STAT3 mutation and its clinical and histopathologic correlation in T-cell large granular lymphocytic leukemia.

Although T-cell large granular lymphocytic leukemia (T-LGLL) is a clinically indolent disorder, patients with moderate to severe cytopenia require therapeutic intervention. The recent discovery of STAT3 mutations has shed light on the genetic basis of T-LGLL pathogenesis. However, the association of STAT3 mutational status with patients' clinical, histopathologic, and other laboratory features has not been thoroughly evaluated in T-LGLL. In this study, STAT3 mutations were identified in 18 of 36 patients with T-LGLL (50%), including Y640F (12/18, 66.7%), N647I (3/18, 16.7%), E638Q (1/18, 5.6%), I659L (1/18, 5.6%), and K657R (1/18, 5.6%). Interestingly, pure red cell aplasia was seen exclusively in T-LGLL patients without STAT3 mutations (6/15 in the wild-type STAT3 group versus 0/13 in the mutant STAT3 group; P = .02); these patients also were the only responders to T-LGLL therapy (mainly cyclophosphamide) in wild-type STAT3 group. Patients harboring STAT3 mutations were more prone to rheumatoid arthritis (4/13 versus 0/15 in the wild-type STAT3 group; P = .04), frequently requiring therapy for neutropenia/neutropenia-associated infections, and demonstrated good therapeutic responses to methotrexate. No significant differences were seen in complete blood count, flow cytometric immunophenotypic features, T-cell receptor γ V-J rearrangement repertoire, and bone marrow biopsy morphology among the STAT3-mutation and wild-type groups other than significantly larger tumor burden in patients with STAT3 mutations. The distinct disease association and therapeutic responses observed in patients with mutant and wild-type STAT3 warrant further investigation to elucidate the underlying mechanisms. They also highlight the importance of identifying STAT3 mutational status in patients with T-LGLL, which may aid in clinical therapeutic choice.