Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.

中文翻译：

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动态分子监测显示 SWI-SNF 突变介导套细胞淋巴瘤对依鲁替尼加维奈托克的耐药性。

依鲁替尼加维奈托克是治疗套细胞淋巴瘤的高效组合。然而，需要能够评估治疗反应的策略。我们在 AIM 研究中对患者的前瞻性分析揭示了明确区分有反应者和无反应者的基因组谱。大多数获得完全缓解的患者都存在 ATM 突变，而所有原发性耐药患者和双三分之二的患者复发。循环肿瘤 DNA 分析显示，可以动态监测这些变化，提供有关治疗反应和肿瘤演变的同步信息。功能建模表明，SWI-SNF 复合物的妥协促进了 BCL2L1 (Bcl-xL) 的转录上调，提供了对依鲁替尼加维奈托克的选择性优势。这些数据共同突出了对治疗反应分子基础的重要见解，并为创新靶向治疗的实时评估提供了模型。