Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine, induced by long-acting crisantaspase (pegcrisantaspase [PegC]) was synergistic with the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study of the combination of Ven and PegC (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary end points were the incidence of regimen-limiting toxicities (RLTs) and the maximum tolerated dose (MTD). Twenty-five patients received at least 1 PegC dose with Ven, and 18 efficacy-evaluable patients completed at least 1 VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36%-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in messenger RNA translation. In patients with RUNX1 mutations, the composite complete remission rate was 100%. This study was registered at www.ClinicalTrials.gov as #NCT04666649.

中文翻译：

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氨基酸调节剂 pegcrisantaspase 和 venetoclax 治疗复发或难治性急性髓性白血病的 1 期研究


谷氨酰胺依赖已被证明是急性髓性白血病 （AML） 中的一种代谢脆弱性。先前使用几种体内 AML 模型的研究表明，长效 crisantaspase （pegcrisantaspase [PegC]） 诱导的血浆谷氨酰胺耗竭与 B 细胞淋巴瘤-2 （BCL-2） 抑制剂维奈托克 （Ven） 协同作用，导致白血病负担显着降低并提高生存率。在这里，我们报告了一项 Ven 和 PegC 联合治疗复发或难治性 AML 成人患者的 1 期研究，包括以前接受过 Ven 的患者。主要终点是方案限制性毒性 （RLT） 的发生率和最大耐受剂量 （MTD）。25 例患者接受了至少 1 次 PegC 剂量的 Ven，18 例疗效可评估的患者完成了至少 1 个 VenPegC 周期;12 例 （67%） 既往接受过 Ven. 高胆红素血症是 RLT，发生在 60% 的接受 VenPegC 治疗的患者中;20% 的患者有 ≥ 级胆红素升高。MTD 确定为每天 Ven 400 mg，每两周 PegC 750 IU/m2。在接受 VenPegC 的 25 例患者中，任何级别最常见的治疗相关不良事件包括抗凝血酶 III 减少 （52%） 、转氨酶升高 （36%-48%） 、疲劳 （28%） 和低纤维蛋白原血症 （24%）。未观察到血栓栓塞或出血性不良事件或临床胰腺炎。疗效可评估患者的总体完全缓解率为 33%。反应与参与信使 RNA 翻译的蛋白质的改变相关。在 RUNX1 突变患者中，复合完全缓解率为 100%。这项研究在 www.ClinicalTrials.gov 上注册为 #NCT04666649。