Close Monitoring of Cyclosporine A Concentration as a Means of Preventing Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Recipients

Introduction

The concentration of cyclosporine A (CsA) after allogeneic stem cell transplantation has been reported to be important in prevention of acute graft versus host disease (aGVHD). The target concentration and method of monitoring CsA concentration varies between transplant centers. More knowledge is needed to tailor the intensity of post transplant immunosuppression in relation to the risk of aGVHD, disease relapse and nephrotoxicity,

Methods

We retrospectively analyzed data from 48 adult patients, who consecutively underwent myeloablative allogeneic stem cell transplantation in the years 2010 and 2011 at Rigshospitalet, Copenhagen. Transplant indications were AML (n=18), ALL (n=14), MDS (n=3), SAA (n=6), MM (n=2) and other (n=5). Whole blood concentration of CsA was measured once daily 8 hours after the administration of CsA. The median CsA concentration in weeks 1 to 4 was calculated, and patients were divided into two equally sized groups according to the median CsA concentration. Renal impairment was defined as doubling of serum creatinine during the first 28 days after transplantation. Comparison of groups with or without aGVHD grade II or more was done using the chi square test for categorical variables. Variables with a p<0.1 were further analyzed using multivariate logistic regression. Probability of developing aGVHD was calculated using the cumulative incidence procedure with death as competing event.

Results

The median concentrations of CsA in each of the first 4 weeks after transplantation are shown in figure 1. The proportion of patients with aGVHD grade II-IV was higher in those with CsA levels below the median 2 weeks after transplantation (p=0.019). This association was also found when assessing the cumulative incidence of aGVHD with death as competing event (p=0.012, figure 2), and furthermore remains significant in multivariate analysis after adjusting for donor relation, TBI and donor sex. All cases of aGVHD (n=20) occurred after 2 weeks from time of transplantation. CsA levels at week 1, 3 and 4 did not affect the risk of aGVHD. Importantly, CsA levels were not correlated with excess risk of developing renal impairment. No relation was found between CsA levels and death from relapse (P=0.73).

Conclusion

This study indicates a close relationship between the concentration of CsA in the early post-transplant period and development of aGVHD grade II or more. Nephrotoxicity was not an obstacle for achieving higher concentrations of CsA. Therefore, close monitoring of the CsA concentration in the early transplant period is important in maintaining CsA within target concentration and thus preventing development of aGVHD. Target concentration of CsA early in the post transplant course should possibly be adjusted to higher levels than we observed in this series of patients.

Figure 1

Figure 2

Cumulative incidence of aGVHD (1) and death (2) for groups with high and low CsA