Schwartz Stefan, Borner Klaus, Müller Krystina, Martus Peter, Fischer Lars, Korfel Agnieszka, Auton Timothy, Thiel Eckhard
Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Oncologist. 2007 Nov;12(11):1299-308. doi: 10.1634/theoncologist.12-11-1299.
Leucovorin and extracorporeal removal of methotrexate (MTX) have limited efficacy in delayed MTX elimination after high-dose methotrexate (HD-MTX) therapy. Glucarpidase (carboxypeptidase G2) cleaves MTX into nontoxic metabolites, but experience with this enzyme is limited in adult patients. We evaluated the effects of glucarpidase intervention in adult and elderly patients with delayed MTX elimination.
Forty-three patients (age, 18-78 years) with MTX serum concentrations (sMTX) of 1-1,187 micromol/l received glucarpidase, leucovorin rescue guided by MTX immunoassay, and standard supportive care. MTX and MTX metabolites were quantified in serum (24 patients) and urine (8 patients) by high-performance liquid chromatography. Contributory risk factors, toxicities, and survival were recorded in all patients.
Glucarpidase was well tolerated and resulted in an immediate >97% reduction in sMTX, with a 0.2%-35% urinary recovery of the total MTX dose as inactive MTX metabolites. Forty (93%) of 43 patients had normalization (n = 25) or improvement (n = 15) of their serum creatinine. Frequent grade III-IV MTX toxicities were hematological (60%) and mucositis (35%); only eight (19%) patients developed grade III-IV nephrotoxicity. Ten (23%) of 43 patients experienced fatal complications associated with HD-MTX therapy. Patients with three or more contributory risk factors for delayed MTX elimination had a significantly poorer survival than patients with fewer than three risk factors (hazard ratio, 3.64; confidence interval, 1.14-17.54).
Glucarpidase is well tolerated and produces a rapid inactivation of substantial amounts of MTX. However, overall results are still unsatisfactory in adult and elderly patients, suggesting that earlier recognition of delayed MTX elimination and more rapid intervention are needed.
在大剂量甲氨蝶呤（HD-MTX）治疗后甲氨蝶呤（MTX）消除延迟的情况下，亚叶酸钙和MTX的体外清除疗效有限。羧肽酶G2（葡糖醛酸酶）可将MTX裂解为无毒代谢产物，但该酶在成年患者中的应用经验有限。我们评估了葡糖醛酸酶干预对成年和老年MTX消除延迟患者的影响。
43例患者（年龄18 - 78岁），血清MTX（sMTX）浓度为1 - 1187微摩尔/升，接受了葡糖醛酸酶、基于MTX免疫测定指导的亚叶酸钙解救以及标准支持治疗。通过高效液相色谱法对24例患者的血清和8例患者的尿液中的MTX及其代谢产物进行定量分析。记录所有患者的促成风险因素、毒性反应和生存率。
葡糖醛酸酶耐受性良好，可使sMTX立即降低>97%，作为无活性MTX代谢产物的总MTX剂量的尿回收率为0.2% - 35%。43例患者中有40例（93%）血清肌酐恢复正常（n = 25）或改善（n = 15）。常见的III - IV级MTX毒性反应为血液学毒性（60%）和黏膜炎（35%）；只有8例（19%）患者出现III - IV级肾毒性。43例患者中有10例（23%）发生了与HD-MTX治疗相关的致命并发症。MTX消除延迟的促成风险因素有三个或更多的患者的生存率明显低于风险因素少于三个的患者（风险比，3.64；置信区间，1.14 - 17.54）。
葡糖醛酸酶耐受性良好，可使大量MTX迅速失活。然而，成年和老年患者的总体结果仍不令人满意，提示需要更早识别MTX消除延迟并进行更快速的干预。
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