Expansion of Large Granular Lymphocytes Following Allogeneic Stem Cell Transplantation: Its Association with Graft-Versus-Host Disease and Graft-Versus-Leukemia Effect.

Expansion of large granular lymphocytes (LGLs) following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported infrequently, and data from large scaled population is still lacking. Expansion of LGLs following HSCT has been suggested to be associated either with the development of graft-versus-host disease (GVHD) associated with graft-versus-leukemia (GVL) effect or with viral infection such as CMV or VZV reactivation.

A total of 500 consecutive patients who received HSCTs from related or unrelated donors between January 2000 and October 2007 at the Princess Margaret Hospital, Toronto, Canada were included in this retrospective study. LGL expansion has been defined as 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. Cases with LGL expansion were investigated prospectively for immunophenotypic profiles and T-cell receptor RT-PCR for T-cell monoclonality.

Out of 500 recipients, 77 cases (15.4%) showed LGL expansion after HSCT. The median onset of LGL expansion was 312 days (95% C.I. 233-390 days). The 1-, 2- and 3-year(s) incidence of LGL expansion was 12.8±1.8%, 20.6±2.4%, and 25.7±2.9%, respectively. Compared to the patients without LGL expansion, improved transplant outcomes were observed in patients with LGL expansion: better overall survival (OS; 90% vs 46%, p<0.001), lower non-relapse mortality (NRM; 3% vs 38%, p<0.001), lower relapse incidence (10% vs 31%, p<0.001) and higher GVHD-specific survival (GSS; 97% vs 64%, 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 CMV seropositive recipients (CMV-R+) compared to CMV seronegative recipients (CMV-R^-) regardless of CMV serostatus of the donor (p<0.001); 2) in patients experiencing CMV reactivation (p<0.001); 3) in patients developing chronic GVHD (p=0.007).

Of interest, when dividing patients according to the recipient's CMV serostatus and the occurrence of chronic GVHD, the group with CMV-R⁺ and cGVHD⁺ showed the highest incidence of LGL expansion up to 46%, while those with CMV-R^- and cGVHD⁺ showed intermediate risk of LGL expansion with 25% incidence, and those with CMV-R⁺/cGVHD^- or with CMV-R^-/cGVHD^- showed only 3-6% incidence of LGL expansion.

Expansion of LGLs following allogeneic HSCT is not uncommon, and strongly associates with favorable transplant outcomes including a lower relapse rate suggesting that LGLs may be involved in the mediation of a GVL effect.

No relevant conflicts of interest to declare.