Outcomes of allogeneic transplantation after hypomethylating agents with venetoclax in acute myeloid leukemia
Authors: Vanessa E. Kennedy, Gavin Hui, Tali Azenkot, Daria Gaut, Matthew J. Wieduwilt, Caspian Oliai, Brian A. Jonas, Varun Mittal, Aaron C. Logan, Lori S. Muffly, Gabriel N. Mannis
Journal: American Journal of Hematology (2022)

To the Editor: Curative treatment for acute myeloid leukemia (AML) traditionally consists of intensive cytotoxic chemotherapy, often followed by allogeneic hematopoietic cell transplantation (allo-HCT). Many AML patients, however, are poor candidates for cytotoxic chemotherapy due to poor performance status, multiple comorbidities, and/or refractory and chemoresistant disease. Recently, the lower intensity combination of a hypomethylating agent plus venetoclax (HMA/Ven) was shown to achieve durable responses in patients with both newly diagnosed and relapsed/refractory (R/R) AML.1, 2 Despite HMA/Ven having been studied primarily in patients ineligible for intensive therapy, there are small or single-center reports of this regimen being successfully used as a bridge to a potentially curative allo-HCT. In a phase Ib trial of 212 newly diagnosed, chemotherapy-ineligible patients treated with HMA/Ven, 30 (14.2%) received allo-HCT; of these, over half remained in remission 1 year post transplant.3 Similarly, in a single-center study of 31 patients who proceeded to allo-HCT following frontline or salvage HMA/Ven, 1-year overall survival (OS) was 62.5%.4 These data suggest HMA/Ven may provide sufficiently deep responses to provide a pathway to allo-HCT without affecting transplant safety. In this study, we analyzed patient characteristics and posttransplant outcomes in a large, multicenter cohort of patients with newly diagnosed or R/R AML who received Ven/HMA and subsequently proceeded to allo-HCT. We identified 88 adults who received HMA/Ven and subsequently underwent HCT between 1/1/2017 and 6/30/20. All patients received azacitidine or decitabine co-administered with venetoclax; dosing was determined by the treating physician. Patients were treated at Stanford University, University of California (UC) San Francisco, UC Davis, UC Los Angeles, and UC San Diego. This study is approved by the institutional review boards of all participating institutions. AML risk stratification was based on European LeukemiaNet (ELN) classification.5 Disease status was stratified into complete response (CR), CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), and progressive/relapsed disease per consensus criteria.5 Measurable residual disease (MRD) was evaluated via flow cytometry (sensitivity limit of 1 × 10−4) per institutional standards. Continuous variables were summarized using medians and binary outcomes using proportions. OS was evaluated 6 months and 1 year following allo-HCT, estimated using Kaplan–Meier curves, and compared using log-rank tests. The gray test was used to compare cumulative incidences of relapse (CIR) and nonrelapse mortality (NRM) as competing risks. Unadjusted covariate effects on survival were evaluated using logistic regression. Analysis was performed using R 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria). Baseline characteristics of 88 patients are summarized in Table S1. Across all centers, the number of patients who received allo-HCT following HMA/Ven increased over time, from 8 patients in 2017 to 41 in 2019 and to 30 during the first 6 months of 2020. Forty-six (52%) patients received HMA/Ven as frontline therapy and 42 (48%) for R/R disease. The median age at allo-HCT was 67 years (range 24–77). Forty-six (52%) patients had adverse-risk disease, 13 (15%) had FLT3 mutations, and 14 (16%) had TP53 mutations. The number of pretransplant HMA/Ven cycles varied, with a median of 3 (range 1–13). Patients with R/R disease had a median of 1 (range 1–4) line of therapy prior to HMA/Ven; 5 patients had undergone prior allo-HCT. Twenty-two (25%) patients had a pretransplant Karnofsky performance status (KPS) of <80, and 30 (35%) had an HCT comorbidity index (HCT-CI) ≥3. Compared to patients with R/R disease, patients who received frontline HMA/Ven were more likely to be older (70 vs. 58 years, p < 0.001) and have a KPS < 80 (35% vs. 14%, p = 0.02). Across the entire cohort, 70% of patients achieved pretransplant CR, 15% CRi, and 15% MLFS. Seventy-three (83%) patients had an MRD assessment prior to allo-HCT, of which 68% were MRD negative. There was no difference in the number of HMA/Ven cycles between patients with MRD-positive versus -negative disease (median 4 vs. 3 cycles, p = 0.24). Twenty-eight percent of patients received myeloablative, 55% reduced-intensity, and 17% nonmyeloablative conditioning; patients who received HMA/Ven in the R/R versus frontline setting were more likely to receive myeloablative conditioning (48% vs. 11% of patients). Donor sources were 25% HLA-matched related, 55% HLA-matched unrelated, 19% haploidentical, and 1% umbilical cord. Following allo-HCT, the median follow-up was 10.9 months. At day 100, 85% of patients were in morphologic CR with 86% MRD negativity. At 6 months post transplant, OS of the entire cohort was 83%, CIR was 22%, and cumulative incidence of NRM was 8%. At 1 year post transplant, OS of the entire cohort was 73%, CIR was 36%, and NRM was 17% (Table S2; Figure 1A–C). Of the patients who achieved MRD negativity, 1-year OS, CIR, and NRM were 81%, 18%, and 19%, respectively (Figure 1G–I). There was no difference in the association between treatment setting (frontline vs. R/R) and post-allo-HCT outcomes (Figure 1D–F). In univariate logistic regression, only pretransplant MRD was a significant predictor of CIR (MRD negative vs. positive: hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.21–0.85, p-value 0.02) (Table S3). In a separate bivalent logistic regression with interaction, conditioning regimen was not predictive of OS after allo-HCT based on MRD status (HR 0.7, 95% CI 