Introduction: Therapy-related myeloid neoplasms (t-MN), including therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML), arise after exposure to cytotoxic or immunosuppressive treatments. Although the 2022 International Consensus Classification (ICC) no longer recognizes t-MN as distinct, the term persists due to historically poor prognosis. Many cases, however, have favorable or intermediate-risk genetics. This study examines clinical and molecular predictors of outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in t-MN.

Methods: We retrospectively analyzed 141 t-MN patients who underwent allo-HSCT from Jan 2010 to May 2024. Collected variables included demographics, prior therapies, disease features, transplant parameters, and outcomes. The primary endpoint was 2-year overall survival (OS); secondary endpoints were 2-year non-relapse mortality (NRM) and cumulative incidence of relapse (CIR). Kaplan-Meier and competing risk analyses were performed.

Results: Among 141 patients (median age 60; 47% male), 62.4% had t-AML, 33.3% t-MDS, and 4.3% other diagnoses. Median time from primary disease to t-MN was 6 years. In t-AML, prior cancers included solid tumors (48.9%) and hematologic neoplasms (35.2%), with 17% having had autologous HSCT. In t-MDS, 74.5% had prior hematologic malignancy and 51.1% had prior autologous HSCT. Overall, 85% had a history of cytotoxic therapy.

Pre-HSCT therapies included induction chemotherapy (61%), hypomethylating agents (HMA) alone (22%), HMA plus venetoclax (7.1%), or none (7.8%). Common cytogenetics were chromosome 7 abnormalities (27%), complex karyotype (20.6%), monosomal karyotype (24.1%), and TP53 mutations (7.1%). ELN 2022 risk classification: 12.1% favorable, 39.6% intermediate, 37.4% adverse.

With 2-year median follow-up, OS was 52.8%, NRM 29.2%, and CIR 21.1%. Grade II–IV acute GVHD occurred in 26.2%; chronic GVHD in 30.2% (with moderate or severe cases in 20.2%). OS was higher in t-AML vs. t-MDS (57.3% vs. 40.6%, p=0.045).

Outcomes did not significantly differ by primary disease type: OS was 50.2% for solid tumors, 53.6% for hematologic neoplasms, 58.8% for benign diseases (p=0.42); NRM: 28.3%, 29.9%, 29.4% respectively (p=0.58); CIR: 25.9%, 19.6%, 11.8% (p=0.31). Among prior hematologic malignancies, prior autologous HSCT did not impact OS, NRM, or CIR.

In t-AML, the 2022 European LeukemiaNet (ELN) risk stratification showed 2-year OS: 63.6% (favorable), 62.8% (intermediate), 54.8% (adverse) (p=0.42). NRM did not significantly differ (36.4%, 28.0%, 9.4%; p=0.15), but CIR was higher in adverse (42.1%) vs. intermediate (11.4%) and favorable (0%) (p=0.002).

Using the Disease Risk Index (DRI) classification (Armand et al., Blood 2014), 2-year OS was 66.7% (low-risk), 59.5% (intermediate-risk), and 36.5% (high-risk) (p=0.007). NRM: 33.3% (low-risk), 29.6% (intermediate-risk), 27.2% (high-risk) (p=0.99); CIR: 6.0% (low-risk), 12.7% (intermediate-risk), 42.8% (high-risk) (p<0.001).

Adverse cytogenetics were associated with inferior outcomes: complex karyotype (OS 35.3% vs. 58.4%, p=0.02; CIR 48.2% vs. 16.1%, p<0.001), chromosome 7 abnormalities (OS 31.1% vs. 61.1%, p<0.001; CIR 43.1% vs. 15.2%, p<0.001), del(5q) (OS 29.2% vs. 55.9%, p=0.005; CIR 56.2% vs. 18.2%, p<0.001). At the time of analysis, no patient with both TP53 mutation and complex karyotype survived beyond 2 years. Conditioning intensity and chronic GVHD severity did not affect OS.

Multivariable analysis identified Karnofsky performance status (KPS) <90, chromosome 7 abnormalities, and del(5q) as adverse OS predictors. Chromosome 7 abnormalities, del(5q), and bone marrow graft source were associated with higher relapse.

Conclusion: Allo-HSCT offers curative potential for t-MN. Outcomes were better in t-AML vs. t-MDS. ELN 2022 effectively predicted relapse, but DRI better predicted both OS and CIR. Adverse cytogenetics (complex karyotype, del(5q), chromosome 7 abnormalities, TP53 mutations) predicted poor survival. These findings underscore the importance of molecular risk stratification and highlight the need for innovative therapies for high-risk groups.

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2025
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