The Secondary Myelodysplastic Neoplasms (MDS) Jigsaw

SIMPLE SUMMARY: The classification of myelodysplastic neoplasms (MDSs) in patients with a previous primary tumor is controversial, as an efficient consensus risk factor-based classification of secondary MDSs has not yet been established. The current classifications consider separate etiologies based on exposure to cytotoxic therapy and genetic predisposition, despite recent studies on the germline landscape and clonal hematopoiesis of indeterminate potential (CHIP) supporting the contention that these different risk factors are overlapping. This review wants to summarize the current status of knowledge of secondary MDS etiologies and foresees future classifications that assess all risk factors and their interactions for achieving a differential diagnosis of patients at risk to aid in routine clinical decision-making related to most adequate clinical management. ABSTRACT: There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive for secondary MDSs and there are multiple overlapping scenarios, a comprehensive and definitive classification is yet to come. In addition, a sporadic MDS might arise after a primary tumor fulfills the diagnostic criteria of MDS-pCT without a causative cytotoxicity. In this review, we describe the triggering pieces of a secondary MDS jigsaw: previous cytotoxic therapy, germline predisposition and clonal hematopoiesis. Epidemiological and translational efforts are needed to put these pieces together and ascertain the real weight of each of these pieces in each MDS patient. Future classifications must contribute to understanding the role of secondary MDS jigsaw pieces in different concomitant or independent clinical scenarios associated with the primary tumor.