Ibrutinib vs FCR: does order of therapy matter? - CLL Support

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Ibrutinib vs FCR: does order of therapy matter?


Time for a really specific question that is at the nub of the decision faced by doctors and patients when it is time to initiate first treatment. Does it matter which treatment we choose first?

If you are a younger patient then clearly one of the critical issues is that sadly our disease is rarely cured. As we saw in yesterdays post on response rates and relapse a certain percentage of patients will relapse even on a drug like ibrutinib. Probably eventually we all will (assuming we are young enough to live that long).

See: healthunlocked.com/cllsuppo... for explanation of some of the terms used below.

In my head, as a 47 year old about to start first treatment who is unumutated, I am assuming I will work my way through multiple treatments over what I hope will be say 30 years or more of life.

It is clear from the data that ibrutinib was associated with better progression free survival and overall survival in the first-line study than it was in the relapsed and refractory study. (ASH 2016, 1102-03 5-year Update; O’Brien et al)

Initial therapy: Five year Progression Free Survival(PFS): 92%, Overall survival (OS): 92%

Relapsed/Refactory study: 5-year Progression Free Survival: 43% and Overall Survival: 57%.

The graphic attached to this post shows this graphically for overall survival.

On the face of it this would seem to indicate that you should use ibrutinib early in the disease. And an attempt was made to look at this in more detail based on the number of treatments someone has received:

0 prior therapies (n=31) Overall Survival at 5 years 92%

1-2 prior therapies* (n=27) Overall Survival at 5 years 60%

3 prior therapies (n=14) Overall Survival at 5 years 85%

≥4 prior therapies (n=60) Overall Survival at 5 years 47%

There are a number of potential problems with this simple assumption, however.

1. The numbers involved are really very small and so subject to quite a lot of random variation in an older population where some people will die of other unrelated causes. A single chance event death in any of these groups could skew these results (e.g. is it Really likely that people with three prior therapies would do better than those with two?)

2. The paper notes that they only had two patients in the R/R group who had only had one therapy, so we don't really know anything about what would perhaps be the most common strategy if you are not opting for ibrutinib firstline: start with FCR then move to ibrutinib when required.

3. The first-line patients were less likely to have bulky disease, an increase B micro globulin level, and 17p or 11q deletions than the R/R group. Thus the R/R group are a sicker group of patients. And when it comes to the deletions the presence of 17p or 11q was associated with a worse outcome even with ibrutinib use.

4. When we say that ibrutinib appears to work better in treatment naive patients are we simply saying that treatment naive patients do better no matter what treatment they have? Or are we saying that chemo can damage the prognosis of patients with CLL making it harder for ibrutinib to work later down the line?

5. Are we really saying that no matter what the treatment patients with good prognostic markers will do better than those with bad markers? And that the longer the patient has the disease the more likely they are to both progress and die no matter what treatment you are given?

The UK model outside of the FLAIR trial is that everyone with any 17p deletions (no matter how infrequently they are expressed) are assumed to be high risk and not given FCR, but move straight to Ibrutinib. The rest are given FCR, then, anyone who relapses after being given FCR may be given ibrutinib.

Do we know for sure that such a strategy is worse then moving everyone to ibrutinib first line?

It may well be that ibrutinib can rescue effectively patients who relapse on other treatments. Of especial note in the Four Years Follow-up of the RESONATE trial was the fact that it allowed patients during follow up to switch from the comparator (chlorambucil) to ibrutinib. This led to over time the survival curves of the two initial groups of patients to significantly narrow. I.e. patients who moved to ibrutinib were more likely to survive. (Byrd J. et al. Long-term efficacy and safety with ibrutinib in previously treated CLL: up to four years follow up of the Resonate study. Poster presented at the American Society of Clinical Oncology (ASCO) 2-6 June 2017;Chicago, Illinois, USA)

What about those with intermediate or low risk markers? Mutated and Un-muated patients do equally well with relapsed/refractory disease when treated with ibrutinib. The survival curves map almost exactly.

