Phenylbutyrate and Tretinoin in Treating Patients With Hematologic Cancer

OBJECTIVES:

• Determine the safety and toxicity of phenylbutyrate and tretinoin in patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.
• Determine the pharmacokinetic interaction of this regimen in these patients.
• Determine any potential therapeutic activity of this regimen in these patients.

OUTLINE: This is a dose escalation study of tretinoin.

Patients receive phenylbutyrate IV continuously on days 1-7 of weeks 1, 5, 7, 9, 11, 13, 15, 17, and 19. Patients also receive oral tretinoin three times daily on days 1-7 of weeks 3, 5, 7, 9, 11, 13, 15, 17, and 19. Treatment continues in the absence of disease progression or unacceptable toxicity.

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 6 patients experience dose limiting toxicities.

An additional cohort of 6 patients is accrued at the MTD. These patients receive phenylbutyrate IV continuously on days 1-3 of weeks 1 and 3-18. These patients also receive oral tretinoin three times daily on days 1-3 of weeks 2-18. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 3-24 patients will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed myelodysplastic syndrome (MDS)

• Refractory anemia
• Primary refractory leukopenia or thrombocytopenia with morphologic features of MDS
• Refractory anemia with excess blasts (RAEB)
• Refractory anemia with ringed sideroblasts
• RAEB in transformation
• Must have excess blasts or be hematopoietically compromised, defined as one of the following:

• RBC transfusion dependent
• Granulocyte count less than 1,000/mm^3
• Platelet count less than 50,000/mm^3 OR
• Diagnosis of chronic myelomonocytic leukemia

• Hematopoietically compromised (as defined above) OR
• Excess blasts OR
• Evaluable disease related symptomatology (organomegaly or leukemia cutis) OR
• Diagnosis of acute myeloid leukemia

• WBC less than 20,000/mm^3 and stable for at least 2 weeks
• Unlikely to require cytotoxic therapy during study
• No CNS or pulmonary leukostasis or CNS leukemia

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics
• Hemoglobin at least 8 g/dL (transfusion allowed)
• No disseminated intravascular coagulation

Hepatic:

• Bilirubin less than 2.0 mg/dL (unless due to hemolysis or Gilbert's syndrome)

Renal:

• Creatinine less than 2.0 mg/dL

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 2 weeks prior, during, and for 3 months after study
• No active infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• At least 3 weeks since prior biologic therapy, including hematopoietic growth factors, and recovered

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks (1 month for MDS patients) since prior chemotherapy and recovered

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 3 weeks since prior radiotherapy and recovered

Surgery:

• Not specified