A long paper and too much information to be able to summarise in this post but a nice account of current treatments, response rates, trial details and issues of resistance/intolerance.
"Over the last years, targeted therapy with small molecule inhibitors and antibodies has much replaced chemoimmunotherapy for CLL. This paper gives an overview of novel targeted agents used for CLL including resistance development. Continuous treatment can cause the evolution and selection of subclones which leads to resistance towards these novel drugs and disease relapse. Hence, comparison of sequential treatment with combinations and discontinuation of therapy are important aspects which need to be investigated. This paper focusses on approved drugs since they they are the ones used in clinical practice."
That was a good read. Nothing really new, but a nice summary of where we are.
The article implies resistance to btk and bcl2 drugs is inevitable, but there was little data offered on treatment naive patients in that respect. We know that people with prior treatments who are relapsed are a difficult group to treat. But it’s not clear to me from the data presented in the article that resistance to the new drugs for first time treaters is inevitable.
There is very little data in that regard on venetoclax. With ibrutinib, however, we are seeing more and more people not develop resistance, at least not in the first 8 years of the data for ibrutinib with treatment naive patients.
If the PFS at ten years out for treatment naive patients is over 50% with ibrutinib, which I think it will be, might this group never need another drug? Only more time will tell. With FCR there was a plateau at about ten yrs out where people stopped progressing. Maybe the ibrutinib or venetoclax PFS curves flatten out to.
Jeff, I think there will definitely be a group of treatment naive patients who never develop resistance to Ibrutinib (or other BTKi's) so will never need another treatment.
However, for nearly half of all patients started on Ibrutinib, the side effects lead to stopping or pausing treatment. This massively affects outcomes and so we need to move to the BTKi's that have a less toxic side effect profile both to reduce the cardiac toxicities and also help people with compliance .
We also need to make sure people are properly tested prior to treatment in terms of genetics, mutation status etc etc so that we understand which patients will have the best response to this treatment.
As with all treatments though, those will the 'best' genetics will always do better than those with high risk. The search for the cure goes on and I think it will be a version of CAR-T or CAR-NK, so safe it can be given very soon after diagnosis but it probably will not happen in our lifetimes.
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