Doubling down: the new deal in the clinical management of double-refractory chronic lymphocytic leukemia.

Targeted therapy with covalent Bruton tyrosine kinase inhibitors (cBTKis) and/or the B-cell lymphoma 2 inhibitor (BCL-2i) venetoclax is now well established in the first-line management of chronic lymphocytic leukemia (CLL).

However, patients with "double-refractory" disease due to the acquired resistance to both drug classes represent an increasing clinical challenge for whom few well-tolerated and effective treatment options currently exist.

The highly selective, noncovalent BTKi pirtobrutinib and CD19-directed chimeric antigen receptor T-cell therapy lisocabtagene maraleucel have both recently gained US Food and Drug Administation approval for use in patients with CLL, which has progressed following ≥2 prior lines, including a cBTKi and a BCL-2i.

Additionally, novel BTK-directed therapies and T-cell-engaging bispecific antibodies have achieved promising responses in pretreated CLL in early-phase clinical trials.

Here, we review the mechanisms responsible for resistance to cBTKi and venetoclax in CLL, appraise recent evidence supporting the use of each of the novel and emerging agent classes, and then suggest innovative treatment strategies incorporating these in patients with double-refractory disease, remaining cognizant of the variability of access to novel therapies and clinical trials.