So there is little evidence that patients would do worse on ibrutinib if they had been previously given FCR as an IVGH unmutated person (provided they don't have 17p deletion), although there IS evidence that FCR itself is less likely to give you a long remission if you are not mutated in your IVGH gene.

In the long term follow up of the original FCR study CLL8, half the patients were still being followed up 12.8 years later. Obviously we do not have anything like this long data for ibrutinib. See bloodjournal.org/content/12...

Progression free survival (PFS) at 12.8 years was 53.9% for patients with mutated IGHV but only 8.9% for patients with un-mutated IGHV.

Median PFS (the point when more than half the patients had relapsed) was not reached (NR) for patients with IGHV Mutations but was 4.2 years for patients who were un-mutated.

When it comes to overall survival it is important for younger patients like me to remember that these groups are much older than me. So many of them will die for other reasons. Nonetheless there are differences seen also in overall survival for FCR treatment.

Median Overall survival (the time till when half of the population had died) was 12.7 years

Predictors of death in the study were: age ≥65, IGHV-Unmutated status, B2M ≥4.0, and del(17p).

Median Overall Survival for patients with IGHV-Unmuated was 9.4 years, with 32.2% still alive at 12.8 years. Remember that these patients typically would not have been able to proceed to ibrutinib due to the time of the study.

65.5% of those who were mutated in IGHV were still alive at 12 years (so the median was not reached), and survival was even higher in patients who had a deep remission to MRD-ve patients had an overall survival rate of 87.2% at 12 years vs 56.5% for MRD-positive. There was no effect of MRD status in IGVH un-mutated individuals.

If a patient has low risk (no poor prognosis deletions and mutated) then FCR first-line does look reasonably likely to give them a long remission. The paper also showed that those who experienced a deep remission with no disease detectable in the body were more likely to experience long remissions. And with low risk patients there is even a suggestion that some of them may have been actually cured by FCR.

If patients are intermediate risk then some patients may still get remissions that last for years, but this is far fewer than the low risk group.

So is it better to 'bank' the response you may get from FCR?

Or is it better to use ibrutinib first then move either to FCR or perhaps Venetoclax plus rituximab?

As my CLL specialists told me, the data is clearer for low and high risk patients but perhaps less clear for intermediate risk.

As a result, I do still think the UK FLAIR trial is a very important study. And I can see arguments for and against using each drug first line.

What do you think?

Note this is an unlocked post and so any comments you make could be indexed by google so you are advised not to share personal medical details you don't want other people to know about.

19 Replies

One of the things that should be accounted for is the normal mortality rate for any given age. Wheather that be car accident; OD on drugs or dying of another disease

You’ve done your homework-love it!

I was dx at 39 & now 46, so similar boat as you (BR ‘12, Ibr since 8/16 and doing great). IMO, FCR should only be used in a TN mutated person. Damage to our dna is too great for younger pts. We’ll have much more data after ASH in December, but some combination of Ven, Ibr & Obinu is going to be the way to go whether you’re TN or R/R. Plus, I won’t have to take Ibr for years & years, worrying that I might develop resistance to it, because for a lot of folks, the new combinations will only be taken for a short period of time (6 mo to 2 yrs depending on the combo).

Last thing...I ran my first Ironman 70.3 last October. Please exercise! It’s the single best thing you can do to control your own fate! The science is now too great to ignore Exercise Oncology (plus, it helps tremendously with side effects and fatigue)!

Best of luck,


North Carolina

Hi Adrian, have you won the prize for longest post yet? Seriously, I find it rather close to what I have been researching myself these past few days. Did you see the video posted by Chris on his post a few days ago, "Emerging Treatments and Evolving Pathways for the Management of CLL", with the lecture by Dr Jennifer Brown? It seems much of research currently is studying the new drugs for high risk (17p), and low risk (13q mutated) in both front line and relapsed contexts. But I am neither (healthy T12 unmutated) and seem to be unstudied! At the end of the lecture there were a few audience questions and someone was expressing disappointment that a clear treatment pathway was not recommended for anyone, least of all for us in the middle. Dr Brown answered that they just don't have the data yet, it's still being studied...

AdrianUK in reply to JustAGuy

I haven’t watched that yet but plan to soon. It seems to me that as a Brit I kind of have a duty to the rest of the world to take part in FLAIR as that will answer some of these questions but not for a few years. Unfortunately even ibrutinib is not likely to hold our unmutated disease for ever so my current Rather depressive thought is I’ll probably end up taking at least theee different treatments so does it matter what order? If we can stay at least one new drug ahead of the illness that’s all we need (ie if we make it through all theee current options we just want to hope there’s a fourth by then and it looks very promising there will be)

Sushibruno in reply to AdrianUK

I'm sorry to say this but my biggest fear is being on meds for a very long time, and i know that's the reality with any disease. 😢😢

Except for the possible problems with ibrutinib or venetoclax, I found that video to be fairly encouraging, most of the data was showing pretty good response for T12, it was very fast paced though and I could not always tell what mutational status was shown...

AdrianUK in reply to JustAGuy

Watched it now....I guess I just wish we had more data and longer term data! Link to the video is here: healthunlocked.com/cllsuppo...

We just need all the Brits to do FLAIR to save the day and help us know more!! healthunlocked.com/cllsuppo...

Adrian I really enjoy and appreciate your postings. Very informative and thought provoking. Let's hope that 5 years from now this all becomes moot due to the fact that a new treatment (or treatment combination) is clearly better than anything used routinely today.

AdrianUK in reply to Benlewis

Thanks! Yes indeed. I do suspect that venetoclax and Ibrutinib in combo (or cleaner son of each drug) may be that perhaps with rituximab as well. If we can get to MRD negative then zap for even longer the hope is surely for a cure as some people are seeing with FCR. But even FCR is too new to really help someone like me know what lies ahead for the next over thirty years I need to get to a reasonable length of life. Slightly depressing we don’t know. But as Claire Dearden says just stay one new drug ahead of your illness progression and you will be fine!

HAIRBEAR_UKFounder Admin

Very in depth and thought provoking post Adrian.

Difficult isn't it? Doing your own research and consulting with expert consultants does take some of the guess work and chance out of the equation when a decision is necessary, but not all, it often throws up many more questions!

It is important to have confidence in timing and what treatment route you select, or treatment you get given on a randomised trial with three arms, where there is a lot of chance involved.

'Claire Dearden says just stay one new drug ahead of your illness progression and you will be fine!' there is no cross over in FLAIR so relapse or failure from treatment in an inhibitor arm, would mean that a patient will be offered FCR or BR as standard of care, unless a trial was available at that time. I believe that applies to mutated and un-muted igVH patients

I agree your question of what order is timely, as this is now being debated by clinicians and the current big stick approach for first line treatment as a standard is being questioned by several experts and FLAIR, along with improving testing to stratify patients further, will, in time , we hope, answer these questions directly and indirectly.

Venetoclax plus rituximab for the relapsed setting is currently being appraised by NICE, this could change the landscape dramatically if comes available to NHS for both those relapsing from chemoimunotherapy, or BCR therapy.

Treatment sequencing considerations are becoming increasingly important when it is time to treat, although long term planning may not be possible, the treatment landscape is expanding and clinical trials evolve. This question now must become an important consideration during appraisal of new treatments too.

Thinking one step ahead seems a sensible approach to me :-)

I rolled the dice for FLAIR and got FCR , CLL is now back so when looking at 2nd line options am trying to keep one step ahead?

Ten years ago there was no chance of choice :-)

Good luck


AdrianUK in reply to HAIRBEAR_UK

Thanks Nick. Are you going to go for ibrutinib second line do you think? That would seem to be a reasonable option from my reading. What does your expert want you to do? Like you I think I will almost certainly go for FLAIR.

HAIRBEAR_UKFounder Admin in reply to AdrianUK

Options are open, I guess we await NICE and NHSE again :-)

AdrianUK in reply to HAIRBEAR_UK

Are you hoping for Venetoclax-Ritux as second line then? You could be waiting a while since as you know the license hasn't been granted yet in the EU/UK. I guess its all about what is available at the time you actually need it isn't it really. Would you have been caught up in the three year rule that just got rescinded? If so you must be relieved not to have to do FCR twice.... once is definitely enough in my mind and my emotions tell me I want to try and avoid it altogether if possible!

HAIRBEAR_UKFounder Admin

Adrian, I am not suitable for FCR second time round, early relapse ! However having lived with chronic fatigue and symptoms for 7 years following diagnosis and before first treatment, it not scary to feel that familiar friend again. I hope my cell lines will hold for some time yet, for me living with symptoms is par for the course unfortunately and nothing unusual. I hope time is my friend. :-) to several options.

Venetoclax plus rituximab for relapsed patients appraisal committee meeting is in September. As the marketing authorisation/license outcome is close, a best case scenario is that a final appraisal determination (FAD) could be issued first time round, however rarely do we get a FAD first time round it could go to an Appraisal Consultation Document (ACD) review. A balanced guess would be to guess at NHS access within 6 months of the September meeting?

Ho Hum

AdrianUK in reply to HAIRBEAR_UK

Its interesting as for me I think if I had already had FCR I think I would prefer ibrutinib second line and holding off for venetoclax after that. But thats just a gut feeling not really based on evidence (I am doing all my reading around FIRST LINE treatment at the moment as I am sure you will appreciate!

HopeME in reply to AdrianUK

Adrian: I am a little older than you (56 Today and 55 at time of diagnosis last October) with similar markers - unmutated and intermediate risk. I am considered very fit with no other health issues. I went on watch and wait when diagnosed and then all hell broke loose in April when I became very anemic and needed treatment ASAP. I wish I had started doing the research you are doing today right away when diagnosed but I didn’t as I assumed I’d have some time before I needed treatment, which in retrospect was a foolish assumption. I also was woefully unaware of the complexity of the disease as well as the variety of treatment options and the developing sequencing and combination possibilities. That didn’t give me the time to do what you are doing and logically analyze options. My doctor laid out the initial treatment options to me as either FCR or BR depending upon mutation status. When it was determined I was unmutated I was offered BR and told the next line of defense would be Ibrutinib. The doctor explained while BR wasn’t a cure it was best to start there and keep Ibrutinib in reserve for the future. This seemed logical at the time but now I wonder about that decision. My question to you is have you ever considered BR as your first line defense and if not why not? Thank you

AdrianUK in reply to HopeME

In the UK as far as I understand it BR is only considered for someone who can't be given FCR as it is better tolerated but not as good in the head to head trial. I do get the feeling that the USA do things very differently in different centres and are less tied to guidelines or what the experts believe is best evidence based. To be honest though, if a drug has worked for you there is little point about questioning the decision, better to enjoy the remission and be aware that it is likely (especially if you are unmutated) that you will need something else so be ready. Do you see a CLL specialist? It is well worth doing that in advance of you needing treatment if you can so you can be clear what you want to do at the time. Though as Haribear points out things change all the time, which is one the reasons to see a true specialist as they have some hope of keeping up to date.

HAIRBEAR_UKFounder Admin

Keeping options open, what is available at the time when needed will be time to consider, until then, upwards and onwards :-)

Good luck with your own exploration


NewdawnAdministrator in reply to HAIRBEAR_UK

I hadn’t realised you may be back on the treatment trail Nick. Good luck with this...you’re well placed to know and access the best options.



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