Therapeutic drug monitoring of venetoclax in Chinese acute myeloid leukemia patients using venetoclax combined with azacitidine
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摘要: 目的 探讨维奈克拉(venetoclax，VEN)联合阿扎胞苷(azacitidine，AZA)治疗中国急性髓系白血病(acute myeloid leukemia，AML)患者中VEN血药浓度监测以及与疗效的关系。方法 回顾性分析2021年4月至2023年2月于北京大学血液病研究所接受VEN联合AZA治疗和持续性VEN血药浓度监测的38例初治不适合强化疗(unfit)及难治/复发(R/R)AML患者。分析真实世界中国人群第1个疗程VEN联合AZA诱导治疗AML期间持续性监测d4、d7、d14、d21、d28 VEN谷浓度及与疗效的关系，以及与可能影响VEN血药浓度的基线患者情况和基线临床特征的相关性。结果 入组38例AML患者，初治unfit AML 21例(55.3%)，R/R AML 17例(44.7%)，中位年龄51.5(16~70)岁，男19例(50.0%)，中位随访时间18.9(5.5~28.1)个月。所有患者均因联合应用伏立康唑而调整VEN剂量为100 mg Qd。根据2022 ELN标准进行危险分层，初治unfit组高危15例(71.4%)，R/R组高危9例(52.9%)。初治unfit组VEN联合AZA中位治疗疗程为1(1~5)个，R/R组VEN联合AZA中位治疗疗程为1(1~2)个。经1个疗程VEN联合AZA治疗后，初治unfit AML患者14例(66.7%)达完全缓解/血细胞计数未完全恢复的完全缓解(CR/CRi)，4例(19.0%)达部分缓解(PR)，总体反应率达85.7%(18/21)。R/R AML患者6例(35.3%)达CR/CRi，4例(23.5%)达PR，总体反应率达58.8%(10/17)。初治unfit组诱导期间VEN稳态谷浓度Cmin在d4、d7、d14、d21、d28分别为1 330(299~6 570) ng/mL、2 158(264~5 050) ng/mL、2 404(533~5 760) ng/mL、2 752(282~4 850) ng/mL、2 251(560~4 410) ng/mL。R/R组再诱导期间VEN稳态谷浓度Cmin分别为1 203(692~3 100) ng/mL、2 245(799~5 580) ng/mL、1 950(890~4 920) ng/mL、1 856(473~3 210) ng/mL、1 650(934~2 584) ng/mL。结果显示VEN谷浓度Cmin在初治unfit组(P=0.23)及R/R组(P=0.24)有反应与未缓解组间均差异无统计学意义。VEN谷浓度与患者基线特征(性别、年龄、身高、体重、体重指数、体表面积)及基线临床特征(白蛋白、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血尿素氮、肌酐、乳酸脱氢酶、中性粒细胞绝对计数、白细胞计数、血红蛋白水平及血小板计数)无明显相关性。结论 VEN联合AZA在初治unfit及R/R AML患者中均获得较高的治疗反应率，VEN稳态谷浓度和临床疗效可能无显著相关。Abstract: Objective To investigate the monitoring of drug plasma concentration of venetoclax(VEN) and its relationship with therapeutic efficacy in Chinese acute myeloid leukemia(AML) patients receiving VEN combined with azacitidine(AZA).Methods A total of 38 AML patients receiving VEN+AZA and undergoing continuous VEN drug plasma concentration monitoring between April 2021 and February 2023 at Peking University Institute of Hematology were retrospectively analyzed. We analyzed continuously monitoring VEN trough concentration on d4, d7, d14, d21 and d28 during the first course of VEN+AZA induction therapy for AML in the real-world Chinese population and its relationship with therapeutic effect, as well as the correlation with the baseline patient conditions and clinical characteristics that may influence VEN drug plasma concentration.Results A total of 38 AML patients were enrolled, including 21(55.3%) unfit de novo AML cases and 17(44.7%) R/R AML cases. The median age was 51.5 years(range 16-70 years), and 19 patients(50.0%) were male. The median follow-up time was 18.9 months(range 5.5-28.1 months). All patients received VEN at an adjusted dose of 100 mg Qd due to the combination of voriconazole. According to the 2022 ELN risk group classification, 15 patients(71.4%) in the unfit de novo AML group were high-risk group, and 9 patients(52.9%) in R/R AML group were high-risk group. The median treatment duration was 1 course(range 1-5 courses) for the unfit de novo AML group and 1 course(range 1-2 courses) for R/R AML group. After one cycle of