Is BCL-xL the Achilles' heel of AEL and AMKL?

Over the last 2 decades, the focus of acute myeloid leukemia (AML) classification has gradually shifted from the microscope to miniaturized chips of increasingly sophisticated next-generation sequencing platforms. The French-American-British (FAB) classification for AML, based on morphological differentiation features and conceptualized in the 1970s, included 2 rare syndromes: FAB AML M6 (acute erythroid leukemia [AEL]) and FAB AML M7 (acute megakaryoblastic leukemia [AMKL]). According to the World Health Organization (WHO) 2001 classification, the diagnosis of AEL required the presence of at least 50% erythroid cells and >= 20% blasts in the non-erythroid compartment. The WHO 2008 revision partitioned AEL into an erythroid/myeloid (M6a) subtype (requiring >= 50% erythroid precursors and >= 20% myeloblasts within the total nucleated fraction) and a pure erythroid (M6b) subtype (requiring >80% erythroid precursors and >= 30% proerythroblasts). In the WHO 2016 update, the term AEL erythroid/myeloid subtype was eliminated and pure erythroid leukemia was retained. In the current WHO 2022 iteration, the term AEL has been reinstated and its association with biallelic TP53 defects, complex karyotype, therapy-related disease, and poor prognosis emphasized.(1) AMKL is diagnosed by the presence of >= 20% marrow blasts, with >50% of the blasts megakaryoblastic or phenotypically positive for factor VIII, CD41, CD42, or CD61.2 AMKL has a favorable outcome in children with Down syndrome (DS), in contrast to poorer outcomes in non-DS children and adult patients. DS-related AMKL is etiologically associated with truncated GATA1, whereas in children lacking DS, the presence of chimeric RBM15::MKL-1 or CBFA2T3::GLIS2 is more prominent.(3) Collectively, these diagnostic entities are exceptionally rare. AEL comprises <5% and AMKL comprises similar to 1% of adult AML, with AMKL being more common in the pediatric population. Expected survival outcomes in adults are poor, ranging between 6 to 8 months and highlighting AEL and AMKL as orphan diseases with high unmet therapeutic need.(2,4)