The optimal first-line treatment for patients with treatment-naïve (TN), TP53 wild-type chronic lymphocytic leukemia (CLL) remains an area of ongoing research. A key factor influencing treatment selection is the immunoglobulin heavy-chain variable region gene (IGHV) mutation status, which affects prognosis and response to therapy. However, the absence of direct, randomized comparisons between continuous BTK inhibitor (BTKi) therapies and time-limited (TL) venetoclax-BTKi regimens makes choosing the most appropriate treatment in relation to IGHV mutation status challenging.

To address this gap, we conducted an indirect comparative analysis. A comprehensive systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines identified seven phase III trials enrolling TN, TP53 wild-type CLL patients. These studies evaluated either continuous BTKi therapy—alone (e.g., RESONATE2, SEQUOIA, FLAIR3 [NEJM 2025])—or in combination with anti-CD20 agents (e.g., ECOG 1912, FLAIR1 [Lancet Oncol 2023]), or TL venetoclax-BTKi regimens (e.g., GLOW, AMPLIFY, FLAIR3).

Using the methodology described by Liu et al., individual patient data (IPD) were reconstructed to enable precise survival analyses across studies. The primary endpoint was progression-free survival (PFS), which we summarized over a four-year horizon using the restricted mean survival time (RMST). This approach provides a nuanced, quantitative measure of treatment benefit by calculating the difference (Δ) in RMST between treatment groups.

Patients were stratified into two groups: (i) continuous BTKi therapy (with or without anti-CD20 agents) and (ii) TL venetoclax-BTKi regimens.The combined cohort comprised 2,037 patients, with 1,380 (67.7%) treated with continuous BTKi and 657 (32.2%) receiving TL venetoclax-BTKi therapy. Amongst those on continuous BTKis, 82.5% received ibrutinib (n=1,137), while 17.4% received zanubrutinib (n=241). The TL venetoclax-BTKi cohort included 366 patients (55.7%) on ibrutinib-venetoclax and 291 (44.3%) on acalabrutinib-venetoclax combinations. The majority of participants (n=1,554 or 76.5%) were younger and fitter, as evidenced by enrollment in FLAIR1, FLAIR3, ECOG 1912, and AMPLIFY trials. A smaller subset (n=483 or 23.7%) comprised individuals older or unfit , as seen in GLOW, RESONATE2, and SEQUOIA.

Our analysis found no statistically significant difference in four-year PFS between patients with mutated versus unmutated IGHV within each treatment modality. Specifically, the RMST Δ was 0.5 months (95% confidence interval [CI], -4.8 to 5.8; p=0.85) for continuous BTKi therapy, and 2.9 months (95% CI, -3.6 to 9.4; p=0.40) for TL venetoclax-BTKi combinations. Subgroup analyses stratified by IGHV mutation status further supported these findings, showing no significant PFS differences between treatment strategies within either IGHV subgroup. Specifically, among patients with unmutated IGHV, the RMST Δ was -2.5 months (95% CI, -8.3 to 3.2; p=0.35), and among those with mutated IGHV, it was -0.2 months (95% CI, -6.3 to 6.0; p=0.95).

Given that FLAIR3 trial implemented a measurable residual disease (MRD)-guided strategy, whereby treatment duration was extended contingent upon MRD status, we conducted a sensitivity analysis excluding participants from this trial within the cohort receiving TL venetoclax-BTKi therapy. This adjusted analysis demonstrated a modest increase in the RMST Δ to 4.2 months (95% CI, -3.7 to 12.2; p=0.35). Nonetheless, the absence of a statistically significant difference in PFS across IGHV subgroups receiving TL venetoclax-BTKi regimens persisted. Moreover, within the subset of patients with unmutated IGHV, four-year PFS estimates remained comparable between treatment strategies, with an RMST difference of -5.1 months (95% CI, -11.8 to 1.5; p=0.10).

In summary, this indirect comparison suggests that, in TN, TP53 wild-type CLL patients, the four-year PFS is similar between TL venetoclax combined with BTKis and continuous BTKi therapy, regardless of IGHV mutation status. These findings imply that treatment selection can be personalized based on patient preferences, tolerability, and logistical considerations without compromising efficacy. The heterogeneity of the included studies and the limitations inherent in indirect comparisons warrant cautious interpretation. The ongoing phase III CLL17 trial is expected to provide definitive evidence to guide frontline therapy in CLL.

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2025
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