112 B-ALL/LBL within a background of U2AF1-mutated MDS: implications for bilineal evolution

Introduction/Objective Hematologic disorders have historically been defined by the abnormal cell population’s cell lineage (myeloid, B-cell, T-cell) with particular genetic alterations associated with specific diseases or disease categories. For example, B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is classified according to genetic findings, including aneuploidy, BCR::ABL1 fusions, transcription factor mutations, and KMT2A rearrangements. Alternatively, certain genetic mutations are more commonly associated with myeloid disorders, including U2AF1 mutations in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Neoplasms exhibiting ambiguous and/or mixed phenotypic or genetic features, including the presence of distinct clonal populations of different lineages, are less common and less well understood. Herein we report a case of B-ALL/LBL presenting with a relatively low blast count within a background of multilineage dyspoesis with cytogenetic and molecular findings suggesting two distinct clonal populations which may have arisen from a common mutational event. Methods/Case Report A 76-year-old male with a history of prostate cancer (treated with resection, radiation, leuprolide, and enzalutamide) presented for evaluation of macrocytic anemia which had been present for two years with new-onset neutropenia. Next generation sequencing (NGS) was performed on peripheral blood and demonstrated a pathogenic missense mutation in U2AF1 S34Y with a variant allele frequency (VAF) of 35%. Flow cytometry of a subsequent bone marrow biopsy showed an abnormal immature B-cell population. Histologic and immunohistochemical evaluation of the bone marrow showed up to 20-30% B-lymphoblasts with mild dyspoietic changes within background erythroid, myeloid, and megakaryocytic precursors. Chromosomal microarray demonstrated a male result with 2 abnormal clones: a major clone (50% of cells) with gain of chromosome 8 and a minor clone (5% of cells) with hypodiploidy. Karyotypic analysis confirmed a gain of chromosome 8 in 14 cells. Next-generation sequencing (NGS) showed the previously reported U2AF1 S34Y (VAF 32%) along with a newly identified pathogenic variant TP53 R342 (VAF 7%). Results NA Conclusion A diagnosis of B-ALL/LBL was rendered, likely arising within a background of U2AF1-mutated MDS. The history of persistent cytopenia(s) for two years prior suggests that the myeloid neoplasm may have pre-dated the development of B-ALL/LBL. The patient received mini-Hyper CVAD chemotherapy, and bone marrow biopsy at day 29 showed no morphologic or immunophenotypic evidence of B-ALL/LBL, and no overt dysplasia. Genetic analyses demonstrate persistence of trisomy 8 and U2AF1 mutation (VAF 12%) but no evidence of TP53 mutation.