The Impact of Subtherapeutic Tacrolimus Levels on the Incidence of Acute Graft-Versus Host-Disease (aGVHD) in Children Following Allogeneic Hematopoietic Cell Transplantation (AlloHCT) – Redefining the Target Range

In an adult study, Nash et al. (Blood, 2000) recommended to maintain tacrolimus levels between 10-20ng/ml for aGVHD prophylaxis. The optimal range for tacrolimus levels in children post-AlloHCT is not well defined. We studied the impact of mean tacrolimus levels and number of days with subtherapeutic tacrolimus levels on the incidence of aGVHD.

One-hundred eight patients received tacrolimus/ mycofenolate mofetil (MMF) for aGVHD prophylaxis between March 2005 and April 2012. Median age, 8 yrs; 37F/71M, malignant (n=61) and nonmalignant (n=47) disorders. Stem cell source: 18 peripheral blood stem cell donors, 49 bone marrow donors, and 41 unrelated cord bloods.  Patients were conditioned with myeloablative (45.4%), reduced toxicity (28.7%), or reduced intensity (25.9%) regimens. Additionally, 30 patients received alemtuzumab (27.8%) and 54 patients received rabbit-ATG (50%). Tacrolimus was initiated at 0.03 mg/kg/d via continuous IV infusion or 0.12mg/kg/d PO, and dose was adjusted to maintain daily steady state concentration or trough levels within 10-20 ng/mL. 

The overall incidence of aGVHD was 45.4%.  Age, gender, ethnicity, non-malignant/malignant diseases, related/unrelated donors, HLA matching, donor source, conditioning regimen, alemtuzumab, r-ATG, and mean tacrolimus levels <15 ng/mL during each of 4 weeks post-AlloHCT, were examined as potential risk factors for aGVHD.  Malignant disease was the only significant risk factor observed (OR 5.41, 95% CI 2.31-12.67, p =0.0001). 

Mean weekly tacrolimus levels < 15 ng/mL were not significantly associated with incidence of aGVHD (p=0.705, p=0.879, p=0.952, p=0.524) and mean levels < 10ng/mL as suggested by Ram et al. (BBMT, 2012) were also not significant. The number of days with subtherapeutic tacrolimus levels (< 10 ng/mL) during the first 4 weeks post-AlloHCT (median = 10d) revealed no significant association between > 10d of subtherapeutic tacrolimus levels and incidence of aGVHD (p=0.49). Further analysis of patients with subtherapeutic levels > 3 days per week or > 14 days over 4 weeks were also not significant.  Risk factor analysis for subtherapeutic tacrolimus levels demonstrated that an increase in  serum creatinine levels by 50% during the 3^rd  and 4^th  weeks post-AlloHCT was significantly associated with > 10 days of subtherapeutic tacrolimus levels (p=0.005, p=0.01), as doses were lowered in response to impending renal insufficiency.

Our results suggest that while prophylactic tacrolimus /MMF is effective in preventing aGVHD, maintaining levels as high as 10-20 ng/mL may not be necessary.  It may be possible to tolerate more subtherapeutic days in the first month post-AlloHCT without increasing the risk of aGVHD. Further studies are necessary to determine an appropriate lower target range for tacrolimus to reduce incidence of aGVHD while preventing additional immune-suppression and other toxic effects.