Molecular characterization and predictors of relapse in patients with Ph + ALL after frontline ponatinib and blinatumomab

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 × 109/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 × 109/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 × 109/L. Neither IKZF1plus 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 × 109/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).