Ponatinib, asciminib and inotuzumab ozogamicin: A novel drug combination in acute lymphoblastic leukemia

Context: Outcomes of patients with relapsed or refractory (R/R) AML remain poor. Only a small fraction achieve second remission and undergo allogeneic transplantation with long term survival. Fludarabine, cytarabine, G-CSF (FLAG)-Ida-Ven has shown promise in a phase I/II for patients with R/R AML reported by DiNardo et al. with ORR 70%; 61% achieved composite CR and 69% of those had MRD negativity. Infectious complications remain a concern, with median count recovery of 37 days in this setting. Objective: To describe the patient population, outcomes, and adverse events of those receiving FLAG-Ida-Ven for R/R AML. Design: Retrospective study; Aug 2019-Dec 2021. Setting: Single center, major academic bone marrow transplantation center. Patients: 31 patients received FLAG-Ida-Ven with a median age of 53 years (20-78), and 68% were male. 65% of patients had adverse risk disease and 32% had TP53 mutations. 6 patients received prior allogeneic transplant. 9 patients were refractory to intensive chemotherapy, 6 to prior hypomethylating agents with venetoclax, and 13 to both. Interventions: Electronic medical records were used for data extraction after IRB approval. Main Outcomes Measured: Overall response rate, MRD status, overall survival, duration of cytopenias, transition to HSCT. Results: 14/30 patients achieved blasts <5% in the BM (10 with morphologic leukemia-free state (MLFS), 3 with CR, 1 CRp; and 12/14 had MRD negativity. The median time to ANC recovery >500 was 35 days (20-67) and to platelet recovery >50k was 39 days (24-206). With a median follow up of 342 days, 20/31 (65%) of patients died, with a median time to death of 90 days (range 33-557). 13/30 (42%) were transplanted at a median time of 87 days (50-151). 23/31 (74%) had febrile neutropenia, 16/31 (52%) had bacteremia, 10/31 (23%) had pneumonia, and 10/31 (23%) had invasive fungal infections. Of the 13 patients who were transplanted 11/13 were alive at Day +100, with an estimated 1-year overall survival of 84% (95%CI: 0.49,0.96). Conclusions: FLAG-Ida-Ven is an effective regimen in the R/R setting for appropriately selected patients and may be a bridge to transplant with MRD negative remission. Infectious complications and count recovery remain a challenge and should be strongly considered as regimen related toxicity.