Frankel Arthur E, Powell Bayard L, Hall Philip D, Case L Douglas, Kreitman Robert J
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, USA.
Clin Cancer Res. 2002 May;8(5):1004-13.
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.
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.
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).
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.
复发或难治性急性髓系白血病患者预后较差。我们测试了一种针对白血病原始细胞中高表达的粒细胞巨噬细胞集落刺激因子（GMCSF）受体的白喉融合蛋白[白喉毒素（DT）388-粒细胞巨噬细胞集落刺激因子（GMCSF）]的安全性和有效性。
在一项患者间剂量递增试验中，通过静脉输注15分钟，每日一次，持续5天，给予含有与人类GMCSF融合的DT388催化和转位结构域的DT388GMCSF融合蛋白。
最大耐受剂量为4μg/kg/天。剂量限制性毒性为肝损伤，发生在4.5 - 5μg/kg/天的剂量水平。在这些剂量下接受治疗的9名患者中，1名患者发生肝衰竭，1名患者出现短暂性肝性脑病。血清DT388GMCSF峰值水平与血清天冬氨酸转氨酶之间存在正相关（P = 0.0002）。DT388GMCSF在体外不损伤肝细胞系；然而，DT388GMCSF在体外可结合巨噬细胞并诱导细胞因子释放。在接受治疗的患者中，我们观察到血清白细胞介素（IL）-18水平早期升高，IL-8水平后期升高，但IL-1β、IL-6、IFNγ、巨噬细胞炎性蛋白-1α、肿瘤坏死因子α或IL-12无显著变化。IL-18升高发生在肝酶升高之前，并与天冬氨酸转氨酶峰值水平相关（P = 0.005）。在31名对化疗耐药的患者中，1名患者完全缓解，2名患者部分缓解；所有这3名患者均接受了等于或高于最大耐受剂量的治疗，所有3名有反应的患者基线骨髓原始细胞百分比均<30%，而在28名无反应的患者中只有6名患者骨髓原始细胞少于30%。这6名患者中有5名接受了低于治疗剂量的治疗。在<4μg/kg/天的19个患者疗程中有8个（42%），在4 - 5μg/kg/天的20个患者疗程中有8个（40%）在第12天显示骨髓原始细胞减少。预处理时抗DT388GMCSF水平较高的患者DT388GMCSF峰值水平显著较低（P = 0.0001）。
DT388GMCSF可使化疗耐药的急性髓系白血病患者获得完全缓解和部分缓解，但在更广泛应用这种新型药物之前，需要采取预防肝损伤的方法。
