Introduction: Limited studies have evaluated the efficacy of different induction regimens in patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and data on outcomes by molecular subgroups remain sparse. In this single-institution retrospective study, we examined treatment responses and survival outcomes of AML-MRC patients, with analyses stratified by molecular and induction regimens.

Methods: We retrospectively reviewed adult AML patients (≥18 years) diagnosed and treated at the Markey Cancer Center between January 2015 and February 2025. AML-MRC was defined per WHO 2016 classification. Demographic, clinical, laboratory, and pathologic data were abstracted from medical records. Treatment response was assessed using ELN 2022 criteria. Primary endpoints were complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse-free survival (RFS), and overall survival (OS). RFS and OS were estimated using the Kaplan–Meier method. Molecular mutations were categorized as follows: Epigenetic regulators: ASXL1, BCOR, EZH2, DNMT3A, TET2; RNA signaling pathway: CALR, CBL, FLT3, KRAS, NRAS, KIT, PTPN11, JAK; RNA splicing factors: SF3B1, SRSF2, U2AF1, ZRSF2 and Transcription factors: RUNX1, GATA.

Induction therapies were grouped into 4:1- Cytarabine plus anthracycline (7+3) with or without targeted therapy; 2-Hypomethylating agent (HMA) plus venetoclax with or without targeted therapy; 3-Cladribine- or fludarabine-based regimens; 4-Low-dose cytarabine with or without HMA or other targeted therapies.

To account for baseline differences in age and performance status, we performed propensity score matching (IPTW) by age, gender, and performance status. Outcomes were censored at the time of allogeneic stem cell transplant. Statistical analysis was performed using R version 4.4.0.

Results: A total of 193 AML-MRC patients were included. The median age was 65 years (range 22–86), and 56% were male. Molecular analysis showed mutations in epigenetic pathways in 45% (n=71), IDH1/2 in 10% (n=15), TP53 in 19% (n=30), RNA signaling in 14% (n=22), RNA splicing in 6.4% (n=10), and transcription factors in 4.4% (n=7). One patient each had NPM1 and CEBPA mutations.

Treatment induction included: HMA-Ven (n=91, 47%), cytarabine + anthracyclines (n=57, 30%), Vyxeos (n=25, 13%), CLIA-Ven (n=5, 3%), and low-dose cytarabine–based therapy (n=6, 3%). Patients receiving CLIA-Ven or 7+3 were younger (median 43 and 58 years, respectively) compared with HMA-Ven (69 years), Vyxeos (66 years), or low-dose cytarabine (78 years; p<0.01).

Overall, 122 patients (60%) achieved CR/CRi after first- or second-line induction, while 40% were refractory after two lines. At median follow-up of 34 months (95% CI: 23.7–58), 71 patients (37%) relapsed. CR/CRi rates varied by regimen: 100% for CLIA-Ven, 70% for Vyxeos, 67% for cytarabine + anthracyclines, 58% for HMA-Ven, and 17% for low-dose cytarabine (p<0.01). No significant difference in CR rates was seen across molecular categories; notably, both patients with CEBPA and NPM1 mutations achieved CR.

Median RFS was 12.2 months (95% CI: 11–18) and OS was 9.4 months (95% CI: 7.4–12.5). Thirty-four patients (18%) underwent allogeneic transplant, achieving improved outcomes: median RFS 18 months (95% CI: 12.4–NR; p=0.04) and OS 21 months (95% CI: 18.6–NR; p<0.01) compared with non-transplanted patients.

After IPTW, comparing the three most common regimens (7+3, HMA-Ven and Vyxeos), no significant differences in RFS or OS were observed after censoring for transplant. The mRFS for 7+3, HMA-Ven and Vyxeos: 23 months (95% CI: 11–NA), 12 months (95% CI: 11–18), 8.8 months (95% CI: 6–NR); (p=0.44), respectively.The mOS for 7+3, HMA-Ven and Vyxeos: 8.7 months (95% CI: 6.1–20), 8.1 months (95% CI: 7.3–13), 11.3 months (95% CI: 6.5–NR); (p=0.56), respectively.

Conclusion: Epigenetic mutations are highly enriched in AML-MRC. CLIA-Ven achieved the highest CR/CRi rates, followed by Vyxeos, 7+3, and HMA-Ven. However, after adjusting for age, gender, and performance status, no differences were observed in RFS or OS among 7+3, HMA-Ven, or Vyxeos. Allogeneic transplantation was associated with significant improvements in both RFS and OS, underscoring its critical role in the management of AML-MRC.

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2025
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