Venetoclax, Azacitidine, Vorinostat and FLAG for Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia
Authors: Graff Zachary , Pan Amy , Zhang Liyun , Gossai Nathan , Azmy Christeen , Kemic Amberley , Frelka Alyssa , Burke Michael J. 
Published: December 2024

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.