Page 270 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Genomic landscape of patients in a phase II study of zanubrutinib in ibrutinib- and/or acalabrutinib-intolerant patients with B-cell malignancies
Bruton tyrosine kinase (BTK) inhibitors have shown remark- able efficacy in the treatment of B-cell malignancies, yet many patients develop intolerance to these drugs leading to treatment discontinuation. Ibrutinib, the first-in-class BTK inhibitor, can cause adverse effects including cardiotoxicities, bleeding, and cytopenias leading to discontinuation in up to 16% of patients, largely due to off-target activity.1 The sec- ond-generation, more selective BTK inhibitor, acalabrutinib, also leads to adverse effects and treatment discontinuation in up to 23% of patients.2 Zanubrutinib is a next-generation covalent, irreversible BTK inhibitor that has been approved world-wide for the treatment of patients with B-cell malig- nancies including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), previously treated mantle cell lymphoma (MCL), Waldenström macroglobulinemia, and relapsed or refractory marginal zone lymphoma. Preclinical and clinical studies have demonstrated that zanubrutinib has superior potency, selectivity, efficacy, and a more favor- able toxicity profile compared to ibrutinib.3-6 Results from BGB-3111-215 (NCT04116437), an ongoing phase II study eval- uating the safety and efficacy of zanubrutinib monotherapy, demonstrate that zanubrutinib could be a safe treatment option for patients with B-cell malignancies who exhibited intolerance to prior treatment with ibrutinib (cohort 1) or to ibrutinib and/or acalabrutinib (cohort 2).6
To date, it is unclear whether the genomic profile of patients with B-cell malignancies who are intolerant to ibrutinib and/ or acalabrutinib is associated with intolerance or response to subsequent therapy. In this post-hoc analysis, a highly sensitive, targeted, next-generation sequencing panel (Pred- icineHEMETM; Predicine, Hayward, CA, USA) with full exon coverage of 106 genes commonly mutated in hematologic malignancies was used to explore the genetic profiles of patients enrolled in study BGB-3111-215.7 This study was con- ducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. Written informed consent was obtained from each patient and institutional review board approval was obtained at each study site.
Samples were sequenced to a median depth of >20,000 reads, with a validated sensitivity of 0.25% mutant allele frequency for all genomic regions and 0.1% for mutational hotspots. Variant allele frequency (VAF) <0.1% for hotspot mutations and VAF <0.25% for non-hotspot mutations were excluded from analysis. Germline and clonal hematopoiesis of indeterminate potential mutations were also excluded from analysis. Baseline blood samples from 95.9% (71/74)
of all patients enrolled in the study and from 77.8% (7/9) of patients with disease progression (CLL: n=5; SLL: n=1; MCL: n=1) at data cutoff were available for analysis. Baseline demographics and disease characteristics were similar be- tween cohorts and are summarized in Online Supplementary Table S1. Of note, most patients enrolled in this study had CLL or SLL (n=54).
We identified mutations in 91.5% (65/71) of baseline sam- ples and in all (7/7) samples from patients with progressive disease (median = 4 mutations per sample; range, 1-14). The types of mutations identified as well as mutation frequen- cies are shown in Figure 1. Across all patients intolerant to BTK inhibitors, the most common baseline mutations were in TP53 (32%), SF3B1 (23%), ATM (18%), NOTCH1 (17%), and CHEK2 (15%) (Figure 1B). The mutation spectra of these genes are visualized as lollipop plots (Online Supplementary Figure S1) and are similar to those that have been observed in other studies.8 As expected, mutation prevalence at baseline dif- fered among diseases and was mostly consistent with the findings in previous studies of relapsed or refractory patients with various B-cell malignancies (Figure 1B).8 In patients with CLL or SLL, the most frequently mutated genes were TP53 (16/54, 30%), SF3B1 (15/54, 28%), ATM (13/54, 24%), and NOTCH1 (11/54, 20%) – all within cell signaling pathways (e.g., DNA damage response and NOTCH signaling) known to be associated with disease susceptibility and/or poor prognosis in these patients. Observed rates of baseline TP53 (5/8 vs. 11/46, P=0.04), ATM (4/8 vs. 9/46, P=0.08), and SF3B1 (5/8 vs. 10/46, P=0.03) mutations were higher in patients who later developed progressive disease (n=8) than in patients who did not (n=46) (Figure 2A). Patients with these mutations also had a shorter progression-free survival compared to that of patients without mutations in these genes, as evi- denced by the observed hazard ratios (and 95% confidence intervals): TP53 3.2 (0.84-11.8), SF3B1 5.9 (1.48-23.77), or ATM 5.5 (1.47-20.72) (Figure 2B-D), which is consistent with previous reports.9,10 However, the mutation frequency of NOTCH1 was similar in patients with and without disease progression (Figure 2A) and NOTCH1 mutation status was not correlated with progression-free survival (Figure 2E), a finding inconsistent with that of a previous study of pa- tients with relapsed or refractory CLL treated with ibrutinib in whom NOTCH1 mutations were strongly associated with shorter progression-free survival (P=0.00002) and overall survival (P=0.0001).11 This discrepant finding was not due to the increased sensitivity of the PredicineHeme panel as pa- tients with NOTCH1 VAF <1% (45.5% [5/11]) exhibited a similar
Haematologica | 109 July 2024
2284