Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia.
Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia.
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发表时间：
2002-05
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通讯作者：
A. Frankel;B. Powell;P. Hall;L. Case;R. Kreitman
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作者：
A. Frankel;B. Powell;P. Hall;L. Case;R. Kreitman
目的复发或难治性急性髓性白血病患者预后较差。我们测试了白喉融合蛋白[白喉毒素（DT）388粒细胞-巨噬细胞集落刺激因子（GMCSF）]针对白血病母细胞强烈表达的GMCSF受体的安全性和有效性。实验设计DT388GMCSF融合蛋白包含DT388的催化和转运结构域融合到人GMCSF，在患者间剂量递增试验中，每天静脉滴注15分钟，持续5天。结果最大耐受剂量为4 μ g/kg/d。剂量限制性毒性为肝损伤，发生在4.5 ~ 5 μ g/kg/天剂量水平。在接受这些剂量治疗的9名患者中，1名患者出现肝功能衰竭，1名患者出现一过性肝性脑病。血清DT388GMCSF峰值与血清天冬氨酸转氨酶呈正相关（P = 0.0002）。DT388GMCSF对肝细胞无损伤；然而，DT388GMCSF结合巨噬细胞并诱导细胞因子在体外释放。在接受治疗的患者中，我们观察到早期血清白细胞介素(IL)-18水平升高，后来IL-8水平升高，但IL-1 β、IL-6、IFNgamma、巨噬细胞炎症蛋白-1 α、肿瘤坏死因子α或IL-12水平无显著变化。IL-18升高发生在肝酶升高之前，且与天冬氨酸转氨酶峰值相关（P = 0.005）。在31例化疗耐药患者中，1例完全缓解，2例部分缓解；所有3例患者均以或高于最大耐受剂量进行治疗，所有3例有反应的患者的基线骨髓原细胞百分比均<30%，而28例无反应的患者中只有6例骨髓原细胞百分比低于30%。这6名患者中有5名接受了亚治疗剂量的治疗。19个疗程中有8个疗程(42%)<4微克/公斤/天，20个疗程中有8个疗程（40%）4-5微克/公斤/天在第12天出现骨髓母细胞减少。预处理抗DT388GMCSF水平较高的患者，其峰值DT388GMCSF水平显著降低（P = 0.0001）。结论：DT388GMCSF对化疗耐药急性髓系白血病患者可产生完全或部分缓解，但在更广泛地应用这种新型药物之前，还需要预防肝损伤的方法。
PURPOSE Patients with relapsed or refractory acute myeloid leukemia have a poor prognosis. We tested the safety and efficacy of a diphtheria fusion protein [diphtheria toxin (DT)388 granulocyte-macrophage colony-stimulating factor (GMCSF)] directed against the GMCSF receptor that is strongly expressed by leukemic blasts. EXPERIMENTAL DESIGN DT388GMCSF fusion protein containing the catalytic and translocation domains of DT388 fused to human GMCSF was administered in an interpatient dose escalation trial by 15 min i.v. infusion daily for up to 5 days. RESULTS The maximal tolerated dose was 4 microg/kg/day. The dose-limiting toxicity was liver injury and occurred at the 4.5-5-microg/kg/day dose level. Among nine treated patients at these doses, one patient developed liver failure, and one patient had transient hepatic encephalopathy. There was a positive correlation between peak serum DT388GMCSF levels and serum aspartate aminotransferase (P = 0.0002). DT388GMCSF did not damage hepatic cell lines in vitro; however, DT388GMCSF binds macrophages and induces cytokine release in vitro. Among the treated patients, we observed an early elevation in serum levels of interleukin (IL)-18 and a later rise in IL-8 but no significant changes in IL-1beta, IL-6, IFNgamma, macrophage inflammatory protein-1alpha, tumor necrosis factor alpha or IL-12. The IL-18 elevations occurred before elevations of liver enzymes and correlated with peak aspartate aminotransferase levels (P = 0.005). Of the 31 patients who were resistant to chemotherapy, 1 had a complete remission and 2 had partial remissions; all 3 of these patients were treated at or above the maximal tolerated dose, all 3 responding patients had baseline marrow blast percentage of <30%, whereas only 6 of the nonresponding 28 patients had less than 30% marrow blasts. Five of these six patients were treated with subtherapeutic doses. Eight (42%) of 19 patient courses at <4 microg/kg/day and 8 (40%) of 20 patient courses at 4-5 microg/kg/day showed marrow blast reductions at day 12. Patients with higher pretreatment anti-DT388GMCSF levels had significantly lower peak DT388GMCSF levels (P = 0.0001). CONCLUSIONS DT388GMCSF can produce complete and partial remissions in patients with chemotherapy-resistant acute myeloid leukemia, but methods to prevent liver injury are needed before more widespread application of this novel agent.