Insights into Large Granular Lymphocytic Leukemia-Associated Hemolytic Anemia: Clinical Associations, Therapeutic Responses, and Optimal Management Strategies from a Large Institutional Study

Introduction Large granular lymphocytic leukemia (LGLL) is characterized by a clonal proliferation of cytotoxic CD8+ T or CD3− natural killer (NK) cells. The disease typically presents with neutropenia in about 39-62% of patients, and anemia in up to 50% 1. While most cases of anemia in LGLL resemble pure red cell aplasia and present as reticulocytopenic and malproductive, we have also observed rare instances of hemolytic anemia (HA) with a high reticulocyte count. This unique and atypical presentation has prompted us to investigate the clinical features of LGLL with HA, aiming to gain insights into the pathogenesis of both conditions. In light of this, we conducted a comprehensive and systematic study of hemolysis within the context of LGLL. Methods We retrospectively examined clinical and molecular features of a large series of LGLL cases (n=262) diagnosed and managed at the Cleveland Clinic Foundation from 1998 to 2023 to identify those experiencing hemolysis. LGLL diagnosis was based on the presence of i) elevated LGL count (>0.5 × 10^9/L), ii) clonal TCR rearrangement, iii) VB expansion, iv) flow cytometric detection of aberrant CTL or NK cell proliferation and v) STAT3/5 mutation and vi) LGLL infiltration of the marrow. A diagnosis was established with >4/6 criteria fulfilled. HA diagnosis was based on evidence at any time during clinical course of laboratory signs of hemolysis. Results Overall, the median age at diagnosis was 63 years (IQR: 55-72) with a M:F ratio of 0.5. Majority of patients had been diagnosed with T-LGLL (n=225), whereas 22 had NK-LGLL. In 32/262 cases (12%), clinical and laboratory features were asserted to establish the diagnosis of HA. Of these, 22 (68%) had T-LGLL and 8 (25%) had NK-LGLL (Table 1). When comparing HA patients to the rest of the cohort, we observed a higher proportion of NK-LGLL cases with HA (25% vs 8%, p < 0.001). HA presented as the initial sign of the disease in majority of patients (88%), and 40% of them required transfusion support based on the degree of anemia and hemodynamics. The direct anti-globin test was positive in 30% of cases. Warm autoimmune HA (AIHA) was observed in 23% of patients, cold agglutinin disease in 7%, and one patient had both. Among 7 patients with IgG AIHA, 5 were also positive for anti-C3b, C3d antibodies. Two-thirds of the patients had multilineage cytopenia. Coexisting B-cell dyscrasia was identified in 13 cases, more frequently in HA than in those without (40% vs 26%, p=0.048),