This year, combination therapies were a hot topic at the American Society for Hematology meeting. In this video, Dr. Brian Koffman interviewed Dr. Neil Kay, a Professor of Medicine and a hematologist at Mayo Clinic. They discussed combination therapies for treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), focusing on the combination of ibrutinib plus venetoclax.
Why are doctors interested in using combination therapies?
Most of the research on CLL/SLL uses combination therapies, which usually combine two or three targeted agents with different mechanisms of action. For example, ibrutinib is a BTK inhibitor that has been combined with the BCL2 inhibitor venetoclax. Both BTK and BCL2 are proteins that are key to the survival of CLL/SLL cells, and by inhibiting both at once, you are blocking two pathways that help cancer cells survive. Preclinical studies also indicate that ibrutinib and venetoclax may work synergistically, meaning their combined effect is more significant than their individual effects. Hopefully, hitting cancer through multiple pathways will eliminate more cancer cells and get patients into deeper remissions with limited-duration therapies.
What have clinical trials shown?
Many different clinical trials were presented at ASH 2022, including several on the combination of ibrutinib plus venetoclax. We have covered many of these:
- Ibrutinib plus venetoclax as a first-line therapy: CAPTIVATE (phase 2), GLOW (phase 3), FLAIR (phase 3), and a phase 2 trial l from MD Anderson Cancer Center
- Ibrutinib plus venetoclax for relapsed/refractory CLL/SLL: CLARITY (phase 2)
- Adding venetoclax to ongoing ibrutinib therapy: Phase 2 trial from MD Anderson Cancer Center
The data from these trials consistently show that the combination of ibrutinib plus venetoclax induces clinical remissions in most patients. Those remissions will likely last for a long time (though it is still too early in these trials to say for sure). Most patients can reach undetectable measurable residual disease (uMRD) in the blood and/or bone marrow, which predicts longer progression-free survival. Keep in mind that many of these trials are still ongoing.
Are there any additional toxicities when you use combination therapies?
When you combine multiple drugs, there is always a concern that this may cause new side effects or more severe side effects that would make the combination hard to tolerate. Thus far in these ongoing trials, there have not been any new safety signals that would cause alarm. The safety profile is typical of what you expect from ibrutinib and venetoclax.
Who should be using combination therapies?
This question is still up for debate. Several trials are looking at ibrutinib plus venetoclax as a first-line therapy for patients who have never been treated. However, it is unclear if this powerful combination therapy would be an appropriate first treatment for all patients. It may be better to reserve it for younger patients with high-risk features or patients with relapsed/refractory disease. In addition, we still don’t know the best way to sequence all these therapies that are now available for treating CLL/SLL.
Interestingly, patients with prognostic markers traditionally associated with worse outcomes (deletion 17p, TP53 mutation, etc.) seemed to respond just as well to combination therapy as patients without these markers. In addition, patients with unmutated IGHV (usually a poor prognostic marker) seemed to do slightly better than those with mutated IGHV.
What is the role of MRD?
While the MRD results from these studies are pretty exciting, all the studies used different methods to assess MRD. Before MRD measurement gets implemented in clinical practice, researchers and clinicians must reach a consensus on how and when MRD should be evaluated and what methodology should be used. There also needs to be a discussion of integrating MRD measurement with traditional clinical evaluations (history, physical, imaging, and bloodwork).
Links and Resources:
Watch the interview here:
