The Ohio State University Comprehensive Cancer Center, Columbus, OH.
Department of Pathology, The Ohio State University, Columbus, OH.
Blood. 2024 Sep 5;144(10):1061-1068. doi: 10.1182/blood.2023023659.
Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.
慢性淋巴细胞白血病 (CLL) 在 Bruton 酪氨酸激酶 (BTK) 抑制剂治疗期间的进展通常表现为 B 细胞受体通路突变的出现。在 ELEVATE-RR 中（NCT02477696；中位 2 次既往治疗），我们报告了复发/难治性 CLL 患者接受阿卡替尼或伊布替尼治疗时的克隆进化数据（中位随访时间，41 个月）。在 47 例（排除 1 例 Richter 转化）接受阿卡替尼治疗和 30 例（排除 6 例 Richter 转化）接受伊布替尼治疗的患者中，可获得进展时的配对（基线和进展）样本。在接受阿卡替尼治疗的 31 例患者（66%）和接受伊布替尼治疗的 11 例患者（37%；中位变异等位基因分数 [VAF]，分别为 16.1%和 15.6%）中观察到新出现的 BTK 突变。两组中最常见的 BTK C481S 突变；T474I（n=9；8 例与 C481 共发生）和 BTK pleckstrin 同源结构域内的新型 E41V 突变（n=1）发生在阿卡替尼中，而伊布替尼中均未发生。1 例伊布替尼治疗患者出现 L528W 和 A428D 共突变。在接受阿卡替尼治疗的 25 例患者（53.2%）和接受伊布替尼治疗的 16 例患者（53.3%）中，在筛查时存在预先存在的 TP53 突变。接受阿卡替尼和伊布替尼治疗的患者分别有 13%（中位 VAF，6.0%）和 7%（中位 VAF，37.3%）出现新的 TP53 突变。6 例阿卡替尼治疗患者和 1 例伊布替尼治疗患者出现新的 TP53/BTK 共突变。3 例阿卡替尼治疗患者（6%）和 6 例伊布替尼治疗患者（20%）出现新的 PLCG2 突变。1 例阿卡替尼治疗患者和 4 例伊布替尼治疗患者出现新的 BTK/PLCG2 共突变。尽管两种治疗方法均观察到常见的 BTK C481 突变，但突变和共突变频率、突变 VAF 以及 BTK 变体的罕见性在该患者人群中随阿卡替尼（T474I 和 E41V）和伊布替尼（L528W 和 A428D）而变化。该试验在 www.clinicaltrials.gov 上注册为 #NCT02477696。
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