A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients

Abstract

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.

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

“…Both groups concluded that the combination was effective and safe. 29,30 Retrospective comparisons revealed that the rate of acute GVHD was at least comparable to standard CYA/MTX.…”

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease

“…infusion or 0.12 mg/kg orally (PO) twice a day was started (dose adjusted to maintain blood levels of 10-20 ng/mL) on day − 8. 19 MMF was administered at 900 mg/m 2 q6-8 h PO or i.v. starting on day +1.…”

“…19,20 MMF was tapered if patients had ⩽ grade II aGVHD on day +180 and tacrolimus was tapered upon conclusion of the MMF taper. 19,20 aGVHD and chronic GVHD (cGVHD) were graded according to Seattle consensus criteria. 21 Supportive care and infection prophylaxis Sargramostim (250 μg/m 2 /day) was started i.v.…”

Twice daily i.v. bolus tacrolimus infusion for GVHD prophylaxis in children undergoing stem cell transplantation

“…tacrolimus in combination with mycophenolate mofetil and 16% in those receiving CSP. 5,21 Only 1 (3%) of our patients developed PRES requiring discontinuation of tacrolimus. One additional patient developed tremors (mild neurotoxicity) associated with tacrolimus; however, this patient did not require discontinuation of the drug.…”

“…administration of tacrolimus. 7,21 Tacrolimus is a proven immunosuppressant effective in the prevention of aGVHD in children. The incidence of aGVHDXGrade II in this study (28%) is similar to the reported incidence of aGVHD in pediatric population using both related and unrelated donors with a variety of GVHD prophylaxis.…”