0.22–4.9, p = 0.70) or for CIR (HR 0.60, 95% CI 0.11–3.3, p = 0.88). In univariate logistic regression stratified by treatment setting, MRD negativity was associated with superior post-allo-HCT outcomes in both the frontline and R/R settings. In patients who received frontline HMA/Ven, TP53 mutations were associated with inferior OS and CIR (Table S4). In this study, we identified 88 patients who achieved CR, CRi, or MLFS after HMA/Ven therapy and immediately proceeded to HCT. Our study confirms this regimen can bridge to successful allo-HCT in select cases. In prior studies of AML patients receiving RIC allo-HCT, 1-year OS ranges from 61% to 68%, comparing similarly to the 1-year OS of 73% in all patients and 81% in MRD-negative patients in our study.6 Our 1-year OS was also similar to the 70% OS observed in patients with sAML receiving transplant following CPX-351. While our cohort only included 45% of patients with sAML, this could suggest lower-intensity treatment with HMA/Ven may not compromise outcomes relative to CPX-351.7 Achievement of MRD negativity at time of transplant was significantly associated with decreased relapse, both across our entire cohort as well as when stratified by treatment setting. This finding corroborates prior studies demonstrating MRD negativity is predictive of post-allo-HCT outcomes in AML and emphasizes the value of achieving MRD negativity prior to transplant.8 In prior studies of HMA/Ven, MRD negativity rates range from 29% to 64%, and our data demonstrate similarly favorable results within this select population.1, 9 In the VIALE-A trial, of the 37% of patients who achieved MRD negativity, only 30% did so after one cycle of HMA/Ven,10 suggesting multiple cycles may be required to achieve optimal response. In our data, the number of HMA/Ven cycles did not significantly differ between MRD-positive versus -negative patients. Factors predictive of achieving MRD negativity with HMA/Ven and the relationship of these with posttransplant outcomes warrant additional study. In our cohort, TP53 mutations were associated with inferior OS and CIR in patients treated with frontline HMA/Ven; these relationships were not observed in patients treated in the R/R setting. In prior studies of patients with newly diagnosed AML, HMA/Ven can lead to CR/CRi rates of 47% to 72% in patients with FLT3 or TP53 mutations; however, these responses are short-lived in the absence of HCT.9 In patients treated with frontline HMA/Ven, median OS was only 9.6 and 7.2 months in patients with high-risk and TP53-mutated disease, respectively.9 In our cohort, FLT3 mutations were not predictive of inferior outcomes in any setting, and TP53 mutations were not predictive in patients with R/R disease. Larger and prospective studies are needed to see whether transplant following HMA/Ven is a promising treatment strategy in these populations. Our analysis is limited by the retrospective nature and relatively short follow-up. While our multicenter cohort allowed for inclusion of a greater number of patients, our cohort was heterogenous, with HMA/Ven dosed per individual physician practice. Transplant practices were also heterogenous, with a significant proportion of patients receiving myeloablative conditioning, reflective of the relatively fitter patients treated in the R/R setting. Posttransplant infectious outcomes were also not captured as part of this study but will be important to include in future analyses. Despite limitations, this represents the largest described series of allo-HCT following HMA/Ven and demonstrates this treatment approach is safe and feasible. These data are particularly relevant as use of HMA/Ven is increasing over time, as demonstrated in our cohort. Elderly patients should be considered for allo-HCT early during HMA/Ven treatment, as the use of low-intensity therapy does not preclude RIC allo-HCT at any age. Notably, the oldest patient in this cohort was 80 years old at time of allo-HCT and remains alive 3 years post transplant. Prospective studies are needed to further optimize HCT-based approaches to consolidation in patients treated with HMA/Ven. Vanessa Kennedy, Gavin Hui, Tali Azenkot, Daria Gaut, Caspian Oliai, and Varun Mittal decline no competing interests. Matthew Wiedubilt declares advisory fees (Gilead, Servier, Reata). Brian Jonas declares consultancy and advisory fees (AbbVie, BMS/Celgene, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Tolero, and Treadwell). Aaron Logan declares consulting fees (AbbVie). Lori Muffly declares consulting fees (Amgen, Pfzier, Jazz) and Research Funding (Japser, Sevier). Gabriel Mannis declares consultancy fees (AbbVie, Agios, Macrogenics, Pfizer), advisory role fees (AbbVie, Agios, Astellas, BMS/Celgene, Genentech, Stemline), and research funding (GlycoMimetics, Forty Seven/Gilead, Jazz, Astex). Vanessa E. Kennedy was responsible for designing and writing the protocol, extracting data, analyzing data, interpreting results, updating reference lists, and writing the manuscript. Gavin Hui, Tali Azenkot, Daria Gaut, and Varun Mittal were responsible for extracting data, analyzing data, interpreting results, and writing the manuscript. Matthew J. Wieduwilt, Caspian Oliai, Brian Jonas, and Aaron C. Logan were responsible for designing the protocol, interpreting results, and revising the manuscript. Lori S. Muffly and Gabriel N. Mannis were responsible for designing the protocol, interpreting results, and writing the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Patient, disease, and treatment characteristics. Table S2. Outcomes after allogeneic hematopoietic cell transplantation (HCT). Table S3. Univariate analysis of patient, disease, and transplant factors on overall survival (OS) and RFS for entire Cohort. Table S4. Univariate analysis of patient, disease, and transplant factors on OS and recurrence-free survival (RFS) stratified by treatment setting. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.