Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia

ABSTRACT

Introduction: Acute megakaryoblastic leukemia (AMegL) is a rare hematological neoplasm most often diagnosed in children and is commonly associated with Down's syndrome (DS). Although AMegLs are specifically characterized and typically diagnosed by megakaryoblastic expansion, recent advancements in molecular analysis have highlighted the heterogeneity of this disease, with specific cytogenic and genetic alterations characterizing different disease subtypes.

Areas covered: This review will focus on describing recurrent molecular variations in both DS and non-DS pediatric AMegL, their role in promoting leukemogenesis, their association with different clinical aspects and prognosis, and finally, their influence on future treatment strategies with a number of specific drugs beyond conventional chemotherapy already under development.

Expert opinion: Deep understanding of the genetic and molecular landscape of AMegL will lead to better and more precise disease classification in terms of diagnosis, prognosis, and possible targeted therapies. Development of new therapeutic approaches based on these molecular characteristics will hopefully improve AMegL patient outcomes.

KEYWORDS:

• Megakaryopoiesis
• pediatric acute megakaryoblastic leukemia
• down syndrome
• GATA1
• cytogenetic translocations
• AMegL prognosis
• novel treatments

Article highlights

• AMegL is a rare myeloid neoplasm that can be diagnosed in children and is often associated with DS.

• Molecular alterations, such as GATA1 and cohesin mutations, are often present in DS AMegL, whereas chromosomal translocations, such as CBFA2T3–GLIS2 and RBM15–MKL1, are recurrent in non-DS AMegL.

• AMegL prognosis varies based on the presence of these specific molecular alterations. DS AMegL has very good rates of CR and long OS, whereas non-DS AMegL prognosis remains poor.

• Standard therapy for AMegL is based on chemotherapeutic protocols, followed or not by alloBMT.

• Relapsed/recurrent DS AMegL and high-risk non-DS AMegL are in need of new therapeutic options.

• Novel drugs targeting disease-driving alterations, inducing megakaryocytic differentiation, or overcoming disease resistance are being tested.

• A better understanding of AMegL biology, individual patient genetics, and phenotypic complexity in association with drug development and testing will hopefully lead to better treatment protocols and improved disease outcomes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded