Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
This phase II trial studies how well giving ofatumumab together with pentostatin and
 cyclophosphamide works in treating patients with untreated chronic lymphocytic leukemia or
 small lymphocytic lymphoma. Monoclonal antibodies, such as ofatumumab, can block the ability
 of cancer cells to grow and spread. Drugs used in chemotherapy, such as pentostatin and
 cyclophosphamide, work in different ways to stop the growth of cancer cells, either by
 killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving
 ofatumumab together with pentostatin and cyclophosphamide may be a better way to block cancer
 growth.
PRIMARY OBJECTIVES:

 I. Arm A: To assess the rate of complete response using pentostatin, cyclophosphamide, and
 ofatumumab in patients with previously untreated chronic lymphocytic leukemia (CLL) or small
 lymphocytic lymphoma (SLL) requiring therapy.

 II. Arm B: To assess the treatment-free survival rate at 18 months using pentostatin,
 cyclophosphamide, and ofatumumab induction therapy followed by ofatumumab consolidation in
 patients with previously untreated CLL or SLL requiring therapy.

 SECONDARY OBJECTIVES:

 I. Arm A and Arm B: To assess the rate of overall response in patients with previously
 untreated CLL or SLL requiring therapy and to determine the proportion of patients who
 achieve a minimal residual disease (MRD) negative state as assessed by flow cytometry in each
 arm independently.

 II. Arm A and Arm B: To monitor and assess toxicity in patients with previously untreated CLL
 or SLL in each arm independently.

 III. Arm A and Arm B: To determine the progression-free survival, treatment-free survival,
 and duration of response in each arm independently.

 IV. Arm A and Arm B: To determine if molecular prognostic parameters (zeta-chain-associated
 protein [ZAP]-70, cluster of differentiation [CD]38, cytogenetic abnormalities identified by
 fluorescence in situ hybridization [FISH], immunoglobulin heavy-chain variable-region [IgVH]
 mutation status, etc) relate to response to therapy in each arm independently.

 V. Arm B: To assess the rate of complete response using pentostatin, cyclophosphamide, and
 ofatumumab induction followed by ofatumumab consolidation in patients with previously
 untreated CLL or SLL requiring therapy.

 VI. Arm B: To evaluate whether consolidation therapy with ofatumumab after pentostatin,
 cyclophosphamide, and ofatumumab (PCO) induction improves the depth of response.

 TERTIARY OBJECTIVES:

 I. Arm A and Arm B: To assess the complete and overall response as well as treatment free
 survival in each arm as compared to a historic control of patients treated with pentostatin,
 cyclophosphamide, and rituximab in an exploratory manner.

 II. Arm A and Arm B: To assess the complete and overall response as well as treatment free
 survival of patients treated with PCO induction followed by ofatumumab consolidation (Arm B)
 as compared to patients treated with PCO induction who did not receive ofatumumab
 consolidation (Arm A) in an exploratory manner.

 III. Arm A and Arm B: Assess the mechanisms of ofatumumab induced cell death and explore
 methods to enhance ofatumumab cytotoxicity.

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

 ARM A (closed to accrual as of 8/23/2011): Patients receive induction therapy comprising
 ofatumumab intravenously (IV) on day 1 (days 1-2 of course 1 only), pentostatin IV over 30
 minutes on day 1, and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every
 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

 ARM B: Patients receive induction therapy as in Arm A. Patients then receive consolidation
 therapy comprising ofatumumab IV on day 1. Treatment repeats every 28 days for 6 courses in
 the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 90 days for 1 year.
Inclusion Criteria:

 -  Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL
 according to the World Health Organization (WHO) criteria, including previous
 documentation of:

 -  Biopsy-proven SLL

 -  Diagnosis of CLL according to NCI working group criteria as evidenced by all of the
 following:

 -  Peripheral blood lymphocyte count of > 5,000/mm^3 consisting of small to moderate
 size lymphocytes, with < 55% prolymphocytes

 -  Immunophenotyping consistent with CLL defined as:

 -  The predominant population of lymphocytes share both B-cell antigens (CD19,
 CD20 [typically dim expression], or CD23) as well as CD5 in the absence of
 other pan-T-cell markers (CD3, CD2, etc.)

