Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT₃₈₈GMCSF) for refractory or relapsed acute myeloid leukemia

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)₃₈₈granulocyte-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 DT₃₈₈fused 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 μg/kg/day. The dose-limiting toxicity was liver injury and occurred at the 4.5-5-μg/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-1β, IL-6, IFNγ macrophage inflammatory protein-1α, tumor necrosis factor α 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 μg/kg/day and 8 (40%) of 20 patient courses at 4-5 μg/kg/day showed marrow blast reductions at day 12. Patients with higher pre-treatment 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.