Other myeloid malignancies, including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs), carry a risk of disease evolution to sAML. The risk varies depending upon the under lying disease and may be facilitated by certain exposures, including genotoxic chemotherapy.
Patients with MPNs have an approximately 10% risk of evolution to AML (MPN in blast phase [MPN-BP]) over 10 years, which varies according to the underlying disease. The risk is lowest in essential thrombocythemia and may be as high as 20% for myelofibrosis. There is a clear association between chemotherapies used in treating MPNs, specifically alkylating agents and radioactive phosphorus, and leukemic evolution; treatment with these agents results in a threefold to fourfold increase in progression to MPN-BP. Another mechanism that may contribute to clonal evolution and disease progression may be a chronic inflammatory state related to the underlying MPN. Sequencing of sAML cases developing in the background of an MPN has identified recurrent mutations in TET2, JAK2, IDH, IKZF1, and ASXL1. Moreover, a number of patients with a JAK2-mutated MPN may progress to MPN-BP that is JAK2 wild-type, thought to arise either from a common pre-JAK2 founding clone, or due to parallel expansion of a distinct hematopoietic clone. MPN-BP with mutated JAK2 typically proceeds through an accelerated myelofibrosis phase, whereas MPN-BP that no longer harbors a JAK2 mutation tends to arise from chronic phase disease and may be associated with the use of cytotoxic therapies.
Prior to the introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), patients with CML typically progressed from chronic phase to blast phase within 5 years, at a rate of more than 20% per year (see Chapter 69). Most cases of blast phase CML have a myeloid phenotype, whereas approximately 30% of patients have a lymphoid phenotype. Additional mutations may occur during transformation of CML, and approximately 80% of patients have additional cytogenetic abnormalities, such as duplication of the Philadelphia chromosome, and other trisomies that are recurrent in de novo AML. Up to one third of patients with CML in myeloid blast phase harbor mutations in the tumor suppressor genes P16 or TP53. In addition, BCR-ABL signaling upregulates transcription factors implicated in AML pathogenesis, including HOXA9 and EVI1, which may contribute to leukemic transformation. The rate of transformation to blast phase CML in the TKI era has decreased markedly to approximately 1% per year, which underscores the continued requirement for BCR-ABL1 signaling in CML evolution.
Approximately one-third of patients with MDS progress to sAML, although this varies significantly according to the underlying MDS subtype and disease characteristics, including the percentage of bone marrow blasts, presence of characteristic cytogenetic abnormalities, and cytopenias. Progression to leukemia is associated with acquisition of additional somatic mutations as well as epi genetic alterations within the MDS clone. Mutations in transcription factors and cytokine signaling genes, including RUNX1, NRAS, and ETV6, are more common at progression to sAML, compared with the frequency of these mutations at MDS diagnosis. Epigenetic modifications of the MDS genome appear to also play a significant role in AML progression, particularly through DNA methylation–mediated silencing of tumor suppressor genes. These alterations are also enriched in the subtype of AML with myelodysplasia-related changes, even where a prior MDS diagnosis was not known.
