Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies
Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies
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DOI：
10.1002/ajh.25000
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发表时间：
2018-03-01
影响因子：
12.8
通讯作者：
Konopleva, Marina
中科院分区：
文献类型：
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作者：
DiNardo, Courtney D.;Rausch, Caitlin R.;Konopleva, Marina
简介：维奈托克（VEN）是一种选择性BCL 2抑制剂，在复发性和难治性（R/R）急性髓性白血病（AML）中具有单药活性，在初治老年AML患者中具有较低强度组合的疗效。VEN联合治疗R/R AML以前没有报道。方法：所有R/R髓系患者（包括AML、骨髓增生异常综合征（MDS）和母细胞浆细胞样树突状细胞肿瘤（BPDCN））在挽救环境中用VEN组合治疗。43例中位年龄为68岁（范围25-83岁）的患者接受了AML（91%）、MDS（5%）或BPDCN（5%）治疗。大多数（n=36，84%）为>=挽救-2治疗状态，包括77%的既往低甲基化剂（HMA）。与VEN联合治疗时，大多数患者接受HMA治疗（n=31，72%）; 8例（19%）接受低剂量阿糖胞苷（LDAC）。患者接受中位2个治疗周期（范围，1-4）。在9例（21%）患者中观察到客观缓解，包括2例完全缓解（CR）、3例CRi和4例形态学无白血病状态（MLFS）。中位生存期为3.0个月（范围0.5-8.0），估计6个月生存率为24%。在21例中危细胞遗传学患者中有5例（24%）、11例IDH 1/2突变患者中有3例（27%）和8例RUNX 1突变患者中有4例（50%）观察到缓解。10例TP 53突变患者中有2例（20%）有反应; 2例患者均同时存在RUNX 1突变。3（15%）响应不良细胞遗传学的患者，所有并发RUNX 1 mutations.Conclusion：低强度化疗，包括HMAs或LDAC，与VEN相结合是一个可行的挽救选择，即使在多次复发/难治性AML，MDS和BPDCN患者。在二倍体/中间细胞遗传学、RUNX 1和/或IDH 1/2突变患者中发现了显著缓解。
Introduction: Venetoclax (VEN), a selective BCL2 inhibitor, has single-agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment-naive elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported.Methods: All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed.Results: Forty-three patients with median age 68 (range, 25-83) were treated for AML (91%), MDS (5%), or BPDCN (5%). Most (n=36, 84%) were >= salvage-2 treatment status, including prior hypomethylating agent (HMA) in 77%. In combination with VEN, most patients received HMA therapy (n=31, 72%); eight (19%) received low-dose cytarabine (LDAC). Patients received a median of 2 treatment cycles (range, 1-4). Objective response was observed in 9 (21%) patients, including 2 complete responses (CR), 3 CRi, and 4 morphologic leukemia-free state (MLFS). Median survival was 3.0 months (range, 0.5-8.0), and estimated 6-month survival was 24%. Responses were observed in five (24%) of 21 patients with intermediate-risk cytogenetics, 3 (27%) of 11 IDH1/2-mutant, and 4 (50%) of 8 RUNX1-mutated patients. Two (20%) of 10 TP53-mutated patients responded; both had concurrent RUNX1 mutations. Of the 3 (15%) responding patients with adverse cytogenetics, all had concurrent RUNX1 mutations.Conclusion: Low-intensity chemotherapy, including HMAs or LDAC, in combination with VEN is a viable salvage option, even in multiply relapsed/refractory patients with AML, MDS, and BPDCN. Notable responses were identified in patients with diploid/intermediate cytogenetics, RUNX1, and/or IDH1/2 mutations.