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Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The BCL-2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single-center experience with venetoclax in combination with the hypomethylating agent 5-azacitidine (aza) in pediatric patients with MDS or AML., Procedure: We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high-grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy., Results: Eight patients received ven/aza, two for high-grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza., Conclusions: Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late-phase clinical trials., (© 2020 Wiley Periodicals, Inc.)

Venetoclax is approved for older untreated acute myeloid leukemia (AML) patients. Venetoclax was available prior to approval off-label. We assessed our single-institution off-label experience with venetoclax/azacitidine, comparing outcomes with a clinical trial cohort that administered this regimen at the same institution. Thirty-three untreated AML patients unfit or unwilling to receive induction chemotherapy and prescribed venetoclax/azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial. Outcomes were compared, and comparisons were made to a theoretical scenario in which off-trial patients received induction. Digital droplet polymerase chain reaction evaluated measurable residual disease (MRD). Off-trial venetoclax was attainable in nearly all patients for whom this was desired. The complete remission (CR)/CR with incomplete blood count recovery rate was 63.3% for off-trial patients who received treatment and 84.9% for trial patients (P = .081). The median overall survival for off-trial patients who received treatment was 381 days (95% confidence interval [CI], 174, not reached) vs 880 days (95% CI, 384, not reached) for trial patients (P = .041). Prior exposure to hypomethylating agents was associated with worse outcomes. Response rates with venetoclax/azacitidine were not inferior to a theoretical scenario in which patients received induction, and early death rates were less than expected with induction. MRD negativity was achievable. Newly diagnosed AML patients treated in a "real-world" scenario with off-trial venetoclax/azacitidine had inferior outcomes compared with patients treated in the setting of a clinical trial. Additionally, this therapy may be as effective, and less toxic, when compared with induction chemotherapy., (© 2019 by The American Society of Hematology.)