A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

OUTLINE:

Patients with adverse interphase cytogenetics (11q22 or 17p13 deletion) receive FCO induction
therapy:

- Ofatumumab is given IV on day 1 (300 mg) and day 8 (1000 mg) of course 1 and on day 1
(1000 mg) of all subsequent courses.

- Fludarabine phosphate (25mg/m2/d) and cyclophosphamide (250mg/m2/d) are given IV on days
2 through 4 of course 1 and on days 1 through 3 of all subsequent courses. Patients age
70 or older will be given reduced doses of fludarabine (20mg/m2/d) and
cyclophosphamide (150mg/m2/d).

- Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression.

Patients without adverse interphase cytogenetics receive FO induction therapy:

- Ofatumumab is given IV on day 1 (300mg) and day 8 (1000mg) of course 1 and on day 1
(1000mg) of all subsequent courses.

- Fludarabine phosphate (25mg/m2/d) is given IV on days 2 through 6 of course 1 and on
days 1 through 5 of all subsequent courses.

- Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression.

All patients are evaluated for minimal residual disease (MRD) by four-color flow cytometric
analysis of the peripheral blood after completion of FO or FCO induction therapy, and are
subsequently stratified into two groups:

- Patients who are MRD-positive and without evidence of disease progression proceed to
consolidation therapy beginning approximately 5 months after completion of
induction therapy, consisting of ofatumumab (1000mg) given IV on day 1 of all courses.
Treatment repeats every 2 months for up to 4 courses in the absence of disease
progression. Patients are followed clinically 2 and 6 months after the last dose of
ofatumumab is given, and then every 6 months thereafter.

- Patients who are MRD-negative and without evidence of disease progression are followed
clinically every 4 months for 1 year and every 6 months thereafter.

- INCLUSION CRITERIA:

Histologically confirmed CLL or SLL as defined by the following:

- B-lymphocytosis greater than 5000 cells/micro L (may be less than 5000 cells/micro L
if lymphadenopathy is present with histologic confirmation of lymph node involvement
by SLL).

- Immunophenotypic profile consistent with CLL as demonstrated by flow cytometry

- Appropriate immunophonotype (CD5/19/23+)

- Clonality of lymphocytosis confirmed by flow cytometry

- large lymphocytes less than 55 % of blood lymphocytes

Active disease as defined by at least one of the following:

- Weight loss greater than or equal to10 percent within the previous 6 months

- Extreme fatigue

- Fevers of greater than 100.5 degree F for greater than or equal to 2 weeks without
evidence of infection

- Night sweats for more than one month without evidence of infection

- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia

- Massive or progressive splenomegaly

- Massive nodes or clusters or progressive lymphadenopathy

- Progressive lymphocytosis with an increase of greater than 50% over a 2 month period,
or an anticipated doubling time of less than 6 months 0

Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic
disease).

Ages 18 and over.

EXCLUSION CRITERIA:

Prior monoclonal antibody therapy with agents having anti-CLL activity

Prior cytotoxic chemotherapy with agents having anti-CLL activity (Fludarabine,
Cyclophosphamide, Bendamustine, Chlorambucil)

Transformed CLL

Active autoimmune hemolytic anemia or thrombocytopenia

Any medical condition that requires the chronic use of corticosteroids

Active or latent Hepatitis B infection

HIV infection

Severe chronic obstructive pulmonary disease, severe cardiac disease, or other uncontrolled
medical condition that would, in the opinion of the principal investigator, place the
subject at an unreasonable risk of life-threatening adverse events due to
chemoimmunotherapy

ECOG performance status 3 or worse

Creatinine greater than or equal to 2 mg/dL or creatinine clearance less than or equal to
30 mL/min

Bilirubin greater than or equal to 2 mg/dL or active hepatic or biliary disease (with
exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic
liver disease per investigator assessment)

Female patients: Current pregnancy or unwilling to take oral contraceptives or refrain from
pregnancy if of childbearing potential or currently breastfeeding. Male patients who are
unwilling to follow the contraception requirements described in this protocol.

Psychiatric illness/social situations that would limit the patient s ability to tolerate
and/or comply with study requirements.

Unable to understand the investigational nature of the study or give informed consent.