Acute Myeloid Leukemia Evolving from Myeloproliferative Neoplasms: Many Sides of a Challenging Disease

Abstract

The evolution to blast phase is a frequently unpredictable and almost invariably fatal event in the course of myeloproliferative neoplasms. The molecular mechanisms underlying blast transformation have not been elucidated and the specific genetic and epigenetic events governing leukemogenesis remain unclear. The result of the long-lasting dynamics, passing through progressive genetic steps, is the emergence of one or more clones often characterized by complex genetics, either at conventional karyotyping or at modern high-throughput sequencing analyses, with all clinical and prognostic correlates. The current therapeutic approaches are largely inadequate and incapable of modifying the inherent unfavorable outcome. In this perspective, the application of targeted strategies should aim to prevent the occurrence of leukemic evolution. At transformation, the crucial target of treatment should be the allocation to allogeneic transplant for eligible patients. With this in mind, novel combination treatments may provide useful bridging strategies, beyond potentially improving outcomes for patients who are not candidates for intensive approaches.

A Case of Primary Myelofibrosis With Transformation to Leukemia Cutis

“…35 The patients with PMF that transform to secondary acute myeloid leukemia have a more dismal prognosis of 3-6 months. 36 Although our patient started chemotherapy with decitabine, he died 2 months later after developing skin manifestations.…”

High-Throughput CRISPR Screening in Hematological Neoplasms

“…Other disorders that can potentially transform to AML aggressive disease are MPNs. Although several NGS studies have identified gene mutations in post-MPN AML patients [ 252 , 253 ], the mechanisms of this transformation remain largely unclear [ 254 ]. Recently, the combination of two custom loss-of-function mouse libraries have revealed Lkb1 and Stk11 kinases as being novel drivers of this leukemic transformation [ 248 ].…”

Acute Myeloid Leukemia Following Myeloproliferative Neoplasms: A Review of What We Know, What We Do Not Know, and Emerging Treatment Strategies

“…It is difficult to apply conventional clinical factors used to risk stratify patients with AML (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, transplant status) to post-MPN AML patients, because their disease differs biologically from de novo disease. And due to the high frequency of older age, complex karyotypes and TP53 mutations, the vast majority of patients would be categorized as having adverse risk [ 42 ]. While it is true that post-MPN AML carries a dismal prognosis, there may still be heterogeneity amongst these patients, and we currently do not have a standardized way to risk stratify them separately from de novo AML.…”