Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group.

Purpose: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML).

Methods: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases.

Results: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 44.2; < .0001) and relapse-free survival (RFS; median months: 9.1 19.2; = .0018). Frequency of , , , and mutations were significantly different in NK-t-AML compared with NK-dn-AML ( 35% 49%; = .0493; 23% 36%; = 0494; 12% 5%; = .0465; 9% 2% = .0105), while mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; = .070).

Conclusion: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.