Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88^L265P 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, MYD88^L265P and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4^NS/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 CXCR4^NS/MS including those with TP53 mutations. In conclusion, genetic testing for MYD88^L265P, 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.

华氏巨球蛋白血症 (WM) 是一种独特类型的惰性淋巴浆细胞淋巴瘤 (LPL)，具有高频率的MYD88 ^L265P突变。WM/LPL 的治疗在临床上变化很大，依鲁替尼（一种布鲁顿酪氨酸激酶抑制剂，BTKi）已成为 WM 的新治疗选择。为了研究 WM 中遗传改变的临床影响，我们将 219 个 WM 和 12 个 LPL 组成的大型队列分为两个子队列：训练队列、通过相同靶向 29 基因下一代测序 (NGS) 面板测序的患者，以及验证队列，通过等位基因特异性 PCR 或其他靶向 NGS 面板测序的患者。在训练和验证亚组中，MYD88 ^L265P和TP53突变分别显示出有利和不利的预后影响。CXCR4无义/错义突变 ( CXCR4 ^NS/MS)、细胞遗传学复杂核型和一级亲属的淋巴瘤/白血病家族史与验证亚队列中仅或更多的显着更差的临床结果相关。我们进一步研究了整个队列中各种治疗的功效以及与遗传因素的相互作用。在接受不含蛋白酶体的化疗作为一线治疗的患者中，预先使用地塞米松与较差的临床结果相关，与遗传因素无关。维持利妥昔单抗与更好的生存相关。依鲁替尼/BTKi 在复发/难治性患者和无CXCR4 ^NS/MS患者（包括TP53突变患者）中显示出潜在益处。总之，MYD88的基因检测^L265P、TP53和CXCR4突变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。这些研究中的发现对于改进 WM/LPL 患者可用疗法的治疗决策很有价值，这些疗法将 NGS 整合到临床中。