A single-center, real-world study of the efficacy and safety of venetoclax in the treatment of acute myeloid leukemia
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摘要: 目的 靶向药物BCL-2抑制剂维奈克拉(VEN)在国内于2020年底获批上市，其联合去甲基化药物(HMAs)已成为≥60岁尤其是不适合强化疗的初治急性髓系白血病(AML)患者的新标准治疗方案，但目前真实世界中VEN的应用人群、应用方案以及疗效与安全性的数据有限，我们对本中心VEN在AML患者的应用情况进行了回顾性研究。方法 回顾性收集和分析2019年9月—2021年12月在我院血研所首次接受VEN治疗的52例AML患者的临床资料。结果 ① VEN应用人群：目前国内AML指南推荐VEN应用人群的年龄为60岁及以上，疾病状态为初治，本研究中有67.3%的患者年龄低于此界限，有38.5%的患者为经治。②VEN应用方案：目前国内AML指南推荐VEN与HMAs联合应用，本研究中初治患者大部分(78.1%)接受此组合方案治疗，且主要为联合阿扎胞苷(64.0%)，而经治患者中超半数(55.0%)采用VEN联合含细胞毒药物方案；40.4%的患者VEN起始剂量高于推荐剂量100 mg，30.8%的患者VEN稳定期剂量低于推荐剂量400 mg；56.5%的患者在合用唑类抗真菌药物时进行VEN剂量调整，但减量程度未达标准，43.5%的患者未进行剂量调整。③疗效与安全性：初治患者中，VEN联合阿扎胞苷或地西他滨均能实现较好的完全缓解/完全缓解伴血液学不完全恢复率(分别为75.0%和77.8%，P>0.999)，与VEN关键注册研究(M14-358研究)的长期随访结果报道一致(分别为71.0%和74.0%)；本研究中VEN联合HMAs的≥3级血液学不良反应的整体发生率(96.6%)较M14-358研究中明显升高，其中联合阿扎胞苷组血小板减少和中性粒细胞减少伴发热的发生率低于联合地西他滨组(70.0% vs 100.0%；70.0% vs 100.0%)；总队列的非血液学不良反应发生率为44.2%，均为1~2级，所有患者均未见肿瘤溶解综合征发生。结论 在真实世界中，VEN已经应用于当前临床指南尚未覆盖的年轻、经治AML患者。大部分初治患者接受指南推荐的VEN联合HMAs方案，且主要为联合阿扎胞苷。接受VEN联合阿扎胞苷或地西他滨治疗的初治患者均能够取得与VEN关键注册研究相仿的良好临床效果，严重血液学不良反应则有所升高。Abstract: Objective The targeted drug BCL-2 inhibitor Venetoclax(VEN) has been approved for marketing at the end of 2020 in China, and its combination with hypomethylating drugs(HMAs) has become the standard treatment of acute myeloid leukemia(AML) who were 60 years of age or older, especially those ineligible for intensive chemotherapy. However, real-world data is limited on the patient population, treatment regimens, and the efficacy and safety of VEN for AML patients. We conducted a single-center, retrospective study on the application of VEN for AML patients.Methods Clinical data of 52 AML patients who received VEN treatment for the first time from September 2019 to December 2021 were retrospectively analyzed.Results ① VEN patient population: current AML guidelines recommend that VEN be used in those who are 60 years of age or older, and the disease state is newly diagnosed. In this study, 67.3% of the patients were younger than this age limit, and 38.5% of the patients were previously treated. ②VEN treatment regimen: VEN combined with HMAs is the recommended regimen in AML guidelines. In this study, most of the treatment-naive patients(78.1%) received this combination, and the majority of them received VEN combined with azacitidine(64.0%). In previously treated AML patients, more than half(55.0%) treated with VEN combined with cytotoxic drugs. 40.4% of the patients had a higher VEN initial dose than the recommended dose of 100 mg, 30.8% of the patients had a lower stable VEN dose than the recommended dose of 400 mg; Of the patients who concurrently received azole antifungal drugs, 56.5% received VEN dose modification, whereas the degree of reduction did not meet standard requirements, and 43.5% of the patients did not receive VEN dose modification. ③The efficacy and safety: In the treatment-naive patients, VEN combined with azacitidine or decitabine both achieved favorable CR/CRi rates(75.0% and 77.8%, respectively,P>0.999), which was consistent with the long-term follow-up results reported in the VEN pivotal registry study(M14-358 study)(71.0% and 74.0%, respectively); The overall incidence of grade ≥3 hematological adverse events(96.6%) in patients who received VEN combined with HMAs was significantly higher in this study than that in the M14-358 study. The incidence of grade ≥3 thrombocytopenia and febrile neutropenia was lower in the azacitidine-combined group than that in the decitabine-combined group(70.0% vs 100.0%; 70.0% vs 100.0%). The incidence of non-hematologic adverse events in the total cohort was 44.2%, were all grade 1-2 and no tumor lysis syndrome was observed.Conclusion In the real-world setting, VEN has been applied to young or previously treated AML patients, who are currently not covered by clinical guidelines. Most of the treatment-naive patients receive the guideline-recommended VEN and HMAs combination regimen, and mainly combined with azacitidine. Treatment-naive patients who received VEN combined with azacitidine or decitabine could both achieve favorable clinical response, similar to the results in the VEN pivotal registry study, but serious hematological adverse events are more common.
