title: Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, USA. afrankel@wfubmc.edu
authors: Arthur E
authors: AE
authors: Frankel
authors: Bayard L
authors: BL
authors: Powell
authors: Philip D
authors: PD
authors: Hall
authors: L Douglas
authors: LD
authors: Case
authors: Robert J
authors: RJ
authors: Kreitman
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002648:Child; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy*; D017093:Liver Failure / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010314:Partial Thromboplastin Time; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000139:chemically induced; D013936:Thymidine / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D016207:Cytokines; D004167:Diphtheria Toxin; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D013936:Thymidine