This is a link to a paper that was released online a couple of months ago. I thought I’d take the opportunity to highlight some things from it and point out what we should and shouldn’t conclude from it. I’d be interested also to know any of your thoughts on this.
Note this is an unlocked post so do not reply with anything that is personally identifiable, or you don’t want to be available via a google search. Feel free to DM me any comments you would like to make more privately.
ncbi.nlm.nih.gov/pmc/articl...
First up, a lot of people still get hung up about whether or not a study is randomized or not. Whilst randomised trials are very helpful and won’t be going away any time soon, they are also highly unlikely to ever be used in such long term as five years. Or at least not if one of the controls is a placebo.
One of the exciting things in early stage CLL at the moment is that the FLAIR trial in the uk will actually follow up a large number of people who have been randomized between several different active treatment arms. But we won’t have results from FLAIR for a very long time.
A study like this which just reports outcomes from open label treatment with one medicine gives us really useful information whilst we are waiting for more data in the future.
Because it is not randomized, to interpret it requires us to have a sense of what the natural history would have been before ibrutinib. Im no expert on that. But the feeling is that especially for the relapsed patients these results are very good.
But we must be careful not to make inaccurate inferences. So for example the fact that a higher percentage of people seem to respond if they are treated early in the disease doesn’t mean that ibrutinib is not any good for those later in the disease. If most of the patients who were treatment native would have continued to do well even without this treatment, it could still be the case that the more unwell people are actually benefiting more.
To illustrate my point. 92% of treatment naive patients remained progression free after five years. Let’s assume for arguments sake if treated with alternative treatments that figure was 80% that would mean really only 12% of people specifically benefited from the new treatment (tho if they were spared the side effects of FCR perhaps the rest did benefit too...).
For those who had already relapsed the progression free survival rate was lower at 44% but if the natural history of this group was that say only 10% of them would have got his outcome without ibrutinib a full additional 34% of them would have benefited.
Of course the biggest weakness of this paper is that it doesn’t attempt to even guess what the natural history was of each group. It’s too bad that we didn’t have historical controls to compare to.
But I guess the authors hope that most of the readers will have a rough idea of what CLL progression looked like before ibrutinib. And that’s where the cll experts come in. As a patients it’s hard for us to fully assess this paper. But if someone has treated cll for years they will have a good idea of what the true response rates would be given best treatment before Ibrutinib came on the scene.
Perhaps one of the most impressive things is that ibrutinib seems to keep benefiting people with response rates actually going up with long term treatment. That sounds good to me, and perhaps a little bit surprising.
One of the best bits of this paper in my view is the introduction. It nicely sets up the problem that ibrutinib sets out to solve. Patients who relapse after FCR treatment don’t do well it seems. So there is a real need there.
Another crucial point is what is the acceptability of the drug to patients. The fact that 77% of TN and 39% of relapsed stayed on for four years or more is certainly impressive and may be higher than would be seen outside a clinical trial setting (remember all these patients were first selected rigorously as being suitable for the early trials and so are not exactly typical).
So overall I am encouraged by this trial. The long term overall survival and progression free survival seems very high even given the caveat that we don’t know what it would be with other treatments.
Does it convince me that I definitely will need to take this drug as my first one? Well, the main concern I have is what happens at ten years or twenty years?
Does the ibrutinib eventually stop working? And if FCR could have bought me a few years before ibrutinib have I then lost those years?
Or would we be better hitting the illness harder with a combination of specific drugs say ibrutinib plus either rituximab or venetoclax so it’s completely wiped our and doesn’t have the chance to evolve and come back.
Ultimately only a long term head to head study such as FLAIR (which includes all the options discussed in this post of mine) will help us understand whether for sure all cll patients should skip FCR in favor of ibrutinib mono or combination treatment.
As tempting as it is to want to avoid chemo (and I do!) what if it still turns out that chemo followed by ibritinib is the best over all strategy in the really long term for some subtypes? If you are in your 40s like me you have a long time left hopefully!
So for UK folks FLAIR looks quite attractive if you aren’t fully convinced by this study or are not able to get ibrutinib even if you want it. But if you just look at the headline figures of survival in this paper and for that matter adverse events ibrutinib monotherapy does look very attractive. No wonder the community is up in arms that the UKs NHs are further limiting its availability. And of course there are many people in the USA and other countries who can’t get it either.
Reading this paper I really get the sense we are on the brink of an exciting world of new treatments. There are others already available and also being studied as we speak.
Having CLL is a lot to do with uncertainty. We are uncertain how long it will be before we need treatment. And then we are uncertain what the best treatment will be. Hopefully future generations will be less uncertain. And papers like this, whilst not the final answer, certainly help point us along the way.
End of FLAIR. No more Ibrutinib. Great improvement!
Potential cure for CLL
