Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

A total of 50 consecutive patients (median age, 57.5 years) with AML (n ¼ 30) or myelodysplasia (MDS, n ¼ 20) underwent HLA matched related donor (MRD, n ¼ 27) or unrelated donor (MUD, n ¼ 23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n ¼ 19) ± mycophenolate mofetil (n ¼ 31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P ¼ 0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Section: Discussionmentioning

confidence: 87%

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia

Nelson

Schwartz

et al. 2010

“…22,23 Studies on the use of MMF as part of GVHD prophylaxis have been limited in size and mostly inconclusive, as most investigators reported insufficient plasma levels of the active metabolite MPA. [3][4][5]8,24,25 Most of these studies revealed a favorable toxicity profile of combinations of MMF with calcineurin inhibitors compared to regimens incorporating MTX. Encouraging results were reported by Nash et al, 7 who demonstrated that the rate of GVHD Targeting mycophenolate mofetil for GVHD prophylaxis I Haentzschel et al after transplantation from matched-sibling donors could be significantly reduced by using higher MMF doses up to 60 mg/kg daily.…”

Section: Discussionmentioning

confidence: 99%

“…administration in combination with CsA as GVHD prophylaxis after allogeneic blood SCT from HLAcompatible related and unrelated donors. 3,8 No severe side effects and adverse events were observed. Compared to a control group receiving MTX and CsA, we saw no significant differences in the mucosal and intestinal toxicities and in the incidence of acute GVHD.…”

Section: Introductionmentioning

confidence: 99%

Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation

Haentzschel¹,

Freiberg-Richter²,

Platzbecker³

et al. 2008

As low trough levels of mycophenolic acid (MPA) have been measured in recipients of allo-SCTs, we performed a pilot study targeting mycophenolate mofetil (MMF) doses according to the MPA area under the concentration (AUC) levels. Twenty-nine patients were transplanted from matched sibling (n ¼ 7) and unrelated donors (n ¼ 22). Tacrolimus was given orally from day À1 to achieve trough blood levels of 5-10 ng/ml. MMF was started on day 0 at 1500 mg intravenously b.i.d. AUC measurements of MPA by HPLC were scheduled on days 3, 7 and 11 after transplantation. The MMF dose was modified to achieve an MPA AUC of 35-60 lg/ml/h. With the respective adjustments 66 and 75% surpassed the lower AUC target on days 7 and 11, respectively. The cumulative incidence of grade III-IV acute GVHD was 28% (8/29). Eight out of 24 evaluable patients (33%) suffer from limited (n ¼ 3) or extensive (n ¼ 5) chronic GVHD. Overall, the results of this study suggest that targeting of MPA exposure is feasible early after transplantation. A simplified MMF targeting strategy based on MPA C max or C 2h levels seems to be warranted in future trials involving more patients at later time points in the outpatient setting.

“…6 This resulted in MPA concentrations below the therapeutic range recommended for SOT. 7 Furthermore, correlations of MPA plasma concentrations at steady state and AUC with degree of T-cell chimerism 8 and incidence of graft rejection 6,8 have been suggested.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Lange

Mueller

Altmann

et al. 2007

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 lg/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.