Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVES:

I. To determine the two-year progression-free survival (PFS) after remission induction with
four different chemo-immunotherapy combinations for patients with untreated, symptomatic,
lower-risk and high-risk chronic lymphocytic leukemia (CLL) to decide which of the four arms,
if any, to take forward into a randomized phase III trial.

II. To determine the induction response to fludarabine phosphate and rituximab (FR) and
fludarabine phosphate, cyclophosphamide, and rituximab (FCR) in each of these arms, along
with the consolidation response to lenalidomide in patients with CLL.

III. To determine the toxicity from these four chemoimmunotherapy combinations and that of
consolidation therapy with lenalidomide.

IV. To determine the induction response and toxicity of FCR in patients with deletion (del)
(11q22.3) along with consolidation response, 2-year PFS and toxicity of lenalidomide in this
specific genetic group.

V. To determine the effect of pretreatment biologic characteristics on clinical outcomes,
such as attaining a complete response to induction therapy and progression-free survival.

VI. To collect relapse samples to determine the frequency of clonal evolution among patients
with immunoglobulin heavy chain variable region (IgVH) mutated and unmutated disease and to
study mechanisms of resistance to chemoimmunotherapy.

VII. To determine if flow cytometry-negative status immediately post-therapy and at 24 months
after study entry is an effective surrogate marker for prolonged progression-free survival
and overall survival.

OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arms A, B, or C). Patients on Arm
A or B who are found to be del (11q22.3) positive are assigned to Arm D beginning with course
2 of induction therapy.

ARM A (remission-induction [RI] therapy with fludarabine phosphate and rituximab):
Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab
intravenously (IV) over 1-4 hours on days 1 (50 mg/m^2), 3 (325 mg/m^2), and 5 (375 mg/m^2)
of course 1 and on day 1 (375 mg/m^2) of all subsequent courses. Patients also receive
fludarabine phosphate 25 mg/m^2/day IV over 30 minutes or orally (PO) on days 1-5.

ARM B (RI therapy with fludarabine phosphate and rituximab followed by
remission-consolidation [RC] therapy with lenalidomide): Participants receive induction
therapy (every 28 days for up to 6 cycles) of: rituximab IV over 1-4 hours on days 1 (50
mg/m^2), 3 (325 mg/m^2), and 5 (375 mg/m^2) of course 1 and on day 1 (375 mg/m^2) of all
subsequent courses. Patients also receive fludarabine phosphate 25 mg/m^2/day IV over 30
minutes or PO on days 1-5. Participants without progression receive consolidation therapy:
lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6 PO once daily (QD) on days 1-21 of 28 day
cycle.

ARM C (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide): Participants
receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 4 hours on
days 1 (50mg/m^2) and 3 (325 mg/m^2) of course 1 and on day 1 (500 mg/m^2) of all subsequent
courses. Patients then receive fludarabine phosphate (age < 70: 25 mg/m^2/day; age >= 70: 20
mg/m^2/day) IV piggyback over 30 minutes or PO (32 mg/m^2/day) followed by cyclophosphamide
(age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) IV piggyback over 30 minutes on days
1-3.

ARM D (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide followed by RC
therapy with lenalidomide): Patients receive the first course of induction therapy as in Arm
A or B before being re-assigned to Arm D. Beginning in course 2, patients receive rituximab
IV (500 mg/m^2) on day 1 and fludarabine phosphate (age < 70: 25 mg/m^2/day; age >= 70: 20
mg/m^2/day) IV piggyback over 30 minutes or PO (32 mg/m^2/day) and cyclophosphamide IV (age <
70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) piggyback over 30 minutes on days 1-3.
Participants without progression receive consolidation therapy: lenalidomide 5mg/day cycle 1,
10 mg/day cycles 2-6 PO QD on days 1-21 of 28 day cycle.

After completion of study therapy, patients are followed up every 3 months for 1 year and
then every 6 months for up to 15 years.

Inclusion Criteria:

- Specific diagnosis of B-cell CLL:

- An absolute lymphocytosis of > 5,000/uL

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

- 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; overall cellularity must be
normocellular or hypercellular

- Local institution lymphocyte phenotype must reveal a predominant B-cell
monoclonal population sharing a B-cell marker (cluster of differentiation
[CD]19, 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 kappa or lambda and have surface immunoglobulin
expression of low density; patients with bright surface immunoglobulin
levels must have CD23 co-expression

- Patients must have symptomatic and active intermediate or high-risk categories of the
modified three-stage Rai staging system:

- Not eligible: low risk, Rai stage 0, lymphocytes (L) in blood (> 5000/uL) and
marrow (> 30%) only

- Intermediate risk, Rai stage I, L + enlarged lymph nodes (LN)

- Intermediate risk, Rai stage II, L + spleen and/or liver (LN + or -)

- High risk, Rai stage III, L + anemia (hemoglobin < 11 gm/dL)

- High risk, Rai stage IV, L + thrombocytopenia (platelets < 100,000/uL)

- 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, hepatomegaly and/or lymphadenopathy

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

- Grade 2 or 3 fatigue

- Fevers > 100.5 degrees Fahrenheit (°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

- No prior therapy for CLL, including no corticosteroids for autoimmune complications
that have developed since the initial diagnosis of CLL

- No medical condition requiring chronic use of oral corticosteroids

- Performance status 0 - 2

- Patients with human immunodeficiency virus (HIV) infection may be eligible provided
they meet the following criteria: no evidence of infection with hepatitis B or C; CD4+
cell count > 350/mm^3; no evidence of resistant strains of HIV; if not on anti-HIV
therapy, an HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL; if on HIV
therapy, HIV viral load < 50 copies HIV RNA/mL; and no history of acquired immune
deficiency syndrome (AIDS)-defining condition; patients receiving concurrent
zidovudine or stavudine may not be enrolled

- Non-pregnant and non-nursing

- In females of child-bearing potential randomized to Arm B or assigned to Arm D, a
negative urine or serum pregnancy test with a sensitivity of at least 25 mIU/mL will
be required: 1) 10-14 days prior to beginning lenalidomide consolidation therapy; and
2) within 24 hours prior to the first dose of lenalidomide consolidation therapy; in
addition, females of childbearing potential in Arm B and Arm D with regular menses
must have a pregnancy test performed weekly during the first 28 days of treatment, and
then every 28 days while taking lenalidomide (including breaks in lenalidomide), at
discontinuation of lenalidomide, and then 28 days following discontinuation of
lenalidomide; if menses are irregular, a pregnancy test must be performed weekly
during the first 28 days of treatment, and then every 14 days while taking
lenalidomide, at discontinuation of lenalidomide, and at 14 and 28 days after
discontinuation of lenalidomide; additionally, females of childbearing potential must
either commit to continued abstinence from heterosexual intercourse or begin TWO
reliable methods of birth control - one highly effective method (intrauterine device
[IUD], hormonal [birth control pills, injections, or implants], tubal ligation, or
partner's vasectomy), and one additional effective method (latex condom, diaphragm, or
cervical cap) - AT THE SAME TIME, at least 4 weeks before she begins lenalidomide
therapy, while participating in the study, and for at least 4 weeks after completing
lenalidomide therapy; "females of childbearing potential" is defined as a sexually
mature woman who has not undergone a hysterectomy or bilateral oophorectomy, or who
has had menses at any time in the preceding 24 consecutive months (not been naturally
postmenopausal for at least 24 consecutive months)

- Male patients randomized to Arm B or reassigned to Arm D must agree not to father a
child and to use a latex condom during any sexual contact with females of childbearing
potential while taking lenalidomide and for at least 4 weeks following completion of
lenalidomide therapy, even if the patient have undergone a successful vasectomy

- All patients randomized to Arm B or reassigned to Arm D must be counseled by a trained
counselor every 28 days during consolidation therapy about pregnancy precautions and
risks of fetal exposure

- Creatinine =< 1.5 x upper limit of normal