How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS, and MYC, in 199 newly diagnosed grade 1 and 2 FLs. BCL2 mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04–8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02–2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05–3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.
如何识别疾病负荷低但早期进展风险高的滤泡性淋巴瘤（FL）患者尚不明确。基于先前一项研究表明，在激活诱导胞苷脱氨酶（AICDA）位点具有高变异等位基因频率（VAF）BCL2突变的FL易发生早期转化，我们在199例新诊断的1级和2级FL中检测了11个AICDA突变靶点，包括BCL2、BCL6、PAX5、PIM1、RHOH、SOCS和MYC。52%的病例出现VAF≥20%的BCL2突变。在97例初始未接受含利妥昔单抗治疗的FL患者中，VAF≥20%的BCL2非同义突变与转化风险升高相关（HR 3.01，95% CI 1.04–8.78，p=0.043），且呈现无事件生存期缩短的趋势（中位生存期：突变组20个月 vs 无突变组54个月，p=0.052）。其他测序基因突变频率较低，未能提升该基因组合的预后评估价值。在整个研究群体中，VAF≥20%的BCL2非同义突变与无事件生存期降低相关（校正FLIPI和治疗方法后HR 1.55，95% CI 1.02–2.35，p=0.043），中位随访14年后总生存期也显著降低（HR 1.82，95% CI 1.05–3.17，p=0.034）。因此，高VAF BCL2非同义突变即使在化学免疫治疗时代仍具有预后价值。
Relationship between BCL2 mutations and follicular lymphoma outcome in the chemoimmunotherapy era
肿瘤(癌症)患者之家