Triplet Therapy for High-Risk Chronic Lymphocytic Leukemia: An Update

TP53-aberrant chronic lymphocytic leukemia (CLL) responds to Bruton tyrosine kinase (BTK) inhibitors and to venetoclax plus an anti-CD20 antibody or a BTK inhibitor, although the durations of response are shorter than among other CLL subtypes.

In the prior industry-sponsored, multicenter, open-label CLL2-GIVe trial (NEJM JW Oncol Hematol 2022 Mar 24 and Blood 2022; 139:1318), treatment with obinutuzumab, ibrutinib, and venetoclax induced high response rates in previously untreated patients with CLL and del(17p) and/or TP53 mutation at 24 months.

Investigators now report a final analysis of the phase 2 CLL2-GIVe trial after a median observation time of 38.5 months. Among 41 patients, 58% had both TP53 mutation and del(17p), 37% had TP53 mutation only, and 5% had del(17p) only. Patients received 6 cycles of obinutuzumab, ibrutinib, and venetoclax, followed by 6 cycles of ibrutinib plus venetoclax and 3 cycles of ibrutinib. Patients with detectable measurable residual disease (MRD) after cycle 9 or 12 or with less than complete remission (CR) following cycle 15 continued ibrutinib through cycle 36 and beyond at the treating physician's discretion.

The complete remission rate at cycle 15 (the primary endpoint) was 58.5%; 17% of patients had disease progression between cycles 27 and 42. Progression-free and overall survival at 36 months were 79.9% and 92.6%, respectively. Atrial fibrillation was observed in 14.6% of patients, and hypertension was observed in 4.9%. Cytopenias were common in the early cycles and were managed with dose interruptions or dose reductions; 20% of patients experienced infections.