Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

Abstract

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.

CsA exposure is associated with acute GVHD and relapse in children after SCT

“…In accordance with reports from others, [14][15][16][17][18] we observed a relationship between CsA trough levels and acute GVHD. However, the AUC did not show any correlation with occurrence of acute GVHD.…”

“…Several investigators have recognized CsA exposure in the early post transplantation period as a risk factor for the development of acute GVHD. [14][15][16][17][18] In children, after HSCT, a CsA trough level lower than o85 mcg/l during the first 2 weeks post transplantation was associated with severe acute GVHD. 15 Using trough levels as a reflection of CsA exposure has the advantage that it is practical.…”

Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model

“…Low exposure to immunosuppressant drugs is one of the risk factors for developing aGVHD. In the early phase following HSCT, it is important to determine the optimal dose of cyclosporin to achieve and maintain the target blood concentration because of the important link between cyclosporin exposure and aGVHD incidence: a negative relationship was found (5)(6)(7)(8)(9)(10)(11). A positive impact of a monitoring cyclosporin regimen on aGVHD incidence and outcome was also demonstrated (12,13).…”

Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

“…Failure or delay to reach target levels can result in both serious immunologic hazards such as GvHD or poor engraftment and toxicities like kidney injury, hypertension, hyperglycemia, CNS toxicities or infectious complications although some of them may occur at therapeutic levels [15,[172][173]. Some of these adverse effects reviewed in Table 3 from a PK point of view.…”