Prevalence of BTK and PLCG2 Mutations in BTK Inhibitor Treated CLL Patients Who Experience Disease Progression: A Meta-Analysis

Background:

Acquired somatic mutations in Bruton Tyrosine Kinase (BTK) or Phospholipase C-gamma 2 (PLCG2) genes are frequently identified in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors (BTKis). Such mutations are associated with disease progression (DP) and resistance to covalent BTKis, such as ibrutinib, acalabrutinib, and zanubrutinib. However, data on the prevalence of these mutations in BTKi-treated CLL patients who experience disease progression are limited to small series.

Methods:

To address this knowledge gap, we conducted a systematic review and meta-analysis following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We included studies describing CLL patients assessed for BTK or PLCG2 mutations at DP with concurrent covalent BTKi therapy. A literature search was performed in PubMed, supplemented by manual searches of conference abstracts from the American Society of Hematology (ASH) and European Hematology Association (EHA). Data heterogeneity was assessed using the chi-squared (χ²) Q test and the I² statistic.

Results:

Thirteen cohorts with a total of 724 CLL patients were assessed for BTK somatic mutations. Only 7.8% had discontinued a BTKi due to an adverse event (AE) or other reasons. Among those patients with DP (n=667), 86.3 % had relapsed/refractory (R/R) CLL, while 13.6 % were treatment-naïve (TN). Patients were derived from post-hoc analyses of five phase 3 clinical trials (ALPINE, ELEVATE R/R, RESONATE, RESONATE-2, FLAIR), five phase 2 trials (PCYC-1122, RESONATE-17,NCT02337829, NCT01500733, and NCT03740529 [BRUIN]), three retrospective multicenter studies from the French CLL Study Group (FILO), the European Research Initiative on CLL (ERIC), the Hungarian Ibrutinib Resistance Analysis Initiative and three separate retrospective monocentric studies from MD Anderson Cancer Center (MDACC), Peter MacCallum Cancer Centre (Peter Mac) and The Ohio State University (OSU) Comprehensive Cancer Center.

An aggregate meta-analysis revealed a BTK mutation prevalence of 52% (95% CI: 39-64), with substantial heterogeneity across studies (Q = 161.54, P =0.00; I² = 91%). A separate analysis was conducted in patients treated with either a first-generation BTKi (ibrutinib) or a second-generation agent such as acalabrutinib or zanubrutinib. All studies except the BRUIN study provided data for such an analysis by BTKi type. Specifically, for ibrutinib-treated patients, the prevalence of BTK mutations was 53.0% (95% CI: 35-71; Q = 134.05, P = 0.00, I² = 93%), while for acalabrutinib- and zanubrutinib-treated patients, BTK mutation prevalence was 51% (95% CI: 26-77; Q = 17.15, P = 0.00, I² = 83%).

Ten cohorts comprising 620 patients were analyzed for PLCG2 mutations. Studies suitable for the PLCG2 analysis included those previously used for BTK mutation analysis with the exclusion of MDACC and Peter McCallum Cancer Center cohorts that did not provide information on PLCG2 mutations. Only 9.2% patients discontinued BTKi therapy due to an AE or other reasons. Among patients with DP (n=563), 86% had R/R and 14% TN CLL. The pooled prevalence of PLCG2 mutations was 11% (95% CI: 7-17), with notable heterogeneity across studies (Q = 40.77, P = 0.00; I² = 73%). Of note, the prevalence of somatic PLCG2 mutations was 13% (95% CI:6-23; Q = 30.52, P = 0.00, I² = 77%) in patients treated with ibrutinib and 9% (95% CI: 0-25; Q = 8.34, P = 0.00, I² = 76%) in those who received acalabrutinib or zanubrutinib.

Finally, the presence of PLCG2 mutations was positively correlated with TP53 mutational burden (r = 0.804; P = 0.02) and exposure time to BTKi (r = 0.851; P = 0.001). The same associations were not found for BTK mutations.

Conclusions:

This meta-analysis, which incorporates data from both clinical trials and real-world studies, confirms that BTK and PLCG2 mutations are present in the majority of CLL patients who experience DP whilst treated with covalent BTKis. However, over one-third of patients do not harbor such mutations, indicating the presence of additional mechanisms of BTKi resistance not fully investigated yet Clinically, the assessment of BTK/PLCG2 mutational profiles has not demonstrated utility in guiding the selection of subsequent therapies for CLL. Indeed, venetoclax-based therapies or non-covalent BTKis may be equally effective options for patients with BTK/PLCG2 mutations progressing on covalent BTKis.

Molica:AbbVie, Janssen, Astra-Zeneca: Honoraria.