Background: The chemotherapy-free combination of blinatumomab and ponatinib improved outcomes in patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This regimen may also induce deeper responses and prolong remissions in patients (pts) with R/R Ph+ ALL and chronic myeloid leukemia in lymphoid blast phase (CML-LBP).
Aims: We evaluated the efficacy and safety of blinatumomab and ponatinib in pts with R/R Ph+ ALL or CML-LBP. 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 trial, pts with R/R Ph+ ALL or CML-LBP received up to 5 cycles of blinatumomab. Pts received ponatinib 30mg daily in Cycle 1, with dose reduction to 15mg daily once in complete molecular response (CMR). After completion of blinatumomab, ponatinib was continued for at least 5 years. 12 doses of prophylactic intrathecal chemotherapy were administered.
Results: 21 patients were treated (14 R/R, 7 CML-LBP) between 2/2018 and 7/2022. Baseline characteristics are shown in Figure 1. The median age of the R/R Ph+ ALL and CML-LBP cohorts were 38 years (range, 24-61) and 67 years (range, 29-82), respectively. BCR::ABL1 transcripts were p190 in 93% in the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in salvage 2 or beyond. Among the CML-LBP pts, 4 were de novo and 3 were transformed from previously treated CML (1 of whom had received prior therapy for LBP).
Among the 14 pts with R/R Ph+ ALL, 1 was in CR but with detectable BCR::ABL1 at enrollment. The rate of CR/CRi was 92% (12 of 13 pts), with CR in 11 (85%) pts. The one non-responding pt had received prior ponatinib-based therapy in an earlier salvage regimen.. MMR was achieved in 86% and CMR in 79%. Six of 7 (86%) pts with CML-LBP achieved CR/CRi, and 1 achieved PR as best response. Rates of MMR and CMR were 57% and 43% overall, respectively.
The median follow-up was 24 months (range, 19-57+) in the R/R cohort, and 27 months (range, 7-46+) in the CML-LBP cohort. Among the 14 pts in the R/R cohort, 1 did not respond, 6 proceeded to allogeneic stem cell transplant (ASCT) (1 of whom relapsed and died), 4 did not undergo ASCT and relapsed after a median of 6.4 months (range, 2.7-8.1), 1 died in CR, and 2 are in ongoing response without ASCT after a median CR duration of 34 months (range, 17-51). Of the 5 relapses, 2 were hematologic only, 2 were in the CNS with MRD positivity in the bone marrow, and 1 was CNS only. The estimated 2-year EFS and OS for the R/R cohort are 50% and 64%, respectively.
Among the 6 responders in the CML-LBP cohort, 3 relapsed (1 of whom had an immunophenotypic switch to a myeloid blast phase CML with loss of CD19 expression) and 3 are in ongoing response without ASCT. The estimated 2-year EFS and OS for the CML-LBP cohort are 38% and 50%, respectively.
Grade 3 adverse events observed were febrile neutropenia, cytokine release syndrome, elevation of lipase and alkaline phosphatase in 1 pt each. No Grade 4-5 events. 1 pt discontinued ponatinib due to treatment-related adverse event: Grade 3 portal vein thrombosis. 1 pt discontinued blinatumomab due to toxicity (persistent Grade 2 tremor). No early deaths were observed.
Summary/Conclusion: Our results show that the combination of blinatumomab and ponatinib represent an effective chemotherapy-free regimen for pts with R/R Ph+ ALL and CML-LBP, with a favorable safety profile. The rate of deep molecular response was relatively low in CML-LBP suggesting that some chemotherapy might still be needed in these pts.
Keywords: Chronic myeloid leukemia, Ph+ ALL, Phase II