Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation

Abstract

There is significant variability in the serum concentrations of tacrolimus attained early post-transplant due to drug interactions and genomic variation. We evaluated whether tacrolimus concentrations early post-transplant correlate with incidence of acute graft-versus-host disease in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard prophylaxis with oral tacrolimus and intravenous methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations in the initial 4 weeks post-transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of acute grade 2 – 4 graft-versus-host disease (HR, .90; 95% CI, .84 to .97; P < .01). This association was driven by a lower risk of acute grade 2 – 4 graft-versus-host disease in patients with week 1 tacrolimus concentrations >12 ng/mL (HR .47; 95% CI, .25 – .88; P = .02). Week 1 tacrolimus concentrations were not associated with chronic graft-versus-host disease, relapse, or overall survival. Lower tacrolimus concentrations at weeks 2, 3, and 4 were not associated with a higher incidence of graft-versus-host disease. In summary, we found that higher tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated with significantly reduced risk of acute grade 2 – 4 graft-versus-host disease without increasing risk of relapse.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

“…Tacrolimus has become a cornerstone of the immunosuppressive regimen used to prevent the occurrence of aGVHD post-allogenic HSCT. Studies have shown that achieving target tacrolimus trough concentrations prior to engraftment is a significant predictor of aGVHD [8,43]. Therefore, we hypothesized that clinical and genetic factors that contribute to tacrolimus PK could ultimately impact tacrolimus PD (e.g., aGVHD incidence and severity, and treatment-emergent toxicities like AKI).…”

“…Calcineurin inhibition leads to decreased IL-2 gene transcription and inhibits T cell activation [7]. Moreover, a higher incidence of treatment-emergent nephrotoxicity has been associated with supratherapeutic tacrolimus levels within the first 2 weeks post-transplant [8][9][10][11]. Tacrolimus is characterized by a narrow therapeutic index, and substantial interindividual pharmacokinetic (PK) variability with standard-of-care weight-based dosing [12][13][14].…”

Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications

“…In terms of the relationship between TAC concentrations and time after allo-HSCT, high PTC was a risk factor for TRC-EC only during days 22 to 28, and TAC concentration in other periods, such as MTC during days 0 to 7, was not a significant factor. Ganetsky et al [5] previously reported that higher MTCs (>12 ng/mL) during days 0 to 7 were associated with reduced risk of acute GVHD. However, MTCs during days 8 to 14, 15 to 21, and 22 to 28 were not associated with a reduction of acute GVHD.…”

“…Calcineurin inhibitors such as cyclosporine and tacrolimus (TAC) have been widely used to manage post-transplantation complications but are known to be causes of hypertension, renal failure, hyperglycemia, and encephalitis. Higher blood levels of TAC would be expected to reduce the risk of GVHD [5]. On the other hand, some reports have shown that TAC may increase the risk of endothelial damage in allo-HSCT as well as in organ transplants [6À10].…”

The Hematopoietic Cell Transplant Pharmacist: Roles, Responsibilities, and Recommendations from the ASBMT Pharmacy Special Interest Group

“…Immunosuppressants are used for prevention and treatment of graft-versus-host disease (GVHD), several of which (sirolimus, CNIs) have a narrow therapeutic window. Maintaining adequate blood concentrations of these medications has been shown to reduce the incidence of GVHD and drugrelated toxicities [11][12][13]. Serum trough concentrations are measured frequently in the peritransplant period, sometimes up to 3 to 5 times a week during the pre-engraftment phase and then 1 to 2 times weekly after engraftment.…”