Abstract
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder where somatic STAT3 mutation is common. Although LGLL has been described as an underlying condition associated with pure red cell aplasia (PRCA), the clinical characteristics and therapeutic response of LGLL - associated PRCA are largely unclear. We evaluated a set of 81 patients with LGLL - associated PRCA. Comparative analysis was performed on the clinical characteristics, responses to immunosuppressive therapy, and survival outcomes in patients with STAT3 mutation. Among the 81 LGLL - associated PRCA patients, 21 cases (26%) were STAT3 mutant, and 60 were wild - type. Of 21 patients with STAT3 mutation, 15 cases (71%) were positive for exon 21 mutation, 4 cases (19%) for exon 20 mutation, one for dual mutation in exon 20 and 21, and one for exon 13 mutation. The Y640F was the most commonly detected mutation (42.9%). Patients with STAT3 mutations had a higher percentage of reticulocytes (0.88% vs. 0.28%, P = 0.039) and red cell distribution width - coefficient of variation (18.8% vs. 15.8%, P = 0.008) compared to wild - type. Those with the STAT3 Y640F mutation had a younger median age at onset (44 years vs. 65 years, P = 0.007) and a higher peripheral blood lymphocyte ratio (63.7% vs. 34.4%, P = 0.033). The complete response rate (CRR) and overall response rate (ORR) of STAT3 mutated patients treated with cyclosporine (CsA) were 31.3% (5/16) and 56.3% (9/16), respectively, with no difference compared to the STAT3 wild - type (32.8%, 50%) (P = 0.909; P = 0.658). Although no statistical significance was found, the CRR and ORR of the CP regimen (consisted of cyclophosphamide and prednisone) were higher than CsA among STAT3 mutated individuals (53.8% vs. 31.3%, P = 0.274; 84.6% vs. 56.3%, P = 0.130). Reduction or discontinuation of immunosuppressive agents was the main cause of relapse. The relapse rate of the CP regimen was lower than CsA in this whole cohort (24.0% vs. 68.4%, P = 0.001), as well as in the STAT3 mutant group (18.2% vs. 77.8%, P = 0.022). STAT3 Y640F was the most common hotspot mutation in LGLL - associated PRCA. Patients with STAT3 mutation treated with CsA showed comparable responses to wild - type. CP regimen had a lower relapse rate and could be considered as a salvage therapy after CsA failure.