Registration - Inclusion Criteria:

• Age ≥ 18 years old.
• Newly diagnosed, untreated, histologically confirmed diffuse large B-cell lymphoma expressing the CD20 antigen, with ANY of the following:
  • Non-GCB subtype by Hans algorithm
  • Myc expression ≥40% by IHC
  • Bcl-2 expression ≥50% by IHC
  • Myc expression ≥40% AND Bcl-2 expression ≥50% by IHC (double expressor)
  • MYC rearrangement by FISH
• Or high-grade B-cell lymphoma MYC with MYC rearrangement AND BCL2 and/or BCL6 rearrangement (double-hit or triple-hit lymphoma) but not a candidate for more aggressive chemotherapy (such as CODOX-M-IVAC)
  • NOTE: Patients with a new diagnosis of concurrent DLBCL and an indolent lymphoma (previously undiagnosed, such as follicular lymphoma or marginal zone lymphoma) are eligible. However, patients with a known prior diagnosis of indolent lymphoma with new transformation to DLBCL (i.e., transformed lymphoma) are not eligible.
• Ann Arbor Stages II (bulky disease; i.e., ≥ 5 cm, or not a candidate for combined modality treatment with R-CHOP plus radiotherapy), III, or IV (See Appendix I for Ann Arbor Staging).
• Measurable disease (at least 1 lesion of ≥ 1.5 cm in one diameter) as detected by CT or the CT images of PET/CT. Skins lesions can be used if the area is ≥ 2 cm in at least one diameter and photographed with a ruler.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤14 days prior to registration:
  • Absolute neutrophil count (ANC) ≥1500/mm^3;
  • Platelet count 100,000/mm^3;
  • Total bilirubin ≤ 1.5 upper limit of normal (ULN), or if total bilirubin is > 1.5 ULN, the direct bilirubin must be normal;
  • Aspartate transaminase (AST) 3 ULN (≤ 5 ULN for patients with direct liver involvement by lymphoma);
  • Alkaline phosphatase ≤ 3 ULN, unless evidence of the direct liver involvement by lymphoma, then ≤ 5 ULN;
  • Calculated creatinine clearance of ≥ 30 mL/min using the Cockcroft-Gault formula below:

    • Creatinine clear for males =     (140 - age) x weight in Kg
                                                   72 x serum creatinine in mg/dL

    • Creatinine clear for females = (140 - age) x weight in Kg x 0.85
                                                      72 x serum creatinine in mg/dL

• Negative urine pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Persons of childbearing potential must agree to use one reliable form of birth control.
• Provide written informed consent.
• Willingness to provide mandatory research blood specimens for banking.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Registration - Exclusion Criteria

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons (lactating persons are eligibile provided that they aree not to breast feel while taking parscaclisib);
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Primary CNS lymphoma, or parenchymal, meningeal or cerebrospinal fluid involvement with malignant lymphoma cells.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy (except for patients on effective antiretroviral therapy with undetectable viral load within 6 months).
  • NOTE: If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • NOTE: If history of hepatitis C virus (HCV) infection, HCV viral load must be undetectable.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • symptomatic congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • ongoing inflammatory bowel disease (such as ulcerative colitis) or other colitis requiring active treatment;
  • oxygen dependent baseline lung disease (such as interstitial lung disease or COPD);
  • or psychiatric illness/social situations that would limit compliance with study requirements.
• Received or receiving any other agent which would be considered as a treatment for the lymphoma (with the exception of corticosteroid).
• Other active malignancy requiring therapy such as radiation, chemotherapy or immunotherapy. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria.
  • EXCEPTIONS: Localized non-melanotic skin cancer or any cancer that in the judgment of the investigator has been treated with curative intent (e.g., disease-free survival equal or more than 5 years) and will not interfere with the study treatment plan and response assessment.
  • NOTE: If there is a history of prior malignancy, they must not require therapy such as radiation, chemotherapy or immunotherapy for their cancer.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• ≥ 25% of bone marrow radiated for other diseases.
• Ejection fraction of < 45% by either MUGA or ECHO.