Characterization of Mechanisms of Resistance in Previously Treated Chronic Lymphocytic Leukemia From a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib

Introduction: Acalabrutinib (Acala) is a highly selective, next-generation covalent Bruton tyrosine kinase inhibitor (BTKi) approved for CLL. In ELEVATE-RR (NCT02477696) at a median follow-up of 41 mo, Acala demonstrated noninferior progression-free survival with fewer cardiovascular adverse events versus ibrutinib (Ibr) in patients (pts) with relapsed/refractory (R/R) CLL. Disease progression on covalent BTKis is often characterized by acquisition of B-cell receptor pathway mutations, but no data have compared mutational profiles of Acala versus Ibr. We report clonal evolution data in pts with CLL progressing on Acala versus Ibr in ELEVATE-RR.

Methods: Peripheral blood samples at baseline and relapse from pts in ELEVATE-RR were used. DNA was extracted from enriched CD19+ cells (RoboSep) and subjected to a 50-gene sequencing assay panel with a sensitivity cutoff for BTK and PLCG2 resistance–associated mutations at 0.5% variant allele fraction (VAF). Forty-eight other CLL-associated genes were assessed at 1%–2% VAF.

Results: Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) and 30 (excluding 6 Richter) pts in the Acala and Ibr groups, respectively. At progression, emergent BTK mutations were seen in 31 (66%) Acala versus 11 (37%) Ibr pts (P = 0.02) (Figure 1; median VAF: 5.7 vs. 5.8). Emergent PLCG2 mutations occurred in 3 (6%) Acala vs. 6 (20%) Ibr pts (P = 0.14). Only 1 Acala pt had co-occurrence of BTK and PLCG2 mutations versus 4 Ibr pts. BTK C481S, C481Y, and C481R mutations occurred at similar frequency in both groups; a novel E41V mutation within the pleckstrin homology domain of BTK (median VAF: 16%) was seen in 1 Acala pt. L528W and A428D co-mutations were observed in 1 Ibr pt. Six Acala pts had TP53 and BTK co-mutations. Emergent TP53 mutations were seen in both groups (13% [Acala] vs. 7% [Ibr], P = 0.47; median VAF: 5% [Acala] versus 37% [Ibr]). Only 2 Ibr pts had TP53 mutations (1 had TP53/BTK co-mutation). No statistical difference was seen in the proportions of Acala versus Ibr pts who acquired BTK mutations among pts with del(17p) (39% vs. 64%; P = 0.18), del(11q) (77% vs. 46%; P = 0.07), complex karyotype (58% vs. 73%; P = 0.48), unmutated IGHV (90% vs. 100%; P = 0.55), or trisomy 12 positivity (3% vs. 18%; P = 0.16). Additional mutations (Acala vs. Ibr) included DNMT3A (5 vs. 1 pts), TET2 (1 pt for each), and NRAS (1 pt; Acala only).

Conclusions: While common mutations were observed with both treatments, patterns of mutation frequency, mutation VAF, and uncommon BTK variants varied with Acala versus Ibr in this R/R CLL population despite shared resistance mutations. Additional studies could help to understand contributions of the differing pharmacologic properties of these 2 BTKis and variations by line of treatment.