Journal
LEUKEMIA RESEARCH
Volume 35, Issue 1, Pages 87-94Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.leukres.2010.06.001
Keywords
Leukemia; Differentiation therapy; Myelodysplastic syndrome; Growth factors; Bryostatin; Drug resistance
Categories
Funding
- Johns Hopkins [U01CA70095, BMT P01CA15396]
- NIH CCSG [P30CA069773]
- Leukemia/Lymphoma Society [6094-10]
- NATIONAL CANCER INSTITUTE [P01CA015396, U01CA070095, R01CA127574, R21CA069773] Funding Source: NIH RePORTER
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Purpose: 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. Experimental design: 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 16 mu g/m(2) for 14 days and subcutaneous GM-CSF at 125 mu g/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. (C) 2010 Elsevier Ltd. All rights reserved.
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