Day 15 Interleukin 15 Levels Affect Natural Killer Cell Recovery After Autologous Stem Cell Transplantation

Abstract

Recently, we reported in a prospective study (Porrata et al. Biology of Blood & Marrow Transplantation 2008;14(7):807–16) that the absolute number of natural killer (NK) cells at day 15 post-autologous stem cell transplantation (ASCT) affects survival. Factors affecting NK cell recovery at day 15 post-ASCT are not completely understood. Interleukin-15 (IL-15) is a cytokine associated with NK cell differentiation and homeostasis. Thus, we studied the role of day 15 IL-15 on NK cell recovery post-ASCT. From February 2002 to February 2007, 50 non-Hodgkin lymphoma (NHL) patients enrolled in the study. We identified higher levels of day 15 IL-15 compared with normal controls and pre-ASCT IL-15 levels [normal IL-15 levels: median = 0 pg/ml (range: 0–3.37 pg/ml); pre-ASCT IL-15 levels: median = 0.09 pg/ml (range: 0–229.42 pg/ml); and day 15 IL-15: median = 5.48 pg/ml (range: 0–36.94), p < 0.0001)]. ROC curve and AUC analysis showed that day 15 IL-15 was a significant marker for NK cell recovery (AUC = 0.87, p < 0.0001). The best cutoff level was 9.5 pg/ml. Groups (≤9.5 or >9.5 pg/ml) were balanced in regard to histology (p = 0.48); gender (p = 0.8); stage (p = 0.7); LDH (p = 0.5); disease status prior to ASCT (p = 0.9); performance status (P = 0.1); and extra nodal involvement (p = 0.4). We identified an inverse correlation between day 15 IL-15 and day 15 NK cell recovery (r = −0.5, p< 0.0001). Patients with a day15 IL-15 ≤ 9.5 pg/ml experienced higher numbers of NK cells compared with those with a day 15 IL-15 > 9.5 pg/ml [median 142 cells/μl (range: 10–416 cells/μl) versus median 57.5 cells/μl (range: 28–999 cells/μl), p < 0.001, respectively]. Using logistic regression models, univariately day 15 IL-15 was a predictor for NK cell recovery (p < 0.0003) and multivariately day 15 IL-15 remained a predictor for NK cell recovery (p < 0.0004). To our knowledge, this is the first study showing an association between day 15 IL-15 and NK cell recovery in ASCT. We showed an inverse relationship between day 15 IL-15 and NK cell numbers consistent with a homeostatic association. The data presented here suggest that day 15 NK cell recovery might be driven by the cytokine milieu post-ASCT. Recently, we reported in a prospective study (Porrata et al. Biology of Blood & Marrow Transplantation 2008;14(7):807–16) that the absolute number of natural killer (NK) cells at day 15 post-autologous stem cell transplantation (ASCT) affects survival. Factors affecting NK cell recovery at day 15 post-ASCT are not completely understood. Interleukin-15 (IL-15) is a cytokine associated with NK cell differentiation and homeostasis. Thus, we studied the role of day 15 IL-15 on NK cell recovery post-ASCT. From February 2002 to February 2007, 50 non-Hodgkin lymphoma (NHL) patients enrolled in the study. We identified higher levels of day 15 IL-15 compared with normal controls and pre-ASCT IL-15 levels [normal IL-15 levels: median = 0 pg/ml (range: 0–3.37 pg/ml); pre-ASCT IL-15 levels: median = 0.09 pg/ml (range: 0–229.42 pg/ml); and day 15 IL-15: median = 5.48 pg/ml (range: 0–36.94), p < 0.0001)]. ROC curve and AUC analysis showed that day 15 IL-15 was a significant marker for NK cell recovery (AUC = 0.87, p < 0.0001). The best cutoff level was 9.5 pg/ml. Groups (≤9.5 or >9.5 pg/ml) were balanced in regard to histology (p = 0.48); gender (p = 0.8); stage (p = 0.7); LDH (p = 0.5); disease status prior to ASCT (p = 0.9); performance status (P = 0.1); and extra nodal involvement (p = 0.4). We identified an inverse correlation between day 15 IL-15 and day 15 NK cell recovery (r = −0.5, p< 0.0001). Patients with a day15 IL-15 ≤ 9.5 pg/ml experienced higher numbers of NK cells compared with those with a day 15 IL-15 > 9.5 pg/ml [median 142 cells/μl (range: 10–416 cells/μl) versus median 57.5 cells/μl (range: 28–999 cells/μl), p < 0.001, respectively]. Using logistic regression models, univariately day 15 IL-15 was a predictor for NK cell recovery (p < 0.0003) and multivariately day 15 IL-15 remained a predictor for NK cell recovery (p < 0.0004). To our knowledge, this is the first study showing an association between day 15 IL-15 and NK cell recovery in ASCT. We showed an inverse relationship between day 15 IL-15 and NK cell numbers consistent with a homeostatic association. The data presented here suggest that day 15 NK cell recovery might be driven by the cytokine milieu post-ASCT.