ASH 2018: Dr. Kipps on antibodies and Venetoclax resistance

[bkoffman]

Venetoclax was changed how we treat CLL, but it doesn't work for everyone and it doesn't always continue to work. In the first part of my interview with Dr. Kipps at ASH 2018, he discusses resistance and how to possibly avoid it: cllsociety.org/2019/04/ash-....

Dr. Kipps is the master of analogy- this time whack-a-mole.

I must admit that I am missing the commentary and context that Chris Dwyer would have brought to this post about this topic.

This Saturday I will be in Minneapolis for the CLL Society/Mayo Educational Forum, so if you are attending please say hello. Mayo has a ridiculously strong faculty lined up.

Stay strong, we are all in this together, through all the good and the bad.

Brian Koffman -CLLSociety.org

[cajunjeff]

Brian, thanks for posting this informative interview. I have a question about the following paragraph that appears in your summary:

"Resistance is the scariest word in the English language for chronic lymphocytic leukemia patients. Novel agents such as ibrutinib and venetoclax are breakthrough drugs to control and perhaps eliminate CLL, but not for everyone. Between a fifth and a third of CLL patients using these novel agents develop resistance—the drugs fail to control the disease after a period of time".

Is the above another way of saying that about 75% of the folks that take ibrutinib and/or venetoclax will never develop resistance and can expect that these drugs may offer a lifetime of control for their cll?

That's one thing I have never been clear on, that is, can ibrutinib (or venetoclax) be a forever drug or is resistance at some point in time inevitable? As a first time user of ibrutinib I am hopeful that one day something could be added to it to put me in remission and get me off drugs. That said, a great result for me would also be knowing that I could control my cll forever with an oral pill a day. Or do they just not know yet if resistance is inevitable?

My other question is of the nitpicking variety. Why would someone not write "about a fourth" instead of somewhere between a "fifth and a third".

Thanks again for the informative information. I have been very curious about the question of whether these drugs might work forever. Jeff

[Hidden in reply to cajunjeff]

i did read on a few of the trials that p17 and p53 and a few others i can't remember have shorter effective times than those with better ones.

[cajunjeff in reply to Hidden]

Yes thanks. I do understand that resistance can be more likely with 17 p and that resistance can be predicted to some extent if we have certain other mutations.

What I am not clear on is if most people will be able to take drugs like Ibrutinib forever. I do know at 7 years out with treatment naive folks that 80% or so are still doing well on ibrutinib (that’s the 80% that tolerate it, some quit not due to resistance but because of intolerable side effects).

I am curious what the thinking is as to whether ibrutinib can likely be a forever drug, assuming something better doesn’t come along that lets us stop all meds.

They might not no the answer, but I have seen Dr Furman quoted as saying Ibrutinib might be the only drug some people will ever need. That’s why he doesn’t see a role for chemo for anyone.

[Hidden in reply to cajunjeff]

since only 7 years since introduced-i think-no way to tell until 20years have passed. I also expect ibrutinib to be replaced with new generations of formula.

[cajunjeff in reply to Hidden]

I understand the data is young and that second generation btks are being developed.

My question is directed to Dr Kipps and Dr Koffman to clarify the statement that only a fourth or so develop resistance to Ibrutinib and provide insight if they have some expectation (or not) that most folks will never develop resistance.

Doctors make predictions on developing data all the time. If the curve which shows resistance begins to flatten, that can be an indication if resistance hasn’t appeared in a certain time it may not likely occur in the future.

When the curve on people progressing on fcr began to flatten at ten years, many were predicting it was a possible cure. Most of those people have made it to twenty years now, so there was merit to assumptions made on developing data.

[bkoffman CLL CURE Hero in reply to cajunjeff]

Unlike with FCR where we have 20 years of data in a small group of IGHV mutated patients with the best prognostics, in Ibrutinib we rarely reach U-MRD and our data only goes out about 8 years. We just don't know what will happen.

[Big_Dee]

Hello bkoffman

Thank you for helping fill the hole left by Chris Dwyer. For many of us Chris was our biggest link to ongoing CLL research and hope.

[Lola69 in reply to Big_Dee]

Miss him so much!

[Smakwater]

Echoing cajunjeff and Big_Dee; Thank You Dr. Koffman, Your contributions to our community are greatly valued.

Here are a few complimentary blasts from the past. According to the Australian CLL research team the primary culprit for venetoclax resistance is GLY101Val.

The strategy discussed - Gene sequencing for observing molecular evolution of CLL.

cllsociety.org/2018/06/ash-...

The observation outcome - GLY101Val.

onclive.com/peer-exchange/c...

ncbi.nlm.nih.gov/pubmed/305...

JM

[bkoffman CLL CURE Hero in reply to Smakwater]

I think GLY101Val is just part of the evolving story of Venetoclax resistance. Brian CLLSociety.org.

[Smakwater in reply to bkoffman]

I agree.

Not necessarily the most desired outcome, although, I suppose that it would be a expected pattern in drug development to see increased resistance over a greater period of time with an expanding pool of genetic variants.

Two strong points for venetoclax are that it has a relatively low toxicity profile, and it buys time while other promising therapies are rapidly advancing.

A form of substantiated Hope.

JM