Triplet Therapy for High-Risk Chronic Lymphocytic Leukemia

Front-line treatment with a Bruton tyrosine kinase inhibitor (BTKi) is the standard of care for patients with symptomatic, advanced-stage chronic lymphocytic leukemia (CLL) and adverse biomarkers, including unmutated IGHV, del(11q), complex karyotype, and del(17p) and/or mutated TP53. However, the latter two biomarkers are associated with poorer outcomes with single-agent BTKi.

Now, investigators have conducted a multicenter, open-label trial (CLL2-GIVe) to test whether combining agents with distinct mechanisms of action might improve outcomes for 41 previously untreated CLL patients with del(17p) and/or TP53 mutation. The regimen comprised induction with obinutuzumab, venetoclax, and ibrutinib; consolidation with 6 cycles of ibrutinib and venetoclax; and maintenance with ibrutinib. Tumor lysis syndrome was monitored during venetoclax initiation. Measurable residual disease (MRD) was determined at prespecified time points and guided duration of therapy.

Complete response at cycle 15 (the primary endpoint) was achieved by 24 patients (59%); peripheral blood undetectable MRD was 78%, and bone marrow undetectable MRD was 66%. At 24 months, progression-free survival and overall survival were 95%; progressive disease occurred in 6 patients within 1 year of treatment completion. Most adverse events occurred during cycles 1–6 and included cytopenias and infections. Three patients stopped treatment prior to cycle 12 (1 from arthralgia and 2 from unrelated fatal adverse events: ovarian cancer and heart failure).