Clinical Relevance Of Large Granular Lymphocyte Expansion Following Allogeneic Hematopoietic Stem Cell Transplantation With HLA Identical Sibling Donors

Large granular lymphocytes (LGLs) are a morphologically distinct but an immunophenotypically heterogeneous set of lymphocytes of activated T- or NK cells that mediate non-MHC-restricted cytotoxicity. LGL expansion following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported although its clinical relevance on transplant outcomes is not clear. Moreover, precipitating factor evoking LGL expansion is unknown. A total of 323 consecutive patients who received allogeneic HSCTs from HLA identical sibling donors between January 2000 and October 2007 at the Princess Margaret Hospital, Toronto, Canada, were included in the retrospective study. The patients' characteristics were: gender (male/female=196/127); median age 49.5 yrs (range 17-71); stem cell source (PBSC/BM=25172); conditioning (myeloablative/reduced intensity=228/95). The definition of LGL expansion is as follows: 1) increasing number of peripheral blood lymphocyte counts≥3.0×109/L for at least 3 months, and 2) the predominance of LGLs in the peripheral blood smears. Out of 323 recipients, 64 cases (19.8%) showed LGL expansion after allogeneic hematopoietic stem cell transplantation (HSCT). The median onset of LGL expansion was 306 days (95% C.I. 205-407 days). The 1- and 2-year(s) incidence of LGL expansion was 14.4±2.2% and 22.0±2.8%. Compared to the patients without LGL expansion, improved transplant outcomes were observed in patients with LGL expansion: better overall survival (2 years OS; 94.8% vs 60.3%, p<0.001), lower non-relapse mortality (2 years NRM; 2.6% vs 23.4%, p<0.001) and lower relapse incidence (5.6% vs 29.5%, p<0.001). Three risk factors were identified for the development of LGL expansion such as CMV serostatus of recipient, CMV reactivation, and occurrence of chronic GVHD. Higher incidence of LGL expansion was noted 1) in recipient CMV IgG (+) group (CMV-R+) compared to CMV-R- group regardless of CMV serostatus of donor (52/193 [27%] vs 11/128 [9%]; p<0.001); 2) in patients experiencing CMV reactivation (43/140 [31%] vs 21/183 [11%]; p<0.001); 3) in patients developing chronic GVHD (61/252 [24%] vs 2/55 [4%]; p=0.02). LGL expansion is not uncommon following allogeneic HSCT with HLA-identical sibling donors, and strongly associates with favorable transplant outcomes esp. in terms of non-relapse mortality. Its association with chronic GVHD suggested that expanded LGLs may mediate GVL effect after allogeneic HSCT.