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

Abstract

CsA is commonly used after haematological SCT (HSCT) as GVHD prophylaxis. In solid organ transplantation, area under the blood concentration vs time curve (AUC) correlates with clinical outcome. However, in HSCT, it has not been determined whether the AUC is superior to trough level monitoring to optimize clinical efficacy of CsA therapy. Therefore, the aim of this study was to investigate the relationships between CsA trough levels and/or AUC early after HSCT with clinical outcome. A total of 91 children (1.1-17.3 years) were treated consecutively with HSCT for a haematological malignancy. CsA trough levels were obtained and were used to estimate the AUC, retrospectively, with a NONMEM (Non-Linear Mixed Effects Modelling) method. Subsequently, these exposure parameters were correlated to the occurrence of acute GVHD, relapse risk (RR) and OS. Low CsA trough levels were found to correlate with the occurrence of acute GVHD. In addition, a CsA AUC over 3000 mcg h/l in AML patients was associated with a higher RR and a reduced OS. This was not the case for ALL patients. Thus, monitoring CsA exposure early after HSCT and adjusting the CsA dose to a predefined target trough level and AUC may provide a tool to influence GVHD/GVL balance.

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

“…[8][9][10] It is now generally agreed that CsA trough blood concentration (TBC) is the pharmacokinetic parameter that best correlates with GvHD outcome. 11,12 Nevertheless, there are no data regarding specific values of CsA TBC to target to favor mild aGvHD without increasing the incidence of severe GvHD. Based on our previous experience, we have been performing therapeutic drug monitoring of CsA TBC combined with Bayesian dose adjustment, and targeting relatively low levels in leukemia patients.…”

Development and Validation of Limited Sampling Strategies for Estimation of Cyclosporine Area Under the Concentration–Time Curve in Hematopoietic Stem Cell Transplant Patients

“…23,24 It has also been suggested that monitoring CsA exposure early after hematological SCT and adjusting the CsA dose accordingly may provide a tool to affect GVHD/GVL (graft-versus-leukemia) balance. 25 AUC monitoring can be more feasible by using an LSS that allows AUC to be estimated using a small number of blood samples collected at specific time points .A few reports are available on defining LSSs for the determination of cyclosporine systemic exposure (AUC) in bone marrow transplant patients. 5,11,26,27 In an attempt to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-hour intravenous infusions in allogeneic hematopoietic SCT, Furukawa et al 26 concluded that c 2 h and c 3 h correlated best with AUC 0-12 h .…”

The Negative Impact of Imatinib Mesylate Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia

“…Therefore, monitoring cyclosporine and tacrolimus exposure early after HSCT and adjusting their doses to a prdefined target trough levels and areas under the blood concentration versus time curve may provide a tool to influence GVHD/GVL (graft versus leukemia) balance and clinical outcome. [27][28][29] Imatinib can also interfere with the metabolism of cytotoxic drugs like cyclophosphamide by competing for metabolization by cytochrome P450-3A4. One potential result of such drug interactions could be a higher incidence of extra-medullary toxicities after myeloablative conditioning therapy.…”