Department of Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam and LYMMCARE (Lymphoma and Myeloma Center Amsterdam), Amsterdam, the Netherlands.
Department of Hematology, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.
J Clin Oncol. 2022 Jan 1;40(1):40-51. doi: 10.1200/JCO.21.00105. Epub 2021 Aug 13.
Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM.
We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction.
A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD.
Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.
蛋白酶体抑制剂在华氏巨球蛋白血症（WM）中有效，但需要注射给药，并且与多发性神经病有关。我们研究了较少神经毒性的口服蛋白酶体抑制剂伊沙佐米联合利妥昔单抗在复发性 WM 患者中的疗效和毒性。
我们进行了一项多中心 I/II 期伊沙佐米、利妥昔单抗和地塞米松（IRD）试验。诱导包括 8 个周期的 IRD，其中利妥昔单抗在第 3 周期开始，随后进行利妥昔单抗维持。I 期研究显示 4 mg 伊沙佐米具有可行性。II 期的主要终点是诱导后总体缓解率（≥最小缓解）。
共纳入 59 例患者（中位年龄 69 岁；范围 46-91 岁）。中位治疗线数为 2（范围 1-7）；70%的患者具有中等或高 WM-IPSS（华氏巨球蛋白血症国际预后评分系统）评分。经过 8 个周期，ORR 为 71%（42/59）（14%非常好的部分缓解[PR]，37%PR，20%轻微缓解）。反应深度一直持续到 12 个月（最佳 ORR 为 85%[50/59]：15%非常好 PR，46%PR，24%轻微缓解）。中位缓解持续时间为 36 个月。诱导后红细胞压积水平显著升高（0.33-0.38 L/L）（<0.001）。伊沙佐米和地塞米松治疗 2 个周期后，免疫球蛋白 M 水平显著下降（中位数 3700-2700 mg/dL，<0.0001）。首次反应的中位时间为 4 个月。中位无进展生存期和总生存期均未达到。中位随访 24 个月（范围 7.4-54.3 个月）后，无进展生存期和总生存期分别为 56%和 88%。毒性包括主要为 2 级或 3 级血细胞减少症、1 级或 2 级神经毒性和 2 级或 3 级感染。使用皮下利妥昔单抗无输液相关反应或免疫球蛋白 M 爆发。诱导后生活质量显著改善。共有 48 例患者（81%）完成了至少 6 个周期的 IRD。
IRD 联合治疗在复发性或难治性 WM 患者中具有有前景的疗效和可控的毒性。
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