OBJECTIVES:

• Determine the maximum tolerated dose of bryostatin 1 when administered with sargramostim (GM-CSF) in patients with refractory myeloid malignancies.
• Determine the toxicity frequency of this regimen in these patients.
• Determine the pharmacokinetics of bryostatin 1 in these patients.

OUTLINE: This is a dose-escalation study of bryostatin 1.

Patients receive bryostatin 1 IV continuously and sargramostim (GM-CSF) subcutaneously once daily on days 1-21. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease stabilization or improvement may continue treatment for up to 12 courses.

Cohorts of 2 patients receive escalating doses of bryostatin 1 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 30% of patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A maximum of 45 patients will be accrued for this study within 12-18 months.

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Myelodysplastic syndromes (MDS) by bone marrow aspiration and/or biopsy indicating primary refractory leukopenia or thrombocytopenia with morphologic features of MDS

    • Refractory anemia (RA) and RA with ringed sideroblasts allowed provided transfusion dependent
    • No RA with 5q syndrome
    • Chronic myelomonocytic leukemia allowed
    • Failure to achieve remission after intensive chemotherapy allowed if received chemotherapy more than 1 month prior to study
    • Progression on other prior institutional trials including phenylbutyrate, tretinoin, or azacitidine allowed

  • Relapsed acute myeloid leukemia (AML) by bone marrow aspiration or biopsy

    • No acute promyelocytic leukemia
    • WBC less than 30,000/mm^3 and stable for at least 7 days
    • Unlikely to require cytotoxic therapy during study

  • Newly diagnosed AML

    • Previously untreated
    • Not a candidate for potentially curative intensive chemotherapy
    • Refused prior chemotherapy or deemed poor medical candidate for AML induction chemotherapy

  • Accelerated or blastic phase chronic myelogenous leukemia (CML)

    • Previously treated chronic phase CML allowed
    • At least 2 weeks since prior treatment for accelerated or blastic phase CML
    • Blast count less than 30,000/mm^3 and stable for at least 7 days
    • No lymphoid blast phase CML

  • Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) associated with disease

    • Life-threatening complications of illness (e.g., abdominal, central vein or cerebral thromboses, active infections, or recurrent symptomatic hemolytic crises) with no other treatment options allowed
• Not a candidate for potentially curative bone marrow transplantation
• Stable bone marrow function for more than 10 days prior to study (no WBC doubling within this time period)

• No active CNS disease

  • Negative cytology by lumbar puncture for suspected CNS disease

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 2 months

Hematopoietic:

• See Disease Characteristics
• Hemoglobin at least 8 g/dL (transfusion allowed)

Hepatic:

• Bilirubin less than 1.6 mg/dL (unless secondary to hemolysis)
• SGOT/SGPT less than 2 times upper limit of normal unless disease related (e.g., PNH or extramedullary disease)

Renal:

• Creatinine less than 2.0 mg/dL

Cardiovascular:

• No disseminated intravascular coagulation

Pulmonary:

• No evidence of pulmonary leukostasis

Other:

• No radiographic evidence of active infection
• No untreated positive blood cultures
• No intolerance to sargramostim (GM-CSF)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• At least 2 weeks since prior hematopoietic growth factors for myeloid disorder
• At least 2 weeks since prior biologic therapy (e.g., monoclonal antibodies) for myeloid disorder
• Recovered from prior biologic therapy

Chemotherapy:

• See Disease Characteristics
• At least 2 weeks since prior chemotherapy (except hydroxyurea for WBC greater than 10,000/mm^3) for myeloid disorder and recovered
• No prior bryostatin 1

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified