I’d be really interested in other people’s thought processes about this. I’m not a haematologist, and this is all in the realm of theory and so may not stand up to clinical trials or the real world. I guess in a way I’m trying to synthesize a philosophy of treatment.
1. Why do we watch and wait?
As I understand it, the reason is simple. The risks of the drugs currently available (especially FCR chemo) is too great for the benefits that an early cll person would achieve. What I’ve been told also is that whilst some people see an improvement in fatigue for example with treatment, some don’t. And some actually experience a worsening energy levels not just during treatment but after. And so for the moment the feeling seems to be that even the newer more selective drugs are not selective enough to warrant their use in early patients.
2. Why FCR may still be best for some patients?
There’s a good reason we are still running a trial in the uk which compares FCR to ibrutinib alone or in combination: we don’t yet know what is best for everyone.
FCR is chemo. But it is not as harsh as some chemo. Nonetheless there are known risks of dna damage and the risk of later cancers. Why would anyone want it you ask?
Well we know that many people (not the 17p deleted, however) do well on FCR. It can buy as much as a decade in some cases before treatment is needed. Often less of course. But during that time of remission new drugs are coming out, and we will be becoming more skilled at using drugs that we already have. Best to delay the use of the new drugs some may say.
3. Sequential treatments
Often a treatment flow will go something like FCR, hopefully get a response and wait, then ibrutinib hopefully get a response and wait, then if you get another relapse venetoclax.
The idea here is that as you use a drug, after a while the illness evolves to be more aggressive and resistant to that treatment. At which point you don’t repeat the old treatment or continue it you switch.
This is all assuming we can’t cure CLL outside of a bone marrow transplant.
But some of the long term data with FCR looks suspiciously like it just might be a cure. People seem to stop relapsing after seven years. In other words if you make it that long, it’s possible you will never relapse. We still don’t know yet if these people will relapse say twenty years down the line. But for that group, they are certainly at least getting a long remission.
4. Combination treatments
FCR has evolved as the gold standard chemotherapy due to trials that showed clear superiority in combining these three agents (one of which isn’t technically chemo) over using only one of them.
Logically this makes sense as if you are hitting a person’s illness simultaneously in three different ways it is less likely to develop resistance and just might be eradicated completely is the hope.
5. What about combining the new treatments?
There’s been a lot of excitement about the combination of ibrutinib with venetoclax. Since these drugs are both specific to killing lymphocytes but do so in different ways perhaps this combo could be the new FCR. Speaking of FCR another option might be to combine ibrutinib with the R of FCR, rituximab. Or who knows maybe use all three together.
If we combine all the main weapons in our arsenal together do we get a better, deeper,longer response? Or possibly even a cure? Or do we just use up all our available bullets so that when the next relapse happens our cancer is resistant to all the currently available treatments?
6. What about a softly softly approach?
A few people in forums are talking about doctors who have tried gentle therapy. For example R on its own, or low dose ibrutinib. Sometimes in people who are not yet really sick enough to justify treatment under normal protocols. Will this help people as some report? Or is there a risk that this softly softly approach leads to clonal evolution And resistance developing early in the disease?
It feels like a bit of a minefield doesn’t it?
My own gut feeling for what it’s worth is I’m not sure whether FCR or some form of more modern treatment is better for me when I need treatment. I’m 13q but unmutated. So the jury is out on whether FCR will give me a good response for all the pain and risk associated with it.
But do I want to take the responsibility on my own head for rejecting FCR and trying to get it via my private insurance when I need treatment? (Yes some do have some private insurance in the uk.) Not sure really.
This is why I keep banging on about the UK FLAIR trial which I think needs a lot more publicity than it currently gets.
If you are cautious about FCR like me, you only have a 1 in 4 chance of getting it if you enroll. But the other three arms all contain ibrutinib (one monotherapy, one with rituximab, one with venetoclax).
The risk of being in a trial like that is you get the “wrong” arm. But we don’t know what the “wrong” one is. FCR may yet turn out to be better than ibrutinib in newly treated patients.
But, if I get the “wrong” arm for me, I was reassuring myself that the NHS would later on fund the other treatment. As I’m sure are many already in the trial. It’s this comfort that I’ve been preparing myself with that the recent funding decision takes away! Some of us like to think ahead and have our options clear. I know that’s not for all of us. But it is for me.
I actually wish there was a clearer road map. That we knew exactly what was the best treatment for me and when I’d need it. But we have to live with the uncertainty we have. And hopefully make it more certain for future generations of CLLers
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