Acute myeloid leukemia with KMT2A rearrangements in children with congenital heart disease: case series and literature review

Introduction Nationwide cohorts had revealed individuals with congenital heart disease (CHD) had increased risk of hematological malignancies, especially leukemia (HR = 1.41, 95% CI 1.08 to 1.84) [1, 2]. CanCHD Study had revealed acute myeloid leukemia had a higher cumulative incidence during early childhood than acute lymphoblastic leukemia [3]. Three non-chromosomal birth defect groups showed AML associating with congenital anomalies of the heart and circulatory system (OR = 2.86, 95% CI: 1.81-4.52) [4]. KMT2A was identified as one of the genes mutated and enriched in CHD cohorts [5, 6]. Purpose KMT2A mutations are associated with cardiac abnormalities and leukemias independently, and we explored relationship between. Methods Between 1991 and 2023, pediatric and adult patients with de novo KMT2A-r AML at a tertiary medical center were investigated retrospectively. After newly diagnosed with AML, patients received induction treatment with intensive chemotherapy. Clinical parameters including comorbidities were also collected. Those with congenital heart diseases, including Tetralogy of Fallot (TOF), ventricular septal defect (VSD), atrial septal defect (ASD), patent foramen ovale (PFO), and coarctation of the aorta (COA), were listed as study subjects. We extracted data of echocardiogram, electrocardiogram (ECG), clinical presentations associated with cardiac abnormalities, and further management of such. All the diagnosis of KMT2Ar AML patients were tested for fusion transcripts were performed with real-time quantitative polymerase chain reaction (RT-qPCR) to detect recurrent KMT2A rearranged fusion transcripts, including KMT2A::MLLT3 (MLL-AF9), KMT2A::MLLT10. Results In 58 pediatric patients, there are 7 patients with CHD or PFO. These pediatric cases had cardiac abnormalities of ASD, VSD, PFO, TOF. All of the patients had KMT2A rearranged AML. Most of them (6/7) had the same binding partner MLLT3. Among these 7 patients, four of them survived. In three cases of mortality, only one of them died of leukemia relapse. All of their left ventricular ejection fraction (LVEF) were above 50%. KMT2A was listed as tier 1 human CHD gene, with inheritance pattern of monoallelic. In a 2,871 CHD probands study, two mutations were found, including p.K1293N midD causing transposition of the great arteries (TGA), and p.R1927fs frameshift causing unspecified abnormalities [6]. Eight variants in KMT2A were identified in whole exome sequencing of non-syndromic 829 patients with TOF [7]. The alterations include frameshifts, stop-gain, and missense, with phenotypes of patent ductus arteriosus (PDA), TOF, and ASD [8]. Conclusions Our case series is a first-in-world study that revealed an exceptionally high percentage of CHD among patients with KMT2Ar AML. Hypotheses include mutations of KMT2A gene triggers DNA repair mechanisms, evoking events such as double-strand break, causing increase possibilities of KMT2A rearrangements.