ALL-424 Updated Results from the Phase II Study of Blinatumomab in Combination With Ponatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Context: Blinatumomab and ponatinib both induce high rates of complete molecular remission (CMR) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Their combination may generate durable responses and decrease the reliance on allogeneic stem cell transplantation (allo-SCT). Objective: To evaluate the combination of blinatumomab and ponatinib in patients with Ph-positive ALL. Study Design and Participants: Patients with newly-diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL were treated on this phase II trial. Blinatumomab was given for up to 5 cycles at standard doses, and ponatinib was started at 30mg daily during cycle 1, then lowered to 15mg daily upon achieving CMR. Among responders, ponatinib was maintained for a minimum of 5 years. Patients received 12 doses of prophylactic intrathecal chemotherapy. Main Outcome Measures: The primary endpoint was the CMR rate in the ND cohort, and the overall response rate (ORR; CR and CRi) in the R/R cohort. Results: Forty-nine patients were treated: 35 ND (median age, 57 years; range, 22-83 years) and 14 R/R (median age, 38 years; range, 24-61 years). Among R/R patients, 43% were in Salvage ≥2. One early death within 4 weeks was observed among ND patients due to intracranial hemorrhage, none among R/R patients. The ORR was 96% in the ND cohort and 92% in the R/R cohort, with respective CMR rates of 85% and 79%. Only one patient with ND disease underwent allo-SCT because of persistently detectable BCR::ABL1 transcript levels; 6 patients (46%) with R/R disease underwent subsequent allo-SCT. After a median follow-up of 11 months (range, 1-46 months), no relapses were observed in the ND cohort with similar 2-year OS and EFS rates of 93%. In the R/R cohort, the estimated 2-year OS and EFS rates were 61% and 42%, respectively. This combination showed a favorable safety profile, with most adverse events of grade 1-2. One patient discontinued ponatinib due to toxicity. Conclusions: The chemotherapy-free combination of blinatumomab and ponatinib demonstrated robust clinical activity in Ph-positive ALL, with high rates of CMR and durable remissions. This strategy will potentially obviate the need for chemotherapy and allo-SCT in many patients, particularly in the frontline setting.