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Phase I Trial of a Novel Diphtheria Toxin/Granulocyte Macrophage Colony-stimulating Factor Fusion Protein (DT₃₈₈GMCSF) for Refractory or Relapsed Acute Myeloid Leukemia¹

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157 [A. E. F., B. L. P., L. D. C.]; Medical University of South Carolina, Charleston, South Carolina 29425 [P. D. H.]; and Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892 [R. J. K.]

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 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-1ß, IL-6, IFN, macrophage inflammatory protein-1, tumor necrosis factor 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 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.

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