What is the best first-line treatment combination for CLL?

[AdrianUK]

I’m taking the liberty of cross posting this post I wrote from the UK CLL Facebook group.

I’m trying to get my own head round what are the best first line treatments for CLL. Not least because I know that I’m obviously quite likely to need treatment at some point.

I believe in the power of many brains being better than one, so I am very keen to hear if I’ve missed something or got something wrong below. And to hear others personal views or perspectives.

I had a quick look at NICE pathways (see pathways.nice.org.uk/pathwa... ).

The take home message I get is that NICE has recommended FCR as the sole first line option for patients without 17p/TP53. Bendamustine (B) is allowable only if FCR is not suitable.

None of the newer small molecules are allowed as first line options in England by NICE unless you have 17p/TP53.

I’d be interested to know if anyone has managed to get NHS or private insurance to fund small molecules rather than FCR in any other circumstances as their first treatment.

This all makes us very different than the USA. And I think we in the UK need to be very aware that these decisions are largely financial. Some CLL experts in the USA are moving completely away from offering FCR first line. Now, having said that I’m not 100% sure if the evidence fully supports that course of action either quite yet, but I may be wrong on that.

I’ve not read as much as I would like. And the NICE evidence reviews linked there are worth us reading if we want to really understand the data.

But from what I have read I’m getting the idea that the following is probably generally true. Would be interested in others comments on this as I may have missed something.

FCR

Pros: time limited treatment, can introduce long-term remissions that can look almost like cures.

Cons: it’s chemotherapy and so you are essentially taking a poison and trying to kill cancer cells but not too many of your own. It has many side effects including the possibility of causing the CLL cells to mutate / evolve and become more aggressive. Hence taken too early and when it’s not yet needed it may even hasten death. It can also because it is chemo also trigger other secondary cancers years later. It also doesn’t have as good a chance to work if you have 17p/TP53 or possibly also if you are unmutated.

Small molecules

Pros: great responses seen even in those who failed chemotherapy especially with both ventoclax (V) and ibrutinib (I) given in combination. It seems that very good responses that look like a cure are also potentially possible. Perhaps if given earlier on when the CLL burden is lower it may even be possible to induce a genuine cure by literally wiping out all the cancer cells.

Cons: long term and possibly life long treatment may be required. Some very positive eight year data is the longest we have at the moment for any of these medicines as far as I’m aware. It’s possible (maybe even likely?) that evolution of CLL to more aggressive and resistant will also happen at some point with these medicines too. One argument against their early use might be, if one of these drugs or a combination of them will buy you a five to ten year remission and you want to live for twenty years or more you might be better to either continue in watch and wait for as long as possible (but not too long...) or be treated with another bullet rather than reaching first for the golden bullet.

As far as I understand it, with the possible exception of very aggressive disease we aren’t usually offered bone marrow / stem cell transplants as first line treatments.

In summary we know that FCR is a very good treatment for some. We know that the newer drugs are also good for many, and indeed are clearly better if you have 17p/TP53, might be better if you are unmutated, and we are not really sure whether FCR first then small molecules or small molecules first then FCR / other chemo / transplants may be better.

When there is genuine clinical uncertainty because of the lack evidence base for a choice between treatment combinations a clinical trial is the best option. Best not just for the patient because there is actually no way of knowing which treatment combination is best for them so letting a computer choose is just as good as a human, but also for the rest of us since it is clinical trials of the past that led doctors to conclude FCR was the best cocktail of chemo drugs available to us. There’s an argument for saying we owe it to those who went before us and put their lives on the line to prove FCR works to similarly help future generations know in which circumstances it should now be replaced.

Since we are now in a transition time where we have one well known clear favorite chemo combination and several newer small molecules, more clinical data is desperately and urgently needed to show us what is the best first treatment combination for future patients.

Given all that, my conclusion is that when I do need treatment I definitely need to consider being part of the FLAIR trial.

Why? Well I’m not personally that keen on taking chemo (is anyone?) but we don’t really know if chemo or the newer drugs are better for those without 17p/TP53.

The options in FLAIR are FCR, IR, I, IV. Any of those could turn out to be the best combination.

Also if you are taking one of those combinations in the trial and it doesn’t work, you can obviously move to a different combination outside the trial at a later stage.

So, fellow UK CLL warriors it would seem to me (and again, have I missed anything?) that if you are offered treatment for CLL you should definitely ensure you know your genetic status and particularly if you have 17p/TP53. And if you don’t, then it may be a good idea to at least consider asking to be referred to a Centre offering FLAIR for a review and discussion of that trial before accepting other treatment.

See lymphomas.org.uk/lymphoma-t... for more information where you can even refer yourself. If you do want to be referred you can ask your existing haematologist or your GP to refer you to one of these sites for a second opinion and discussion of the trial without committing yourself to definitely take part.

[zaax]

I suspect its down to price. I understand that Ibrutinb is £300 for 90 pills (India prices) which makes it more expensive than the one off FCR, which can last for years. As CART-T is a one off and if they can get it in to a pill or a lot cheaper option than it is now. It might be cheaper not to W&W and as there are less CLL cells in the body it might be less dangerous.

[Newdawn Administrator]

A very useful and comprehensive post Adrian and highlights the dilemma many of us face in the U.K. as we approach the need for first treatment. Like you, I’m trying to get my head round combinations and complications with the ever present fears for the future should FCR be the only option.

I’ve not heard of much success in trying to get the NHS to pay for small molecule treatment first line over FCR except for the 17p/TP53 deletions and unless you have a super duper private insurance, I’d think it was a non starter for private funding.

Clonal evolution is a serious concern for me with FCR but I also fear the side effects of Ibrutinib with having existing joint problems.

I’m not yet at treatment stage but sense it’s coming to a place near me within the next year or so unless my spleen stabilises massively in the interim. It’s starting to gobble up the platelets and is significantly enlarged.

The link to the Flair trial is very helpful and like you, my mind has taken me through the various combinations and pitfalls with no clear sense of what would be right. However, I haven’t as yet had cytogenetic testing but have to hope I’m not in the higher risk bucket.

Having heard Prof Hillmen speak recently however, I’d consider myself very lucky to get onto the Ibrutinib-Venetoclax arm.

Best wishes and hoping you’re a long way off treatment yet. As I recall, you’re not a longer term W&W’er as yet? Well done for doing the homework and posting your summation however.

Newdawn

[AdrianUK in reply to Newdawn]

Thanks Newdawn. If you looked only at my lymphocyte count which is around 20 and has been for the eleven months since I was diagnosed, or at my lymph nodes which are only slightly enlarged, or at my spleen which is still normal, or my other blood counts, you would think I was an early stage A and had loads of time before treatment is required.

However, I presented during a slow to respond pneumonia that led to sepsis. I have had two episodes of shingles over the years before diagnosis. And since diagnosis I have seen a drop in my antibody levels to below normal, which might help explain the recurrent throat infections, I’ve had cll lymphomas growing in my tonsils and lingual tonsils and have had to have two throat operations (one of which was as an emergency since I was chocking). I’ve also developed oropharangeal and toenail fungal infections, oh and I nearly forgot, had a precancerous polyps removed from my bowell. And I’m so fatigued I can’t work, use a stick, and struggle to get through a normal day even without work. So my specialist calls this a stormy course. And it does make me wonder “what’s next...” and to think it’s possible treatment might come sooner than I might hope. I’m 13q but unmutated. And just turned 47. Big family. Used to work as the medical director for a pharmaceutical company. On top of that ran a blog and published two books, and served as part of the leadership team of a large church. All that has gone. I just get thru the day, try and help a couple of people, do what I can around the home, and very occasionally write. If anyone ever tells me this is the best kind of cancer I’m going to struggle!

[AnneHill in reply to AdrianUK]

Hi, Iv just replied before Iv seen this reply. Sorry you are so unwell. I have introvenus immunaglobulin. Seems I have been lucky apart from the fatigue which like you has taken over my life. Good luck.

[AdrianUK in reply to Newdawn]

Regarding the IV arm, I’m in two minds theoretically. On the one hand maybe we should do that and something like rituximab and just wipe ALL those cll cells out and go for a cure. But if you didn’t get a cure only a remission, what would happen when the cells grow back. Would there be clonal evolution? What would you reach for then, FCR? To me this is a genuine dilemma and we don’t know the answer. That’s why FLAIR is so crucial and seems to me to be asking exactly the right question.

[Newdawn Administrator]

I was just about to reply with more details of my personal journey Adrian but I see your post isn’t locked to the community.

Listening to Prof Hillmen speak at the recent CLLSA event in Leeds and listening to the feedback from one of his patients, I was deeply impressed and enthused by the ‘kill off and clear out’ effects of Ibrutinib & Venetoclax but obviously we don’t have the longer term data yet. No treatments are without some price to pay. Look very promising however.

Newdawn

[AdrianUK in reply to Newdawn]

Thanks Newdawn. I’ll look forward to hearing more in the private community. It’s good that some of our posts remain open so new members can chance across them on the internet.

[AnneHill]

Hi, I found your summary really helpful. I had FCR 7 yrs ago and was in remission for 5 yrs. I imagine it wont be long before Im given Ibrutinib. The advantage of FCR is that the treatment is for 6 mths.Maybe I was lucky to have a 5 yr remission. It was the best at the time. Hopefully when you need treatment things will have moved on. I would consider a drug trial. Iv got debillitating fatigue and I would love to find a cure for that. If you feel well dont dwell on the Cll. It may be a while before you need treatment. Enjoy life. Anne

[AdrianUK in reply to AnneHill]

Thanks Anne. Unfortunately I don’t feel well. Fatigue to the point of using a stick and unable to work. Repeated throat infections. CLL Lymphomas in tonsils and lingual tonsils. I worry sometimes about what it will be like when I’m no longer in “early” leukemia.