Ofatumumab (O) in Combination With Chemotherapy: Hyper-Fractionated Cyclophosphamide, Doxorubicin, Vincristine and Dexamethasone (O-HyperCVAD) Alternating With Ofatumumab High-Dose Cytarabine and Methotrexate (O-MA) for Patients With Newly Diagnosed Mantle Cell Lymphoma

Inclusion Criteria:

- Histologically documented mantle cell lymphoma with co-expression of CD20 and CD5 and
lack of CD23 expression by immunophenotyping and at least one of the following
confirmatory tests: 1.) Positive immunostaining for cyclin D1; 2.) The presence of
t(11;14) on cytogenetic analysis; OR 3.) Molecular evidence of bcl-1/IgH
rearrangement

- Cases that are CD5-negative and/or CD23-positive will be eligible provided that
the histopathology is consistent with mantle cell lymphoma AND positive for
cyclin D1, t(11;14), or bcl-1/IgH rearrangement

- A tissue block or unstained slides (10 - 20 slides) will be submitted to the
Roswell Park Cancer Institute (RPCI) Pathology Department for central pathology
review

- A diagnosis based on peripheral blood or bone marrow aspirate is allowed; if the
diagnosis is based only on blood, in addition to the immunophenotype and
molecular confirmation above, a peripheral blood smear must be available for
central pathology review; if the diagnosis is based on a bone marrow, the tissue
block (core biopsy or clot if available) or otherwise the diagnostic smears will
be submitted to the RPCI Pathology Department

- Extent of disease: stage I - IV; patients with nodular histology mantle cell lymphoma
must have Ann Arbor stage III or IV disease to be eligible

- Patients with mantle zone type histology will not be eligible because of their
relatively favorable prognosis

- Patients with other mantle cell histologies are eligible regardless of stage

- Measurable or assessable disease is required; measurable tumor size (at least one
node measuring 2.25 cm^2 in bidimensional measurement)

- No active central nervous system (CNS) disease defined as symptomatic meningeal
lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating mantle
cell lymphoma at the time of registration to this study is not an exclusion for study
enrollment

- Patients must be previously untreated

- No prior radiation therapy for MCL

- >= 2 weeks since major surgery

- No known hypersensitivity to murine products

- No medical condition requiring chronic use of high dose systemic corticosteroids
(i.e., doses of prednisone higher than 10 mg/day or equivalent)

- No human immunodeficiency virus (HIV) infection; patients with a history of
intravenous drug abuse or any behavior associated with an increased risk of HIV
infection should be tested for exposure to the HIV virus; patients who test positive
or who are known to be infected are not eligible; an HIV test is not required for
entry on this protocol, but is required if the patient is perceived to be at risk

- Non-pregnant and non-nursing; women and men of reproductive potential should agree to
use an effective means of birth control

- Patients who test positive for Hepatitis C antibody (Ab) are eligible provided all of
the following criteria are met: 1.) total bilirubin =< 2 x upper limit of normal; 2.)
AND aspartate aminotransferase (AST) =< 3 x upper limit of normal; AND 3.) liver
biopsy (pathology) demonstrates =< grade 2 fibrosis and no cirrhosis

- Specific guidelines will be followed regarding inclusion of MCL based on hepatitis B
virus (HBV) serological testing as follows:

- Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb)
negative, hepatitis B surface antibody (HBsAb) positive MCL patients are
eligible

- Patients who test positive for HBsAg are ineligible (regardless of other
hepatitis B serologies)

- MCL patients with HBsAg negative, but HBcAb positive (regardless of HBsAb
status), should have HBV DNA testing done and protocol eligibility determined as
follows:

- If HBV DNA is positive the subject is excluded

- If HBV DNA is negative, patient may be included but must undergo at least
every 2 months HBV DNA polymerase chain reaction (PCR) testing from the
start of treatment throughout the duration the study

- Monitoring during the study is required at least every 2 months and during
follow-up at a minimum of every 2 - 3 months up to 6 months after the last
dose

- Prophylactic antiviral therapy with lamivudine (3TC) or investigator's
preferred antiviral regimen throughout protocol therapy and for 6-12 months
thereafter may be initiated at the discretion of the investigator

- If the patients' HBV DNA becomes positive during the study, the
investigator should manage the clinical situation as per the standard of
care of participating institution; the investigator should weigh the risks
and benefits of continuing ofatumumab or discontinuing ofatumumab before
appropriate treatment decisions are made for that individual patient

- Patients must not have a history of cardiac disease, defined as New York Heart
Association Class II or greater or clinical evidence of congestive heart failure
(CHF)

- No known hypersensitivity to ofatumumab, humanized antibodies or chemotherapy agents
throughout the protocol

- Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or
echocardiogram (ECHO) >= 45%

- Neutrophils > 1000/μL

- Platelets >= 75,000/μL (unless significant bone marrow involvement with MCL)

- Creatinine =< 2.0 mg/dL

- Total bilirubin =< 2.0 mg/dL (unless MCL related or attributable to Gilbert's
disease)

- Urine or serum beta-human chorionic gonadotropin (HCG) or serum HCG = negative (if
female patient of childbearing potential)

- Patient or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Prior history of HIV-positivity (routine HIV testing is not required pre-treatment)

- Positive serology for HBV defined as a positive test for HBsAg; in addition, if
negative for HBsAg but HBcAb positive, a HBV DNA test will be performed and if
positive the patient will be excluded

- Serious non-malignant disease (e.g., active uncontrolled bacterial, viral, or fungal
infections) or other medical conditions (including psychiatric) which, in the opinion
of the Principal Investigator (PI) would compromise other protocol objectives

- Presence of symptomatic CNS lymphoma

- Pregnant or lactating females

- Prior history of radiation or chemotherapy for MCL

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ofatumumab or other agents used in study

- Patients with a "currently active" second malignancy, other than non-melanoma skin
cancer or in situ carcinoma of the cervix or breast; patients are not considered to
have a "currently active" malignancy if they have completed anti-cancer therapy, are
considered by their physician to be at less than 30% risk of relapse and at least 2-5
years have lapsed

- Major surgery, other than diagnostic surgery, within 2 weeks

- Patients with non-Hodgkin lymphoma (NHL) other than MCL

- Patients must not have a history of cardiac disease, defined as New York Heart
Association Class II or greater or clinical evidence of CHF; all patients must have a
MUGA scan or 2-D echocardiogram indicating an ejection fraction of >= 45% within 42
days prior to registration; the method used at baseline must be used for later
monitoring

- Unwilling or unable to follow protocol requirements

- Any condition which in the Investigator's opinion deems the patient an unsuitable
candidate to receive study drug

- Received an investigational agent within 30 days prior to enrollment