Background:

Patients with secondary acute myeloid leukemia (sAML) have inferior outcomes compared to de novo AML (dn-AML) when treated with intensive chemotherapy. Azacitidine plus venetoclax (Aza-Ven) is increasingly used in patients with sAML due to its improved efficacy and lower treatment-related mortality, which may also serve as a lower-risk effective approach to bridge eligible patients to allogeneic stem cell transplantation. In this study, we aimed to evaluate the outcomes of Aza-Ven in patients with therapy-related AML (t-AML) or myelodysplasia-related AML (AML-MR) at our center.

Methods:

We performed a retrospective study of adults with AML treated with frontline Aza-Ven at the Princess Margaret Cancer Center (Toronto, Canada) between 2017 and 2024. They were categorized into three mutually exclusive groups: t-AML, AML-MR and dn-AML. Patients who previously received cytotoxic therapy or radiotherapy were categorized as t-AML. Patients with prior myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) or with MDS-related gene mutations (MRGM) or cytogenetic abnormalities (MRCA) were categorized as AML-MR. Remaining patients were categorized as dn-AML. Composite complete remission (CRc) was defined as complete remission (CR) and CR with incomplete or partial hematological recovery (CRi/CRh). Overall response rate (ORR) was defined as CRc and morphological leukemia‐free state (MLFS). Kaplan–Meier analysis with log‐rank tests were used to compare overall survival (OS) between subgroups.

Results:

A total of 132 patients were included: 29 with t-AML, 73 with AML-MR, and 30 with dn-AML. Compared to dn-AML, patients with t-AML had similar age (median 70 vs 76 years, p=0.16), ECOG 0–1 status (74% vs 57%, p=0.26) and non-favorable ELN 2024 risk (52% vs 57%, p=0.79), but more TP53 mutations (29% vs 4%, p=0.03), complex karyotype (CK) (45% vs 13%, p<0.01) and non-favorable ELN 2022 risk (83% vs 53%, p=0.03). CRc rate at any time was 71% vs 69% in patients with t-AML and dn-AML, respectively (p=0.25), including 58% vs 59% after cycle 1 (p=0.25). ORR at any time was 75% vs 86% in patients with t-AML and dn-AML, respectively (p=0.15), including 67% vs 79% after cycle 1 (p=0.11). 60-day mortality was 17% vs 7% in t-AML and dn-AML, respectively (p=0.25). Median OS was 13.1 months in t-AML and 16.0 months in dn-AML, with 24-month OS rates of 29% and 48%, respectively (p=0.30). Within the t-AML subgroup, TP53 mutation (HR 2.67, 95% CI 0.99 – 7.15, p=0.05) and ELN 2022 non-favorable risk (HR 8.07, 95% CI 0.99–65.14, p=0.05) were marginally associated with inferior OS, while CK had a non-significant trend towards inferior OS (HR 1.79, 95% CI, 0.68-4.73, p=0.24). Prior chemotherapy or radiotherapy exposure, non-favorable ELN 2024 and presence of MRGM were not associated with OS in t-AML.

Compared to dn-AML, patients with AML-MR had comparable age (median 74 vs 76 years, p=0.36), ECOG 0–1 status (74% vs 57%, p=0.14), and non-favorable ELN 2024 risk (45% vs 57%, p=0.37), but more TP53 mutations (18% vs 4%, p=0.11), CK (32% vs 13%, p=0.04) and non-favorable ELN 2022 risk (97% vs 53%, p<0.01). CRc rate at any time was 65% vs 69% in patients with AML-MR and dn-AML, respectively (p=0.82), including 45% vs 59% after cycle 1 (p=0.11). ORR at any time was 87% vs 86%, in patients with AML-MR and dn-AML, respectively (p=0.92), including 69% vs 79% after cycle 1 (p=0.15). 60-day mortality was 7% in both groups (p=1.00). Median OS was 12.4 months in AML-MR and 16.0 months in dn-AML, with 24-month OS rates of 33% and 48%, respectively (p=0.30). Within the AML-MR subgroup, signaling pathway mutations (FLT3-ITD, NRAS/KRAS) were associated with inferior OS (HR 3.32, 95% CI 1.66-6.63, p<0.01) along with ELN 2024 non-favorable-risk (HR 1.99, 95% CI 1.02–3.90, p=0.04). TP53 mutations were not associated with OS (HR 1.18, 95% CI, 0.52-2.58) along with non-favorable ELN 2022 risk, individual MRGM and CK.

Conclusion:

Patients with sAML in our cohort achieved remission rates comparable to dn-AML with frontline Aza-Ven with non-significant difference in OS. The ELN 2022 and 2024 risk classifications had different prognostic utility between t-AML and AML-MR mostly related to the inclusion of cytogenetic abnormalities in the former and weight of FLT3-ITD and NRAS/KRAS mutations in the latter. Further studies are needed to refine and adapt prognostic classification systems considering the heterogeneity of sAML in patients treated with Aza-Ven.

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2025
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