Acute myeloid leukaemia (AML) harbouring KMT2A-PTD: should it be considered as a myelodysplasia-related abnormality?

Aims: Although acute myeloid leukaemia (AML), myelodysplasia-related (AML-MR), can be defined solely by molecular abnormalities, legacy studies did not analyse the KMT2A gene. The KMT2A-partial tandem duplication (KMT2A-PTD) is described in myelodysplastic neoplasms (MDS) as well as AML. We describe the clinical, morphological, immunophenotypic and molecular features of AML harbouring KMT2A-PTD.

Methods: We studied 802 adult AML patients, for whom next-generation sequencing- based mutation and copy number analysis were available. For the patients harbouring KMT2A-PTD, the immunophenotypic analysis including measurable residual disease (MRD), mutational landscape and the patient outcomes were analysed.

Results: We identified 45 patients of de novo and secondary AML harbouring KMT2A-PTD. Morphological dysplasia and immunophenotypic abnormalities, described in MDS, were observed in 35.6% and 40% of de novo cases respectively. Furthermore, 44% of AML with KMT2A-PTD could be diagnosed as AML-MR based on cytogenetics or genomics. We observed progenitor abnormalities, commonly aberrant CD7 (33%) and CD15 (59%), and granulocytic abnormalities like loss of side scatter (50%), asynchronous maturation patterns and loss of CD177 in mature granulocytes. Frequent mutations involving IDH2 (30% of which were R172), FLT3 (32% each), RUNX1 (29%), DNMT3A and U2AF1 (24% each) were noted. We also found that more than 25% of patients did not achieve morphological remission, and the remaining 60% were MRD positive. The outcomes of AML with KMT2A-PTD with or without MR-associated abnormalities were similar.

Conclusions: AML harbouring KMT2A-PTD frequently displays MR immunophenotypic abnormalities and is frequently associated with AML-MR type mutations. In addition, they have similar outcomes as compared with AML-MR.