Fludarabine Followed by Alemtuzumab in Treating Patients With Chronic Lymphocytic Leukemia

A Phase II Study of Fludarabine Induction Followed by CAMPATH-1H Consolidation in Untreated Patients With B-Cell Chronic Lymphocytic Leukemia

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as alemtuzumab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells.

PURPOSE: Phase II trial to study the effectiveness of fludarabine followed by alemtuzumab in treating patients who have chronic lymphocytic leukemia.

OBJECTIVES: I. Determine the overall response rate of previously untreated patients with stage I, II, III, or IV B-cell chronic lymphocytic leukemia when treated with fludarabine induction followed by alemtuzumab consolidation. II. Determine the infectious toxic effects and feasibility of this regimen in this patient population. III. Determine the treatment-related toxic effects, including infection and injection site reactions, of subcutaneous vs intravenous alemtuzumab in patients treated with this regimen. IV. Determine the progression-free and overall survival of patients treated with this regimen. V. Determine the immunologic effects of this regimen in these patients.

OUTLINE: Patients receive fludarabine IV over 30 minutes 5 days a week. Treatment repeats every 28 days for 4 courses in the absence of disease progression. Patients undergo clinical staging after completion of course 4 of fludarabine followed by 2 months of observation. Patients with stable or responding disease receive alemtuzumab subcutaneously 3 days a week for 6 weeks. Patients undergo clinical staging again after completion of 6 weeks of alemtuzumab followed by 2 more months of observation. Patients are followed every 3 months for 1 year and then every 6 months for 8 years.

1. Specific Diagnosis of B-Cell CLL

   1.1 An absolute lymphocytosis of > 5,000/µl

   1.1.1 Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes.

   1.1.2 Bone marrow examination must include at least a unilateral aspirate and biopsy. The aspirate smear must show > 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL. The overall cellularity must be normocellular or hypercellular.

   1.1.3 Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23, CD24) with the CD5 antigen, in the absence of other pan-T-cell markers. Additionally, the B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density. Patients with bright surface immunoglobulin levels must have CD23 co-expression.

   1.2 Staging

   1.2.1 Patients must be in the intermediate- or high-risk categories of the modified three-stage Rai staging system (i.e., stages I, II, III, or IV) per the protocol.

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

   • Massive or progressive splenomegaly and/or lymphadenopathy
   • Presence of weight loss > 10% over the preceding 6 month period;
   • Grade 2 or 3 fatigue
   • Fevers > 100.5°C or night sweats for greater 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 less than 6 months.

2. Prior Treatment: No prior therapy for CLL including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL.

3. No medical condition requiring chronic use of oral corticosteroids.

4. Age ≥18 years.

5. Performance Status 0 - 2.

6. No HIV disease. Due to alterations in host immunity, patients with HIV may not be enrolled.

7. Non-pregnant and non-nursing. Due to the unknown teratogenic potential of Campath-1H, pregnant or nursing women may not be enrolled. Women and men of reproductive potential should agree to use an effective means of birth control.

8. Initial Required Laboratory Values:

Creatinine <1.5 x upper limit of institutional normal value Coomb's Testing NEGATIVE