Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

Abstract

Large granular lymphocyte (LGL) proliferation typically follows a chronic course during which major features are cytopenia and immune abnormalities. Elevated numbers of LGL were reported in a few cases following allogeneic stem cell transplantation (allo-SCT). In this report, we present a retrospective analysis of LGL cases that occurred following allo-SCT in a cohort of 201 consecutive patients transplanted over a period of 7 years. Six cases were identified and LGL expansion occurred more frequently following a reduced fludarabine and anti-T lymphocyte globulin-based preparative regimen (4 cases/49), than after a conventional myeloablative regimen (2 cases/152). Expansion of LGL was seen between 3 and 15 months following allo-SCT. Hematopoiesis, with mild to severe cytopenia, was a favored target for LGL. Autoimmune manifestations including polyarthritis and hypergammaglobulinemia were also observed. LGL proliferation was observed in the context of chronic antigenic stimulation associated with recurrent viral infections especially CMV. Moreover, five out of these six high risk patients achieved a long-term complete remission concomitant or following LGL expansion. These data suggest that LGL might be a subset of effector lymphocytes which may participate to the graft-versus-tumor effect.

Refining the diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns of antigen expression with T-cell clonality studies

“…Other notable findings were that non-clonal expansions of LGLs were seen more frequently in patients with bone marrow transplantation (P ¼ 0.0059) consistent with previous reported studies. 14,15 In addition, the percentage of LGLs was significantly higher in cases of T-LGL leukemia compared with non-clonal LGL proliferations (26.5 vs 18%; P ¼ 0.01), again in agreement with prior studies. 8 Finally, morphologic features such as size, granularity or homogeneity of the LGL population were unable to stratify cases into clonal T-LGL leukemia vs reactive LGL proliferations ( Figure 1).…”

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

“…Of note, LGL expansions have been associated with long-term remission in leukemic states. 32 Indeed, this favorable outcome also applies to dasatinib-treated patients with monoclonal or oligoclonal LGL expansions (Table 1). [15][16][17] It is tempting to speculate that crossreactive CD8 þ T-cells 35,36 driven by viral recrudescence and fortuitously targeting leukemia-associated antigens, might mediate these beneficial effects.…”

“…Our dasatinib sensitivity studies support this hypothesis (Figure 2 and Supplementary Figure S1). Furthermore, monoclonal or oligoclonal LGL expansions have been described in states of reduced immunity, for example after allogeneic stem cell transplantation, 32 and during chronic viral infections. 33,34 After allogeneic stem cell transplantation, LGL expansions typically occur within 3-15 months and are primarily observed in the context of chronic viral infections.…”

Molecular evidence for repertoire skewing of T large granular lymphocyte proliferation after allogeneic hematopoietic SCT: report of two cases

“…2 Here, both patients experienced unexplained neutropenia persisting for several months; immunology and virology were negative, while the rapid onset of neutropenia after the first administration of Rituximab precluded the diagnosis of the recently recognized syndrome of Rituximab-associated late-onset neutropenia. T-LGL expansions in allo-HCT patients can be monoclonal, 1,4 however, with this monoclonality not translating to an aggressive (that is, malignant) clinical course.…”

“…2 Strong association with viral infections in many cases implicates pathogenetically a chronic antigenic stimulation.…”