Osunkwo Ifeyinwa, Bessmertny Olga, Harrison Lauren, Cheung Ying-Kuen, Van de Ven Carmella, del Toro Gustavo, Garvin James, George Diane, Bradley M Brigid, Wolownik Karen, Wischhover Cheryl, Levy Joseph, Skerrett Donna, Cairo Mitchell S
Department of Pediatrics, Children's Hospital of New York-Presbyterian, Columbia University, New York, New York, USA.
Biol Blood Marrow Transplant. 2004 Apr;10(4):246-58. doi: 10.1016/j.bbmt.2003.11.005.
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.
他克莫司（FK506）/霉酚酸酯（MMF）已被证明是治疗类固醇难治性慢性移植物抗宿主病（GVHD）的有效挽救疗法，但其作为急性GVHD（aGVHD）预防措施的有效性尚不清楚。我们研究了FK506/MMF在预防儿童和青少年异基因造血干细胞移植（AlloSCT）受者发生aGVHD以及避免使用甲氨蝶呤和甲基泼尼松龙方面的安全性和有效性。34例儿童和青少年患者（中位年龄7岁；范围0.5 - 21岁；男24例，女10例）接受了37次AlloSCT，治疗恶性疾病（n = 22）和非恶性疾病（n = 12），接受FK506（通过持续静脉输注，0.03 mg/kg/d）和MMF（每剂量15 mg/kg，口服或静脉注射，每日两次）。干细胞来源包括22例脐带血供者（21例无关供者和1例亲属供者）、6例亲属骨髓供者和9例亲属外周血供者。恶性疾病诊断包括7例急性淋巴细胞白血病、3例急性髓细胞白血病、1例急性早幼粒细胞白血病、2例非霍奇金淋巴瘤、4例霍奇金病、3例慢性髓细胞白血病和2例神经母细胞瘤；非恶性疾病诊断包括2例β地中海贫血、1例镰状细胞病、4例再生障碍性贫血、1例维斯科特-奥尔德里奇综合征、1例黏多糖贮积症I型、2例噬血细胞性淋巴组织细胞增生症和1例骨髓增生异常综合征。发生≥II级aGVHD的概率为45.4%±9.7%（7例亲属骨髓/亲属外周血；5例脐带血），慢性GVHD的概率为38.1%±19.7%。FK506/MMF耐受性良好。3例患者出现III至IV级神经毒性（定向障碍和白质脑病）；4例患者出现III至IV级肾毒性（均接受了伴随的肾毒素）。在+30天前达到目标霉酚酸水平（1.0 - 3.5μg/mL）的患者发生≥II级aGVHD的发生率显著降低（16.7%±15.2%对100%；P <.02）。这些结果表明，FK506/MMF耐受性良好，可能是AlloSCT后一种安全有效的避免使用甲氨蝶呤和甲基泼尼松龙的GVHD预防方案。针对儿童和青少年AlloSCT受者的进一步药代动力学和药效学研究正在进行，以确定MMF的最佳给药剂量。
