Safety and Efficacy of Adding Venetoclax to Reduced Intensity Conditioning Chemotherapy Prior to Allogeneic Hematopoietic Cell Transplantation in Patients with High Risk Myeloid Malignancies

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.38-39
• Main Authors: Garcia, Jacqueline S., Kim, Haesook, Cutler, Corey, Winer, Eric S., Stone, Richard M., Ho, Vincent T., Romee, Rizwan, Koreth, John, Gooptu, Mahasweta, Nikiforow, Sarah, Shapiro, Roman M, Steensma, David P., Luskin, Marlise R., Wadleigh, Martha, Loschi, Fiona, Ryan, Jeremy, Letai, Anthony, Lindsley, R. Coleman, Brock, Jennifer, Soiffer, Robert J., DeAngelo, Daniel J., Antin, Joseph H.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-134947

▪ Background: The outcomes for patients (pts) with myeloid malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT) is poor, and relapse occurs more frequently for those with high-risk mutations or cytogenetics. The oral selective BCL-2 inhibitor and BH3 mimetic venetoclax (VEN) increases mitochondrial apoptotic priming even in chemoresistant myeloblasts. Reasoning that VEN would selectively increase the anti-leukemic effect of HCT conditioning chemotherapy without undue toxicity, we evaluated the safety and efficacy of adding VEN to fludarabine and busulfan (FluBu2) reduced intensity conditioning (RIC) chemotherapy. Here, we report on the completed dose-escalation and expansion cohorts from the phase 1 trial. Methods: Pts received escalating doses of VEN (dose level (DL)1, 200 mg on Days -8 to -3 (n=3); DL2, 200 mg on Days -8 to -2 (n=3); DL3, 400 mg on Days -8 to -2 (n=16)) in combination with FluBu2 (fludarabine 30 mg/m2/d on Days -5 to -2 and IV busulfan 0.8 mg/kg bid on Days -5 to -2), followed by PBSC infusion on Day 0 and tacrolimus/methotrexate GVHD prophylaxis. Eligible pts included those with adverse risk AML per ELN criteria or secondary AML in complete remission (CR); MDS (t-MDS; Int-2 or higher IPSS; presence of TP53 or RAS pathway gene mutation) or MDS/MPN (including +8; chr 7 abnl; complex karyotype; or ASXL1 mutation) with £10% blasts pre-transplant; and an 8/8 HLA-matched donor. Dose-limiting toxicity (DLT) was defined (first dose of VEN until Day +28) as any treatment-related death, failure to achieve an absolute neutrophil count (ANC) ≥ 500/mL on 2 consecutive occasions, or any gr 4 non-heme toxicity or tumor lysis syndrome. Targeted sequencing of 88 genes on a clinical assay (sensitivity 1-3%) was performed on pre-VEN and day +100 marrow samples. Flow cytometry-based BH3 profiling was performed on pre-VEN treatment bone marrow in pts with measurable residual myeloblasts. Results: Twenty-two pts (median age 64 y, range 25-71) were treated including 9 AML, 11 MDS, and 2 MDS/MPN cases. 45% of the cohort had an ECOG 2 (n=10). A mutation in TP53 was identified immediately pre-transplant in 55% of pts (n=12). Median HCT-CI score was 4 (range 1-8). 35% and 65.2% had intermediate- and adverse- cytogenetic risk. 20 received HLA-matched unrelated and 2 received HLA-matched related grafts. Median bone marrow leukemia blasts prior to study was 5% (range 5-10). The most common grade 3 or higher non-heme toxicity observed we