A new generation of chimeric antigen receptor (CAR) T-cell therapy, HD-CAR-1, is showing promising efficacy and safety results in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The early- to mid-stage study, published in Leukemia, indicates that this third-generation CAR T-cell approach could offer a new treatment avenue for patients who have exhausted other options.
Efficacy of HD-CAR-1 in Heavily Pretreated CLL
The study involved nine patients with relapsed or refractory CLL who had previously received a median of five prior treatments, including Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based regimens. Three months after treatment with HD-CAR-1, six patients (67%) achieved a complete response (CR), with five (83%) demonstrating undetectable minimal residual disease (MRD).
After a median follow-up of 27 months, 69% of patients were still alive, and the progression-free survival (PFS) rate was 30%. Achieving a CR was significantly associated with better PFS, with a median PFS of 12.1 months for patients achieving CR compared to 3.8 months for those who did not (P = .024).
Addressing the Challenges in CLL Treatment
"Over the past two decades, the landscape of CLL therapy has undergone a significant transformation... However, challenges persist as in particular patients with genetically high-risk CLL tend to develop resistance to these targeted therapies with a consecutive dismal outlook," the researchers noted. Second-generation CAR T-cell therapies, like lisocabtagene maraleucel (liso-cel; Breyanzi), have improved outcomes in B-cell malignancies, but responses in CLL have been less robust compared to other indolent B-cell lymphomas.
The third-generation CAR T-cell therapies aim to overcome the exhaustion observed with second-generation options by modifying the CAR vector to include two costimulatory domains, enhancing expansion and persistence. The low CR rates observed in trials of second-generation CAR-Ts in CLL prompted the researchers to attempt debulking of leukemia cell load prior to HD-CAR-1 treatment.
Safety Profile
The safety data from the study revealed one case of grade 3 cytokine release syndrome (CRS), with overall CRS occurring in seven patients. Notably, there were no cases of neurotoxicity. Immune effector cell–associated hematotoxicity (ICAHT) was observed early in eight patients (89%), with one patient experiencing grade 4 ICAHT. Late ICAHT occurred in three patients (one grade 1 and two grade 2), none of whom required granulocyte colony-stimulating factor therapy.
These findings contrast with data from the pivotal liso-cel trial (TRANSCEND CLL 004), which reported grade 3 CRS in 9% of patients and grade 3 neurological events in 18%.
