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Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network.

ABSTRACT: There are limited data as to the effectiveness of mycophenolate mofetil (MMF) plus high-dose corticosteroids for the treatment of acute graft-versus-host disease (aGVHD), and even less data regarding the pharmacokinetic disposition and exposure-response relationship of MMF in individuals with GVHD. MMF pharmacokinetics were studied in a multicenter Blood and Marrow Transplant Clinical Trials Network randomized phase II trial evaluating the effectiveness of MMF as one of 4 agents added to corticosteroids as treatment of aGVHD. Thirty-two of the patients randomized to receive MMF underwent pharmacokinetic sampling in weeks 1 and 2 were studied. Mean age was 41 +/- 13.6 years. Twenty one (65.6%), 5 (15.6%), 6 (18.8%) patients had a complete response (CR), partial response (PR) or lesser response by day 28, respectively. Twenty-five (78.1%), 2 (6.3%), 5 (15.6%) patients had a CR, PR, or other response by day 56 to treatment, respectively. Mycophenolic acid (MPA) pharmacokinetic measurements from weeks 1 and 2 did not correlate with CR at either day 28 or day 56 (P > .07); however, if the mean of weeks 1 and 2 total MPA troughs was >0.5 microg/mL or that of an unbound trough was >0.015 microg/mL, then a significantly greater proportion achieved CR + PR at days 28 and 56. CR + PR at day 28 was observed in 19 of 19 patients (100%) with a mean total trough >0.5 mg/mL, but in only 7 of 13 (54%) with a mean total trough < or =0.5 microg/mL (P = .002). Similarly, CR + PR at day 28 was seen in 15 of 15 patients (100%) with an unbound trough concentration >0.015 microg/mL, but in only 11 of 17 (65%) with an unbound trough concentration < or =0.015 microg/mL (P = .02). There was no association between the pharmacokinetic measures and risk of infection by day 90 or overall survival (OS) at day 180 postrandomization. About one-half of subjects did not achieve the favorable MPA total and unbound trough concentrations. The current practice of MMF 1 gm twice daily dosing provides low plasma concentrations in many patients. Higher doses may improve the efficacy of MMF as aGVHD therapy.

SUBMITTER: Jacobson PA

PROVIDER: S-EPMC3104501 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network.

Jacobson Pamala A PA Huang Jiayin J Wu Juan J Kim Miae M Logan Brent B Alousi Amin A Grimley Michael M Bolaños-Meade Javier J Ho Vincent V Levine John E JE Weisdorf Daniel D

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20100301 3

There are limited data as to the effectiveness of mycophenolate mofetil (MMF) plus high-dose corticosteroids for the treatment of acute graft-versus-host disease (aGVHD), and even less data regarding the pharmacokinetic disposition and exposure-response relationship of MMF in individuals with GVHD. MMF pharmacokinetics were studied in a multicenter Blood and Marrow Transplant Clinical Trials Network randomized phase II trial evaluating the effectiveness of MMF as one of 4 agents added to cortico ...[more]

PMID: 19925875

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Project description:Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.

Dataset Information

Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network.

Publications

Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network.

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