A complex KMT2A::AFF3 fusion resulting from a three-way chromosomal rearrangement in pediatric B lymphoblastic leukemia

•KMT2A::AFF3 is a rare fusion in B-lymphoblastic leukemia.•Complex rearrangement resulting in KMT2A::AFF3 has not been previously reported.•Comprehensive genomic analysis is important for molecular characterization of B-ALL. The KMT2A::AFF3 fusion, t(2;11)(q11.2;q23.2), is a very rare fusion occurring in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Our patient is a 2-year-old male who presented with three weeks of intermittent fever. Bone marrow biopsy showed 82% blasts and cytogenetic analysis demonstrated a complex 3-way chromosomal rearrangement involving KMT2A and an unknown fusion partner. Molecular testing identified the fusion partner as AFF3, a FLT3-TKD non-D835 mutation, and an NF1 mutation. This case demonstrates a highly complex three-way variant translocation resulting in the rare KMT2A::AFF3 fusion with only a few cases previously described in the literature.