Venetoclax 联合低剂量阿糖胞苷治疗未经治疗的急性髓系白血病患者：来自 Ib/II 期研究的结果。

Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study.

机构信息

1 The Alfred Hospital and Monash University, Melbourne, VIC, Australia.

2 Vanderbilt-Ingram Cancer Center, Nashville, TN.

出版信息

J Clin Oncol. 2019 May 20;37(15):1277-1284. doi: 10.1200/JCO.18.01600. Epub 2019 Mar 20.

DOI:10.1200/JCO.18.01600

PMID:30892988

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6524989/

Abstract

PURPOSE

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.

PATIENTS AND METHODS

Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).

RESULTS

Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).

CONCLUSION

Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.

摘要

目的

对于不能耐受强化化疗的急性髓系白血病（AML）患者，有效的治疗选择有限。一项国际 1b/2 期研究评估了 venetoclax（一种选择性 B 细胞白血病/淋巴瘤-2 抑制剂）与低剂量阿糖胞苷（LDAC）联合用于不适合强化化疗的老年 AML 患者的安全性和初步疗效。

患者和方法

纳入年龄在 60 岁及以上、初治 AML 且不适合强化化疗的成年人。允许先前治疗骨髓增生异常综合征，包括低甲基化剂（HMA）。82 例患者接受推荐的 2 期剂量治疗：每天口服 600 毫克 venetoclax，28 天为一个周期，LDAC（每天 20 毫克/平方米）皮下给药，第 1 至 10 天。主要终点是耐受性、安全性、缓解率、缓解持续时间（DOR）和总生存期（OS）。

结果

中位年龄为 74 岁（范围 63 至 90 岁），49%为继发性 AML，29%有先前 HMA 治疗史，32%有不良细胞遗传学特征。常见的 3 级或更高级别的不良事件包括发热性中性粒细胞减少症（42%）、血小板减少症（38%）和白细胞计数下降（34%）。早期（30 天）死亡率为 6%。54%的患者达到完全缓解（CR）/CR 伴不完全血细胞计数恢复（首次缓解的中位时间为 1.4 个月）。中位 OS 为 10.1 个月（95%CI，5.7 至 14.2），中位 DOR 为 8.1 个月（95%CI，5.3 至 14.9 个月）。在没有先前 HMA 暴露的患者中，62%的患者达到 CR/CR 伴不完全血细胞计数恢复，中位 DOR 为 14.8 个月（95%CI，5.5 个月至未达到），中位 OS 为 13.5 个月（95%CI，7.0 至 18.4 个月）。