Drs. Chadi Nabhan, Catherine Coombs, Alexey Danilov Highlight CLL Abstracts of Note at ASH 2023

Chadi Nabhan, MD, MBA, FACP, host of The HemOnc Pulse, stopped to chat with Catherine Coombs, MD, an Associate Clinical Professor at the University of California, and Alexey Danilov, MD, of the City of Hope National Medical Center, about important abstracts in chronic lymphocytic leukemia (CLL) presented at the 65th American Society of Hematology Annual Meeting & Exposition.

First, the trio discussed the US Food and Drug Administration approval of pirtobrutinib for CLL, which was based on the phase I/II BRUIN trial. That trial included patients with CLL who were treated with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

“The efficacy is extremely impressive,” Dr. Coombs noted. “Pirtobrutinib is such a safe drug, so even with a longer follow-up, we’re seeing very good safety signals. I’m very thankful that this drug is now more widely available, and I’ll be looking forward to future development of this drug, maybe even moving it to earlier lines of therapy.”

“I think the approval of pirtobrutinib in this patient population is very timely,” Dr. Danilov added. However, he also noted that while this drug works in BTK C481S-mutant disease, novel mutations can emerge, such as T474. “Resistance to this drug will again be a problem after [progression-free survival (PFS)] of maybe two to three years, and we will need additional options in that setting as well,” he explained.

Next, Dr. Danilov brought up the TRANSCEND trial, which studied chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory CLL. Dr. Danilov noted that while CAR-T is a very effective agent in a subset of patients, with a complete response rate of 20% for patients who have been exposed to a BTK inhibitor, physicians should be selective about who receives the therapy due to the unique toxicities associated with CAR-T, such as cytokine release syndrome.

“I think we can do better,” he added. “I think we need to look for strategies [for] how to enhance CAR T-cell efficacy in CLL patients.”

Dr. Coombs noted two challenges unique to CLL that explain why it may be harder to treat compared with other aggressive malignancies, such as diffuse large B-cell lymphoma. First, inherent T-cell exhaustion decreases the efficacy of patients’ T cells. Secondly, patients in the TRANSCEND trial have received multiple prior lines of therapy across a decade.

“CLL patients have been beat up for so long,” she said. “I think it was a very challenging population.”

Finally, Drs. Coombs and Danilov discussed the FLAIR trial, which compared ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab treatment in patients with CLL. While ibrutinib plus venetoclax improved PFS and overall survival, there are still unanswered questions surrounding one of the trial’s secondary endpoints, measurable residual disease (MRD).

“This study will not necessarily answer whether MRD-based therapy adjustment is the way to go,” Dr. Danilov noted. “At this point, we still don’t know how to use MRD outside of a clinical trial…but it is an interesting approach to these patients.”