Thomsen Anna M, Gulinello Maria E, Wen Jing, Schmiegelow Kjeld, Cole Peter D
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
Departments of Pediatrics.
J Pediatr Hematol Oncol. 2018 Mar;40(2):e91-e96. doi: 10.1097/MPH.0000000000000888.
Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 μM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.
脂质体阿糖胞苷目前正在进行临床测试，作为鞘内注射（IT）甲氨蝶呤（MTX）的替代药物，用于预防急性淋巴细胞白血病患者中枢神经系统内的复发。为了比较IT MTX与脂质体阿糖胞苷所引起的毒性和认知缺陷，对幼年Long Evans大鼠进行如下处理：在8天内鞘内注射1mg/kg×4剂量的MTX，或单次注射0.8mg脂质体阿糖胞苷。给药后2周，脑脊液中游离阿糖胞苷的平均浓度保持在0.4μM的细胞毒性阈值以上。注射脂质体阿糖胞苷的动物在注射后4周表现出正常的识别和空间记忆。相比之下，接触IT MTX会导致认知功能受损。此外，与脂质体阿糖胞苷治疗的动物（39.5%；95%置信区间，38.4%-40.6%；n=6）相比，MTX治疗的动物在第11天的平均血细胞比容显著更低（30.8%；95%置信区间，27.0%-34.7%；n=6；P<0.0001）。我们的数据表明，与IT MTX相比，脂质体阿糖胞苷引起的神经认知缺陷和急性血液学毒性更少。因此，如果脂质体阿糖胞苷在预防复发方面同样有效，那么它可能比IT MTX具有治疗优势。
