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.

Abstract

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 <i>TP53</i> 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). 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. Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 <i>v</i> 44.2; <i>P</i> < .0001) and relapse-free survival (RFS; median months: 9.1 <i>v</i> 19.2; <i>P</i> = .0018). Frequency of <i>NPM1</i>, <i>FLT3</i>, <i>KRAS</i>, and <i>GATA2</i> mutations were significantly different in NK-t-AML compared with NK-dn-AML (<i>NPM1</i> 35% <i>v</i> 49%; <i>P</i> = .0493; <i>FLT3</i> 23% <i>v</i> 36%; <i>P</i> = 0494; <i>KRAS</i> 12% <i>v</i> 5%; <i>P</i> = .0465; <i>GATA2</i> 9% <i>v</i> 2% <i>P</i> = .0105), while <i>TP53</i> 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; <i>P</i> = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; <i>P</i> = .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; <i>P</i> = .070). 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.