Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study.
Authors: Short Nicholas James , Kantarjian Hagop M. , Konopleva Marina , Jain Nitin , Huang Xuelin , Ravandi Farhad , Wierda William G. , Borthakur Gautam , Sasaki Koji , Issa Ghayas C. , Alvarado Yesid , Pemmaraju Naveen , Garcia-Manero Guillermo , Thankachan Jennifer , Garris Rebecca , Jabbour Elias 
Published: June 2021

7001 Background: Achievement of a complete molecular remission (CMR) is associated with superior outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib and blinatumomab both produce high rates of molecular remission in Ph+ ALL. The combination of these two agents may lead to durable responses and reduce the need for allogeneic hematopoietic stem cell transplant (AHSCT). Methods: This is a single-arm phase 2 study in adults with newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL. Patients received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once CMR was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding patients. Twelve doses of prophylactic intrathecal chemotherapy were administered. For patients with ND Ph+ ALL, the primary endpoint was the CMR rate. For patients with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Twenty-eight patients were treated (19 FL and 9 R/R). Median age was 59 years (range, 25-83 years); 62 years (range, 34-83 years) in the ND cohort and 36 years (range, 25-61 years) in the R/R cohort. Transcripts were p190 in 69% of patients the ND cohort and 100% in the R/R cohort. Among R/R patients, 44% were in Salvage 2+. No early death within 4 weeks were observed. Overall, 95% of patients responded; the response rate was 100% in the ND cohort and 88% in the R/R cohort. Among responding patients, 86% achieved CMR: 87% in the ND cohort and 86% in the R/R cohort. Median time to CMR was 1 month (range, 1-13 months). None of the patients in the ND cohort underwent AHSCT; 4 patients (44%) with R/R disease underwent subsequent AHSCT. With a median follow-up of 14 months, the estimated 1-year overall survival (OS) rate was 94% and event-free survival (EFS) rate was 81% for the entire study population. In the ND cohort, no patients have relapsed or died, and the 1-year OS and EFS rates were both 100%. In the R/R cohort, 1-year OS and EFS rates were 88% and 55%, respectively. The treatment was well-tolerated. Most side effects were grade 1-2. No patient discontinued ponatinib due to toxicity. One patient discontinued blinatumomab due to recurrent grade 2 tremor. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab shows encouraging results in Ph+ ALL. The regimen results in high rates of CMR and durable responses, potentially obviating the need for chemotherapy and AHSCT in many patients, particularly when used as frontline therapy. Clinical trial information: NCT03263572.