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Key words:
- venetoclax /
- acute myeloid leukemia /
- real-world study
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表 1 52例AML患者基线临床特征
例(%) 临床特征 总队列(52例) < 60岁(35例) ≥60岁(17例) 性别 男 29(55.8) 16(45.7) 13(76.5) 女 23(44.2) 19(54.3) 4(23.5) ECOG PS评分 < 2 30(57.7) 23(65.7) 7(41.2) ≥2 22(42.3) 12(34.3) 10(58.8) 伴基础合并症 有 27(51.9) 9(25.7) 14(82.4) 无 25(48.1) 26(74.3) 3(17.6) 疾病情况 初治 32(61.5) 16(45.7) 16(94.1) 经治 20(38.5) 19(54.3) 1(5.9) 既往接受HMAs 13(25.0) 12(34.3) 1(5.9) 细胞遗传学预后分层 低危 7(13.5) 5(14.3) 2(11.8) 中危 39(75.0) 25(71.4) 14(82.4) 高危 6(11.5) 5(14.3) 1(5.9) 分子生物学特征 IDH1/2 10(19.2) 7(20.0) 3(17.6) FLT3-ITD 9(17.3) 6(17.1) 3(17.6) NPM1 9(17.3) 5(14.3) 4(23.5) K/NRAS 7(13.5) 5(14.3) 2(11.8) CEBPA双突变 6(11.5) 6(17.1) 0 ASXL1 5(9.6) 2(5.7) 3(17.6) RUNX1 5(9.6) 4(11.4) 1(5.9) NOTCH1 4(7.7) 3(8.6) 1(5.9) TP53 3(5.8) 1(2.9) 2(11.8) ≥3级血常规异常 中性粒细胞减少 51(98.1) 34(91.7) 17(100.0) 贫血 46(88.5) 30(85.7) 16(94.1) 血小板减少 45(86.5) 30(85.7) 15(88.2) 
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表 2 VEN联合方案与反应率△
例(%) 疾病情况 HMAs 含细胞毒药物方案▲ 其他联合方案▼ AZA DEC▽ 总队列(52例) 方案 29(55.8) 14(26.9) 9(17.3) 20(69.0) 9(31.0) CR+CRi 22(75.8) 9(64.3) 5(55.6) 15(75.0) 7(77.8) 初治(32例) 方案 25(78.1) 3(9.4) 4(12.5) 16(64.0) 9(36.0) CR+CRi 19(76.0) / / 12(75.0) 7(77.8) 经治(20例) 方案 4(20.0) 11(55.0) 5(25.0) △本研究中缓解率基于VEN使用后第1个疗程的数据得出；▽DEC：地西他滨；▲细胞毒药物：去甲氧柔红霉素、阿糖胞苷、高三尖杉酯碱、氟达拉滨、阿克拉霉素；▼其他联合方案：靶向药物(HMAs、索拉非尼、吉瑞替尼)和(或)免疫疗法(PD-1抑制剂替雷利珠单抗)。
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表 3 VEN+HMAs使用中血液学不良反应
例(%) 血液学不良反应 VEN+AZA (20例) VEN+DEC (9例) 分级 1~2级 1(5.0) 0 ≥3级 19(95.0) 9(100.0) 中性粒细胞减少 19(95.0) 9(100.0) 贫血 18(90.0) 9(100.0) 血小板减少 14(70.0) 9(100.0) 中性粒细胞减少伴发热 14(70.0) 9(100.0)
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