Treatment Innovations in Relapsed/Refractory CLL

In an interview, Matthew S. Davids, MD, MMSc director, Clinical Research, Division of Lymphoma and physician at Dana-Farber Cancer Center and associate professor of Medicine, Harvard Medical School, explores recent advances and ongoing challenges in the management of relapsed/refractory chronic lymphocytic leukemia (CLL). The discussion highlights the growing heterogeneity of the relapsed population, including patients who relapse following chemoimmunotherapy, covalent Bruton tyrosine kinase (BTK) inhibitors, or time-limited venetoclax-based regimens.

Patients with high-risk genomic features, such as unmutated IGHV and TP53 aberrations remain a population of significant unmet need due to aggressive disease biology and limited durable responses. Richter transformation also remains a critical area where effective therapies are lacking.

Recent therapeutic advances include the development and regulatory approval of noncovalent BTK inhibitors, particularly pirtobrutinib. Findings from the phase 3 BRUIN-321 trial demonstrated prolonged progression-free survival and a median time to next treatment of approximately two years, even in heavily pretreated patients. However, real-world evidence suggests reduced durability in patients who are double refractory to BTK and BCL-2 inhibitors.

The interview also addresses the role of chimeric antigen receptor T-cell therapy, now FDA approved for CLL. While effective in select cases, its use is limited by patient eligibility due to age and comorbidities. The potential of pirtobrutinib as a bridge to cellular therapies is discussed.

Novel agents in development, such as BTK degraders and bispecific antibodies, show encouraging early-phase results. BTK degraders have demonstrated clinical activity post–noncovalent BTK inhibitor therapy, and bispecific antibodies like epcoritamab have achieved complete remissions in approximately 40% of heavily pretreated patients.

The speaker concludes with optimism for future therapeutic advances and the potential to shift novel agents into earlier lines of treatment, with the ultimate goal of achieving long-term remission or cure in patients with CLL.