Dr. John Byrd out of Ohio State University (OSU) had done much of the research on both ibrutinib and acalabrutinib. He also has been my treating physician for the last 7 years.
Ibrutinib was the first BTK inhibitor, an important part of the pathway that B cells use for “talking” with other cells. It blocks the B-cell receptor (BCR), in other words blocking how the CLL cells communicate. Since CLL cells live to communicate, when their raison d’etre is gone, they die off, usually rather slowly compared to traditional chemotherapy.
Ibrutinib is highly effective and generally very well tolerated. And it works well in all varieties of chronic lymphocytic leukemia, including the tough cases of those of us with del 17p. As a result, it has revolutionized the treatment of CLL, but unfortunately some folks can’t tolerate it due to side effects.
Acalabrutinib is a second generation BTK inhibitor that has more of a focused target on BTK and so may have fewer side effects.
- The research presented at ASH 2017 included 134 relapsed and refractory CLL patients who had had an average of two prior therapies.
- With a follow-up now of over 24 months, the overall response rate (ORR) climbs over time to 93% with only a 2% complete response CR, similar to the ORR seen with ibrutinib.
- At the time of analysis, 78% were still on therapy suggesting it is generally well tolerated and effective for most patients
- Most side effects were mild and including diarrhea.
- Headaches were a new problem seen in 46% of patients with acalabrutinib, but they tended to be mild.
- There is an ongoing trial comparing acalabrutinib to ibrutinib but until it reads out in years from now, it is difficult to make true comparisons between the two in terms of safety or efficacy in treating chronic lymphocytic leukemia.
Acalabrutinib is not yet approved to treat CLL, but it is approved for a similar B cell lymphoma, Mantle Cell Lymphoma and is recommended in some CLL guidelines as a possible option.
It would not be helpful for those who progress on ibrutinib, as it works the same way and binds at the same site, but it would be a strong option now for those who respond but cannot tolerate ibrutinib. Whether ibrutinib’s “off target effect” are a problem or an advantage or both is not yet clear. Here is a link to a discussion of these issues by Janssen’s Mark Wildgust.
CLL patients need several options and I look forward to acalabrutinib receiving approval for a broad range of chronic lymphocytic leukemia indications.
For some background on just how far we have come with novel targeted therapies, please enjoy this interview with Dr. Rick Furman from Greece, ESH 2014: https://cllsociety.org/2015/03/esh-2014-dr-rick-furman-discusses-how-the-novel-therapies-demand-novel-approaches/
Here is the link to Dr. Byrd’s abstract from ASH 2017 that he references in our interview:
Here is a link to a much larger meta-analysis of several acalabrutinib trials including CLL and other blood cancer patients, also presented at ASH 2017 by Dr. Byrd:
You can view my interview with Dr. Byrd below or read the transcript here.
We are all in this together
Brian Koffman, MD 6/26/18