Acalabrutinib Versus Venetoclax Plus Obinutuzumab in Treatment-Naive Chronic Lymphocytic Leukemia: A Real-World...

Therapy for chronic lymphocytic leukemia (CLL) has shifted from chemoimmunotherapy to targeted agents such as Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors. Approved first-line options include acalabrutinib, a second-generation BTK inhibitor, and the fixed-duration combination venetoclax-obinutuzumab, yet real-world head-to-head data are scarce.

Using the TriNetX global federated health database, we retrospectively compared outcomes in treatment-naïve patients with TP53-unmutated CLL who received either regimen as initial therapy. After applying eligibility criteria and 1:1 propensity score matching, 669 matched pairs were analyzed. The primary endpoint was time to next treatment (TTNT); secondary endpoints included overall survival (OS) and adverse events.

The results showed that patients treated with venetoclax plus obinutuzumab had a significantly longer TTNT (median not reached vs. 47.7 months) and improved 4-year OS. Across all subgroups, the venetoclax-based regimen performed better. Cytopenias and infections were more common with venetoclax-obinutuzumab-neutropenia 54.3% versus 33.3%, thrombocytopenia 45.9% versus 31.9%, febrile neutropenia 7.1% versus 3.4%, and tumor lysis syndrome 6.3% versus 2.3%. Acalabrutinib caused fewer severe hematologic toxicities.

In real-world practice, venetoclax plus obinutuzumab was associated with longer TTNT and improved OS compared to acalabrutinib as first-line therapy in patients with TP53 wild-type CLL.