Blinatumomab and ponatinib vs. hyper-CVAD and ponatinib in patients with Philadelphia-chromosome positive acute lymphoblastic leukemia: A propensity score analysis

Abstract Introduction: The outcome of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has drastically improved with the availability of potent tyrosine kinase inhibitors (TKIs) and immunotherapy. Ponatinib is superior to first- and second-generation TKIs. Ponatinib suppresses T315I mutation clones and deepens molecular response, as shown in a randomized phase 3 trial. Blinatumomab and ponatinib have been shown to be highly effective with a 4-year survival rate around 90%. However, there is no randomized trial comparing two different approaches of blinatumomab and ponatinib vs. chemotherapy and ponatinib. Therefore, we performed a propensity score matching. Methods: We performed a propensity score matching among patients with newly diagnosed Ph+ALL who were enrolled in phase 2 studies (hyper-CVAD + ponatinib, N=86; ponatinib + blinatumomab, N=85). The following covariates were included in the propensity score matching after multiple imputation for missing variables (age, gender, race, ethnicity, performance status, body mass index, smoking history, complete response at the time of enrollment, white blood cell [WBC] counts, hemoglobin, platelet count, lactate dehydrogenase, percentage of blasts in bone marrow, the presence of central nervous system [CNS] disease, percentage of CD19 and CD20, BCR::ABL1/ABL1 ratio, and BCR::ABL1 transcript type). We assessed progression-free survival and overall survival. Results: Propensity score matching identified 41 patients in each group. Before matching, the median age was 46 years (range, 21-80 years) and 50 years (range 18.3-83.7 years) in the blinatumomab + ponatinib and hyper-CVAD + ponatinib, respectively (P=0.095); after matching, the median age was 45 years (range, 18.3-79.1) and 47 years (range, 21.0-75.0), respectively (P=0.806). After matching, baseline differences were minimized without statistical significance. The median follow-up was 31 months (range, 3.2-80.8) and 108 months (range, 3.2-156.4), respectively (P<0.001). In the pre-matched groups, the 30-month PFS rates were 80% and 72% in the blinatumomab + ponatinib and hyper-CVAD + ponatinib, respectively (P=0.235); the 30-month survival rates were 92% and 81%, respectively (P=0.079). In the matched groups, the 30-month PFS rates were 84% and 63% in the blinatumomab + ponatinib and hyper-CVAD + ponatinib, respectively (P=0.038); the 30-month survival rates were 96% and 73%, respectively (P=0.003). In the prematched groups, relapse was observed in 11 patients (13%) and 17 patients (20%) in the blinatumomab + ponatinib and hyper-CVAD + ponatinib, respectively (P=0.159); after matching, each group had 5 relapses (P=0.287). CNS relapse was observed in 6 patients (7%) and 1 patient (1%), respectively (P=0.057); after matching, CNS relapse was observed in 2 patients (5%) and 0 patients (0%), respectively (P=0.247). Overall, death in CR was observed in 5 patients (6%) and 17 patients (20%) in the blinatumomab + ponatinib and hyper-CVAD + ponatinib, respectively (P=0.006); after matching, 0 patients (0%) and 11 patients (27%) died in CR, respectively (P<0.001). Conclusions: The combination of blinatumomab with ponatinib is superior to the combination of chemotherapy with ponatinib. A randomized clinical trial is warranted to confirm the findings.