Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia

OBJECTIVES:

Primary

- To compare the rate of complete and overall response in elderly patients with
progressive chronic lymphocytic leukemia (CLL) treated with one of two doses of
rituximab combined with alemtuzumab to determine if the use of modified-dose rituximab
significantly affects outcome.

Secondary

- To monitor and assess toxicity of these regimens.

- To determine the overall and progression-free survival, time to clinical response, time
to next treatment, and duration of response in patients treated with these regimens

- To assess the correlation between risk stratification prognostic markers (i.e., CD38,
ZAP-70, fluorescent in situ hybridization (FISH), and IgVH mutation) and clinical
outcome.

- To assess response to these regimens using both the 1996 National Cancer Institute
Working Group (NCI-WG 96) criteria and an expanded definition of response for patients
in complete remission, including immunohistochemical examination of the bone marrow and
sensitive flow cytometry (4-6 color) of blood for minimal residual disease and computed
tomography (CT) scans for residual adenopathy.

- To determine the mechanism of action of rituximab and alemtuzumab and to determine
mechanisms of resistance of a subpopulation of CLL cells to these drugs.

OUTLINE: This is a multicenter study. Patients are stratified according to FISH risk (low
[13q14-] vs intermediate [12+, no abnormality, all other abnormalities] vs high
[17p13-,11q22-]). Patients are randomized to 1 of 2 treatment arms.

- Arm A: Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15,
17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab intravenously (IV) on days 8,
15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day
cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24,
and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every
28 days for up to 3 cycles.

- Arm B: Patients receive alemtuzumab as in arm A. Patients also receive low-dose
rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 and on
days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in cycless 2 and 3. Treatment
repeats every 28 days for up to 3 cycles.

Blood and bone marrow samples are collected periodically for cytogenetic and biomarker
analysis.

Alemtuzumab dose for Cycle 1 Week 1 of both Arms A and B requires a 'dose ramp' (3 mg day 1,
10 mg day2, and 30 mg day 3 of cycle 1).

After completion of study therapy, patients are followed up periodically for 5 years.

Inclusion Criteria:

- Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:

- Minimum threshold peripheral lymphocyte count of 5 x 10^9/L (CLL variant) OR
palpable adenopathy > 1 cm or palpable splenomegaly 9small lymphocytic lymphoma
[SLL] variant)

- Immunophenotypic demonstrations of a population of B-lymphocytes (as defined by
CD19+) that are monoclonal (by light-chain exclusion) AND have ≥ 3 of the
following characteristics:

- CD5+

- CD23+

- Dim surface light chain expression

- Dim surface CD20 expression

- FISH analysis is negative for immunoglobulin heavy chain/cyclin D1 gene
(IGH/CCND1) and/or immunostaining is negative for cyclin D1 expression (to
exclude mantle cell lymphoma)

- Progressive, symptomatic CLL, defined by at least one of the following:

- Weight loss > 10% within the past 6 months attributable to progressive CLL (grade
2 or higher)

- Extreme fatigue attributable to progressive CLL (grade 3 or higher)

- Fevers > 100.5° F for 2 weeks without evidence of infection (grade 1 or higher)

- Night sweats without evidence of infection (drenching)

- Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet
count < 100 x 10^9/L

- Rapidly progressive lymphadenopathy for which the largest node is ≤ 5 cm in any
dimension

- Largest lymph nodes involved in the neck, axilla, and groin need to be
measured and followed for response

Exclusion Criteria:

- Prior treatment for CLL

- Massive splenomegaly > 6 cm below left costal margin, at rest, on clinical examination

- Lymphadenopathy > 5 cm in any diameter

- New York Heart Association class III or IV heart disease

- Recent myocardial infarction (within the past month)

- Uncontrolled infection

- Infection with the human immunodeficiency virus (HIV/AIDS)

- Serological evidence of active hepatitis B infection (HBsAg or HBeAg positive)

- Positive hepatitis C serology

- Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red
blood cell aplasia

- Other active primary malignancy requiring treatment or that limits survival to ≤ 2
years, except for in situ carcinoma of the cervix or breast or non-metastatic basal
cell or squamous cell carcinoma of the skin

- Major surgery within 4 weeks prior to pre-registration

- Concomitant use of continuous systemic corticosteroids

- Prior corticosteroids are allowed but not at time of pre-registration to the
study