What do you do when you get recurrent disease activity on cladribine?
I am repeatedly being asked what to do about disease activity in patients treated with cladribine. The following is my suggestions on how to approach this thorny issue.
As you know disease activity on immune reconstitution therapies (IRTs) don’t necessarily mean you failed or are failing the therapy. Disease activity could be an indication to retreat with an additional course. Interpreting when and what to do depends on when the disease activity emerges and how severe it is.
Post-course 1
If you have a relapse after the first course (cycles 1 & 2) of cladribine I would hold fast and have the second course. There is no reason why someone who has disease activity in year 1 post-cladribine won’t necessarily respond to the second course. There is, however, one proviso here. With alemtuzumab, another IRT, rare patients get rebound activity, over and above baseline activity, around months 7-9 post the first course of alemtuzumab infusions. Why this happens we don’t know. We have not observed this with cladribine yet, but it could theoretically happen. In this situation, the disease activity is so severe that most of these patients are offered alternative treatments, in particular, anti-CD20 therapies (rituximab or ocrelizumab), mitoxantrone, cyclophosphamide or HSCT.
When we see recurrent disease activity in year 1 post-alemtuzumab we have often brought forward the second course of alemtuzumab. I see no reason why we wouldn’t consider this with cladribine as well, provided the total lymphocyte counts have recovered to above 800/mm3.
Post-course 2 – year 2
If disease activity occurs in year 2 this is not good news. This would indicate that the patient has not responded to cladribine and would be an indication to switch therapeutic strategies.
Post-course 2 – year 3 & 4
If you have disease activity in years 3 & 4 the timeframe covered by the current cladribine label you are not meant to retreat with cladribine. However, this makes no sense to me. IRT works by depletion and reconstitution. In some people, the two cycles of depletion with cladribine may not be sufficient to deplete the autoreactive pool and hence MS disease activity resurfaces. I personally think there is no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is exactly how we use alemtuzumab in this situation; the difference being alemtuzumab is now licensed to be used in this way. Clearly there is an evidence gap around cladribine and hopefully, this will be filled as real-life data sets emerge in the future.
Post-course 2 – after 4 years
Similar to the above I see no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is how we use alemtuzumab and other IRTs. I am aware of one patient in the US has had 7 courses of intravenous cladribine over a period of 21 years.
The future
Cladribine has a variable treatment effect on the total lymphocyte counts. There are biochemical reasons why this may occur. I see in the future adapting the dose of cladribine we use to achieve an optimal level of lymphocyte depletion. This makes sense.
I also see cladribine being used as induction therapy, i.e. after an initial course of cladribine, we will be following it with maintenance therapy. Based on the memory B-cell hypothesis BTKi (Bruton’s Tyrosine Kinase inhibitor) or teriflunomide (antiproliferative/antiviral) makes the most sense at present.
I would love to do a trial of an IRT followed by maintenance therapy. Any takers? Any funders? In terms of safety and cost, I would go off-label and test rituximab followed by leflunomide vs. rituximab as an IRT.
The following is a visual summary of some of the information above.
CoI: multiple
Are you able in really simplistic terms to explain why you would use cladribine over any of the other therapies you mention here which are I believe accepted as more effective?
To expand on the this idea….. why are some drugs offered in preference to others .Is the decision influenced by a Neurologist’s relationship with drug companies?
My thinking of the drugs you mention:
Hsct great if you can get it early on although no one really entirely sure
Alemtuzumab potentially as effective as hsct but currently unavailable
Ocrelizumab obviously understandably offered for ppms yes but regarding rrms is being offered in the absence of alemtuzumab but still confused what would have happened if alemtuzumab was still readily available
Mitoxantrone I thought this was considered too risky now so has been replaced by cladribine at some hospitals for example st Bart
Cyclophosphamide I thought that at the strength it is given on its own it was considered pretty ineffective
I really do feel we are all drowning in pretty similar drugs which personally makes me really anxious as to what I should pursue if any at all!
It is horses for courses and DMT choice really depends on the individual and what they want.
Cladribine has many attributes that make it a suitable choice for treating MS. This is probably why NHS England has selected it as one of the innovations it wants the NHS to adopt rapidly and widely.
Everything you write makes perfect sense. All my Neurologists would agree with you. However, they simply aren’t willing to prescribe Mavenclad off-label..
So the question remains: by when do you expect to have sufficient proof in place to justify your EMA request for approval of further cycles of Mavenclad?
Maybe you need to change neurologist and get one that thinks. If we only accepted what is in the FDA and EMA labels we would not evolve the MS treatment landscape. Most of our DMTs are repurposed and relied on brave neurologists and patients being treated off-label. Without off-label prescribing, we won’t get innovation.
I have no idea why anyone would choose an IRT. The anxiety of waiting for disease activity to return, or not, would concern me about this treatment strategy.
You take an IRT because it may cure MS. The idea is for the IRT to destroy the autoimmune cells, or cells harbouring the viral infection, and when the immune system reconstitutes the disease remains in remission. The only offer of a cure are the IRTs. If you don’t like this strategy you won’t buy into the HSCT paradigm either. HSCT is an IRT that is usually only given once. However, there are a few reports of MSers having more than one HSCT cycle.
