The issue of ibrutinib resistance may be becoming an increasingly important issue. More and more of us are doing great with our BTK inhibited, but we still have residual disease and if you are similar to me with bad markers such as clonal diversity, 17p deletion, 11q deletion, and have a history of having been heavily pretreated (I have the first three for sure and many would say the 4th with my bone marrow transplant), then the fear of a resistant sub-clone starting to act out, while still not the case for most of us even with the worst of the worst disease, is based on a growing reality of a droopy Kaplan-Meier (KM) Curve. In a study out of OSU published in NATURE in early 2014, you can see the downward drift in progression free and overall survival for those of us that are 17p deleted. The curves are way better than anything else out there, but they are hardly perfect.
This whole ibrutinib resistance issue might be largely obviated in the future by moving the new therapies up to frontline status. Dr. Furman and I both agree that is the direction we need to encourage with appropriate trials and struggles with insurers to pay for these drugs in all treatment-naive patients.
Since this video interview at ASCO 2014 with Dr. Rick Furman of Weill Cornell, was recorded and edited by Andrew Schorr and his team at Patient Power, idelalisiib has been approved for CLL (see this post for discussion of its labeled indication) as predicted by Dr. Furman, and ibrutinib was approved for frontline therapy in 17p deleted patients (see this post).
YEAH to both!
New mathematical models that consider evolution of resistant sub-clones have been published by Dr. Burger out of MDACC and a high powered mathematical team headed by Dr. Natalia Komorova out of UCI.. Similar research, but this time using deep genetic analysis of the cancer’s evolution over time by Dr. Cathy Wu from Dana Farber was presented at AACR 2014 Hematologic Malignancies Conference. For more information on this topic see part 1 and part 2 of my interview with Dr. Wu.
Dr. Furman also mentioned two promising new BTK inhibitors, ACP-196 and ONO-4059. Click on the drugs’ names to be linked to their currently available trials. We are just in the first chapters, but it is looking that the stories they will tell should have very happy endings. Please consider trials that offer these drugs among your treatment options.
Here is my ASCO 2014 interview with Dr. Rick Furman.
Also there is a small but significant cohort of FCR patients that do great for years and years. There is a rapidly growing cohort of patients taking ibrutinib and other small molecules, now with more than four years of data, that should continue to do well year after year.
I am so happy for all these patients. But I worry about the minority who won’t do well, who will relapse. I am not giving up on my plea: Don’t leave us stranded on 3rd base. Get us to the home plate of a cure with a follow up therapy.
We discuss obinutuzumab and ABT-199 as mop up therapies.. Maybe it will be cirmtuzumab, a new ROR1 mAB discussed in my recent post with Dr. Kipps from the very same meeting. We will only find out with clinical trials.
Brian Koffman 9/27/14 Updated 3/19/15