Background: Effective treatment for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) remains an unmet need. We previously reported that decitabine and vorinostat with fludarabine, cytarabine, and G-CSF (FLAG) was well tolerated and effective in R/R pediatric AML (Pommert Am J Hematol 2022). However, in contrast to patients with known epigenetic alterations (including KMT2A, CEBPA, IDH1/2, NUP98 mutations), patients without epigenetic lesions had worse outcomes. We identified non-responders to be enriched with anti-apoptotic genes, providing rationale for susceptibility to the BCL-2 inhibitor, venetoclax (Ven). We are thus investigating Ven in combination with 5-azacitidine, vorinostat, and FLAG in a Phase 1, multicenter, dose-escalation study in patients with R/R AML (NCT05317403). We report preliminary safety and response data among pediatric and AYA patients treated on this Phase 1 trial, as well as real-world results using this regimen.
Methods: Eligible patients 1-25 years with R/R AML or therapy-related AML (t-AML) were enrolled at 2 treating institutions (Children's Wisconsin and Children's Minnesota). Ven was administered daily on days 1-14 at 2 dose levels (DL1: 240mg/m2/dose, DL2: 360mg/m2/dose) with a one-day ramp-up dose. Dose escalation decisions were guided by standard 3+3 dose escalation Phase 1 design. 5-Azacitidine (75mg/m2 IV daily) and vorinostat (180mg/m2 PO daily) were given days 1-5. G-CSF started day 5 until neutrophil recovery. Fludarabine (30mg/m2 IV daily) and cytarabine (2 gm/m2 IV daily) were given days 6-10. Response was assessed by end-of-cycle bone marrow. Primary measures included safety assessment. Secondary measures included efficacy assessments. Exploratory assessments included epigenetic profiling and BH3 testing.
Results: As of July 31, 2024, 4 patients enrolled, with 3 patients receiving DL1 Ven and 1 patient receiving DL2 Ven. Median age at enrollment was 4.5 (range, 2-5) years, 50% of patients were male, 50% were Black and 50% were Asian, and 0% of patients identified as Hispanic. Median number of prior therapies was 1 (range, 0-1), and 25% had received prior allogeneic transplant. Median follow-up was 10 months. Grade 3/4 AEs occurred in all 4 patients (100%), including neutropenia (100%), anemia (100%), and thrombocytopenia (100%). Nonhematologic Grade 3 AEs included febrile neutropenia (50%), sepsis (25%), mucositis (25%), lung infection (25%), upper respiratory infection (25%), and hyperbilirubinemia (25%). There were no nonhematologic Grade 4 AEs and no dose-limiting toxicities (DLTs). No patients experienced tumor lysis syndrome. Three patients (75%) achieved complete response (CR) with 1 patient developing progressive disease. All 3 patients achieving a CR also achieved undetectable measurable residual disease (MRD). All responding patients (100%) proceeded to allogeneic transplantation. One-year estimate of overall survival was 75%. Exploratory correlative analyses will be batched and presented separately.
Additionally, we report 6 patients who received protocol therapy off-study at 3 institutions (with venetoclax dosing of 240mg/m2/dose) and are presented as real-world data. Median age was 11 (range, 1-17) years, median number of prior therapies was 2 (range, 1-6), and 33% received prior allogeneic transplant. Median follow-up was 7.5 (range 1-34) months. Five patients (83%) achieved CR with 3 of 5 in CR (60%) achieving undetectable MRD. Four of 5 patients achieving CR (80%) proceeded to transplant. One-year estimate of overall survival was 53%.
Overall, CR of the entire cohort (on study and real-world, n=10) was 80% after cycle 1. 75% of all patients achieving CR obtained undetectable MRD. 88% of patients achieving CR proceeded to transplantation. Median overall survival has not yet been reached. One-year estimate of overall survival was 63%.
Conclusions: Our Phase I study and real-world data report Ven with 5-azacitidine, vorinostat, and FLAG was well tolerated with promising response rates in pediatric R/R AML. Our ongoing study will help inform the recommended Phase 2 dose for Ven in this combination, and correlative studies will help determine which patients may benefit most from this novel regimen.
No relevant conflicts of interest to declare.
Venetoclax is a BCL-2 inhibitor approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. It does not currently have an approved use for the treatment of acute myeloid leukemia in pediatric patients.
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