Phase 2 Fludarabine, Cytoxan and FCCAM <Alemtuzumab> in Untreated B-Cell Chronic Lymphocytic Leukemia

Recruitment & Eligibility

Inclusion Criteria

≥ age 18
Karnofsky performance status 60% or above
Confirmed immunohistological diagnosis of Chronic Lymphocytic Leukemia (CLL)
Rai Stage I to IV as follows:
- Advanced stage disease (Rai Stage III or IV, or modified Rai High Risk)
- OR
- Patients with Rai Stage I - II or (Modified Rai Intermediate-Risk) disease must have an indication for therapy based on 1996 NCI revised criteria for active disease as follows:
  - Any one of the following disease-related symptoms:
    1. Weight loss ≥ 10% body weight within the previous 6 months
    2. Extreme fatigue
    3. Fever greater than 100.5° F for ≥ 2 weeks without evidence of infection
    4. Night sweats without evidence of infection
  - Evidence of progressive marrow failure based on the development of worsening of anemia or thrombocytopenia
  - Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy
  - Massive (> 6 cm below the left costal margin) or progressive splenomegaly
  - Bulky (>10 cm in cluster) or progressive lymphadenopathy
  - Progressive lymphocytosis > 50% increase over 2 months, or anticipated doubling time < 6 months
Patients with immunoglobulin VH gene in unmutated nucleotide sequence configuration, as defined by ≥ 98% homology with the nearest germline counterpart
Serum creatinine ≤ 2x the upper limit of normal
Total serum bilirubin ≤ 2x the upper limit of normal.
AST ≤ 2x the upper limit of normal.
ALT ≤ 2x the upper limit of normal.
Signed written informed consent

Exclusion Criteria

Prior pharmacological treatment for CLL
Past history of anaphylaxis following exposure to monoclonal antibodies
Active secondary malignancy or a history of malignant disease (other than CLL or non-melanoma skin cancer) within the preceding 5 years
Any medical condition requiring systemic corticosteroids
Active systemic infection
Major systemic or other illness (including Coombs positivity and active hemolysis) that would, in the opinion of the investigator, interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of study results
HIV positive by serologic testing
Pregnant or nursing female
Unwilling/unable to practice an acceptable form of contraception.

Study & Design

Arm && Interventions

Group	Intervention	Description
Fludarabine, cytoxan, then alemtuzumab	Alemtuzumab	Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed.
Fludarabine, cytoxan, then alemtuzumab	Cytoxan	Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed.
Fludarabine, cytoxan, then alemtuzumab	Fludarabine	Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed.

Primary Outcome Measures

Name	Time	Method
Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR)	24 weeks	Response criteria as per the NCI-WG Revised Guidelines for B-CLL Complete remission: No lymphadenopathy by physical exam No hepatomegaly or splenomegaly Absence of constitutional symptoms Polymorphonuclear leukocytes \> 1,500/uL, Platelets \> 100,000/uL, Hemoglobin \> 11.0 g/dL Bone marrow aspirate and biopsy normocellular with \< 30% lymphocytes Absent lymphoid nodules Partial remission: * 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value * 50% reduction in lymphadenopathy and/or ≥ 50% reduction in the size of the liver and/or spleen AND one or more of the following Polymorphonuclear leukocytes \> 1,500/uL or 50% improvement over baseline Platelets \> 100,000/uL or 50% improvement over baseline Hemoglobin \> 11.0 g/dL or 50% improvement over baseline

Secondary Outcome Measures

Name	Time	Method
Duration of Response	105 months

Recruitment & Eligibility