Tuesday, 3 March 2015

ClinicSpeak: sequencing DMTs, alemtuzumab after mitoxantrone

Time is brain. #ClinicSpeak #MSBlog #MSResearch

"The new buzz word in MS is sequencing of therapies. The study below is reassuring in that MSers with very active disease despite being treated with mitoxantrone responded to alemtuzumab. I have personally treated one such patient in the UK and he has done very well, in that he is NEDA. Unfortunately, prior to receiving mitoxantrone, and subsequently alemtuzumab, he had accumulated already accumulated severe disability (EDSS 7.0) and a lot of cognitive impairment. He has also subsequently become hypothyroid. This case and the study below reinforces the message that if you want to maximise the treatment benefits of alemtuzumab you need to use it as early as possible in the course of the disease."

"To maximise the benefits of highly effective treatments you need to use them early before you have acquire irreversible damage or lost brain and hence reserve capacity. Time is brain!"



Objective: Our study aimed to describe safety and neurological impact of alemtuzumab as last-line rescue therapy in MSers with aggressive MS, previously treated by Mitoxantrone (MITOX). 


Methods: Between June 2004 and October 2013, 13 MSers received alemtuzumab at 20 mg/day and 3 at 12 mg/day for 5 days. EDSS, relapses, secondary progression were prospectively assessed 12 and 6 months before treatment, at baseline and every 3 months. 

Results: Mean follow-up was 6.2 years [1-10]. Mean age at alemtuzumab start was 40 years [26-49] for 8 Secondary Progressive (SP) and 30 years [26-35] for 8 Relapsing-Remitting (RR) MSers. MS duration was 13.7 (±3) and 8.3 (±4) years, respectively. During the 12 months before alemtuzumab, annual relapse rate was 0.75 and 3.14, respectively and the 16 MSers accumulated 2-30 new gadolinium enhancing lesions. 4 MSers (suboptimal responders) received alemtuzumab during MITOX and 12 MSers 1-7.8 years after MITOX. Out of 8 SPMS, 2 were disease free up to last visit (4.7 and 8 years), 5 improved or stabilized but only transiently and 1 worsened. Out of 8 RRMS, 1 remained stable up to last visit (8.7 years) despite 1 relapse and active MRI at 18 months and 7 improved (1-4 point EDSS): 4 remained disease free up to last visit (12, 24, 38 months and 7 years), 2 were successfully retreated at 25 and 33 months and 1 worsened progressively 24 months after alemtuzumab. 2 MSers developed Grave's disease and 1 hypothyroidism. 

Conclusion: Alemtuzumab controls aggressive RRMS despite previous use of MITOX.

CoI: multiple

8 comments:

  1. What does Alemtuzumab do that Mitoxantrone doesn't i.e. Why is is more effective?

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    1. RFe: "What does Alemtuzumab do that Mitoxantrone doesn't i.e. Why is is more effective?"

      Az is very different to Mx. Firstly, the reconstitution kinetics of the immune system is different and there is no secondary autoimmune signal with Mx. I suspect Az works by resetting something that Mx does not. We also don't use Mx at very high-doses in MS due to cumulative toxicity problems, which may explain why its treatment effect is not as durable as Az. We seldom use Mx now in clinical practice.

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  2. Prof. G thanks for the information. my question is, what was the time for washout period from Mito to Alemtuzumab???

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    1. Re: "Prof. G thanks for the information. my question is, what was the time for washout period from Mito to Alemtuzumab?"

      Between 1 and 8 years.

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  3. I'm particularly interested in your patient who has an EDSS 7.0, as little is reported about the difference that novel ways of using treatments work. I am at least an 8.0, but not yet 8.5! As you say, the damage is already done. I would happily live my days out like this, with NEDA, but I wonder if his EDSS improved at all?

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    1. This patient had malignant MS and when he was treated with Mx he had an EDSS of 8.5. He had gone from being well to this state in about 6-8 months. Post-mitox he recovered to EDSS 6.0, before having a severe relapse about 18 months after completing 6 monthly cycles of Mx (Edan Protocol). At this stage his MRI was very active and we referred him to Cambridge for Az. Because of his age, short disease duration and level of activity he was treated with Az. He is now NEDA. Although he is in a wheelchair he has not in my opinion developed secondary progressive MS. Unfortunately, he has a lot of cognitive and mood problems. I would not use this case as an argument to use Az in MSers with high disability levels. We were expecting him to make a good recovery, but unfortunately his attacks had left him with damage that was too severe for repair.

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    2. Poor guy. To go from being well to being that disabled in 6 - 8 months is simply heart breaking and puts the terror of this disease quite firmly at the forefront of my mind. I don't understand why the less effective DMT's are even considered let alone used these days given the living horror which is MS.

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    3. Thanks! Other than my MS not being malignant, he sounds similar to me. I too went from no disease to a wheelchair in 6 months. Tecfidera seems to be keeping me in a holding pattern right now. I tried Tysabri, but had a big reaction from one dose, and Gilenya. However my continuing and most disabling feature is what my neurologist calls "rare and somewhat unique" fatigue which "shuts down my motherboard", leaving me unable to move or speak. There's nothing out there that seems to have an impact on that, so while my baseline ms doesn't seem to be progressing, no new lesions and so on, the fatigue does! I'm always trying to find a combination that'll have an impact on that, but there doesn't seem to be anything. Az does not seem to be offering me anything new.

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