A Phase II/III Randomized Study of R-miniCHOP With or Without Oral Azacitidine (CC-486) in Participants Age 75 years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma, Grade IIIb Follicular Lymphoma, Transformed Lymphoma, and High-Grade B-cell Lymphomas With MYC and BCL2 and/or BCL6 Rearrangements.

Inclusion Criteria

- Participants must have histologically or cytologically confirmed diffuse large B-cell

lymphoma (DLBCL), Ann Arbor Stage IIX (bulky), III or IV. Participants with DLBCL

transformed from follicular lymphoma (FL) or marginal zone lymphoma (MZL, including

mucosa-associated lymphoid tissue [MALT] lymphomas), lymphoplasmacytic lymphoma (LPL),

or nodular lymphocyte-predominant Hodgkin Lymphoma (NLPHL) are eligible. Participants

with Grade IIIB follicular lymphoma (FL) or high-grade B-cell lymphomas with MYC and

BCL2 and/or BCL6 rearrangements are also eligible. Participants with DLBCL that arose

from prior CLL (Richter's transformation) are not eligible.

- As defined by the World Health Organization (WHO), eligible lymphoma subtypes include

the following:

- DLBCL, not otherwise specified (NOS)

- DLBCL, germinal-center B-cell type (GCB)

- DLBCL, activated B-cell type (ABC)

- T-cell histiocyte-rich B-cell lymphomas (THRBCL)

- Primary cutaneous DLBCL, leg type

- Intravascular large B cell lymphoma

- EBV+ DLBCL, NOS

- DLBCL associated with chronic inflammation

- HHV8+ DLBCL, NOS

- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements

- High grade B-cell lymphoma, NOS

- Follicular lymphoma grade 3b

- Participants must have staging imaging performed within 28 days prior to registration,

as follows. Positron emission tomography (PET)-computed tomography (CT) baseline scans

are strongly preferred; diagnostic quality magnetic resonance imaging (MRI),

contrast-enhanced CT, or contrast-enhanced MRI scans are also acceptable if PET-CT is

not feasible at baseline. Note: PET-CT will be required at end of treatment (EOT) and

progression for response assessment. All measurable lesions (longest diameter >= 1.5

cm) must be assessed within 28 days prior to registration. Tests to assess

non-measurable disease must be performed within 42 days prior to registration.

- Participants with known human immunodeficiency virus (HIV)-infection are eligible

providing they are on effective anti-retroviral therapy and have undetectable viral

load at their most recent viral load test (must be within 26 weeks prior to

registration). Participants with known HIV must have a CD4 count checked within 28

days prior to registration, but may proceed with therapy regardless of CD4 count.

- All participants must be screened for chronic hepatitis B virus (HBV) within 28 days

prior to registration. Participants with known HBV infection (positive serology) must

also have a HBV viral load performed within 28 days prior to registration, and

participants must have an undetectable HBV viral load on suppressive therapy within 28

days prior to registration. Participants found to be HBV carriers during screening are

eligible and must receive standard of care prophylaxis. Participants with active

hepatitis B (HBV viral load > 500 IU/mL) within 28 days prior to registration are not

eligible

- Participants with a known history of hepatitis C virus (HCV) infection must have an

undetectable HCV viral load within in 28 days prior to registration

- Participants must have a Zubrod performance status of 0-2

- Participants must have adequate renal function, as demonstrated by a creatinine

clearance, calculated by the Cockcroft and Gault formula, of >= 30 ml/min that was

obtained within 28 days prior to registration

- Aspartate aminotransferase (AST) =< 2.5 x institutional upper limit of normal (IULN),

alanine aminotransferase (ALT) =< 2.5 x IULN (within 28 days prior to registration)

- Total bilirubin =< 2 x institutional upper limit of normal (IULN), unless due to

Gilbert's disease, hemolysis, or lymphomatous involvement of liver (within 28 days

prior to registration). Note: If total bilirubin is elevated, and direct bilirubin is

subsequently performed (within 28 days prior to registration) and resulted to be =< 2

x IULN, the participant will be considered eligible

- Absolute neutrophil count (ANC) >= 1000/mcL (within 28 days prior to registration)

- Platelets >= 75,000/mcL (within 28 days prior to registration)

- Hemoglobin (Hgb) >= 8 g/ dL (within 28 days prior to registration)

- If there is a documented lymphomatous involvement of the bone marrow, bone marrow

function within 28 days prior to registration, as evidenced by:

- ANC >= 500/mcL

- Platelets >= 50,000/mcL

- Hemoglobin (Hgb) >= 8 g/ dL

- Participants must have a left ventricular ejection (LVEF) fraction >= 45% as measured

by echocardiogram or radionuclide (multigated acquisition scan [MUGA])

ventriculography within 56 days prior to registration

- For the duration of the study treatment period and for at least 4 months following the

last dose of study drug, male participants must agree to use effective contraceptive

methods during sexual contact with a female of childbearing potential (FCBP) and must

agree to refrain from semen or sperm donation during the same timeframe. Effective

contraceptive methods include a history of vasectomy, use of hormonal contraception or

an intrauterine device (IUD) by the female partner, or use of condoms

- 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)

Exclusion Criteria

- Participants must not have known lymphomatous involvement of the central nervous

system (CNS)

- Participants must not have active inflammatory bowel disease (such as, Crohn's

disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper

bowel removal, or any other gastrointestinal disorder or defect that would interfere

with the absorption, distribution, metabolism, or excretion of the study drug and/or

predispose the subject to an increased risk of gastrointestinal toxicity

- Participants must not have received any prior cytotoxic chemotherapy or rituximab for

treatment of the newly diagnosed DLBCL except for the pre-phase treatment (within

specified dose range) that may have either started before or may start after

registration to S1918. Inhaled, nasal, and topical steroid use is allowed. Prior

cytotoxic chemotherapy and/or antibody therapy for an indolent lymphoma prior to

transformation is allowed. Up to 4 doses of intrathecal (IT) chemotherapy administered

for central nervous system (CNS) prophylaxis is allowed in addition to protocol

therapy. High-dose intravenous methotrexate is not allowed.

- Participants must not have received more than a cumulative of dose 250 mg/m^2 of prior

doxorubicin (or equivalent dose of another anthracycline, such as epirubicin) therapy

(at any time prior to registration).

- Participants must not currently be receiving any other investigational agents

- Participant must not have a history of allergic reactions attributed to azacitidine,

mannitol, or other hypomethylating agents

- Participants must not have active infection (systemic fungal, bacterial, or viral

infection) that is not controlled (defined as ongoing signs/symptoms related the

infection without improvement despite appropriate antibiotics, antiviral therapy,

and/or other treatment)

- Participants must not have active cardiac disease within 26 weeks prior to

registration, including: symptomatic congestive heart failure (New York Heart

Association [NYHA] class 4), unstable angina pectoris, hemodynamically unstable

cardiac arrhythmia, or myocardial infarction

- Participants must not have >= grade 2 neuropathy, by Common Terminology Criteria for

Adverse Events (CTCAE) version (v.) 5.0, within 28 days prior to registration

- Participants must not have any other known uncontrolled intercurrent illness

including, but not limited to ongoing psychiatric illness/social situations that would

limit compliance with study requirements