of relapse there was not alot of difference between the two

Zhukovsky C, Sandgren S, Silfverberg T, Einarsdottir S, Tolf A, Landtblom AM, Novakova L, Axelsson M, Malmestrom C, Cherif H, Carlson K, Lycke J, Burman J. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study. J Neurol Neurosurg Psychiatry. 2020 Oct 26:jnnp-2020-323992.

Objective: To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis.

Methods: Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly.

Results: The Kaplan-Meier estimates of the primary outcome measure ‘no evidence of disease activity’ was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005.

Conclusions: In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining ‘no evidence of disease activity’. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.

Miller AE, Chitnis T, Cohen BA, Costello K, Sicotte NL, Stacom R; National Medical Advisory Committee of the National Multiple Sclerosis Society. Autologous Hematopoietic Stem Cell Transplant in Multiple Sclerosis: Recommendations of the National Multiple Sclerosis Society. JAMA Neurol. 2020 Oct 26. doi: 10.1001/jamaneurol.2020.4025. but what do the NMS think

Importance: Autologous hematopoietic stem cell transplant (AHSCT) for multiple sclerosis has gained increasing interest in recent years. Despite the availability of many US Food and Drug Administration-approved disease-modifying therapies, some patients do not respond adequately and others may have very early aggressive disease that prompts consideration of alternative, highly effective, long-lasting therapy. The National Medical Advisory Committee of the National Multiple Sclerosis Society has reviewed recent literature on AHSCT for the purpose of making recommendations about its use based on current knowledge, as well as pointing out areas of controversy and issues requiring further research.

Observations: Studies on AHSCT have repeatedly demonstrated high efficacy and a durable outcome in people with relapsing multiple sclerosis. Recent studies have shown considerable improvement in the safety of the procedure, with much lower mortality rates than were reported earlier. Consensus is emerging about the characteristics of the best candidates for the procedure. Questions remain about the ideal protocol, particularly about the best conditioning regimen to be used to kill immune cells. Larger randomized clinical trials are needed to address the question of whether AHSCT has advantages over the most efficacious disease-modifying agents currently available. One such trial (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis [BEAT-MS) is currently in progress.

Conclusions and relevance: The National Multiple Sclerosis Society believes that AHSCT may be a useful treatment option for people with relapsing multiple sclerosis who demonstrate substantial breakthrough disease activity (ie, new inflammatory central nervous system lesions and/or clinical relapses) despite treatment with high-efficacy disease-modifying therapy or have contraindications to high-efficacy disease-modifying therapies. The best candidates are likely people younger than 50 years with shorter durations of disease (<10 years). The procedure should only be performed at centers with substantial experience and expertise. Ideally, recipients of the procedure should be entered into a single database, and further research is needed to establish ideal cell mobilization and immune-conditioning regimens.

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MouseDoctor

9 comments

  • Do you think relapses rate is more important than NEDA? Because you are commenting and emphasising on relapse rate instead of NEDA.

    • The problem I have with NEDA is that it is a tainted outcome. Relapse and MRI lesion I think are related to the same biological process, disability progression is product of two processes, one the progression due to relapses and two the progression as a consequence of the progressive disease that does not respond to the diisease modifying drugs so NEDA-3 fails for the wrong reasons.

      • Isn’t that because DMT’s like lemtrada do not act on the innate immune system as they cannot pass the BBB opposed to HSCT in which the cyclofos does pass the BBB and not only acts on the adaptive immune system but also on the innate? If that’s the case HSCT in general cannot be compared to existing DMT’s as they have different working mechanisms and act differently. Acting on innate immune system should have effect on progressive ms and therefor possibly enable NEDA. Since DMT’s don’t NEDA isn’t a possibility?

        • Myabe, activated cyclophosphamide may target the innate system if it is divididing but HSCT is a miles more agressive depleter of the adaptive immune system than alemtuzumab. However with HSCT how much of the brain is scrubbed clear yes cyclophosphamide can enter the brain but it can only kill dividing cells many of the immune cells in the brain wont be divididing.

          • That could explain why HSCT isn’t effective (long enough) in progressive MS. Usually you see some stabilization for 1 or 2 years and then patients keep progressing. However, that could also be because progressive patients are usually older and have less brain reserve capacity due to cumulative nervous system damage which causes increased aging of the brain and therefor faster neurodegeneration. The question is if HSCT can also reset the innate immune system so that microglia do not mistakenly attack myelin anymore. Post mortem brain tissue would probably be the only way to assess that? Or long term monitoring NfL?

          • Cladribine can cross the BBB, correct? I was under the impression the small molecule nature of the drug’s mode of action, is what sets it apart from the other high efficacy DMTs.

          • Yes it can cross the BBB and the NEDA was closer to 50-60% in the phase III trials and it is not dependent on proliferation at the doses used it does not particularly target the innate syetm in most peolple

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