Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia

OBJECTIVES:

Primary

- To determine if early treatment with chemoimmunotherapy comprising fludarabine phosphate
and rituximab extends the time to second treatment in patients with genetically
high-risk (unmutated IgV_H), asymptomatic, previously untreated chronic lymphocytic
leukemia (CLL).

- To determine the time to disease progression that would warrant second treatment.

- To determine overall survival.

Secondary

- To measure the proportion of patients with asymptomatic, previously untreated CLL who
have mutated and unmutated IgV_H genes.

- To determine the differences in acute and chronic toxicity of administering
chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting
until symptoms develop.

- To determine the effect of select pretreatment clinical and biological characteristics
(such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction
[primary and secondary]) on response, time to second treatment, and overall survival of
patients with genetically high-risk CLL randomized to early treatment.

- To determine the effect of select pretreatment clinical and biological characteristics
(such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction)
on response, time to first and second treatments, and overall survival of patients with
genetically high-risk CLL randomized to standard treatment (observation until symptoms
occur).

- To describe the natural history of patients with genetically low-risk (mutated IgV_H
genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment,
response, progression, and survival.

- To determine the effect of select pretreatment characteristics on time to first
treatment, response, progression, and survival of patients with genetically low-risk
CLL.

- To correlate patterns of resistance that emerge in patients with unmutated IgV_H genes
who have relapsing or refractory CLL following receipt of chemoimmunotherapy with clonal
evolution, including acquisition of high-risk karyotype abnormalities, p53 mutations,
p53 dysfunction (primary and secondary), altered mRNA and protein expression related to
treatment resistance, DNA mutations, microRNA gene expression, and methylation changes.

- To determine whether highly sensitive flow cytometry negativity at completion of therapy
in patients randomized to early treatment is an effective surrogate marker for prolonged
time to second treatment, overall survival, and other clinical benefits.

- To collect demographic data on familial CLL in newly diagnosed patients participating on
this study.

OUTLINE: This is a multicenter study.

- Genetically high-risk disease: Patients are stratified according to age (< 50 years vs
50 to 70 years vs > 70 years) and presence of the high-risk genetic feature
[del(11)(q22.3) or del(17)(p13.1)] by FISH (yes vs no). Patients are randomized to 1 of
2 treatment arms.

- Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and
then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine
phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After
completion of chemoimmunotherapy, patients are followed every 3 months until
disease progression. At the time of disease progression, patients receive
retreatment with chemoimmunotherapy as above or another treatment regimen.

- Arm II: Patients are followed every 3 months until disease progression. At the time
of disease progression, patients receive rituximab and fludarabine phosphate as in
arm I. Patients are then followed every 3 months until second disease progression.
Patients with a second disease progression receive retreatment with
chemoimmunotherapy as above or another treatment regimen.

- Genetically low-risk disease: Patients are followed every 3 months until disease
progression. At the time of disease progression, patients receive rituximab and
fludarabine phosphate as in arm I. Patients are then followed every 3 months until
second disease progression. Patients with a second disease progression receive
retreatment with chemoimmunotherapy as above or another treatment regimen.

Patients undergo blood sample collection periodically for correlative studies.

After finishing treatment, patients are followed periodically.

Eligibility Criteria for Pre-Registration:

1. Patients must be within 6 months of the initial flow cytometric confirmation of B-cell
chronic lymphocytic leukemia (CLL). This interval begins with the initial flow
cytometric confirmation of disease.

2. Clinical and immunophenotypic evidence of CLL including:

2.1 An absolute lymphocytosis of > 5,000/μL

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

- Local institution lymphocyte phenotype must reveal a predominant B-cell
monoclonal population sharing a B-cell marker (CD19, CD20, CD23) 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 coexpression
and absence of t(11;14) on interphase cytogenetics or have negative tumor protein
staining for cyclin D1.

2.2 Staging - Patients must be in the low category (i.e., only stages 0 or I) of the
modified three-stage Rai staging system as described in the protocol.

3. Patients should not have evidence of active disease as demonstrated by any of the
following criteria:

- Splenomegaly and/or massive/progressive lymphadenopathy that would require
therapy

- Presence of weight loss > 10% over the preceding 6 month period

- Grade 2 or 3 fatigue

- Fevers > 100.5°F 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.

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

5. Age ≥ 18 years

6. Performance Status 0 - 1.

7. No HIV disease. Due to alterations in host immunity, patients known to have HIV
infection may not be enrolled.

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

9. Required Initial Laboratory Values:

- Creatinine ≤ 1.5 x upper limit of normal

Eligibility Criteria for Registration (to Low-Risk Cohort or High-Risk Cohort Randomization
between Early Intervention Versus Observation with Later Treatment)

1. Successful determination of IgVH mutational status by reference laboratory.

2. Absence of progression of CLL, i.e., absence of the following:

- Progressive splenomegaly and/or lymphadenopathy on two independent measures
spaced two weeks apart. If one assessment notes progression, this should be
repeated prior to re-registration.

- Development of anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets <
100,000/μL).

- Progressive lymphocytosis with an increase of > 50% over a 2 month period or an
anticipated doubling time of less than 6 months.

- Symptoms referable to CLL, including weight loss > 10% over the preceding 6 month
period; grade 2 or 3 fatigue; or fevers > 100.5°F and/or night sweats for greater
than 2 weeks without evidence of infection.

3. Required Laboratory Value:

- Creatinine ≤ 1.5 x upper limit of normal