OBJECTIVES: Chronic lymphocytic leukemia is a B-cell malignancy that is most common in older patients and has a variable course. The unmutated status of the IGHV genes is a well-known and common predictor of a poorer prognosis. The objective of this study was to compare the efficacy of AKA, a selective covalent BTK inhibitor, and VEN+OBI in previously untreated patients with chronic lymphocytic leukemia (CLL) and unmutated IGHV genes.

METHODS: A systematic review was conducted on June 13, 2023, using PubMed, Embase, and Cochrane databases, following the Polish Health Technology Assessment (HTA) guidelines. Due to the absence of direct head-to-head trials, an indirect Bucher comparison was performed using a common comparator (OBI + chlorambucil).

RESULTS: Two RCTs were included: ELEVATE-TN (AKA vs OBI+CHB, N = 356) and CLL14 (VEN+OBI vs OBI+CHB, N = 432). These trials presented results for patients with unmutated IGHV genes, accounting for 66.0% and 59,8% of the respective study populations. The longest available follow-up periods were selected for analysis, yielding 58.2 vs. 76.4 months overall and 58.2 vs. 65.4 months for high-risk subgroups. Comparison of AKA vs. VEN+OBI demonstrated a significant improvement in favour of AKA in terms of progression-free survival (PFS) in both the overall population (HR = 0.53, 95% CI: 0.34-0.81) and the unmutated IGHV subgroup (hazard ratio [HR] = 0.44, 95% [CI]: 0.26-0.76), with a consistent trend observed in the TP53mut/del17p subgroup. Overall survival did not differ significantly between the two interventions.

CONCLUSIONS: Compared to previously published evaluations, the use of longer follow-up periods with a larger number of events in the calculations demonstrates that AKA compared to VEN+OBI significantly reduces the risk of progression or death by 47% in the overall population and by 56% in the subgroup of patients with unmutated IGHV genes.