Novel Approaches to Treating Relapsed/Refractory CLL
Insights From: Michael Choi, MD, UC San Diego Medical Center; Matthew S. Davids, MD, Dana-Farber Cancer Institute; William Wierda, MD, PhD, MD Anderson Cancer Center
Matthew S. Davids, MD: I think from a biological standpoint, one of the most exciting combinations is the ibrutinib (Imbruvica) and venetoclax (Venclexta) combination. Several groups, including our own, have shown synergy of this approach in the laboratory side. At the ASH meeting, we saw some very exciting initial results in patients in some of the first clinical trials to explore this combination.
In the relapsed/refractory setting, there’s the study being led by Dr. Nitin Jain and colleagues at MD Anderson Cancer Center looking at this doublet for relapsed patients. It seems to be highly effective: Nearly all patients are responding with very impressive rates of complete remission, MRD undetectability, and excellent tolerability.
The other important study that was presented at the ASH meeting is the CLARITY study, which is led by Dr. Peter Hillmen and his group in the United Kingdom. They are looking at a very similar combination of ibrutinib and venetoclax and seeing very similar results in terms of achieving MRD undetectability without the need for chemotherapy.
One of the things that I think is important about Dr. Hillmen’s study is that it has now become an arm in a large phase III study called the FLAIR study, ongoing in the United Kingdom, which is comparing that combination to older chemotherapy-based regimens and other ibrutinib-based regimens. Those types of phase III studies are really the ones that are going to help define the standard of care for the disease going forward.
William Wierda, MD, PhD: In the relapsed setting, there are new treatments in development that are evolving. One of the recent reports that Dr. John C. Byrd presented at ASH this last year was an update on the experience of acalabrutinib (Calquence) in relapsed patients with CLL. Acalabrutinib is an irreversible binder of Bruton’s tyrosine kinase. It inhibits through binding of the cysteine 481 moiety, and, therefore, it works very similarly to ibrutinib. It has activity in treating the disease. It has a smaller scope of inhibition of kinases. The important point behind this is that perhaps it has a narrower toxicity profile: less rash, perhaps less atrial fibrillation. It’s an appealing agent from the toxicity profile side of things, and, again, it works very similarly to ibrutinib. The report at ASH was a large report of a trial done in patients with relapsed CLL treated with acalabrutinib. Clearly, there’s activity, there’s durability to the activity, and the drug is very well tolerated.
There is a randomized trial that has completed enrollment comparing ibrutinib with acalabrutinib for high-risk patients with 17p or 11q in the relapsed setting. That will be a head-to-head comparison, and we’ll get an idea about the toxicity profile and the efficacy between those 2 agents in what is considered a high-risk category of patients.
It is currently approved for patients with mantle cell lymphoma, and, depending on whether or not you can access it, it potentially affords an option for patients with ibrutinib intolerance in CLL. If you have a patient who can’t tolerate ibrutinib and you still want to use a BTK inhibitor, in the near future we will see acalabrutinib become an option for those patients; that’s probably where we’ll see acalabrutinib first in CLL. There are other randomized trials—not just the head-to-head comparison with ibrutinib. There’s a frontline trial with acalabrutinib, so there will be phase III data that will support the approval of acalabrutinib in the near future.
Duvelisib is a PI3-kinase inhibitor. It was presented at ASH by Dr. Ian W. Flinn in a large, randomized, phase III clinical trial in comparison with ofatumumab. That trial demonstrated improvement in progression-free survival in patients who received duvelisib versus ofatumumab as a treatment for their relapsed disease. It is not yet approved by the FDA. I think they’re undergoing review of the data now, so we don’t know when and whether or not it will be approved. If it is approved, it will be another option among the drugs of that category. The main one that has been approved already is idelalisib, the PI3-kinase delta inhibitor. Therefore, duvelisib may be another option among drugs in that category for relapsed disease.