Kadia Tapan M, Jen Wei-Ying, Bataller Alex, Bazinet Alexandre, Borthakur Gautam, Jabbour Elias, Qiao Wei, Short Nicholas J, Takahashi Koichi, Issa Ghayas C, DiNardo Courtney D, Montalban-Bravo Guillermo, Pemmaraju Naveen, Tran Andrew, Bharathi Vanthana, Loghavi Sanam, Alousi Amin M, Popat Uday, Daver Naval G, Ravandi Farhad, Kantarjian Hagop M
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Am J Hematol. 2025 Aug;100(8):1365-1373. doi: 10.1002/ajh.27723. Epub 2025 May 22.
Outcomes in patients with relapsed/refractory (RR) AML are poor. We sought to investigate if CPX-531 in combination with venetoclax (CPX + VEN) was tolerable and effective in RR AML. This was a single institution phase 1b/2 trial of CPX + VEN. Patients aged ≥ 18 years with RR AML who were fit for intensive chemotherapy were eligible. Prior venetoclax exposure was allowed. The phase 1b portion followed a 3 + 3 design to identify the recommended phase 2 dose (RP2D) for the expansion cohort. At the starting dose level of -1, prolonged myelosuppression was observed, leading to dose level -2 (CPX-351 dosed at daunorubicin 44 mg/m on days 1,3, and 5 and venetoclax 300 mg days 2-8) being chosen as the RP2D. Thirty three patients with a median age of 58 years (range, 26-72) were treated. Patients were heavily pretreated, with 58% with prior venetoclax exposure, 44% in the second salvage or later, and 30% with prior stem cell transplant (SCT). Adverse cytogenetics were present in 51% of patients, with myelodysplasia-related mutations in 64%, and TP53 in 21%. The overall response rate (ORR) was 46% (95% CI, 30-62), with a composite CR rate (CRc) of 39% (95% CI, 25-56). Patients in first salvage with wildtype TP53 had a CRc rate of 70% (95% CI, 40-89), with undetectable MRD in 71% (95% CI, 36-92) and a 2-year OS of 49% (95% CI, 23-100). Eleven (73%) responding patients underwent SCT. The 30-day mortality was 9%, with a 60-day mortality of 21%. The most common adverse events were related to myelosuppression. CPX + VEN has activity in RR AML, particularly when used in first salvage and in patients who do not harbor TP53 mutations. ClinicalTrials.gov Identifier: NCT03629171.
复发/难治性（RR）急性髓系白血病（AML）患者的预后较差。我们试图研究CPX-531联合维奈克拉（CPX + VEN）在RR AML中是否耐受且有效。这是一项关于CPX + VEN的单机构1b/2期试验。年龄≥18岁、适合强化化疗的RR AML患者符合条件。允许既往使用过维奈克拉。1b期部分采用3+3设计以确定扩展队列的推荐2期剂量（RP2D）。在起始剂量水平-1时，观察到骨髓抑制延长，导致选择剂量水平-2（CPX-351在第1、3和5天以柔红霉素44 mg/m给药，维奈克拉在第2 - 8天给药300 mg）作为RP2D。33例患者接受治疗，中位年龄58岁（范围26 - 72岁）。患者接受过大量预处理，58%既往使用过维奈克拉，44%处于第二次挽救治疗或更晚期，30%既往接受过干细胞移植（SCT）。51%的患者存在不良细胞遗传学特征，64%存在骨髓增生异常相关突变，21%存在TP53突变。总缓解率（ORR）为46%（95%CI，30 - 62）），完全缓解复合率（CRc）为39%（95%CI，25 - 56）。首次挽救治疗且TP53野生型的患者CRc率为70%（95%CI，40 - 89），71%（95%CI，36 - 92）的患者微小残留病（MRD）不可检测，2年总生存率（OS）为49%（95%CI，23 - 100）。11例（73%）缓解患者接受了SCT。30天死亡率为9%，60天死亡率为21%。最常见的不良事件与骨髓抑制有关。CPX + VEN在RR AML中具有活性，特别是在首次挽救治疗以及不存在TP53突变的患者中。临床试验.gov标识符：NCT03629171。
