Is it time to ditch the term induction therapy? #ClinicSpeak #MSBlog #MSResearch
Are you up for a PIRT or pulsed immune reconstitution therapy? #ClinicSpeak #MSBlog #MSResearch
Are you up for a PIRT or pulsed immune reconstitution therapy? #ClinicSpeak #MSBlog #MSResearch
“It is time to ditch the term induction therapy and invent a new one? The term ‘induction’ is not a very useful term when describing the mode of action of alemtuzumab, cladribine and HSCT, because it comes with baggage and is often misrepresented. I am now beginning to realise that most people in the field equate the term ‘induction’ with the use of high-efficacy treatment early on in the course disease. For example, at the AAN I heard several people refer to the use of natalizumab as a first-line therapy as an induction strategy. Similarly, the use of mitoxantrone before interferon-beta or glatiramer acetate is frequently referred to as induction strategy (see below). Therefore, I think it is time to rebrand ‘induction’ therapies with a term that describes their mode of action and usage more clearly. Dare I suggest the term ‘pulsed immune-reconstitution therapy/ies’ or ‘PIRT(s)‘. The term pulsed gets across the concepts of short intermittent courses and immune reconstitution explains how these drugs probably work.
PIRTs have many advantages over maintenance therapies, which I have highlighted in the past. The main advantage is that PIRTs (1) they tend to be on average highly-effective treatments, (2) they only remain in the body for a short period of time, which is a very useful attribute if you are a woman who is thinking about falling pregnant, (3) they induce long term remission in some patients, which may turn out to be a cure in the future and (4) they frontload risk. Most of the adverse events associated with PIRTs occur early in the treatment hence the term frontloading. In comparison with maintenance therapies the risks accumulate over time. The latter point is not a trivial point; with immunosuppressive drugs the risks of opportunistic infections and treatment-related malignancies increases with time.”
Edan et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1344-50.
OBJECTIVES: The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients.
METHODS: In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months.
RESULTS: The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point.
CONCLUSIONS: Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.
Ramtahal et al. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. J Neurol. 2006 Sep;253(9):1160-4. Epub 2006 Sep 21.
Background: Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity.
Objectives and methods: We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment.
Results: Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans.
Conclusions: Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.
CoI: multiple
"A rose by any other name would smell as sweet". Call it whatever. All patients want is the best possible chance of not accruing disability – over to you neurologists (you have the tools at your disposal).
Any new on alemtuzumab 10 year data? I read somewhere new data was being presented? Optic disc improvements? Many thanks as always
I would like to save your slides, anyway to make it oublic on google slides or place on slideshare? Download as PDF doesnt work on mobile
There is that word again 'cure' it's so dangerous and misleading,Answer me this, if the average onset of SPMS is between 10-12 years from RRMS, and the average of people who have so called 'benign MS' until progression is 15 years. How can you go around calling alemtuzumab are potential cure. It's the same logic that the diet people use to say a healthy diet will cure MS. You have to wait 20 years for all these milestones to be passed and have a significant number (25%) who are NEDA before you can mention a cure.Do you have/know of patients who are close to 20 years and are NEDA from alemtuzumab? If not it is irresponsible for you as a doctor to mention cure to desperate patients in my opinion.
Difference is there is hard no evidence for diet
It's interesting that he sites two studies of Mitoxantrone induction therapy followed by longterm maintenance with first line injectables. If this was a highly effective treatment strategy that has been available for years and are now generic, it seems the new products Pharma has to offer aren't much more of a evolution for MS treatment.
Off-topic, but not sure where else to post: I thought this was the most interesting poster at AAN: http://aan16.posterview.com/nosl/i/P1_370The poster looks at Swedish registry data, and shows that OCB status has no effect on time to SPMS, i.e. OCB- patients transition to SPMS as quickly as OCB+ patients. This comes pretty close to falsifying Dr. Giovannoni's hypothesis that OCBs are driving progression.
Off topic there is unrelated blogger comments for this purposeIt is not ProFG hypothesis concerning B cell driving progression, this is just one idea. This is based on the presence of B cell follicles in MS brain and other aspects. Problem is half the pathological world or more can't find them. So abit of a hole in the idea. OCB negative status presented here may be another hole, inabitility of B cell immunotherapy maybe another. However you get a hypothesis and you test it properly. Antibodies in CSF are clearly pathogenic in some peole with MS, but there are other routes to progression that do not inovle B cells.
MD what do you think is driving progression of MS? Is it a cellular response that varies in severity from individuals with MS to areas of myelin stripped off by the immune system (ie. addition of Na channels, mitochondrial dysfunction, influx of Ca then cell death?). Or do you think it is some not yet discovered autoimmune response, like B-cells?Will remyelination, with things like clemastine, anti-lingo, rhigm22, etc. reverse this process and restore neuron homeostasis? If you were a progressive MS patient today would you discuss starting a Na channel blocker (like phenytoin, valproic acid, etc) with your own neurologist, as studies may take years to become mainstream recommendations?
yes-Innate glial responseUndiscovered autoimmune response No altough will play its partWill remyelination…maybe it depends if they can repair chronic demyelination they have never shown these drugs can do it experimentallyIf you were…I can't really advise of this, but you should always be discussing treatment options, Na have some evidence to support their use however their use come with side effects
" In comparison with maintenance therapies the risks accumulate over time"Are you saying that Natalizumab has a higher risk of cancer than Alemtuzumab on the long term?
Dr G, for any PIRT or induction therapy, and in particular CLAD, what does one do at year 6 once the disease begins to worsen or progress? Is another round of CLAD warranted? Or do you move to…?
If you have had treatment at 0 and 1 and at six years disease returns then another round may give you another 5 years NEDA. However you should monitor aevery year and if you are NEDA fine, but if not then a switch may be in order, but what can you switch too that is more efficacious?
As a newby, is it fair to say that the most interesting new(ish) treatments are A-HSTC & Ocrelizumab? If not what other things in the pipeline are of interest? Or will the work on repairing myelin ultimately prove to be the best option.