• Hematologic and nonhematologic toxicities as measured by NCI CTC v2.0 (Phase I) [ Designated as safety issue: Yes ]
  
• Maximum tolerated dose of tretinoin when administered with decitabine as determined by NCI CTC v2.0 (Phase I) [ Designated as safety issue: Yes ]
  
• Clinical remission rate (complete and partial remission) (Phase II) [ Designated as safety issue: No ]
  
• Rate of hematologic improvement as measured by responding cell lines (erythroid, platelet, and neutrophil response) (Phase II) [ Designated as safety issue: No ]
  

• Change in bone marrow function as measured by frequency of transfusion, bleeding, and infection as well as changes in bone marrow morphology and cytogenetics [ Designated as safety issue: No ]
  
• Differentiation as measured by morphology and flow cytometry and apoptosis as measured by flow cytometry [ Designated as safety issue: No ]
  
• Gene expression changes as measured by Affymetrix gene profiling studies [ Designated as safety issue: No ]
  
• Demethylation of specific genes as measured by gene promoter methylation studies [ Designated as safety issue: No ]
  
• Correlation of clinical response, with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Determine the hematologic and nonhematologic toxicities of decitabine in combination with tretinoin in patients with myelodysplastic syndromes. (Phase I)
• Determine the maximum tolerated dose of tretinoin when administered with decitabine in these patients. (Phase I)
• Determine the clinical remission rate (complete and partial remission) in patients treated with this regimen. (Phase II)
• Determine the rate of hematologic improvement in these patients. (Phase II)

Secondary

• Determine the efficacy of this regimen, in terms of improved bone marrow function, by monitoring frequency of transfusion, bleeding, and infection, as well as changes in bone marrow morphology and cytogenetics in these patients.
• Assess differentiation by morphology and flow cytometry and apoptosis by flow cytometry in patients treated with this regimen.
• Determine if gene expression changes in these patients are induced by this regimen.
• Determine the efficacy of this regimen, in terms of inducing demethylation of specific genes, in these patients.
• Correlate clinical response with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis.

OUTLINE: This is a phase I, dose-escalation study of tretinoin followed by a phase II, open-label study.

• Phase I: Patients receive decitabine IV over 1 hour once daily on days 1-5 followed by oral tretinoin twice daily on days 10-19. Treatment repeats every 28 days for a minimum of 4 courses in the absence of disease progression or excessive toxicity. Patients who achieve a partial or complete response after completing 6 courses of treatment may receive 4 additional courses up to a total of 10 courses. Patients with stable disease or hematologic improvement are removed from study.

Cohorts of 3-6 patients receive escalating doses of tretinoin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity attributable to tretinoin at any dose level during course 1. A total of 6 patients are treated at the MTD.

• Phase II: Patients receive decitabine as in phase I and tretinoin at the MTD. Patients undergo blood and bone marrow collection periodically during study for correlative demethylation and gene profiling studies and for evidence of differentiation and apoptosis. Samples are examined by flow cytometry, cytogenetics, histochemistry, and polymerase chain reaction-based assays.

After completion of study treatment, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.