Correlation between low CSA plasma concentration and severity of acute GvHD in bone marrow transplantation

Schmidt, Helmut; Ehninger, Gerhard; Dopfer, R.; Blaurock, M; Naumann, Ralph; Einsele, Hermann; Haen, M.; Schüch, K.; Jaschonek, K.; Niethammer, D.; Waller, H. D.

doi:10.1007/bf00320154

Cited by 10 publications

(10 citation statements)

References 14 publications

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“…Yee et al 20 have found a relationship for the week before the onset of aGVHD. According to Schmidt et al, 35 TBC were decreased during the days preceding the onset of severe aGVHD. In the study of Przepiorka, et al, 38 TBC during the second week post transplant were lower in patients developing grade II-IV aGVHD, and according to Santos et al, 41 CsA exposure during the first week is essential.…”

Section: Discussionmentioning

confidence: 94%

“…The first correlation between TBC and aGVHD was established by Gluckman et al 34 but was general, showing only that patients with aGVHD had lower TBC. Other studies showed a lower risk of aGVHD when the CsA trough concentration was greater than 200-350 ng/ml by serum RIA 20,35 or greater than 400 ng/ml by whole blood RIA 36,37 in matched-sibling BMT. Przepiorka et al 38 and Ghalie et al 21 demonstrated a lower risk associated with TBC above 250 ng/ml and 200 ng/ml, respectively, during the first weeks after transplantation.…”

Section: Discussionmentioning

confidence: 97%

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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

Martin

Bleyzac

Souillet

et al. 2003

Bone Marrow Transplant

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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...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

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

Martin

Bleyzac

Souillet

et al. 2003

Bone Marrow Transplant

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“…In the setting of GVHD prophylaxis, a number of authors have demonstrated an inverse relation between trough CsA levels and incidence of GVHD. [31][32][33][34] However, other authors have failed to demonstrate a significant relationship between trough concentrations and aGVHD [35][36][37][38] and conflicting findings have also been reported when studying the association between CsA levels and the risk of nephrotoxicity. [37][38][39] Given that there appears to be a lack of a strong association between trough CsA concentrations and measures of both efficacy and toxicity in the SCT setting, it is instructive to focus on the solid organ transplantation literature, where the issue of how best to monitor CsA has generated significant interest in the past two decades.…”

Section: Pharmacology Of Csamentioning

confidence: 99%

Optimizing the use of cyclosporin in allogeneic stem cell transplantation

Duncan

Craddock

2006

Bone Marrow Transplant

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“…Yet, a relationship between trough CSA concentrations and the incidence of aGvHD has not been consistently demonstrated. 16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Even among those studies that identified a relationship between trough CSA concentration and aGvHD, the trough CSA concentrations reported to be of significance vary widely. Substantive differences have been observed between pediatric HSCT centers in their approach to CSA dosing, 8 and the usefulness of dose adjustment based on trough concentrations continues to be controversial.…”

Section: Introductionmentioning

confidence: 99%

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

Punnett

Sung²,

Price³

et al. 2007

Therapeutic Drug Monitoring

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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.

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Correlation between low CSA plasma concentration and severity of acute GvHD in bone marrow transplantation

Cited by 10 publications

References 14 publications

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

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

Optimizing the use of cyclosporin in allogeneic stem cell transplantation

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

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