Impacto clínico de la distribución de las poblaciones linfocitarias en el inóculo y en sangre periférica post-trasplante alogénico de progenitores hematopoyéticos

Resum

In the initial phase of immunological reconstitution after allogeneic haematopoietic stem cell transplantation (allo-HSCT), persistent expansions of cytotoxic T lymphocytes (CTLe) have been detected, which in most cases were considered a physiological response, although the description of cases of large granular lymphocyte (LGL) leukemia creates uncertainty. On the other hand, the use of peripheral blood (PB) grafts has replaced bone marrow when treating patients with malignancies, although it is associated with an increase in graft-versus-host disease (GVHD). Various infused graft cell populations have been associated to the development of GVHD. In a different setting, according to Kariminia et al., a higher proportion of Natural Killer (NK) CD56bright cells is related to a lower rate of chronic GVHD. The analysis of the main immune populations in PB during the post-transplant period, and in the infused graft allowed us to study the clinical impact of the CTLe and validate the recent communication of the predictive value of the NK CD56bright cells compartment of the infused graft. In order to discern the clinical impact of CTLe, we included 154 patients characterized by a mean age of 42 years, male predominance and similar proportion among those who had received reduced or myeloablative intensity conditioning regimen. For the clinical analysis we established two definitions of CTLe: relative CTLe, defined by ratio between CD8+/CD4+ T cells greater than 1,5; and absolute CTLe, characterized by a number of CD8+ T cells greater than 2 x 109/L. In both scenarios, the condition must persist for, at least, 6 months. Relative CTLe were detected in 75 of the 154 patients, characterized by an older age, having received reduced intensity conditioning, antithymocyte globulin for GVHD prophylaxis, an unrelated donor, a cytomegalovirus reactivation and the diagnosis of severe acute GVHD. A group of 14 patients developed absolute CTLe, which was significantly associated with the development of moderate and severe chronic GVHD. None of the patients with absolute CTLe relapsed, while 31 patients (22%) without this type of expansion did. The absolute CTLe shows an homogemeous pattern: increasing between days +30 and +100, keeping this dynamic until a year in most cases (92%), when they began to decrease. The absence of clinical impact of the relative or absolute CTLe on the potential development of (LGL) leukemia, and the absence of somatic mutations in exon 21 of the STAT3 gene, supports their physiological nature. Regarding the study of the impact of the NK CD56bright cells, patients undergoing allo-HSCT in our center were included if they had a flow cytometry quantitative determination of lymphocyte subpopulations in the infused graft, the donor mobilization included G- CSF and the infused graft was unmanipulated. Two cohorts were differentiated for independent analysis. One ruled out those patients with unrelated donor allo-HSCT, haploidentical and/or who had died before the +100 day (Kariminia et al. criteria). This cohort was finally composed of 104 patients. Two variables, the percentage of CD56bright NK cells and gender disparity, showed a prognostic independence of the development of severe GVHD (RR of 3,2 and 2,5 respectively). In the global cohort of 207 patients, three variables were related to the RR of suffering a severe GVHD: percentage of NK CD56bright cells, gender disparity and HLA identity. To conclude, our experience has allowed us to confirm the benign nature of the CTLe in our cohort of patients undergoing allo-HSCT and their relationship with the development of GVHD. We also restate the significant relationship of a lower proportion of NK CD56bright cells in the PB graft mobilized with G-CSF and the development of severe GVHD in the context of donor related allo-HSCT and, in addition, its prognostic independence from other factors, immune subpopulations and clinical variables, which have been recurrently associated with chronic GVHD.