Bevacizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

• Toxicity Associated With This Regimen in Participants With Relapsed/Refractory CLL. [ Time Frame: From the date of registration to the to the date of last treatment evaluation, median number of days on treatment was 56 days. ] [ Designated as safety issue: Yes ]
  As per NCI CTCAE Version 3.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The number of participants experiencing grade 3 or higher toxicity will be reported here.
• Overall Survival [ Time Frame: From the date of registration to the date of the event (i.e., death or the date of last follow-up), up to 5 years. ] [ Designated as safety issue: No ]
  The Kaplan-Meier method will be used to estimate distributions in the B-CLL population.
• Time to Progression [ Time Frame: From the date of registration to the date of the event (i.e., death or disease progression) or the date of last follow-up, up to 5 years ] [ Designated as safety issue: No ]

  Progression is defined as one of the following:

  • A ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive determinations 2 weeks apart (at least one node must be ≥2 cm) or the appearance of new palpable lymph nodes, or
  • A ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or the appearance of hepatomegaly or splenomegaly which was not previously present, or
  • The transformation to a more aggressive histology (e.g. Richter's transformation), or
  • A ≥ 50% increase in the absolute number of circulating lymphocytes.

  The Kaplan-Meier method will be used to estimate time to progression.

This phase II trial is studying how well bevacizumab works in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bevacizumab may also stop the growth of cancer cells by blocking blood flow to the cancer

PRIMARY OBJECTIVES:

I. Assess the treatment success rate of Bevacizumab in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL).

II. Assess the toxicity associated with this regimen in patients with relapsed or refractory CLL

SECONDARY OBJECTIVES:

I. Overall Survival [Time Frame: From the date of registration to the date of the event (i.e., death or disease progression) or the date of last follow-up, up to 5 years] II. Time to Progression [Time Frame: From the date of registration to the date of the event (i.e., death or disease progression) or the date of last follow-up, up to 5 years] III. Duration of Response Defined for All Evaluable Patients Who Have Achieved an Objective Response (i.e., CR, nPR, PR) [Time Frame: From the date at which the patient's objective status is first noted to be a response to the date that progression or death is documented or to the date of last follow-up, up to 5 years]

OUTLINE: This is a multicenter study. Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15.

Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 5 years.

• B-cell Chronic Lymphocytic Leukemia
• Refractory Chronic Lymphocytic Leukemia

Inclusion Criteria:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL)*, as defined by the following phenotypic characteristics:

  • Predominant population of cells share both B-cell antigens (CD19, CD20, or CD23) as well as the T-cell antigen (CD-5), in the absence of other pan-T-cell markers (CD-3, CD-2, etc.)

    • Mantle cell lymphoma must be excluded by demonstrating the absence of the t(11;14) by fluorescent in situ hybridization (FISH)
  • Dim surface immunoglobulin expression
  • Exclusively kappa and lambda light chains

• Peripheral blood absolute lymphocyte count > 5,000/mm^3

  • Lymphocytosis must consist of small to moderate size lymphocytes, with ≤ 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically

• Requires chemotherapy, as indicated by any of the following:

  • Disease related symptoms, including the following:

    • Weight loss ≥ 10% within the previous 6 months
    • Extreme fatigue
    • Fevers > 100.5°F for 2 weeks without evidence of infection
    • Night sweats without evidence of infection
  • Evidence of progressive marrow failure, as manifested by the development of or worsening anemia (hemoglobin ≤ 10 g/dL) and/or thrombocytopenia (platelet count ≤ 100,000/mm^3)
  • Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly
  • Measurable and progressive lymphadenopathy
  • Measurable (i.e., > 5,000/mm^3) and progressive lymphocytosis
• Progressive disease or relapsed after or refractory to 1 course of an alkylating agent-based or purine nucleoside-based (e.g., fludarabine) regimen
• No marrow function attributable to dysplasia related to prior therapy
• ECOG performance status 0, 1, or 2

• Serum creatinine < 2 mg/dL

  • If serum creatinine > 1.5 mg/dL but < 2 mg/dL, creatinine clearance must be ≥ 30 mL/min
• Platelet count > 30,000/mm^3
• Direct bilirubin ≤ 2 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other second malignancy within the past 2 years except squamous cell or basal cell carcinoma of the skin or in situ carcinoma of the cervix
• No New York Heart Association class III or IV heart failure
• No blood pressure > 150/90 mm Hg
• No unstable angina
• No myocardial infarction or stroke within the past 6 months
• No clinically significant peripheral vascular disease
• No evidence of bleeding diathesis or coagulopathy
• No significant traumatic injury within the past 28 days

• Urine protein:creatinine (UPC) ratio ≤ 1.0

  • Patients with a UPC ratio > 1.0 must undergo a 23-hour urine collection and must demonstrate < 1 gram of protein per day
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• No serious, non-healing wound, ulcer, or bone fracture
• No active infections requiring oral or intravenous antibiotics
• No active bleeding or pathological conditions that carry a high risk of bleeding (e.g., known varices)
• No thrombocytopenia requiring transfusion
• See Disease Characteristics
• More than 4 weeks since prior participation in an experimental drug study
• At least 8 weeks since prior rituximab
• At least 6 weeks since prior chemotherapy
• More than 28 days since prior major surgery or open biopsy
• More than 7 days since prior minor surgery, fine needle aspirations, or core biopsies
• No concurrent major surgery
• No concurrent participation in another experimental drug study
• Concurrent full-dose warfarin or low molecular weight heparin allowed provided patient is on a stable dose AND INR is in range