Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
Department of Medicine, Weill Cornell Medicine, New York.
NEJM Evid. 2023 Oct;2(10):EVIDoa2300074. doi: 10.1056/EVIDoa2300074. Epub 2023 Sep 21.
Hairy cell leukemia (HCL) is characterized by the underlying genetic lesion of BRAFV600E and responsiveness to BRAF inhibitors. We assessed the safety and activity of the BRAF inhibitor vemurafenib combined with obinutuzumab in patients with previously untreated HCL. METHODS: We conducted a single-arm, multicenter clinical study of vemurafenib plus obinutuzumab. Vemurafenib 960 mg twice daily was administered for four cycles, and obinutuzumab was administered in cycles 2 to 4. The primary end point was complete remission (CR). Secondary end points included assessment of safety, minimal residual disease (MRD), and BRAF allele burden according to digital droplet polymerase chain reaction (ddPCR). RESULTS: Thirty patients were enrolled in the study, and 27 patients completed all four cycles of treatments and achieved CR (90%; 95% confidence interval [CI], 73 to 98). Three patients discontinued the study early because of adverse events and were not evaluable for response. Of the 27 patients who achieved CR, 26 patients (96%; 95% CI, 81 to 99) achieved MRD negativity. BRAFV600E allele was undetectable by ddPCR in all 21 evaluable patients. At a median follow-up of 34.9 months (95% CI, 29.6 to 36.9), no patient experienced disease relapse. The most common vemurafenib-related adverse events were rash and arthralgia. Febrile neutropenia occurred in two patients, and blood or platelet transfusions were required in two patients. CONCLUSIONS: Combined time-limited vemurafenib and obinutuzumab achieved CR in more than 90% of patients with previously untreated HCL. In this small study, acquired vemurafenib resistance or dose-limiting toxicity was not observed. Patients were not observed long enough to reveal secondary malignancies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03410875.)
毛细胞白血病（HCL）的特征是存在 BRAFV600E 潜在遗传病变和对 BRAF 抑制剂的反应性。我们评估了 BRAF 抑制剂维莫非尼联合奥滨尤妥珠单抗在未经治疗的 HCL 患者中的安全性和疗效。
我们进行了一项维莫非尼联合奥滨尤妥珠单抗的单臂、多中心临床研究。维莫非尼每天两次给药 960mg，共 4 个周期，奥滨尤妥珠单抗在第 2 至 4 个周期给药。主要终点为完全缓解（CR）。次要终点包括根据数字液滴聚合酶链反应（ddPCR）评估安全性、微小残留病（MRD）和 BRAF 等位基因负担。
共有 30 名患者入组该研究，27 名患者完成了所有 4 个周期的治疗并达到 CR（90%；95%置信区间[CI]，73%至 98%）。3 名患者因不良事件提前退出研究而无法评估缓解情况。在达到 CR 的 27 名患者中，26 名患者（96%；95%CI，81%至 99%）达到 MRD 阴性。21 名可评估患者的 ddPCR 均未检测到 BRAFV600E 等位基因。在中位随访 34.9 个月（95%CI，29.6 至 36.9）时，无患者疾病复发。最常见的维莫非尼相关不良事件为皮疹和关节痛。2 名患者发生发热性中性粒细胞减少症，2 名患者需要输血。
联合使用有限时间的维莫非尼和奥滨尤妥珠单抗可使超过 90%未经治疗的 HCL 患者获得 CR。在这项小型研究中，未观察到获得性维莫非尼耐药或剂量限制性毒性。患者的随访时间不足以发现继发性恶性肿瘤。（由美国国立癌症研究所等资助；ClinicalTrials.gov 编号，NCT03410875）