VEN+AZA, for the unfit de novo AML group, 14 patients(66.7%) achieved complete remission(CR)/CR with incomplete hematological recovery(CRi), and 4 patients(19.0%) achieved partial remission(PR), with an overall response rate(ORR) of 85.7%(18/21). For R/R AML group, six patients(35.3%) achieved CR/CRi, 4 patients(23.5%) achieved PR, and the ORR was 58.8%(10/17). The VEN steady-state Cmin of unfit patients during induction therapy were 1 330(299-6 570) ng/mL, 2 158(264-5 050) ng/mL, 2 404(533-5 760) ng/mL, 2 752(282-4 850) ng/mL, 2 251(560-4 410) ng/mL on d4, d7, d14, d21 and d28, respectively. The VEN steady-state Cmin of R/R patients during re-induction therapy were 1 203(692-3 100) ng/mL, 2 245(799-5 580) ng/mL, 1 950(890-4 920) ng/mL, 1 856(473-3 210) ng/mL, 1 650(934-2 584) ng/mL, respectively. The results showed there was no significant difference in the Cmin of VEN between patients achieving ORR and no response in unfit(P=0.23) and R/R patients(P=0.24). The Cmin of VEN were not significantly correlated with baseline patient characteristics(gender, age, height, weight, body mass index, and body surface area) or baseline clinical features(albumin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, lactate dehydrogenase, absolute neutrophil count, white blood cell count, hemoglobin level, and platelet count).Conclusion VEN+AZA achieved high therapeutic response rates in both unfit and R/R AML patients, and there may be no significant correlation between the VEN steady-state Cmin and clinical efficacy.
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表 1 38例接受VEN联合AZA治疗AML患者的基线特征
指标 初治unfit组(21例) R/R组(17例) 性别/例(%) 女 10(47.6) 9(52.9) 男 11(52.4) 8(47.1) 中位年龄(范围)/岁 58(16~70) 34(16~59) ECOG评分/例(%) 0 0 1(5.9) 1 4(19.0) 5(29.4) 2 10(47.6) 6(35.3) 3 7(33.3) 5(29.4) FAB分型/例(%) M1 1(4.8) 0 M2 14(66.7) 8(47.1) M4 5(23.8) 6(35.3) M5 1(4.8) 2(11.8) M6 0 1(5.9) 2022 ELN危险分层/例(%) 低危 0 3(17.6) 中危 6(28.6) 5(29.4) 高危 15(71.4) 9(52.9) 特殊基因标志/例(%) NPM1 0 1(5.9) IDH1/IDH2 3(14.3) 0 TP53 3(14.3) 0 FLT3-ITD 0 3(17.6) RUNX1-RUNX1T1 1(4.8) 3(17.6) MLL 1(4.8) 1(5.9) CEBPA框突变 1(4.8) 4(23.5) 序贯移植/例(%) 8(38.1) 8(47.1) 身高/cm 165(146~183) 165(152~185) 体重/kg 65(42.5~105) 59(45~80) BMI/(kg/m2) 23.6 (17.9~33.5) 21.7 (16.1~27.9) BSA/m2 1.69 (1.31~2.27) 1.60 (1.35~1.95) ALB/(g/L) 36.2 (30.2~42.7) 37.2 (31.4~45.4) ALT/(U/L) 15.9 (8.9~61.0) 19.2 (5.2~327.1) AST/(U/L) 20.3 (8.9~40.6) 17.2 (9.5~247.8) BUN/(mmol/L) 5.29 (2.67~17.89) 4.60 (1.22~7.65) CREA/(μmol/L) 61.7 (35.8~182.1) 57.5 (38.8~100.4) LDH/(U/L) 247 (94~769) 194 (117~685) ANC/(×109/L) 0.13 (0.01~9.79) 0.58 (0.04~31.00) WBC/(×109/L) 3.42 (0.41~85.40) 15.82 (1.82~222.05) Hb/(g/L) 70(49~131) 81(43~136) PLT/(×109/L) 62(6~408) 38(4~273) 
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表 2 38例患者诱导期间的VEN谷浓度Cmin
ng/mL 时间 初治unfit组(21例) R/R组(17例) 中位数 范围 中位数 范围 d4 1 330 299~6 570 1 203 692~3 100 d7 2 158 264~5 050 2 245 799~5 580 d14 2 404 533~5 760 1 950 890~4 920 d21 2 752 282~4 850 1 856 473~3 210 d28 2 251 560~4 410 1 650 934~2 584
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