Lee J L, Gooley T, Bensinger W, Schiffman K, McDonald G B
Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Biol Blood Marrow Transplant. 1999;5(5):306-15. doi: 10.1016/s1083-8791(99)70006-6.
The purpose of this study was to determine the incidence of veno-occlusive disease (VOD) after a high-dose regimen of busulfan, melphalan, and thiotepa and the risk factors for a more severe outcome. We followed 253 consecutive patients with malignant disorders who received autologous transplants after stem cell harvest followed by 12 mg/kg busulfan, 100 mg/m2 melphalan, and 500 mg/m2 thiotepa. Diagnosis of VOD was based on weight gain, hepatomegaly, and jaundice. Risk factors for moderate or severe VOD were identified using logistic regression models. VOD occurred in 70 of 253 patients (28%), of whom 31 (12%) had moderate and 11 (4%) severe VOD. The median day of onset of hyperbilirubinemia was day 9, significantly later than the onset of jaundice after our cyclophosphamide-based regimens (p < 0.001). Resolution of weight gain and jaundice, followed by their reappearance several weeks later, occurred in 23 of 70 patients with VOD and was an adverse prognostic sign. Risk factors for moderate or severe VOD were a diagnosis of lymphoma or myeloma (odds ratio [OR] 2.65 compared with breast cancer), tumor involvement in the liver (OR 3.95), fever in the month before transplant (OR 3.32), and prior radiation therapy (OR 2.70). We conclude that VOD after busulfan, melphalan, and thiotepa was less frequent and less severe and developed later than VOD after our historical cyclophosphamide-based regimens. Significant risk factors included a diagnosis other than breast cancer, hepatic metastases, persistent fever, and prior radiation therapy. This study suggests that alkylating agents of comparable overall toxicity differ in their liver toxicity.
本研究的目的是确定在接受大剂量白消安、美法仑和噻替派方案后静脉闭塞性疾病（VOD）的发生率以及出现更严重结局的危险因素。我们对253例连续的恶性疾病患者进行了随访，这些患者在采集干细胞后接受了自体移植，随后接受12mg/kg白消安、100mg/m²美法仑和500mg/m²噻替派治疗。VOD的诊断基于体重增加、肝肿大和黄疸。使用逻辑回归模型确定中度或重度VOD的危险因素。253例患者中有70例（28%）发生了VOD，其中31例（12%）为中度VOD，11例（4%）为重度VOD。高胆红素血症的中位发病时间为第9天，明显晚于我们基于环磷酰胺方案后的黄疸发病时间（p<0.001）。70例VOD患者中有23例出现体重增加和黄疸消退，随后在数周后再次出现，这是一个不良预后征象。中度或重度VOD的危险因素包括淋巴瘤或骨髓瘤诊断（与乳腺癌相比，比值比[OR]为2.65）、肝脏肿瘤累及（OR为3.95）、移植前1个月发热（OR为3.32）和既往放疗（OR为2.70）。我们得出结论，白消安、美法仑和噻替派治疗后的VOD比我们既往基于环磷酰胺方案后的VOD发生率更低、严重程度更低且发病更晚。显著的危险因素包括非乳腺癌诊断、肝转移、持续发热和既往放疗。本研究表明，总体毒性相当的烷化剂在肝脏毒性方面存在差异。
