Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors

Abstract

Summary:In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n ¼ 36), mismatched-related (MMRD) (n ¼ 3) and unrelated donors (UD) (n ¼ 55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42710 and 9077 ng/ml, respectively, in patients with grade II-IV and 0-I aGVHD (P ¼ 0.001). In SCT from UD and MMRD, TBC were 7374 vs 9578 ng/ml (P ¼ 0.284). For TBC 485 ng/ml, no patient developed grade II-IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC o65 ng/ ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD-or MMRD-SCT developed grade II-IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101710 ng/ml, mild: 77711 ng/ml, moderate: 61713 ng/ml, severe: 56715 ng/ml (Po0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT. Bone Marrow Transplantation (2003) 32, 777-784. doi:10.1038/sj.bmt.1704213 Keywords: acute GVHD; stem cell transplantation; cyclosporine; paediatrics; Bayesian modelling Allogeneic stem cell transplantation (SCT) is curative in several malignant haematological diseases, aplastic anaemia, inborn errors of metabolism and immunodeficiencies. Unfortunately, the success of allogeneic SCT is offset by leukaemia relapses and transplant-related mortality (TRM) due to graft-versus-host disease (GVHD), toxicity of the conditioning regimen and infectious complications. Numerous risk factors for the development of acute GHVD (aGVHD) have been identified. 1-4 Even if there have recently been many advances in prophylaxis, aGVHD continues to account for significant morbidity and mortality after BMT. 3,4 Although aGVHD is less frequent 1 and less severe 5 in younger patients than in adults, grade II-IV aGVHD incidence was 35% in paediatric-matched sibling donor-BMT (MSD-BMT), using a fixed cyclosporine A (CsA) dosing regimen. 5 The risk of aGVHD is strongly increased in paediatric unrelated donor-BMT (UD-BMT) requiring intensive immunosuppressive therapy. 6 However, Souillet et al 7 reported only 26% of grade II-IV aGVHD using in vivo T-cell depletion associated with CsA and MTX, despite a majority of HLA-mismatched donors in their cohort.Although aGVHD can result in mortality, the major cause of failure and death following paediatric SCT for malignant disease, is leukaemia relapse: relapse rate (RR) reaches 41% in MSD-BMT using a fixed CsA regimen (3 mg/kg/day intravenously followed by 6 mg/kg/day orally) 8 and 37% in UD...

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

“…Indeed, we previously reported a strong relationship between CsA TBC during the first 2 weeks post-transplantation, and the severity of aGVHD occurring at engraftment. 8 In the present study, CsA TBC were maintained around 120 ng/mL, even if the intraindividual variability of CsA pharmacokinetics might have led to transient lower or higher concentrations. Our results confirm that the cutoff value 120 ng/mL seems the most relevant to target to trigger off a mild aGvHD in both ALL and AML patients.…”

“…15,16 Patients with relapsed ALL were treated according to the risk stratification of BFM relapses protocols. 17 For AML patients in CR1, HSCT was recommended for all patients with monosomy 5 or 7, translocation t(6,9) and mixed lineage leukemia rearrangement, except for translocation t(9,11) with related or unrelated donors, and was performed in other cases with matched sibling donors (MSDs) only, except for patients with translocation t (8,21). 18 All AML relapses were indications to transplant after CR2 was achieved.…”

“…Early post-transplantation exposure to CsA has been related to acute GvHD (aGvHD) severity. [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.…”

Risk factors for acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: retrospective analysis of 73 patients who received cyclosporin A

“…1 Previous studies showed that low trough CsA concentration and reduction to less than 80% of the scheduled CsA dose were associated with the onset of grades II-IV acute GVHD. [2][3][4][5] However, these studies did not clarify fully whether low CsA concentrations, after the start of administration, are associated with the onset. Recent study reported that the incidence of grades II-IV acute GVHD was lower in the patients treated with twicedaily infusion of CsA than in those treated with the continuous infusion.…”

Human herpes virus-6 encephalitis in a paediatric bone marrow recipient: successful treatment with pharmacokinetic monitoring and high doses of ganciclovir

“…Immunosuppressive therapy between BMT day þ 1 and þ 13 consisted only of cyclosporine infusions, with a twice weekly therapeutic drug monitoring (TDM), to keep a trough blood concentration level between 80 and 100 ng/ml. 10 A grade II GVHD occurred on day þ 13 post BMT and it was decided to add corticoid therapy and increase cyclosporine doses (to reach trough blood concentration levels of 150 ng/ml). GVHD was rapidly controlled.…”