 -  Clonality as evidenced by kappa or lambda light chain expression (typically
 dim immunoglobulin expression)

 -  Note: splenomegaly, hepatomegaly, or lymphadenopathy are not required for
 the diagnosis of CLL

 -  Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by
 demonstrating a negative FISH analysis for t(11;14)(immunoglobulin heavy
 [IgH]/cyclin D1 [CCND1]) on peripheral blood or tissue biopsy or negative
 immunohistochemical stains for CCND1 on involved tissue biopsy

 -  Patients must be previously untreated and meet at least one of the following
 indications for chemotherapy:

 -  Evidence of progressive marrow failure as manifested by the development of or
 worsening anemia (=< 11 g/dl) and/or thrombocytopenia (=< 100,000/mm^3) not due
 to autoimmune disease

 -  Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly

 -  One or more of the following disease-related symptoms:

 -  Weight loss > 10% within the previous 6 months

 -  Extreme fatigue attributed to CLL

 -  Fevers > 100.5 degree Fahrenheit for 2 weeks without evidence of infection

 -  Drenching night sweats without evidence of infection

 -  Progressive lymphocytosis due to CLL with an increase of > 50% over a two-month
 period or an anticipated doubling time of less than six months

 -  Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL
 will be considered prior therapy; nutraceutical treatments with no
 established benefit in CLL (such as epigallocatechin gallate [EGCG], found
 in green tea or other herbal treatments) will not be considered "prior
 treatment"

 -  Marked hypogammaglobulinemia or the development of a monoclonal protein in
 the absence of any of the above criteria for active disease are not
 sufficient for protocol therapy

 -  Serum creatinine =< 1.5 x upper normal levels (UNL)

 -  Total bilirubin =< 1.5 x UNL unless due to Gilbert's disease; if total bilirubin is >
 1.5 x UNL, a direct bilirubin should be performed and must be < 1.5 mg/dL for
 Gilbert's to be diagnosed

 -  Aspartate aminotransferase (AST) =< 3.0 x UNL and alanine aminotransferase (ALT) =<
 3.0 x UNL (unless due to hemolysis or CLL)

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1, or 2

 -  Willingness to provide blood samples as required

 -  Able to adhere to the study visit schedule and other protocol requirements

 Exclusion Criteria:

 -  Any of the following comorbid conditions:

 -  New York Heart Association Class III or IV heart disease

 -  Recent myocardial infarction (< 1 month)

 -  Uncontrolled infection

 -  Infection with the human immunodeficiency virus (HIV/acquired immunodeficiency
 syndrome [AIDS])

 -  Infection with known chronic, active Hepatitis C

 -  Positive serology for hepatitis B (HB) defined as a positive test for HB surface
 antigen (HBsAg); in addition, if negative for HBsAg but HB core antibody (HBcAb)
 positive (regardless of HBsAb status), a HB deoxyribonucleic acid (DNA) test will
 be performed and if positive the subject will be excluded

 -  Pregnant women

 -  Nursing women

 -  Men or women of childbearing potential who are unwilling to employ adequate
 contraception

 -  Other active primary malignancy requiring treatment or limiting survival to =< 2 years

 -  Any radiation therapy =< 4 weeks prior to registration

 -  Any major surgery =< 4 weeks prior to registration

 -  Current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of
 prednisone or equivalent dose of other steroid) used for treatment of non-hematologic
 medical conditions; Note: previous use of corticosteroids is allowed

 -  Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
 treatment; patients who have a positive Coombs test but no evidence of hemolysis are
 NOT excluded from participation