Outcomes in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have improved significantly with the advent of BCR::ABL1 tyrosine kinase inhibitors (TKIs) 1, 2. Ponatinib, a third-generation TKI active against the T315I mutation, and blinatumomab, a CD3/CD19 bispecific T-cell engager, have each demonstrated high rates of deep molecular response and durable survival 3-9. Recent studies combining blinatumomab with potent TKIs suggest that chemotherapy-free approaches may achieve outcomes comparable to intensive chemotherapy-based regimens 7, 9-11. However, no randomized trial directly compares these strategies. We, therefore, conducted a propensity score analysis comparing the outcomes of patients with newly diagnosed Ph + ALL who received Hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine) with ponatinib versus blinatumomab with ponatinib. Patients ≥ 18 years with newly diagnosed Ph + ALL treated on clinical trial with Hyper-CVAD plus ponatinib (NCT01424982; 2011–2019) or blinatumomab plus ponatinib (NCT03263572; 2018–2025) were included. Details of each regimen have been previously reported 12-14. Allogeneic stem cell transplantation (alloSCT) was offered to patients in first complete remission at the discretion of the treating physician. The protocols were approved by the MD Anderson Institutional Review Board and the study was conducted in accordance with the Declaration of Helsinki. Complete response (CR) and CR with incomplete count recovery (CRi) were defined per standard definitions. Complete molecular response (CMR) was defined as the absence of detectable BCR::ABL1 transcripts measured by polymerase chain reaction (sensitivity, 0.01%) in either bone marrow or peripheral blood. Measurable residual disease (MRD) was evaluated by multiparameter flow cytometry (MFC) (sensitivity, 1 × 10−4) and by next-generation sequencing (NGS) for IG/TR rearrangements (sensitivity, 1 × 10−6 by clonoSEQ) in patients in the blinatumomab plus ponatinib cohort. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan–Meier method. Cumulative incidence of relapse (CIR) was calculated with death and relapse as competing events. Baseline patient characteristics were compared between groups utilizing χ2 or Fisher's exact test for categorical data and Mann–Whitney U for continuous data. Multiple imputations were performed for missing variables to reduce the potential for bias. Logistic regression was utilized for propensity score calculation based on baseline covariates including age, gender, race, ethnicity, Easter Cooperative Oncology Group (ECOG) performance status, body mass index (BMI), smoking history, white blood cell (WBC) count, hemoglobin, platelet count, percentage of blasts in bone marrow, the presence of central nervous system (CNS) disease, percentage of CD19 and CD20 expression, BCR::ABL1/ABL1 ratio, and BCR::ABL1 transcript type. Propensity score matching was performed using the nearest neighbor method with a caliper of 0.2. Overall, prior to matching, 62 patients treated with blinatumomab plus ponatinib and 68 patients treated with Hyper-CVAD plus ponatinib were identified. Baseline characteristics before and after propensity matching are included in Table 1. Propensity score matching identified 40 patients in each cohort and eliminated any significant differences in baseline characteristics between the groups. The median age was 52 years (range, 18–83) in the blinatumomab plus ponatinib cohort and 53 years (23–74) in the Hyper-CVAD plus ponatinib group (p = 0.637). The response rates for both the pre-matched and matched patients are included in Table 2. After matching, all patients achieved a response with either treatment. After cycle 1, 56% of patients achieved a CMR with blinatumomab plus ponatinib versus 38% with Hyper-CVAD plus ponatinib (p = 0.115). The 3-month and anytime CMR rates were 68% and 80%, respectively, with blinatumomab plus ponatinib and 78% (p = 0.453) and 90% (p = 0.348) with Hyper-CVAD plus ponatinib. With blinatumomab plus ponatinib, MRD was also evaluated by NGS, with 15 of 34 patients (44%) achieving NGS MRD-negativity after cycle 1 and 53 of 55 patients (96%) achieving NGS MRD-negativity overall. Among the matched patients, after a median follow-up of 28 months for blinatumomab plus ponatinib and 143 months for Hyper-CVAD plus ponatinib, the 2-year PFS rates were 91% versus 70%, respectively (p = 0.039). Median PFS was not reached with blinatumomab plus ponatinib and 111 months with Hyper-CVAD plus ponatinib. The 2-year OS rates were 100% and 78% (p = 0.027), respectively, with median OS was not reached for either (Figure 1A,B). Survival analyses of the pre-matched patients are included in Figure S1. The estimated 2-year CIR rate was 9% and 13% for the blinatumomab plus ponatinib and Hyper-CVAD plus ponatinib cohorts, respectively (p = 0.48) (Figure S2A). Outcomes for patients who achieved CMR were similar to the entire cohort with a median PFS that was not reached in blinatumomab plus ponatinib and 96 months in Hyper-CVAD plus ponatinib (p = 0.08). In this subgroup, the estimated 2-year CIR rate was 10% in blinatumomab plus ponatinib versus 14% in Hyper-CVAD plus ponatinib (p = 0.52). CNS relapse was observed in 1 patient in each cohort. Subgroup survival analyses in the matched patients by age (60 years of age (E, F), PFS and OS of patients with the p210 transcript (G, H), PFS and OS of patients with baseline WBC > 30 × 109/L (I, J), and PFS and OS of patients with baseline WBC > 70 × 109/L (K, L). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Sasaki et al. (Fri,) studied this question.