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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Clinical Cancer Research|
|State||Published - May 2002|
ASJC Scopus subject areas
- Cancer Research