Novel Agents Transform Double-Refractory CLL Care

Medscape

3 days ago

TOPLINE:
Noncovalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib and chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel have gained FDA approval for double-refractory chronic lymphocytic leukemia (CLL). Novel BTK-directed therapies and T-cell-engaging bispecific antibodies demonstrate promising responses in early-phase trials for pretreated CLL.
METHODOLOGY:
Researchers conducted a comprehensive review of mechanisms responsible for resistance to covalent BTK inhibitors and B-cell lymphoma 2 inhibitor (BCL-2i) venetoclax in CLL.
Analysis included evaluation of recent evidence supporting novel and emerging agent classes, including noncovalent BTK inhibitors, CAR T-cell therapy, and T-cell-engaging bispecific antibodies.
Investigators examined treatment strategies incorporating these therapies in patients with double-refractory disease, considering variability in access to novel therapies and clinical trials.
TAKEAWAY:
Pirtobrutinib demonstrated an overall response rate of 72% in patients with chronic lymphocytic leukemia, with a median progression-free survival of 14 months compared with 8.7 months for control therapies.
Lisocabtagene maraleucel achieved an overall response rate of 44% in double-refractory patients, with grade ≥ 3 cytokine release syndrome occurring in 8% and neurologic events in 19% of patients.
BTK degraders showed promising early results, with BGB-16673 achieving responses in heavily pretreated patients, most of whom (92%) were exposed to covalent BTK inhibitors and BCL-2i.
Epcoritamab demonstrated an overall response rate of 53% in double-exposed patients, with a complete response rate of 37% and undetectable measurable residual disease in two thirds of responders.
IN PRACTICE:
'Within the current regulatory environment, either ncBTKi [noncovalent BTK inhibitor] or CAR T-cell therapy should be considered as first-line management for double-refractory disease, with the choice individualized based on disease stage, BTK mutational status, toxicity from prior therapies, performance status, comorbidities, and geographic and financial constraints,' the authors of the study wrote.
SOURCE:
This study was led by Brian T. Grainger of Sir Charles Gairdner Hospital in Nedlands, Australia. It was published online in Blood.
LIMITATIONS:
The literature describing CLL in the post-covalent BTK inhibitor and BCL-2i setting varies in criteria used to identify double-refractory patients, complicating assessment of disease prevalence and prognosis. Additionally, there were limited prospective data for outcomes following one class of targeted agent after disease progression on the other.
DISCLOSURES:
Philip A. Thompson disclosed relationships with AbbVie, Ascentage Pharma, AstraZeneca, BeiGene, Genentech, Genmab, Janssen Pharmaceuticals, Eli Lilly and Company, Merck, Adaptive Biotechnologies, Roche, and Sana Biotechnology. Additional disclosures were noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.