Eosinophilia with STAT5BN642H Mutation: A Heterogeneous Entity with Overlapping Morphological Features and Poor Outcome

Loss of function STAT5B mutations can lead to immunodeficiency and autoimmune diseases, and activating mutations are associated with large granular lymphocytic leukemia (LGL), T-cell lymphomas, rarely myeloid malignancies [1][2][3][4][5][6]; and are potential candidates for targeted therapeutic intervention [6].We report three cases of eosinophilia with STAT5BN642H mutation that underscore several critical insights into this category (Table 1 and supplementary figure S1).Case-1: 63-year-old female presented with transfusion-dependent anemia, generalized-itching, and hepatosplenomegaly for five months.Investigations revealed anemia, leukocytosis, eosinophilia (absolute eosinophil count/AEC 4.7x10^9/L), thrombocytopenia, and a leucoerythroblastic picture in the peripheral blood film(PBF).Bone marrow examination(BME) showed eosinophil hyperplasia and patchy myelofibrosis.Flowcytometry(FCM) identified clonal T-cells (3.8%) with CD7dim, CD5dim, CD8pos immunophenotype, confirmed by T-cell receptor beta gene rearrangement assay.FISH testing using eosinophilia-panel showed no rearrangement, leading to a diagnosis of a lymphocytic variant of hypereosinophilic syndrome(L-HES).The patient did not respond to steroids or imatinib.A repeat BME after five months showed diffuse myelofibrosis.NGS revealed a STAT5BN642H mutation(variant allele frequency/VAF-24%).The diagnosis was revised to chronic eosinophilic syndrome (CEL) with STAT5BN642H mutation.The patient had chronic refractory cytopenias and succumbed to pneumonia two years after diagnosis.Case-2: 13-year-old male presented with cytopenias requiring transfusions, cervical lymphadenopathy, and hepatosplenomegaly.Investigations showed anemia, thrombocytopenia, normal leukocyte count, and mild eosinophilia(AEC 0.9x10^9/L).BME revealed 21% eosinophils, suboptimal erythroid response(10%), and mild myelodysplasia.Cytogenetic testing showed 7q deletion and trisomy 8 in 60% of cells, but no tyrosine-kinasedomain rearrangements on FISH testing for the eosinophilia panel.Diagnosed with myelodysplastic syndrome (MDS), he was treated with azacytidine, eltrombopag, and steroids without response.A repeat BME showed extensive myelofibrosis, mastocytosis, and dysplastic megakaryocytes.NGS revealed a STAT5BN642H mutation(VAF-45%).The patient had a refractory course and succumbed to infection-related complications after 14 months.Case-3: 25-year-old female presented with fatigue and massive splenomegaly.The hemogram showed anemia, leukocytosis, eosinophilia(AEC 63x10^9/L), normal platelet counts, and a leucoerythroblastic picture resembling chronic myeloid leukemia-chronic phase(CML-CP).BME revealed hypercellular marrow with eosinophilia but no dysplasia or myelofibrosis.FISH and molecular studies were negative for BCR::ABL1, JAK2V617F, CALR mutations, and other tyrosine kinase fusions.There was no response to imatinib.