Oblimersen Sodium and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage I, Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES: I. To assess the feasibility and determine the rate of rapid turn around,
that is within 7 working days of receipt of adequate tissue at UNMC for a AFFYmetrix
microarray study of newly diagnosed patients with Diffuse Large B-cell Lymphoma (DLBCL) who
will then receive treatment on this protocol. II. To evaluate efficacy (complete response
rate) of Genasense (antisense bcl-2) given in addition to standard cyclophosphamide,
vincristine, doxorubicin, and prednisone -rituximab (CHOP-R) to newly diagnosed patients with
DLBCL who are found to have the ABC type after gene expression profiling or IHC as compared
to newly diagnosed patients with DLBCL who do not express the ABC type that go on to receive
standard CHOP-R (control). III. To evaluate the toxicity of Genasense (antisense bcl-2) given
in addition to standard cyclophosphamide, vincristine, doxorubicin, and prednisone -rituximab
(CHOP-R) for newly diagnosed patients with DLBCL who are found to have the ABC type after
gene expression profiling. OUTLINE: Patients with diffuse large B-cell lymphoma (DLBCL) that
expresses ABC type proceed to treatment in group I. Patients with DLBCL that does not express
ABC type proceed to treatment in group II. GROUP I (oblimersen sodium and standard CHOP-R):
Patients receive oblimersen sodium IV continuously on days 1-7. Patients also receive CHOP-R
comprising rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine
sulfate IV on day 5 and prednisone orally on days 5-10. Treatment repeats every 3 weeks for
up to 8 courses in the absence of disease progression or unacceptable toxicity. GROUP II
(standard CHOP-R alone): Patients receive CHOP-R comprising rituximab IV, cyclophosphamide
IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1 and prednisone orally
on days 1-5. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease
progression or unacceptable toxicity. After completion of study therapy, patients are
followed periodically.

Inclusion Criteria:

- Newly diagnosed patients with Diffuse Large B-cell Lymphoma (DLBCL) (any stage) OR
composite lymphoma with >= 50% DLBCL

- Adequate diagnostic tissue for microarray gene expression analysis or IHC analysis

- Karnofsky Performance Status >= 70 (ECOG 0, 1)

- No prior chemotherapy (with the exception of 1 cycle CHOP-R based on current
diagnosis, clinical condition, and availability/feasibility of initiating Genasense),
immunotherapy, radiotherapy, or investigational therapies for NHL; steroid therapy is
allowed only if required for maintenance of another chronic disease (e.g., rheumatoid
arthritis)

- Patients aged >= 60 years, or patients with a history of coronary artery disease,
congestive heart failure, hypertension, diabetes, or hyperlipidemia must have an
estimated ejection fraction >= 0.45 (45%) by MUGA or echocardiography, performed
within two months of study entry

- Patients must be willing to give written informed consent, and sign an institutionally
approved consent form prior to initiating genasense or any study related activities
(i.e., Genasense & microarray)

- Females of childbearing potential must have a negative serum pregnancy test prior to
enrollment in the study

- Adequate venous access for 7-day continuous infusion

- Patients without evidence of severe organ dysfunction as determined within two weeks
of 1st cycle of CHOP-R: 1) Hemoglobin > 8 g/dl; 2) Absolute neutrophil count > 1000/;
3) Platelets > 100,000 (lower blood counts may be acceptable if due to lymphoma after
review with principal investigator); 4) Creatinine =< 2.0 mg/dL (unless due to NHL);
5) Bilirubin =< 2.0 mg/dL; 6) AST =< 3 x upper normal; 7) ALP =< 3 x upper normal
(unless due to NHL)

- Men and women of reproductive potential must agree to use TWO of the following forms
of birth control every time they have sex throughout the study and for up to 3 months
following discontinuation of study drug: hormonal birth control methods, condoms (male
or female) with or without a spermicidal agent, diaphragm or cervical cap with
spermicidal, IUD, or surgical sterilization while participating in this study

Exclusion Criteria:

- Significant medical disease other than cancer including: 1) Any bleeding or
coagulation disorder including a history of autoimmune hemolytic anemia or autoimmune
thrombocytopenia; 2) Severe pulmonary disease; 3) Uncontrolled congestive heart
failure; 4) New York Heart Association class III or IV disease; 5) Uncontrolled
seizure disorder; and 6) Active infections

- Less than 3 weeks from prior major surgery

- Prior organ allograft

- Known HIV infection (due to expected frequent occurrence of myelo-suppression and
immunosuppression)

- Women who are pregnant (confirmed by a serum pregnancy test in females of reproductive
potential) or breast-feeding (women of child-bearing potential and sexually active
males must be advised to take precautions to prevent pregnancy during treatment or
remain abstinent)

- Women of child-bearing potential and sexually active males must be advised to take
precautions to prevent pregnancy during treatment (unless the subject or subject's
partner(s) is sterile, i.e., women who have had a hysterectomy or have been
post-menopausal for at least twelve consecutive months) or remain abstinent

- Known hypersensitivity to phosphorothiate-containing oligonucleotides

- Concurrent investigational, corticosteroid therapy or any other anti-cancer treatments
(such as chemotherapy, radiation, biologic or investigational therapies) while
receiving protocol therapy; other than one cycle CHOP-R allowed based on current
diagnosis, clinical condition, and availability/feasibility of initiating Genasense;
other than chronic steroid use for another indication (For stage I/II or as clinically
indicated- involved field irradiation as per standard practice is accepted)

- Other investigational drug therapy within 30 days of study entry

- Secondary leukemia or history of antecedent hematologic disorder

- History of second cancer (except for adequately treated basal cell or squamous cell
skin cancer, in situ cervical cancer, or other cancer for which the patient has been
disease-free for three or more years)

- No active CNS disease defined as symptomatic meningeal lymphoma or known CNS
parenchymal lymphoma

- Concomitant anticoagulant therapy is not permitted (with the exception of 1 mg/day of
warfarin for central line prophylaxis)

- Known hypersensitivity to G3139 (Genasense) or R-CHOP

- Neurologic disorders, overt psychosis, mental disability or evidence of limited
capacity to provide fully informed consent or cooperation with the complexities of the
treatment program