Tag: Switching

To switch or not to switch that is the question

Barts-MS rose-tinted-odometer: ★★★

The one good thing about thinking aloud is that your colleagues’ chip in and provide feedback. Case 2 from my ‘ethical quandary post‘ is generating an important debate about whether to support this patient’s decision to switch therapy or not.

As a reminder, this is the 40-year old woman who started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no relapses, no MRI activity and no change in her EDSS). In fact, her original disabilities from the two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.

The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware from reading The MS-Blog (formerly the Barts-MS blog) that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range (please see BEYOND NEDA).

What I didn’t say to you is that this lady has already made the decision that she wants to be treated with AHSCT, either on the NHS (not possible at present), abroad at one of the reputable private BMT units or in the private sector within the UK. The problem we have is that we have no idea what will happen to her BVL once she makes the switch. I suspect she will have accelerated BVL in the first year post-AHSCT, which is well described and is likely to be due to the neurotoxicity of the chemotherapy. After year-1 the BVL may or may not normalise. We have no idea what happens to the MS brain after being subjected to smouldering MS pathology on natalizumab for a decade.

Fortunately, we do have data from interferon-beta to alemtuzumab switching and, yes, after 2 years of interferon-beta therapy switching to alemtuzumab does normalise BVL. What is clear from the 8-year alemtuzumab follow-up data (see below) is that the rate of brain volume loss is age-dependent. Being in the 35-45 year age group the BVL was 0.13% per annum ((1.51-0.71)/6) on alemtuzumab. When you compare this to the 0.06% per annum in study subjects 18-25 years of age ((1.24-0.87)/6) you realise how important age is in determining treatment effects. 

Figure from MSARDs.

Is this data sufficient to talk this young woman down from her decision to have AHSCT and to go with alemtuzumab? What do you think? If this patient is reading this blog post will it affect your decision?

Another thing this ‘thinking out loud’ exercise has taught me is that having annual BVL measurements on our patients with MS on DMTs could be very helpful. I also think we should ask around to see if we can get a case series of natalizumab to alemtuzumab switchers to see what happens to the trajectory of BVL before, on natalizumab, and after the switch to alemtuzumab. At least then we will have data to inform such difficult decisions.

Bass et al. Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years. Mult Scler Relat Disord. 2021 Apr;49:102717. 

Background: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]).

Methods: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years).

Results: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts.

Conclusions: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.

Conflicts of Interest

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

DMT churn

Please note that I am so conflicted when it comes to giving advice about DMTs that you need to take what I say and think with a ‘pinch of salt’; including the contents of this post. 

Meaning: To take something with a “grain of salt” or “pinch of salt” is an English language idiom that means to view something with scepticism or not to interpret something literally.

The endless churn or cycling of DMTs is creating problems for MSologists and their patients alike. I am increasingly seeing patients who have been on six or more DMTs. Why? Many switching decisions are related to tolerance issues, unacceptable adverse events, family planning and breakthrough disease activity. However, some churn sadly is due to unrealistic expectations, over- or under-stretched healthcare systems or simply fashion. 

Let’s deal with unrealistic expectations. If you are on DMT x and you are NEDA 1&2, i.e. no relapses or new focal MRI activity, but are still getting worse many patients are being switched in the hope that a different DMT will get on top of smouldering MS. The reality is that we have no data on the efficacy of DMTs in this situation; in fact, we have data from more advanced MS trials that anti-inflammatory DMTs don’t actually make much difference to the pathology driving this stage of the disease. This is why we are pushing so hard for combination therapy trials and the oncologising of MS to create the infrastructure to run multiple, parallel, add-on trials to address smouldering MS. 

Overstretched healthcare systems are incentivising their HCPs to switch patients onto treatments that are less of a burden to the healthcare system, i.e. less monitoring and less hassle for the neurologists and nurse specialists. I have seen this with many patients who are relatively low risk of PML on natalizumab who have been switched off natalizumab to another DMT without having the relative risks, nor the strategies we can use to lower the risk of PML explained to them. In addition, some of the switch therapies, in particular anti-CD20 therapies, come with undefined long-term risks of their own. One of the patients I saw in this situation wants to go back onto natalizumab as she does not feel ‘as well’ on an anti-CD20 as she did on natalizumab. She is complaining that her brain fog has returned. If she had had things explained to her I suspect she would not have switched-off natalizumab.

Switching as a result of under-stretched healthcare systems is the switching of patients onto treatments to increase clinical activity and hence profits. This is more common in fee-for-service healthcare systems but also occurs in the NHS. In short, if you want to maximise your income it is better to have patients on treatments that you can charge extra for, i.e. infusions, monitoring visits, etc. Neurologists are no different from other people; if you create a perverse incentive for doing something we neurologists respond to it, it is human nature.

Fashion refers to the trend that patients often want to be on the newest and coolest DMT. The trend for the latest, brightest and most expensive DMT is often driven by social media influencers; pwMS who promote officially or unofficially DMTs. Switching therapies based on these criteria is not ideal, but some neurologists give-in to their patient’s demands and switch treatments for no apparent treatment benefit. If you are doing well on one treatment moving to another DMT is no guarantee that you are necessarily going to do better on the new drug. In fact, the new treatment may be associated with adverse events and long-term complications that have yet to emerge (known-unknowns on unknown-unknowns).  

When I push the early-diagnosis, early-treatment, high-efficacy-first-line, flipping-the-pyramid philosophy of treating MS, I know that some patients will be harmed for the benefit of the overall population of pwMS. The counter-argument is to maximise the safety of the individual by using a slower-escalation strategy. This strategy, however, comes at a cost for the overall population; i.e. a less favourable group outcome. The path between these two extremes is a narrow one and full of obstacles or cognitive biases that in my opinion get in the way of doing what is best for pwMS. What we can do as neurologists, regardless of what treatment philosophy we subscribe to, is to avoid unnecessary DMT churn. 

Marangi et al. Changing therapeutic strategies and persistence to disease-modifying treatments in a population of multiple sclerosis patients from Veneto region, Italy. Mult Scler Relat Disord. 2020 Feb 10;41:102004. 

BACKGROUND: The availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy.

METHODS: Demographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence.

RESULTS: Of 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among second-line DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation.

CONCLUSION: The use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.

CoI: multiple