Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan.
Clinical Research Center, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan.
Int J Hematol. 2019 Sep;110(3):355-363. doi: 10.1007/s12185-019-02684-0. Epub 2019 Jun 14.
Individual busulfan (BU) dosing based on pharmacokinetic (PK) data is preferable for hematopoietic stem cell transplantation (HSCT) conditioning, but information on BU PK in infants is scarce. We report BU PK data on HSCT conditioning for infants with KMT2A-gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL). Infants showed wide variation in BU PK indices, such as clearance (CL) and volume of distribution (V) value, which are distributed more widely among those who received oral, rather than intravenous (IV), BU. Because the steady state concentration (C) fluctuates readily in infants, dose re-adjustment based on PK at the initial administration was important even if the initial dose was determined by a PK test. HSCT can be performed safely within the C range of 600-900 ng/mL per dose, although it was difficult to fit within the therapeutic index of BU. The clinical outcome of engraftment, graft-versus-host disease, adverse events, including sinusoidal obstruction syndrome, and survival did not correlate with the BU PK data, which paradoxically suggests that remaining within this C range helped minimize transplant-related toxicities, while securing engraftment in infants with MLL-r ALL.
基于药代动力学（PK）数据的个体化白消安（BU）剂量给药在造血干细胞移植（HSCT）预处理中是优选的，但婴儿 BU PK 的信息却很少。我们报告了 KMT2A-基因重排阳性急性淋巴细胞白血病（MLL-r ALL）婴儿 HSCT 预处理时的 BU PK 数据。婴儿的 BU PK 指数（如清除率（CL）和分布容积（V）值）存在广泛差异，口服 BU 而非静脉内（IV）BU 的婴儿分布更广泛。由于婴儿的稳态浓度（C）容易波动，因此即使初始剂量是通过 PK 试验确定的，在初始给药时根据 PK 进行剂量调整也很重要。在每个剂量 600-900ng/mL 的 C 范围内可以安全地进行 HSCT，尽管这很难符合 BU 的治疗指数。植入、移植物抗宿主病、包括窦状阻塞综合征在内的不良事件的临床结果与 BU PK 数据无关，这矛盾地表明，在此 C 范围内可以帮助最大限度地减少与移植相关的毒性，同时确保 MLL-r ALL 婴儿的植入。
