Kytölä Sari, Vänttinen Ida, Ruokoranta Tanja, Partanen Anu, Holopainen Annasofia, Saad Joseph, Kuusisto Milla E L, Koskela Sirpa, Räty Riikka, Itälä-Remes Maija, Västrik Imre, Suvela Minna, Parsons Alun, Porkka Kimmo, Wennerberg Krister, Heckman Caroline A, Jalkanen Tero, Huttunen Teppo, Ettala Pia, Rimpiläinen Johanna, Siitonen Timo, Pyörälä Marja, Kuusanmäki Heikki, Kontro Mika
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.
Blood. 2025 Jan 23;145(4):409-421. doi: 10.1182/blood.2024024968.
The B-cell lymphoma 2 inhibitor venetoclax has shown promise for treating acute myeloid leukemia (AML). However, identifying patients likely to respond remains a challenge, especially for those with relapsed/refractory (R/R) disease. We evaluated the utility of ex vivo venetoclax sensitivity testing to predict treatment responses to venetoclax-azacitidine in a prospective, multicenter, phase 2 trial. The trial recruited 104 participants with previously untreated (n = 48), R/R (n = 39), or previously treated secondary AML (sAML) (n = 17). The primary end point was complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate in ex vivo sensitive trial participants during the first 3 therapy cycles. The key secondary end points included the correlations between ex vivo drug sensitivity, responses, and survival. Venetoclax sensitivity was successfully assessed in 102 of 104 participants, with results available within a median of 3 days from sampling. In previously untreated AML, ex vivo sensitivity corresponded to an 85% (34/40) CR/CRi rate, with a median overall survival (OS) of 28.7 months, compared with 5.5 months for ex vivo resistant patients (P = .002). For R/R/sAML, ex vivo sensitivity resulted in a 62% CR/CRi rate (21/34) and median OS of 9.7 vs 3.3 months for ex vivo resistant patients (P < .001). In univariate and multivariate analysis, ex vivo venetoclax sensitivity was the strongest predictor for a favorable treatment response and survival. This trial demonstrates the feasibility of integrating ex vivo drug testing into clinical practice to identify patients with AML, particularly in the R/R setting, who benefit from venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04267081.
B细胞淋巴瘤2抑制剂维奈托克已显示出治疗急性髓系白血病（AML）的潜力。然而，识别可能有反应的患者仍然是一项挑战，尤其是对于复发/难治性（R/R）疾病患者。我们在一项前瞻性、多中心、2期试验中评估了体外维奈托克敏感性测试预测维奈托克联合阿扎胞苷治疗反应的效用。该试验招募了104名参与者，其中包括先前未接受治疗的患者（n = 48）、R/R患者（n = 39）或先前接受过治疗的继发性AML（sAML）患者（n = 17）。主要终点是体外敏感试验参与者在前3个治疗周期中的完全缓解或伴有血液学不完全恢复的完全缓解（CR/CRi）率。关键次要终点包括体外药物敏感性、反应和生存之间的相关性。104名参与者中的102名成功评估了维奈托克敏感性，结果在采样后中位数3天内可得。在先前未接受治疗的AML中，体外敏感性对应的CR/CRi率为85%（34/40），总生存期（OS）中位数为28.7个月，而体外耐药患者为5.5个月（P = 0.002）。对于R/R/sAML，体外敏感性导致CR/CRi率为62%（21/34），体外耐药患者的OS中位数为9.7个月，而体外耐药患者为3.3个月（P < 0.001）。在单变量和多变量分析中，体外维奈托克敏感性是有利治疗反应和生存的最强预测因素。该试验证明了将体外药物测试纳入临床实践以识别AML患者的可行性，特别是在R/R情况下，这些患者可从维奈托克中获益。该试验在www.clinicaltrials.gov上注册，编号为#NCT04267081。
