Division of Hematology and Hematologic Malignancies, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA.
Department of Medicine, Harvard Medical School, Boston, MA; Bing Center for Waldenstrom Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA.
Clin Lymphoma Myeloma Leuk. 2022 Aug;22(8):547-556. doi: 10.1016/j.clml.2022.02.005. Epub 2022 Feb 24.
Waldenström Macroglobulinemia (WM) is a rare hematologic malignancy characterized by the presence of lymphoplasmacytic lymphoma cells involving the bone marrow and production of a monoclonal IgM paraprotein. Recurrent somatic mutations in MYD88 and CXCR4 have been reported in 90% to 95% and 30% to 40% of patients with WM, respectively. Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamustine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost.
华氏巨球蛋白血症（WM）是一种罕见的血液系统恶性肿瘤，其特征是骨髓中存在淋巴浆细胞淋巴瘤细胞，并产生单克隆 IgM 副蛋白。分别有 90%到 95%和 30%到 40%的 WM 患者存在 MYD88 和 CXCR4 的复发性体细胞突变。标准治疗方案将抗 CD20 抗体利妥昔单抗与烷化剂（如苯达莫司汀、环磷酰胺）、核苷类似物（如氟达拉滨、克拉屈滨）或蛋白酶体抑制剂（如硼替佐米、卡非佐米和伊沙佐米）联合使用。共价 BTK 抑制剂（如伊布替尼、阿卡替尼、泽布替尼）已被证明在 WM 患者中安全且非常有效。该疾病中具有前景的新型药物包括下一代共价 BTK 抑制剂（如替拉鲁替尼、奥雷巴替尼）、非共价 BTK 抑制剂（如泊替尼、ARQ531）、BCL-2 拮抗剂（如维奈托克）和 CXCR4 靶向药物（如 mavorixafor、ulocuplumab）等。未来的研究将集中于开发这些新型药物的固定疗程联合方案，旨在提高持久缓解率的同时最大限度地降低毒性和成本。
