Lenalidomide and Vaccine Therapy in Treating Patients With Early-Stage Asymptomatic Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

I. To determine the proportion of early-stage, high-risk chronic lymphocytic leukemia (CLL)
patients achieving a response (>= 4-fold increase from baseline and/or antibody
concentrations >= 0.35 ug/mL in 6 of 7 type-specific anti-pneumococcal antibody levels) after
2 doses of pneumococcal 13-valent conjugated vaccine (Prevnar 13, PCV13 [pneumococcal
polyvalent vaccine]) administered concurrent with versus sequential to low-dose lenalidomide.

SECONDARY OBJECTIVES:

I. To determine the complete response (CR) rate after 2 years of lenalidomide therapy.

II. To determine the time to first treatment (TFT), defined as the time from diagnosis to
first non-lenalidomide therapy for progressive CLL as described by International Workshop on
Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria.

III. To determine the incidence of infection and invasive pneumococcal infections following
treatment with the PCV13 vaccine and either concurrent or sequential lenalidomide.

IV. To determine the frequency of humoral and cellular immune response to CLL tumor antigens
following treatment with the PCV13 vaccine and either concurrent or sequential lenalidomide.

V. To determine the safety and toxicity associated with long-term lenalidomide exposure.

VI. To perform correlative pharmacodynamic and pharmacokinetic studies and correlate these
with vaccine/tumor immunologic and disease response.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A (concurrent PCV13 and lenalidomide): Patients receive low-dose lenalidomide orally (PO)
once daily on days 1-28. Treatment repeats every 28 days for at least 24 courses in the
absence of disease progression or unacceptable toxicity. Patients also receive 13-valent
protein-conjugated pneumococcal vaccine (PCV13) intramuscularly (IM) on day 1 of courses 3
and 5.

ARM B (sequential PCV13 and lenalidomide): Patients receive PCV13 IM on days 1 and 78
(courses 1 and 3). Patients also receive low-dose lenalidomide as in arm 1 beginning on day 1
of course 4. Treatment repeats every 28 days for at least 24 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 3 months for
1 year, and then every 6 months thereafter.

Inclusion Criteria:

- Patients must have histologically identified chronic lymphocytic leukemia (CLL) or
small lymphocytic lymphoma (SLL) as defined by the World Health Organization (WHO)
classification of hematopoietic neoplasms

- CLL/SLL cells must demonstrate one or more of the following high-risk genomic
features:

- Deletion (Del) (17p13.1) as detected by fluorescence in-situ hybridization (FISH)
in > 20% of cells

- Del(11q22.3) as detected by FISH in > 20% of cells

- Complex karyotype (>= 3 cytogenetic abnormalities on stimulated karyotype)

- Unmutated immunoglobulin variable heavy chain (IgVH) (>= 98% sequence homology
compared with germline sequence)

- Patients cannot meet any of the following consensus criteria for initiating treatment:

- Progressive splenomegaly and/or lymphadenopathy identified by physical
examination or radiographic studies

- Progressive lymphocytosis with total white blood cell (WBC) >= 300,000/uL

- Anemia (< 11 g/dL) or thrombocytopenia (< 100,000/uL) due to bone marrow
involvement

- Presence of unintentional weight loss > 10% over the preceding 6 months

- National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) grade 2 or 3 fatigue

- Fevers > 100.5 degrees or night sweats for > 2 weeks without evidence of
infection

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

- No prior therapy for CLL/SLL, including chemotherapy, radiotherapy, and/or
immunotherapy will be allowed

- Estimated life expectancy of greater than 24 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Total bilirubin =< 1.5 times upper limit of normal (ULN) (unless secondary to Gilbert
disease)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate-pyruvate transaminase [SGPT])
=< 2.5 times ULN

- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal according to the Cockcroft-Gault formula

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelet count >= 100,000/uL

- Able to swallow capsules without difficulty and no history of malabsorption syndrome,
disease significantly affecting gastrointestinal function, or resection of the stomach
or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or
partial or complete bowel obstruction

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again
within 24 hours of starting lenalidomide; further, they must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control: one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to
ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature
woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months); all patients must be
counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal
exposure

Exclusion Criteria:

- Patients who have had any treatment for their CLL/SLL, including but not limited to
chemotherapy, radiotherapy, or immunotherapy, prior to entering the study

- No corticosteroid use will be permitted within two weeks prior to study, except for
maintenance therapy for a non-malignant disease; maintenance therapy dose may not
exceed 20 mg/day prednisone or equivalent

- Patients who meet consensus criteria for the treatment of CLL/SLL

- Patients may not be receiving any other investigational agents

- Patients with a recent history (within 6 months of study entry) of deep vein
thrombosis (DVT)/pulmonary embolism (PE) are not eligible; patients with a distant
history (greater than 6 months before study entry) of venous thromboembolic disease
are eligible, but should receive prophylactic aspirin or low molecular weight heparin

- History of allergic reactions attributable to compounds of similar chemical or
biologic composition to thalidomide, lenalidomide or any component of PCV7 or PCV13,
including the diphtheria toxoid

- Prior malignancy, except for adequately treated basal cell or squamous cell skin
cancer, in situ cervical cancer, or other cancer from which the subject is considered
by his or her physician to have a 2 year survival expectation

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with lenalidomide

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy will be eligible if they otherwise meet required hematologic parameters and
are not receiving an antiviral agent with known or potential interaction with
lenalidomide; because the primary aim of this study is to measure the immune response
to pneumococcal vaccination, only patients with cluster of differentiation (CD)4 cell
counts >= 200 and viral load < 50 will be eligible

- Patients who have been treated for autoimmune hemolytic anemia or autoimmune
thrombocytopenia within the last 6 months or are direct antiglobulin test/Coombs test
or indirect antiglobulin test positive at the time of screening

- Patients who have developed erythema nodosum characterized by a desquamating rash
while taking thalidomide or similar drugs in the past are excluded

- Patients must discontinue treatment with H2-blockers (cimetidine, ranitidine, etc.)
prior to beginning protocol therapy