Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
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DOI：
10.1056/nejmoa1506583
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发表时间：
2015-10-29
期刊：
影响因子：
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通讯作者：
Tallman MS
中科院分区：
文献类型：
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作者：
Tiacci E;Park JH;De Carolis L;Chung SS;Broccoli A;Scott S;Zaja F;Devlin S;Pulsoni A;Chung YR;Cimminiello M;Kim E;Rossi D;Stone RM;Motta G;Saven A;Varettoni M;Altman JK;Anastasia A;Grever MR;Ambrosetti A;Rai KR;Fraticelli V;Lacouture ME;Carella AM;Levine RL;Leoni P;Rambaldi A;Falzetti F;Ascani S;Capponi M;Martelli MP;Park CY;Pileri SA;Rosen N;Foà R;Berger MF;Zinzani PL;Abdel-Wahab O;Falini B;Tallman MS
BRAF-V600 E是毛细胞白血病的遗传病变。我们评估了口服BRAF抑制剂vemurafenib在嘌呤类似物治疗后复发或难治的毛细胞白血病患者中的安全性和活性。我们在意大利和美国进行了两项关于维罗非尼（960 mg，每日两次）的2期单臂多中心研究，中位给药时间分别为16周和18周。主要终点为完全缓解率和总缓解率。意大利试验于2013年4月完成患者入组（n=28），美国试验仍在开放（n=26/36）。药物相关不良事件通常为1-2级，最常需要降低剂量的是皮疹和关节痛/关节炎; 50例患者中有6例发生继发性皮肤肿瘤（采用简单切除术治疗）。总体缓解率分别为96%（25/26例可评价的意大利患者）和100%（24/24例可评价的美国患者），分别在中位8周和12周后获得。完全缓解率分别为34.6%（9/26）和41.7%（10/24）。在意大利试验中，中位随访23个月后，完全缓解者的中位无复发和无治疗生存期分别为19和25个月，部分缓解者为6和18个月。在美国试验中，1年无进展生存率和总生存率分别为73%和91%。治疗结束时磷酸化ERK+骨髓白血病细胞的频繁持续表明旁路MEK-ERK再激活是一种耐药机制。在复发性/难治性毛细胞白血病患者中，维罗非尼的短期口服疗程被证明是安全和高效的（由AIRC、ERC、Roche/Genentech等资助; EudractCT编号：2011-005487-13，ClinicalTrials.gov编号NCT 01711632）。
BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues. We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial. Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism. A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632).