S114: ponatinib and blinatumomab for patients with philadelphia chromosome-positive acute lymphoblastic leukemia: updated results from a phase ii study

Background: Ponatinib and blinatumomab are both highly effective therapies for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination of these two agents may offer an effective chemotherapy-free strategy in these patients (pts). Aims: We evaluated the efficacy and safety of ponatinib and blinatumomab in pts with newly diagnosed (ND), relapsed/refractory (R/R) Ph+ ALL or CML in lymphoid blast phase (CML-LBP). For pts with ND Ph+ ALL, the primary endpoint was the complete molecular response (CMR) rate. For pts with R/R Ph+ ALL, the primary endpoint was the CR/CRi rate. Secondary endpoints included safety, event-free survival (EFS) and overall survival (OS). Methods: In this phase II study, adults with ND Ph+ ALL, R/R Ph+ ALL, or CML-LBP were eligible. Pts were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and ALT and AST ≤3x the ULN. Pts with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Pts received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1 and was decreased to 15mg daily once CMR was achieved. After 5 cycles of blinatumomab, ponatinib was continued for at least 5 years. Twelve doses of prophylactic IT chemotherapy with alternating cytarabine and methotrexate were administered. Results: Between 2/2018 to 1/2022, 55 pts were treated (35 with ND Ph+ ALL, 14 with R/R Ph+ ALL and 6 with CML-LBP). Baseline characteristics are shown in Table 1. Among the 35 pts with ND Ph+ ALL, 12 were in CR at enrollment (including 2 pts in CMR). 22 of the 23 evaluable pts (96%) achieved CR/CRi. One pt died on day 18 from intracranial hemorrhage in the setting of chemotherapy administered prior to enrollment. After one cycle, 21/33 pts (64%) achieved CMR, and 28/33 pts (85%) achieved CMR at any time. 11 of 15 tested pts (73%) also became MRD-negative by an NGS assay with sensitivity of 1x10-6. CR/CRi was achieved in 12/13 (92%) evaluable pts with R/R Ph+ ALL. CMR was achieved in 10 pts (71%) after cycle 1 and in 11 pts (79%) overall. 5 of 6 pts with CML-LBP achieved CR/CRi, and 1 pt achieved PR as best response. 2 pts (40%) achieved CMR. In the ND Ph+ ALL cohort, 1 of 34 pts who received at least 1 full cycle died in CR; the other 33 are in ongoing hematologic remission. Only one pt underwent stem cell transplant (SCT) in first remission for persistently detectable BCR/ABL1 transcripts. Among 13 responding pts in the R/R Ph+ ALL cohort, 6 proceeded to SCT, 4 did not undergo SCT and subsequently relapsed, 1 died in CR, and 2 are in ongoing remission without SCT. In the CML-LBP cohort, 3 of the 5 responding pts subsequently relapsed. The median follow-up is 11 months (range, 1-46+). For ND Ph+ ALL, the 2-year EFS and OS are both 93% (Figure 2). There were no relapses or leukemia-related deaths in this cohort. In the R/R Ph+ ALL cohort, the 2-year EFS rate was 42% and the 2-year OS rate was 61%. In the CML-LBP cohort, the 2-year EFS was 33% and the 2-year OS was 60%. The treatment was well-tolerated, and most toxicities were grade 1-2 and consistent with the known toxicities of the two agents. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). One pt discontinued blinatumomab due to persistent grade 2 tremor. Image:Summary/Conclusion: The chemotherapy-free regimen of simultaneous ponatinib and blinatumomab is safe and effective in pts with Ph+ ALL. For pts with ND Ph+ ALL, SCT does not appear to be needed in first remission.