维莫非尼联合利妥昔单抗治疗难治或复发的毛细胞白血病。
Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia.
机构信息
From the Institute of Hematology, Ospedale S. Maria della Misericordia, and the Department of Medicine, University of Perugia, Perugia (E.T., L.D.C., E.S., M.C., S.A., V.M.P., B.F.), the Department of Medicine, Section of Hematology, University of Verona, Verona (A. Ambrosetti), the Hematology Unit, Ospedale di Cosenza, Cosenza (E.L.), the Hematology Unit, Department of Transfusional Medicine-SIMMT, Maria Paternò-Arezzo Hospital, Ragusa (A. Antolino), the Hematology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome (A.P., R.F.), and the Hematology and Stem Cell Transplant Unit, A.O. San Camillo Forlanini (L.R.), Rome, the Department of Hematology, Spedali Civili di Brescia, Brescia (S.F.), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna (P.L.Z.), the Department of Translational Medicine, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara (G.G.), the Hematology Unit, Ospedale di Carrara, Carrara (R.D.S.), the Hematology Unit, Ospedale di Frosinone, Frosinone (N.F.), the Hematology Unit, Ospedale di Ronciglione, Viterbo (P.F.), the Hematology Unit, Ospedale di Pesaro, Pesaro (G.V.), and the Hematology Unit, Azienda Sanitaria Universitaria Integrata-Ospedale Maggiore, Trieste (F.Z.) - all in Italy.
出版信息
N Engl J Med. 2021 May 13;384(19):1810-1823. doi: 10.1056/NEJMoa2031298.
BACKGROUND
Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped.
METHODS
In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment.
RESULTS
Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents.
CONCLUSIONS
In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
背景
多毛细胞白血病（HCL）是一种 CD20+惰性 B 细胞癌，其中 BRAF V600E 激酶激活突变起着致病作用。在涉及难治性或复发性 HCL 患者的临床试验中，口服 BRAF 抑制剂 vemurafenib 靶向 BRAF V600E 导致 91%的患者有反应；35%的患者有完全缓解。然而，治疗停止后，无复发生存中位数仅为 9 个月。
方法
在一项涉及难治性或复发性 HCL 患者的 2 期、单中心、学术试验中，我们评估了 vemurafenib（每天两次 960mg，连续 8 周）联合同期和序贯利妥昔单抗（375mg/平方米体表面积，18 周内共 8 剂）的安全性和疗效。主要终点是计划治疗结束时的完全缓解。
结果
在纳入的 30 名 HCL 患者中，中位治疗次数为 3 次。意向治疗人群中 26 名患者（87%）观察到完全缓解。所有对化疗（10 例）或利妥昔单抗（5 例）难治的化疗难治性 HCL 患者以及所有先前接受过 BRAF 抑制剂治疗的患者（7 例）均有完全缓解。血小板减少在中位 2 周后缓解，中性粒细胞减少在中位 4 周后缓解。在 26 名完全缓解的患者中，17 名（65%）患者清除了微小残留病（MRD）。所有 30 名患者的无进展生存率在中位随访 37 个月时为 78%；26 名有反应的患者的无复发生存率在中位随访 34 个月时为 85%。在事后分析中，MRD 阴性和无先前 BRAF 抑制剂治疗与更长的无复发生存时间相关。毒性作用主要为 1 级或 2 级，与这些药物以前观察到的毒性作用一致。
结论
在这项小型研究中，短疗程、无化疗、非髓毒性的 vemurafenib 联合利妥昔单抗方案在大多数难治性或复发性 HCL 患者中引起持久的完全缓解。（由欧洲研究理事会等资助；HCL-PG03 EudraCT 编号，2014-003046-27.）。
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