Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia.
Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia.
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DOI：
10.1016/j.neo.2021.02.002
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Young KH
中科院分区：
文献类型：
--
作者：
Wang Y;Gali VL;Xu-Monette ZY;Sano D;Thomas SK;Weber DM;Zhu F;Fang X;Deng M;Zhang M;Hagemeister FB;Li Y;Orlowski RZ;Lee HC;Young KH
Waldenström巨球蛋白血症(WM)是一种特殊类型的惰性淋巴浆细胞性淋巴瘤(LPL)，其MYD88L265P突变频率较高。WM/LPL的治疗在临床上变化很大，伊布鲁替尼(一种Bruton酪氨酸激酶抑制剂，BTKi)已成为WM的新治疗选择。为了研究基因改变在西医中的临床影响，我们收集了一个由219个WMS和12个LPL组成的大队列，分为两个子队列：训练队列，由相同的靶向29基因下一代测序(NGS)小组进行测序的患者，以及验证队列，通过等位基因特异性-PCR或其他靶向NGS小组对患者进行测序。在训练和验证子队列中，MYD88L265P和TP53突变分别显示出有利和不利的预后影响。在验证子队列中，CXCR4无义/错义突变(CXCR4 NS/MS)、细胞遗传学复杂核型和淋巴瘤/白血病家族史与显著的不良临床结局相关。我们进一步研究了不同治疗方法的疗效以及与整个队列中遗传因素的相互作用。在接受非蛋白酶体化疗作为独立于遗传因素的一线治疗的患者中，预先使用地塞米松与较差的临床结果相关。维持性利妥昔单抗与更好的存活率相关。Ibrutinib/BTKi在复发/难治患者和没有CXCR4NS/MS的患者中显示出潜在的益处，包括那些带有TP53突变的患者。总之，MYD88L265P、TP53和CXCR4突变的基因检测和细胞遗传学分析为预后预测和治疗选择提供了重要信息。这些研究结果对改善西医/腰椎管综合征患者的治疗决策有价值，并将NGS整合到临床。
Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88L265P mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88L265P and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4NS/MS), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4NS/MS including those with TP53 mutations. In conclusion, genetic testing for MYD88L265P, TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.
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