AMKLs

Acute megakaryoblastic leukemia (AMKL) is a rare form of acute myeloid leukemia defined by the proliferation of megakaryoblasts, the precursors of platelets. The plural AMKLs is used to cover the spectrum of leukemias with megakaryocytic differentiation, including cases that occur with and without Down syndrome.

Pathology and classification: AMKL cells typically express megakaryocytic markers such as CD41 and CD61 (and sometimes CD42b) and may be negative for myeloperoxidase. The World Health Organization classifies these cases as AML with megakaryocytic differentiation (formerly termed AML-M7). In Down syndrome–associated AMKL, there is often a GATA1 mutation, and these cases can arise after a prior neonatal condition known as transient abnormal myelopoiesis. Non–Down syndrome AMKL shows a broader range of cytogenetic abnormalities, including predefined rearrangements such as RBM15-MKL1 in some infant cases, as well as other chromosomal alterations.

Clinical features and diagnosis: Patients typically present with symptoms of acute leukemia, including fatigue, pallor, bruising, recurrent infections, and Barbara-like organomegaly. Diagnosis relies on bone marrow examination with flow cytometry and immunohistochemistry to confirm megakaryocytic lineage, along with cytogenetic and molecular testing to identify characteristic abnormalities and guide risk stratification.

Genetics and subtypes: DS-associated AMKL is distinguished by the accompanying biology of Down syndrome and GATA1 mutations, which influence disease course and response to therapy. Non–Down syndrome AMKL comprises a heterogeneous group with various cytogenetic and molecular changes, including cases with RBM15-MKL1 and other rearrangements.

Treatment and prognosis: Management follows AML induction protocols, with treatment intensity often tailored to the patient’s biology and comorbidities. DS-AMKL generally shows a more favorable response to therapy in children compared with non-DS AMKL, which can be higher risk and may require additional strategies such as stem cell transplantation in selected cases. Ongoing research aims to refine risk stratification and expand targeted therapeutic options.