Acute Leukemias of Ambiguous Lineage With MDS-Associated Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With MDS-Associated Mutations: A Study From the Bone Marrow Pathology Group

1 Introduction

To the Editor: Acute myeloid leukemia (AML) and acute leukemia of ambiguous lineage (ALAL) comprise a diverse variety of acute leukemias that are defined by their morphologic, immunophenotypic, and genetic features. AML is characterized by clonal expansion of immature hematopoietic precursors of myeloid lineage in the peripheral blood and bone marrow. AML may arise de novo, evolve from prior myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or after exposure to cytotoxic or radiation therapy, called therapy-related AML [1]. The recent classifications of the World Health Organization (WHO), the 5th Edition Classification of Haematolymphoid Tumours, and the International Consensus Classification of Myeloid and Lymphoid Neoplasms (ICC) both allow for classification of AMLs that arose from, or are otherwise related to, MDS as distinct entities, if diagnostic and exclusionary criteria are met [2, 3]. These subcategories include AML, myelodysplasia-related in the WHO and AML with myelodysplasia-related gene mutations, or AML with myelodysplasia-related cytogenetic abnormalities in the ICC.

Both classifications have moved more toward genetically defined classifications of acute leukemias. Both now recognize MDS-associated mutations as defining of MDS-related AML (AML-MR), a disease with poor prognosis. Among the features that define AML-MR are mutations known as secondary-type or MDS-associated mutations, so named because, in the context of AML, they are highly specific for AML arising from preceding MDS, MPNs, or therapy-related clonal aberrations. The presence of mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 genes is > 95% specific for these “secondary” AMLs [4]. Somatic mutations in RUNX1 are commonly associated with mutations in other genes characterizing AML-MR and are included in this category in the ICC. AML with mutated RUNX1 is a provisional entity in the WHO 4th edition.

ALALs have blast populations that either do not show any clear lineage, acute undifferentiated leukemia (AUL), or those that show multi-lineage differentiation, mixed phenotype acute leukemias (MPAL). ALALs are rare, comprising ~4% of acute leukemias, the majority of those being MPAL [3]. However, leukemias that meet the criteria for other defined categories, such as AMLs with defining genetic abnormalities, are excluded from MPAL. Investigations into the genetic basis of ALAL are limited and have shown great heterogeneity in associated genetic mutations, with some associated with ALL, others with AML, and others with neither. Mutations in MDS-associated genes may be present in a significant proportion of ALAL cases with RUNX1 mutations among the most common [5].

The current classifications are unclear on how ALALs should be classified in the presence of MDS-associated mutations. They suggest excluding leukemias with ambiguous lineage phenotypes that harbor MDS-associated genetic abnormalities from classification under ALAL. However, the clinical and genetic features of ALAL remain poorly characterized, including those with MDS-associated mutations. Our goals for this study are to determine the significance of MDS-associated mutations in ALAL as compared with cases of de novo AML with MDS-associated mutations.