Evaluation of Tacrolimus Levels and Risk of Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant

Abstract

Background Achieving therapeutic tacrolimus blood concentrations is crucial for decreasing the risk of developing acute graft-versus-host-disease (aGvHD) in allogeneic hematopoietic stem cell transplant (aHSCT) patients. Studies have suggested that tacrolimus levels in the first 1-2 weeks may affect the risk of aGVHD but therapeutic goals are not well established. This study explores tacrolimus levels and risk of GVHD during that time frame. Methods This study is a retrospective cohort single center chart review performed with 348 consecutive adult patients who received an aHSCT and were followed for at least 100 days post-transplant for aGvHD development. Patients that received a transplant from a cord blood or participated in aGvHD prophylaxis clinical trials were excluded. The primary endpoint was aGvHD grades II - IV incidence. Serum tacrolimus levels were evaluated from days -1 to +100 post-transplant. Serum tacrolimus levels were divided into time intervals of days 0 - 7 and days 0 - 14 post-transplant. Receiver operator characteristic curves (ROC) were used to quantify serum tacrolimus levels as predictors of aGvHD grades II-IV. Using the ROC analysis and Youden's Index, optimal cutpoints in the tacrolimus level distribution for the individual time intervals were assessed. From this, patients were analyzed based on whether they achieved mean tacrolimus serum levels below the cutpoint (low group) or if they achieved a mean tacrolimus level above the cutpoint (high group). Results Within the URD group during days 0-7 post-transplant, the low group and high group demonstrated a mean tacrolimus level of 11.3 and 14.5 respectively, with significantly less aGVHD observed in the high group (38% vs 57.2%, p = 0.021). In respect to days 0-14, the low group and high group demonstrated a mean tacrolimus level of 10.4 and 13 respectively, again with significantly less aGVHD in the high group (35.6% vs 57.3%, p = 0.012). Within the RD group during days 0-7 post-transplant, the low group and high group demonstrated a mean tacrolimus level of 10.9 and 13.7 respectively, also with significantly less aGVHD in the high group (21.7% vs 38.7%, p = 0.042). In respect to days 0-14, the low and high group demonstrated a mean tacrolimus level of 10.2 and 13.1 respectively. However, there was not a significant difference in aGVHD (25.7% vs 35.9%, p = 0.272). Conclusion Higher levels of tacrolimus in the first 2 weeks after allogeneic stem cell transplant appear to correlate with a lower incidence of grade II-IV aGVHD. Higher levels in both weeks 1 and 2 were associated with a 37% reduction in the URD group while higher levels in week 1 were associated with a 44% in the RD group. While larger studies would help to clarify more specific ranges, this data suggests that target tacrolimus levels should be 14-15 ng/ml in the first 2 weeks post allogeneic transplant to decrease rates of grade II-IV aGVHD.