I like the induction-maintenance idea. Can you elaborate on the BTKi’s? Thanks.
BTK inhibitors block B-cell receptor signalling and hence stop B-cell activation. The logic is you first deplete the memory B-cell and you then stop new memory B cells developing or becoming activated.
Is there any way to get a copy of the visual summery?
Very informative!
You write ”I see in the future adapting the dose of cladribine we use to achieve an optimal level of lymphocyte depletion. This makes Sense”
Do you have any idea what that optimal level might be? Would be interesting to hear your thoughts on this
Ofatumab just passed its phase 3 clinical trial. Beating Aubagio hands down. Hmmm. Given they are measuring Brain atrophy in this trial as a 2nd endpoint. Do we now know if b therapy is better than T and b therapy such as caldribine and Alemtuzumab?
Your concepts makes sense. When are you planning to start this study? Are you interested in data contribution from a different country ? Let me know if you are interested.
I received these questions via email:
1. Is Cladribine able to cross the blood-brain barrier and destroy lymphocytes in the CNS?
2. Can Cladribine destroy lymphocytes in the lymph glands?
1. Is Cladribine able to cross the blood-brain barrier and destroy lymphocytes in the CNS?
Yes, cladribine crosses the blood-brain barrier and preliminary evidence suggests it depletes CNS lymphocytes. The latter needs to be reproduced.
2. Can Cladribine destroy lymphocytes in the lymph glands?
Yes, this has been clearly shown in the oncology in relation to CLL and hairy cell leukaemia.
Prof G – you mention potentially setting up a trial for IRT followed by maintenance therapy – is this suitbale for those who are already on the St Barts cladribine programme? If so, who’s it best to get in touch with?
By cladribine program do you mean the off label program or the pending trial?
I did a second round of alemtuzumab this spring. So far so good, but I would consider signing back up for a maintenance therapy even if I stay relapse-free. I’m not sure if that is fear, wisdom, or both speaking. I told my neuro that I felt like I was just waiting for my next relapse now that I am not taking a maintenance med, and he asked how that was different than waiting for the relapses when I was on one. He has a point, but after failing 6 other medicines I’m still scared to just let it ride.
I agree with this.
I hope prof g response to your question and to mine below…,.
I had two courses of alemtuzumab and there is a definite lack of clarity as to whether you need to have further alemtuzumab (this was before it was withdrawn) if for example your hands seem a little weaker.
Would have been worse without alemtuzumab?
Does it show it has not worked?
Was the slight deterioration inevitable because of therapeutic lag (something my neurologist does not believe in)
Prof g
How many people were ever given a third alemtuzumab at st. Bart’s?
What about fludarabine, or other purine analogues. Are they all equally effective? A friend i know thinks highly of flud. Are the 2, clad and fludarabine, interchangeable?
Fludaradine is cladribine with a fluorine on it.
Buonasera professore, mi chiamo Francesca ho 47 e mi é stata diagnosticata la SM due anni fa. Ho molteplici lesioni al cervello, cervelletto e alle prime vertebre dorsali. Ho assunto la terapia a maggio/giugno 2019 e ripetuta a luglio/agosto 2020. Non ho mai avuto una forte riduzione dei linfociti, ante Mavenclad erano 2.40 e hanno toccato il valore più basso di 1.19. Non vedendo una caduta linfocitaria, ho sempre pensato che su di me il farmaco non stesse facendo il suo dovere. Rispetto allo scorso anno, posso tranquillamente sostenere di essere peggiorata soprattutto nella deambulazione infatti oggi zoppico vistosamente. Le RMN fino ad ora effettuate hanno evidenziato una situazione stabile, nessuna nuova lesione. Proprio stamattina ho fatto RMN e solo tra 1 settimana avrò il referto. Sono ingrassata di 15kg in 1 anno e leggendo diversi post su fb, ho visto che é stato un problema per tanti. Quando ho iniziato la terapia avevo molte aspettative, certo non pensavo di guarire ma speravo di poter star meglio ed invece mi rendo conto che sono peggiorata. Spero mi vorrà rispondere in merito alla non caduta dei linfociti per capire se questo può essere un problema o una mancata risposta del farmaco.
Francesca
buonasera
I am sorry we cannot give individual advice. In terms of lymphocyte depletion with cladribine it is not a strong depletor of T cells 25-40% so you may not see a marked fall total white blood cells , there are some people that deplete very well but there are also about 10% of people who dont. Do these people deplete their B cells and this is the key? Do these people respond well I dont know. But obviously we think B cells need to be depleted for drugs to work. Can you get worse on a drug. No drug is 100% effective and also sometimes it takes time for the damage to show itself. You neuro is best placed to judge on whether to switch
I wudnt use rituxin or ocrevus. They don’t cross the bbb. Injectable cladribine is another possibility. Very inexpensive compared to the pills even fludarabine