title: Differentiation therapy in poor risk myeloid malignancies: Results of a dose finding study of the combination bryostatin-1 and GM-CSF.
abstract: OBJECTIVE
  Pharmacologic differentiating agents have had relatively limited clinical success outside of the use of ATRA in acute promyelocytic leukemia and DNA methyltransferase inhibitors in myelodysplastic syndromes. The differentiating effects of such agents can be enhanced in combination with lineage-specific growth factors. We developed a dose finding trial to assess toxicity, differentiating activity, and clinical impact of the combination of bryostatin-1 and GM-CSF.
  
  
  METHODS
  Patients with poor risk myeloid malignancies were eligible to enroll in a dose finding study of continuous infusion bryostatin-1 combined with a fixed dose of daily GM-CSF. Toxicities were graded per NCI CTC version 2.0 and pharmacokinetic and correlative study samples were obtained to assess the combination's clinical and biologic differentiating effects.
  
  
  RESULTS
  Thirty-two patients were treated with the combination therapy and the dose determined to be most suitable for study in a larger trial was continuous infusion broystatin-1 at 16μg/m(2) for 14 days and subcutaneous GM-CSF at 125μg/m(2) daily for 14 days every 28 days. Arthralgias and myalgias limited further dose escalation. Clinically, the combination impacted differentiation with improvement of absolute neutrophil counts (p=0.0001) in the majority of patients. Interestingly, there were two objective clinical responses, including a CR after a single cycle. Both the bryostatin-1 plasma concentrations and the correlative studies supported biologic activity of the combination at the doses where clinical responses were observed.
  
  
  CONCLUSIONS
  Combining growth factors with pharmacologic differentiating agents may increase their clinical effectiveness and further studies should focus on such combinations.
authors.affiliation: Johns Hopkins Medical Institute, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. bdsmith@jhmi.edu
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Eunpi
authors.initials: E
authors.lastname: Cho
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Milada
authors.initials: M
authors.lastname: Vala
authors.forename: Brooke
authors.initials: B
authors.lastname: Meade
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Steven
authors.initials: S
authors.lastname: Piantadosi
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Gideon
authors.initials: G
authors.lastname: Blumenthal
authors.forename: Erica D
authors.initials: ED
authors.lastname: Warlick
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.forename: Anthony
authors.initials: A
authors.lastname: Murgo
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: William H
authors.initials: WH
authors.lastname: Matsui
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D054713:Bryostatins / Q000008:administration & dosage* / Q000627:therapeutic use; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; C046785:bryostatin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor