Short Nicholas J, Kantarjian Hagop, Furudate Ken, Jain Nitin, Ravandi Farhad, Karrar Omer, Loghavi Sanam, Nasr Lewis, Haddad Fadi G, Senapati Jayastu, Garris Rebecca, Takahashi Koichi, Jabbour Elias
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Unit 428, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Hematol Oncol. 2025 May 14;18(1):55. doi: 10.1186/s13045-025-01709-y.
Several studies have suggested that chemotherapy-free regimens consisting of blinatumomab and a BCR::ABL1 tyrosine kinase inhibitor are highly effective in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, the clinical and molecular characteristics that predict for relapse with these chemotherapy-free regimens are largely unknown.
We conducted a prospective phase II clinical trial of the combination of blinatumomab and ponatinib in 76 patients with newly diagnosed Ph + ALL. Patients received 12-15 doses of intrathecal chemotherapy as central nervous systemic (CNS) prophylaxis. The patterns of relapse and the clinical and molecular predictors of relapse were analyzed.
With a median follow-up of 29 months, the estimated 3-year event-free survival rate was 78% and the 3-year overall survival rate was 88%. Ten patients (13%) relapsed, with a median time to relapse of 18 months (range, 8-24 months). Six relapses occurred only in extramedullary sites (CNS, n = 5; peritoneum and lymph nodes, n = 1). CD19 expression remained high at relapse in all patients. On univariate analysis, factors associated with an increased risk of relapse were: white blood cell (WBC) ≥ 70 × 10/L at diagnosis (sHR 8.86 [95% CI 2.33-33.70]; P = 0.001), CNS involvement at diagnosis (sHR 6.87 [95% CI 1.54-30.68]; P = 0.01), and VPREB1 deletion (sHR 4.06 [95% CI 1.05-15.76]; P = 0.04). WBC ≥ 70 × 10/L was present in 22% of the cohort and was associated with a 53% cumulative incidence of relapse (CIR), as compared with a CIR rate of 6% for patients with WBC < 70 × 10/L. Neither IKZF1 genotype, BCR::ABL1 transcript type, nor measurable residual disease kinetics by next-generation sequencing for IG/TR rearrangements significantly impacted the risk of relapse. High WBC at diagnosis was the only variable significantly associated with relapse on multivariate analysis (sHR 16.29 [95% CI 2.35-113.00; P = 0.005).
WBC ≥ 70 × 10/L is a high-risk feature in patients with Ph + ALL receiving frontline blinatumomab and ponatinib and may supersede the prognostic importance of baseline molecular features. Alternative frontline treatment strategies may be needed for these patients to reduce the risk of relapse and improve long-term outcomes.
ClinicalTrials.gov (NCT03263572).
多项研究表明，由博纳吐单抗和一种BCR::ABL1酪氨酸激酶抑制剂组成的无化疗方案在费城染色体阳性急性淋巴细胞白血病（Ph+ALL）中具有高度有效性。然而，预测这些无化疗方案复发的临床和分子特征在很大程度上尚不清楚。
我们对76例新诊断的Ph+ALL患者进行了博纳吐单抗与波纳替尼联合应用的前瞻性II期临床试验。患者接受12 - 15剂鞘内化疗作为中枢神经系统（CNS）预防措施。分析了复发模式以及复发的临床和分子预测因素。
中位随访29个月，估计3年无事件生存率为78%，3年总生存率为88%。10例患者（13%）复发，中位复发时间为18个月（范围8 - 24个月）。6例复发仅发生在髓外部位（CNS，5例；腹膜和淋巴结，1例）。所有患者复发时CD19表达仍高。单因素分析显示，与复发风险增加相关的因素为：诊断时白细胞（WBC）≥70×10⁹/L（标准化危险比[sHR] 8.86 [95%置信区间2.33 - 33.70]；P = 0.001）、诊断时CNS受累（sHR 6.87 [95%置信区间1.54 - 30.68]；P = 0.01）以及VPREB1缺失（sHR 4.06 [95%置信区间1.05 - 15.76]；P = 0.04）。该队列中22%的患者WBC≥70×10⁹/L，其累积复发率（CIR）为53%，而WBC < 70×10⁹/L的患者CIR率为6%。IKZF1基因型、BCR::ABL1转录本类型以及通过下一代测序检测IG/TR重排的可测量残留病动力学均未显著影响复发风险。诊断时高WBC是多因素分析中唯一与复发显著相关的变量（sHR 16.29 [95%置信区间2.35 - 113.00；P = 0.005]）。
WBC≥70×10⁹/L是接受一线博纳吐单抗和波纳替尼治疗的Ph+ALL患者的高危特征，可能取代基线分子特征的预后重要性。可能需要为这些患者采用替代的一线治疗策略以降低复发风险并改善长期结局。
ClinicalTrials.gov（NCT03263572）
