Outcomes of Acute Myeloid Leukemia Relapsed Post-Allogeneic Hematopoietic Stem Cell Transplant Treated with Hypomethylating Agents and Venetoclax Combination: A Single Center Experience

Introduction: The combination of hypomethylating agents (HMA) and the Bcl-2 inhibitor venetoclax (HMA+Ven) has changed the treatment landscape for acute myeloid leukemia (AML). For relapsed AML post-allogeneic hematopoietic stem cell transplant (alloHCT), there is no established standard treatment and outcomes remain poor. In this largest report to date, we systemically investigated the outcomes of post-alloHCT relapsed AML treated with HMA+Ven to identify key factors associated with clinical responses.

Methods: This was a retrospective analysis of AML patients with relapse following alloHCT between May 2016 and April 2022. The study population was obtained via the BMT Research Analysis Information Network (BRAIN) database. Co-primary endpoints were the rates of complete responses with or without hematologic recovery (CR/CRi), the duration of CR (DoCR) and overall survival (OS) measured from the date of HMA and/or Ven initiation. Secondary endpoints explored the toxicity of HMA+Ven, as well as rates of conversion to 100% donor chimerism and minimal residual disease (MRD) negativity assessed by multiparametric flow cytometry (sensitivity 0.1%) or qPCR. Exploratory analyses focused on molecular aberrations associated with CR/CRi rate and DoCR. Cytogenetic and molecular risks were considered according to ELN 2017 criteria.

Results: A total of 51 patients with relapsed AML post-alloHCT were included. Baseline characteristics are presented in Table 1. Information on response was available in 48/51 subjects: 22 had CR/CRi (46%) and 4 had partial response (PR, 8%). Non-responders included 2 with stable disease (4%) and 20 with progressive disease (PD, 42%). The median number of HMA +Ven cycles/patient was 2 (IQR 1-4, range 1-20) and CR/CRi was achieved after a median of 2 cycles (IQR 1-3 cycles). HMA+Ven led to two deaths (4%) in responders due to neutropenic fever. One patient discontinued Ven due to toxicity. The rate of CR/CRi was similar if HMA+Ven was given as the first or subsequent regimen at relapse (46.2% vs 44%; p = 1.0), if AML was secondary vs de novo (52.6% vs 41.4%; p = 0.56) and if HMA had been used prior to alloHCT (35.7% vs 51.5%; p = 0.35). Adverse-risk cytogenetics at relapse were associated with lower CR/CRi rate (33.3% vs 60.9%; p = 0.08). The median DoCR was 16.6 months (mos) (95% confidence interval [CI] 5.5 months to not reached [NR]). The DoCR was not impacted by the time from alloHCT to relapse, prior history of MDS/MPN and adverse-risk cytogenetics at relapse. IDH 1/2 mutation was associated with a numerically longer DoCR (16.6 [95% CI 6.7 to NR] vs 5.5 [95% CI 2.5 to NR] mos, p=0.5). Among CR/CRis, MRD negativity was documented in 3/4 tested subjects while disappearance of pathogenic mutations on next generation sequencing occurred in 12/18 and conversion to 100% donor genotype on chimerism studies in 16/17. Four went on to receive DLI and two a second alloHCT. Overall, 38 patients died (75%) and the median OS was 5.4 mos (95% CI 3.1 to 8.7 months). Median OS was superior for patients who achieved CR/CRi (19.7 [95% CI 5.6 to NR] vs 3.4 [95% CI 1.9 to 5.8] mos, Figure). Compared to wild-type alleles, certain recurrent mutations were associated with higher CR/CRi rates [FLT3-ITD or FLT3-TKD (75.0% vs 41.0%; p = 0.12), NPM1 (77.8% vs 39.5%; p = 0.06), IDH1/2 (87.5% vs 38.5%; p = 0.02)], whereas TP53 mutations were not (40.0% vs 48.6%; p = 0.73). In a multivariate logistic regression model, female sex (adjusted odds ratio [aOR] 5.8, p = 0.03), time from alloHCT to relapse (aOR 1.08 per 1-mo increase, p = 0.02) and mutated IDH 1/2 (aOR 14.0, p = 0.03) significantly increased odds of CR/CRi. In a separate multivariate model not including mutations, favorable/intermediate-risk cytogenetics at relapse were associated with higher odds of CR/CRi (aOR 3.62, p = 0.04). Notably, a new high-risk cytogenetic or molecular abnormality at relapse compared to original diagnosis was recorded in 6/50 (12%) and 10/41 (24%) patients with evaluable data, respectively.

Conclusions: The prognosis of relapsed AML post-alloHCT remains poor. In this largest retrospective cohort study to date, HMA+Ven appeared to be effective and well-tolerated in this setting, with the potential for durable remissions and MRD negativity, especially in the presence of certain molecular aberrations such as NPM1 and IDH 1/2 mutations. Prospective trials evaluating the efficacy, safety and immunogenicity of this approach are warranted.

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