Large Granular Lymphocytosis and Its Impact on Long Term Clinical Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: 14-Year Follow-up Data

Introduction Several studies have attempted to describe the characteristics associated with Large granular lymphocytosis (LGL) lymphocytosis following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its clinical significance. The aim of current study to define the cumulative incidence of LGL lymphocytosis, to identify associations with transplant-related clinical parameters and to assess the impact on transplant related outcomes. Patients and Methods During a 14-year follow up period (2005-2017) in this unicentric cohort study, we identified 19 patients (2.8%) with a significant LGL lymphocytosis, among 667 consecutive adult patients who underwent allo-HSCT. Results A total of 19 (Female/ male: 10 [52.6 %]/ 9 [47.4 %]) patients included into the study met the morphological criteria for LGL lymphocytosis. The median onset of LGL lymphocytosis was 11.5 (2.1- 55.7) months and median lymphocyte count at the time of diagnosis of LGL lymphocytosis was 5400/ mL (5170- 8700/ mL). None of the patient showed palpable splenomegaly, and none of them had typical signs or symptoms of an autoimmune disease. GvHD, viral infections, disease relapse and loss of donor chimerism were excluded during lymphocytosis. Flow cytometry studies confirmed a T cell phenotype of LGLs in the majority of patients (n=12). Two patients presented with LGLs consistent with NK cells and seven showed properties of a mixed NK/T-cell lineage. A monoclonal LGL population of T-cell origin was identified in eight (42.1%) of these patients. None of the 19 patients experiencing LGL lymphocytosis had shown unexplained fever, night sweats, weight loss or lymphadenopathy suggestive of lymphoproliferative neoplasms. In subgroup analysis, we compared the OS of monoclonal and oligoclonal LGL lymphocytosis and 1-year-OS was longer but non-significantly in monoclonal LGL lymphocytosis group; 75 ± 1.6% vs. 44.4 ± 2.2%, respectively. Median PFS was 28.8 months in oligoclonal LGL lymphocytosis group and 8.3 months in monoclonal LGL lymphocytosis group but the number of patients in this group does not provide enough statistical power to confirm whether the differences in PFS were statistically significant. At the time of this report, 2 of 3 patients died of TRM (10.5%). Discussion In conclusion, we observed LGL lymphocytosis in 2.8 % of a large cohort of post allo-HSCT survivors. Regardless of clonality, all patients were clinically asymptomatic with respect to LGL lymphocytosis. Our data indicate that, even if monoclonal, post-transplantation LGL expansion may be considered as an expression of chronic stimulation triggered by GVHD or relapse of the disease rather than the result of a malignant transformation. Whether the presence of LGL expansion is the expression of a balanced chronic immune response with a possible effect after allogeneic HSCT should be evaluated in a larger cohort of patients.