Therapy-related myeloid neoplasms.

Abstract

Advances in the genetic characterization of patients with therapy-related myeloid neoplasms (t-MNs) have changed our understanding of the pathogenesis of these diseases. In addition, extensive sequencing studies have identified recurrent mutations with diagnostic and prognostic impact. Thus, the revised version of the WHO classification combines therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute myeloid leukemia (t-AML) in the one entity of t-MNs because of their similar pathogenesis, rapid progression from t-MDS to t-AML, and their equally poor prognosis. Fifteen percent of t-AML patients present with favorable risk fusion genes, whereas 50% have adverse cytogenetics. The most frequent molecular aberration in t-AML and t-MDS affects TP53 (33%). Selection of a pre-existing treatment-resistant hematopoietic stem cell clone with TP53 mutation has been shown as an important mechanism in the development of t-MNs and explains the high frequency of TP53 mutations in these patients. Following previous cytotoxic therapy, patients develop specific vulnerabilities, which become especially evident as high nonrelapse mortality of t-MN patients after allogeneic hematopoietic cell transplantation. Patients are treated according to their genetic risk profile. Assessment of minimal residual disease helps to guide allogeneic transplantation for patients with favorable risk and genetic markers.