Denileukin Diftitox in Treating Patients With Fludarabine-Refractory B-Cell Chronic Lymphocytic Leukemia

A Phase II Study of ONTAK® (Denileukin Diftitox, DABIL-2) in Patients With Fludarabine-Refractory B-Cell Chronic Lymphocytic Leukemia

RATIONALE: Biological therapies, such as denileukin diftitox, may interfere with the growth of cancer cells and slow the growth of chronic lymphocytic leukemia.

PURPOSE: This phase II trial is studying how well denileukin diftitox works in treating patients with fludarabine-refractory B-cell chronic lymphocytic leukemia.

OBJECTIVES:

Primary

• Determine the complete and partial response rate in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia treated with denileukin diftitox.

Secondary

• Determine the toxicity profile of this drug in these patients.
• Determine the response rate in patients (regardless of CD25 receptor density) treated with this drug.
• Determine the progression-free survival and overall survival of patients treated with this drug.

OUTLINE: This is a multicenter study.

Patients receive denileukin diftitox IV over 1 hour on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving a complete response after 8 courses proceed to follow-up. Patients achieving a partial response or stable disease after 8 courses may continue treatment at the discretion of the investigator.

Patients are followed every 3 months for 1 year and then annually until relapse.

PROJECTED ACCRUAL: A total of 12-44 patients will be accrued for this study within 1 year.

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting the following criteria at any time during the course of disease (e.g., at initial diagnosis or relapse):

  • Absolute lymphocytosis > 5,000/mm^3
  • Lymphocytes must appear mature with < 55% prolymphocytes
  • More than 30% of all nucleated cells are lymphoid on bone marrow aspirate smear
  • Lymphoid infiltrates compatible with bone marrow involvement by CLL on core bone marrow biopsy
  • Predominant B-cell monoclonal population of cells share the B-cell marker (CD19) with the CD5 antigen in the absence of other pan-T-cell markers by lymphocyte immunophenotyping

• High-risk disease OR intermediate-risk disease

  • Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least 1 of the following criteria:

    • Massive or progressive splenomegaly and/or adenopathy
    • Weight loss > 10% within the past 6 months
    • Common toxicity grade 2-4 fatigue
    • Fevers > 100.5°F OR night sweats for more than 2 weeks without evidence of infection
    • Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of < 6 months

• Failed at least 1 prior fludarabine regimen, as defined by 1 of the following criteria:

  • Refractory or intolerant to fludarabine
  • Relapsed within 6 months after completion of fludarabine

• No CNS leukemia

• No mantle cell lymphoma in leukemic phase

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• More than 2 months

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 50,000/mm^3
• Hemoglobin ≥ 8 g/dL (transfusion allowed)

Hepatic

• Albumin ≥ 3 g/dL
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• No hepatitis B or C infection

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance ≥ 40 mL/min

Cardiovascular

• LVEF ≥ 40%

Other

• No uncontrolled infection
• No other concurrent serious illness
• No HIV infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use two effective methods of contraception (one must be non-hormonal) during and for at least 1 month after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior denileukin diftitox allowed

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• No concurrent corticosteroids as anti-emetics

Radiotherapy

• No concurrent radiotherapy

Surgery

• Not specified

Other

• At least 28 days since prior anticancer therapy and recovered
• No other concurrent antineoplastic drugs