Treatment Advances in Double-Refractory CLL Signal a Shift in Outlook

Novel therapies have led to more options for patients with double-refractory chronic lymphocytic leukemia (CLL), a historically challenging population to treat.

Two pivotal clinical trials have helped reshape the treatment landscape for this disease with additional exciting therapies under investigation, which Susan O’Brien, MD, of the University of California, Irvine, discussed during a presentation at the Pan Pacific Leukemia Conference held July 15-18, 2025, in Lahaina, Hawaii.

The lecture, “Double-Refractory CLL: An Emerging Clinical Challenge,” described how agents, such as pirtobrutinib, lisocabtagene maraleucel (liso-cel), epcoritamab, and BGB-16673, are being explored and used in the treatment of CLL.

Given the Green Light

“We now have two FDA-approved agents (pirtobrutinib and liso-cel) for the treatment of refractory patients with CLL, and there are other agents, which look very promising, that are on the horizon,” O’Brien said in an interview with Blood Cancers Today.

Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton’s tyrosine kinase inhibitor (BTKi), was approved in December 2023 for adult patients with CLL or small lymphocytic lymphoma (SLL) who received at least two prior lines of therapy, including a BTKi and a B-cell lymphoma 2 (BCL2) inhibitor. The accelerated approval was based on findings from the BRUIN CLL-321 study.

In the BRUIN CLL-321 study, previously treated patients with CLL or SLL were randomized to receive pirtobrutinib monotherapy (n=119) or investigators’ choice of  idelalisib plus rituximab (IdelaR; n=82) or bendamustine plus rituximab (BR; n=37). Investigators observed a median progression-free survival  of 14 months with pirtobrutinib compared with 8.7 months with IdelaR or BR. Moreover, adverse events of interest with pirtobrutinib were comparable to those seen in the phase 1/2 BRUIN study, O’Brien explained.

In March 2024, the FDA granted another accelerated approval to liso-cel, a CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.

The phase 1/2 TRANSCEND CLL 004 trial evaluated the CAR T-cell therapy in patients with CLL or SLL who experienced disease progression after treatment with a BTKi and venetoclax. A single dose of liso-cel resulted in a 20% complete response rate and durable remission in patients with double-refractory CLL, O’Brien said. Any-grade cytokine release syndrome (CRS) was seen in 85% of patients, and 45% of patients experienced neurologic events. More than half of the study population had prolonged cytopenias. However, all toxicities were manageable.

Bispecifics and Beyond

O’Brien shared encouraging early findings from studies that are evaluating a bispecific antibody and a chimeric degradation activating compound (CDAC) degrader.

Epcoritamab, already FDA approved for other hematologic malignancies, is a bispecific antibody that targets CD3 on T cells and CD20 on CLL cells. The EPCORE CLL-1 study has shown clinical promise. Preliminary data determined that the agent could produce high response rates with undetectable minimal residual disease in patients with highly refractory CLL, O’Brien emphasized. Although CRS rates were high, they were mainly grade 1 or 2, with 8% experiencing grade 3 CRS.

BGB-16673, a CDAC degrader, was the final investigational agent discussed by O’Brien. She highlighted updated safety and efficacy findings from the ongoing phase 1 CaDAnCe-101 trial of 66 patients with highly refractory disease who received a median of four prior lines of therapy.

Investigators observed an overall response rate of 94% in patients who were given a 200-mg dose, taken once daily (n=16). Furthermore, toxicity was minimal, O’Brien said. The most common treatment-emergent adverse events included fatigue (37%) and contusions (30%).

Together, the approved therapies and those in the pipeline offer renewed hope for patients with double-refractory CLL.