OBJECTIVES:

• Determine the toxic effects and maximum tolerated dose of bryostatin 1 and fludarabine in patients with symptomatic or advanced chronic lymphocytic leukemia or relapsed indolent non-Hodgkin's lymphoma.
• Monitor apoptosis, differentiation, and protein kinase C activity in leukemic lymphocytes exposed in vivo to bryostatin 1 and fludarabine.
• Observe the antitumor activity of this combination therapy in these patients.

OUTLINE: This is a dose-escalation, multicenter study. Patients are assigned to one of two treatment groups.

• Group I: Patients receive bryostatin 1 IV over 24 hours followed by fludarabine IV over 30 minutes daily on days 1-5.
• Group II: Patients receive fludarabine IV over 30 minutes daily on days 1-5 followed by bryostatin 1 IV over 24 hours.

In both groups, courses repeat every 4 weeks for patients with stable or responding disease.

Cohorts of 3-6 patients receive escalating doses of fludarabine and bryostatin 1 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD for fludarabine is determined, the dose of bryostatin 1 is escalated.

PROJECTED ACCRUAL: Approximately 30-60 patients will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed chronic lymphocytic leukemia

  • Stage I (symptomatic or with bulky lymphadenopathy)
  • Stage II, III, or IV
  • Prior chemotherapy allowed, including fludarabine or other purine nucleoside analog therapy OR

• Histologically confirmed indolent non-Hodgkin's lymphoma

  • Progressive or relapsed following chemotherapy

• Includes the following histologies:

  • B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/lymphomas

    • Lymphoplasmacytoid lymphoma (Waldenstrom's)/immunocytoma
    • Mantle cell lymphoma

    • Follicular lymphoma

      • Small cell
      • Mixed small and large cell
      • Diffuse (predominately small cell type)

    • Marginal zone B-cell lymphoma

      • Extranodal (MALT-type with or without monocytoid B-cells)
      • Provisional subtype: nodal (with or without monocytoid B-cells)
    • Provisional entity: splenic marginal zone lymphoma (with or without villous lymphocytes)
    • Hairy cell leukemia

• Peripheral T-cell and NK-cell neoplasms

  • T-cell chronic lymphocytic leukemia/polylymphocytic leukemia

  • Large granular lymphocyte leukemia

    • T-cell type
    • NK-cell type
  • Mycosis fungoides/Sezary's syndrome (cutaneous T-cell lymphoma)
• No CNS disease

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Granulocyte count at least 1,000/mm3
• Platelet count at least 75,000/mm3
• Hemoglobin at least 8 g/dL
• Coombs negative

Hepatic:

• AST/ALT no greater than 2.5 times upper limit of normal
• Bilirubin no greater than 2 mg/mL

Renal:

• Creatinine clearance at least 40 mL/min

Other:

• No concurrent neurologic condition
• No other concurrent medical condition that would preclude study
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 3 months after study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent systemic immunoglobulin therapy
• No prior bone marrow or peripheral stem cell transplantation

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior systemic chemotherapy

Endocrine therapy:

• No concurrent systemic glucocorticoid therapy

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• No other concurrent anticancer therapy