意大利佩鲁贾埃马托肿瘤研究中心Brunangelo Falini团队研究了维莫非尼联合利妥昔单抗治疗难治或复发性毛细胞白血病的疗效。2021年5月12日，该研究发表在《新英格兰医学杂志》上。

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抑制剂维莫非尼靶向BRAF V600E导致91%的患者出现缓解；35%的患者完全缓解。然而，停止治疗后中位无复发生存期仅为9个月。

在一项涉及难治性或复发性HCL患者的临床2期单中心学术试验中，研究组评估了维莫非尼联合同时和序贯利妥昔单抗治疗的安全性和有效性。主要终点是治疗结束时的完全缓解率。

在30例HCL患者中，既往治疗的中位次数为3。在意向治疗人群中，26名患者（87%）观察到完全缓解。所有患HCL且对化疗（10例）或利妥昔单抗（5例）以及以前服用过BRAF抑制剂（7例）无效的患者均完全缓解。血小板减少在平均2周后消失，中性粒细胞减少在平均4周后消失。

在26例完全缓解的患者中，17例（65%）清除了微小残留病灶（MRD）。平均随访37个月，30例患者的无进展生存率为78%；在平均随访34个月的26例有缓解的患者中，无复发生存率为85%。在事后分析中，MRD阴性和既往无BRAF抑制剂治疗与较长的无复发生存期相关。毒性作用主要为1级或2级。

在这项小型研究中，维莫非尼联合利妥昔单抗的短期、无化疗、非髓质毒性方案与大多数难治性或复发性HCL患者的持久完全缓解相关。

附：英文原文

Title: Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia

Author: Enrico Tiacci, M.D.,, Luca De Carolis, M.D.,, Edoardo Simonetti, M.D.,, Monia Capponi, M.D.,, Achille Ambrosetti, M.D.,, Eugenio Lucia, M.D.,, Agostino Antolino, M.D.,, Alessandro Pulsoni, M.D.,, Samantha Ferrari, M.D.,, Pier L. Zinzani, M.D.,, Stefano Ascani, M.D.,, Vincenzo M. Perriello, M.D.,, Luigi Rigacci, M.D.,, Gianluca Gaidano, M.D.,, Roberta Della Seta, M.D.,, Natalia Frattarelli, M.D.,, Paolo Falcucci, M.D.,, Robin Foà, M.D.,, Giuseppe Visani, M.D.,, Francesco Zaja, M.D.,, and Brunangelo Falini, M.D.

Issue&Volume: 2021-05-12

Abstract:

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.

DOI: 10.1056/NEJMoa2031298

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2031298