A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.
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.
Osunkwo
Ifeyinwa
I
Department of Pediatrics, Children's Hospital of New York-Presbyterian, Columbia University, New York, New York, USA.
Bessmertny
Olga
O
Harrison
Lauren
L
Cheung
Ying-Kuen
YK
Van de Ven
Carmella
C
del Toro
Gustavo
G
Garvin
James
J
George
Diane
D
Bradley
M Brigid
MB
Wolownik
Karen
K
Wischhover
Cheryl
C
Levy
Joseph
J
Skerrett
Donna
D
Cairo
Mitchell S
MS
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D006402:Hematologic Diseases / Q000628:therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007223:Infant; D008297:Male; D008059:Mucopolysaccharidosis I / Q000628:therapy; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D009447:Neuroblastoma / Q000628:therapy; D010865:Pilot Projects; D011379:Prognosis; D033581:Stem Cell Transplantation; D016559:Tacrolimus / Q000008:administration & dosage*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus