复发性/难治性急性髓系白血病（AML）是一种遗传复杂、异质性强、预后不良、治疗选择有限的疾病。因此，迫切需要开发治疗组合来克服AML的耐药性。这项开放标签、多中心、国际性、1b期研究评估了venetoclax与alvocidib联合治疗R/R AML患者的安全性、有效性和药代动力学。患者在28天循环中接受递增剂量的venetoclax（400、600和800mg QD，口服，1-28天）和alvocidib（45和60 mg/m2，静脉注射，1-3天）治疗。该联合治疗方案安全可耐受，无最大耐受剂量。23例患者（65.7%）与venetoclax有关的3级以上不良事件，24例患者（68.6%）与alvocidib有关的不良事件。无与药物有关的不良事件导致死亡。胃肠道毒性包括腹泻、恶心、呕吐是值得关注且频繁的，除此之外，报告的毒性与两种药物的安全性无关。响应率不高（完全缓解[CR] + 部分缓解+形态学白血病无病状态，20%，完全缓解[CR] + 部分缓解[CRi]，11.4%）。随着venetoclax剂量的增加，alvocidib的药代动力学没有改变。然而，当venetoclax与alvocidib一起使用时，AUC24和Cmax分别降低了18%和19%。由于与每种单一药物相比，所有队列的疗效没有实质性增加，因此建议二期剂量未得出。未来的研究可以考虑序列的作用、剂量和对R/R AML人群使用更选择性的MCL1抑制剂。© 由John Wiley＆Sons Ltd出版的血液学肿瘤科。

Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC24 and Cmax decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.© 2023 AbbVie Inc. Hematological Oncology published by John Wiley & Sons Ltd.