Dr Porter on Understanding Gaps in CAR T-Cell Therapy for R/R CLL

David L. Porter, MD, director, Cell Therapy and Transplant, Jodi Fisher Horowitz Professor in Leukemia Care Excellence, Penn Medicine, discusses knowledge gaps regarding the optimal use of CAR T-cell therapy for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), as presented at the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium.

CAR T-cell therapies have shown high responses in relapsed/refractory CLL, with some patients remaining in remission for nearly 14 years, Porter begins. Despite the efficacy of this drug class, limited patients will experience this benefit, he notes. For instance, the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) demonstrated high responses with the CAR T-cell therapy lisocabtagene autoleucel (liso-cel; Breyanzi) in pretreated patients for whom no other treatment is effective, supporting the FDA's decision to grant accelerated approval to liso-cel in pretreated relapsed/refractory CLL or SLL in March 2024. However, the complete response rate achieved with liso-cel in the overall population (n = 65) was only 20% (95% CI, 11.1%-31.8%), Porter details.

Improving these response rates is crucial, Porter continues. One promising approach involves combination therapies, such as administering CAR T-cells alongside ibrutinib (Imbruvica) or other BTK inhibitors. These combinations may enhance response rates and durability, he explains. Additionally, long-term follow-up is essential to monitor these patients effectively. Given that CLL is a chronic disease, late relapses are possible, although the likelihood is low among patients with advanced multiple-relapsed disease, Porter adds.

Another critical aspect is addressing the recent concerns about secondary primary malignancies and T-cell lymphomas associated with CAR T-cell therapies, Porter says. The FDA has updated the boxed warnings for all approved CAR T-cell therapies to include the serious risk of T-cell malignancies, highlighting the need for ongoing long-term follow-up. This vigilance is necessary not only for patients with CLL, but for all patients receiving CAR T-cell therapies. These efforts will help address the serious risks and optimize the long-term benefits of CAR T-cell therapies for CLL and other hematologic malignancies, he concludes.