Luskin Marlise R, Shimony Shai, Keating Julia, Winer Eric S, Garcia Jacqueline S, Stone Richard M, Jabbour Elias, Flamand Yael, Stevenson Kristen, Ryan Jeremy, Zeng Zhihong, Letai Anthony, Konopleva Marina, Jain Nitin, DeAngelo Daniel J
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.
Blood Adv. 2025 Feb 11;9(3):617-626. doi: 10.1182/bloodadvances.2024014405.
In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose reductions. This phase 1b study of venetoclax plus attenuated chemotherapy enrolled 19 patients with ALL either newly diagnosed (aged ≥60 years, n = 11 [B-cell, n = 8; T-cell, n = 3]) or relapsed/refractory (R/R; aged ≥18 years, n = 8 [B-cell, n = 3; T-cell, n = 5]). Venetoclax was given for 21 days with each cycle of mini-hyper-CVD (mini-HCVD; cyclophosphamide, vincristine, dexamethasone alternating with methotrexate and cytarabine). There were no dose-limiting toxicities at dose level 1 (DL1; n = 3, 400 mg/d) or DL2 (n = 6, 600 mg/d); DL2 was the recommended phase 2 dose and explored further (n = 10). The most common nonhematologic adverse events were grade ≥3 infections. There were no deaths within 60 days. There was no tumor lysis syndrome, hepatotoxicity, prolonged cytopenias, or early discontinuation for toxicity. Among patients with newly diagnosed ALL, 10 of 11 (90.9%) achieved a measurable residual disease-negative (<0.01% sensitivity) complete remission (CR) including 6 patients with hypodiploid TP53-mutated ALL. All patients in CR bridged to hematopoietic stem cell transplant (n = 9) or completed protocol (n = 1). With a median follow-up of 60 months, median disease-free survival (DFS) for patients with newly diagnosed ALL was 54.6 months (95% confidence interval [CI], 35.5 to not available), with a 2-year DFS rate of 90% (95% CI, 71-100). Among patients with R/R ALL, 3 of 8 (37.5%) achieved CR. In summary, for patients with newly diagnosed ALL, venetoclax plus mini-HCVD is well tolerated with promising efficacy. This trial was registered at www.clinicaltrials.gov as #NCT03319901.
在急性淋巴细胞白血病（ALL）中，B细胞淋巴瘤2抑制剂维奈克拉可能会增强化疗疗效，从而允许降低化疗剂量。这项维奈克拉联合减量化疗的1b期研究纳入了19例ALL患者，其中新诊断患者（年龄≥60岁，n = 11 [B细胞型，n = 8；T细胞型，n = 3]）或复发/难治性（R/R；年龄≥18岁，n = 8 [B细胞型，n = 3；T细胞型，n = 5]）。维奈克拉在每个小剂量高强度环磷酰胺、长春新碱、地塞米松与甲氨蝶呤和阿糖胞苷交替使用（mini-HCVD）周期中给药21天。在剂量水平1（DL1；n = 3，400 mg/d）或DL2（n = 6，600 mg/d）时没有剂量限制性毒性；DL2是推荐的2期剂量并进一步探索（n = 10）。最常见的非血液学不良事件是≥3级感染。60天内无死亡病例。没有发生肿瘤溶解综合征、肝毒性、长期血细胞减少或因毒性而提前停药的情况。在新诊断的ALL患者中，11例中有10例（90.9%）达到了可测量残留病阴性（<0.01%敏感性）完全缓解（CR），其中包括6例低二倍体TP53突变的ALL患者。所有达到CR的患者都接受了造血干细胞移植（n = 9）或完成了方案治疗（n = 1）。中位随访60个月，新诊断ALL患者的中位无病生存期（DFS）为54.6个月（95%置信区间[CI]，35.5至不可用），2年DFS率为90%（95%CI，71 - 100）。在R/R ALL患者中，8例中有3例（37.5%）达到CR。总之，对于新诊断的ALL患者，维奈克拉联合mini-HCVD耐受性良好，疗效 promising。该试验在www.clinicaltrials.gov上注册为#NCT03319901。 （注：原文中“promising”翻译为“有前景的”，但这里“疗效promising”表述不通顺，推测原文可能有误，也许是“疗效显著”之类意思，可根据实际情况调整）
