Combination Chemotherapy and TAK-659 as Front-Line Treatment in Treating Patients With High-Risk Diffuse Large B Cell Lymphoma

Inclusion Criteria:

* Patients must have a pathologically confirmed diagnosis of DLBCL (including DLBCL not otherwise specified \[NOS\], DLBCL germinal center B-cell \[GCB\] type, DLBCL activated B cell \[ABC\]/non-GCB type, T cell/histiocyte-rich large B cell lymphoma, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B cell lymphoma NOS). NOTE: DLBCL transformed from low-grade lymphoma among treatment-naive patients or patients previously treated with a non-anthracycline containing regimen are permitted
* Patients may have completed the first cycle of R-CHOP (off study not combined with TAK-659) =\< 21 days prior to the first dose of TAK-659 or plan to receive the first cycle of R-CHOP after registration
* Patients must have at least one high-risk feature, including:

  * ABC/non-GCB subtype determined by gene expression profiling or Hans algorithm by immunohistochemistry per treating institution standards
  * High-intermediate or high-risk group by National Comprehensive Cancer Network - International Prognostic Index (NCCN-IPI) with score \>= 4, at time of diagnosis
  * MYC gene rearrangement (by \[fluorescent in situ hybridization\] FISH)
  * MYC overexpression by immunohistochemistry (IHC) (\>= 40%) and BLC2 overexpression by IHC (\>= 50%) or
  * Previously treated transformed low-grade lymphoma to large B cell lymphoma with prior treatment not including an anthracycline
  * NOTE: BCL2 and/or BCL6 aberrancy are not required for enrollment, but assessment for rearrangement by FISH and overexpression by IHC are required if there is presence of MYC rearranged by FISH
* Patients must have measurable disease (defined as \>= 1.5 cm in diameter) with correlated fluorodeoxyglucose (FDG)-avidity on positron emission tomography (PET) scan with Deauville score of 4 or 5 at time of diagnosis
* Patients must have recovered (i.e., =\< grade 1 toxicity) from the reversible effects of prior anticancer therapy, if applicable
* Life expectancy of greater than 3 months
* Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Absolute neutrophil count \>= 1000/mcL (within 14 days prior to registration)
* Platelets \>= 75,000/mcl (NOTE: Patients with bone marrow involvement may be eligible with platelets \>= 50,000) (within 14 days prior to registration)
* Hemoglobin \>= 8 g/dL (within 14 days prior to registration)

  * NOTE: Red blood cell (RBC) and platelet transfusion allowed \>= 14 days prior to registration
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to registration)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x institutional ULN (within 14 days prior to registration)
* Creatinine clearance \>= 60 mL/min either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours) (within 14 days prior to registration)
* Lipase =\< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis (within 14 days prior to registration)
* Amylase =\< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis (within 14 days prior to registration)
* Patients must have blood pressure =\< grade 1

  * NOTE: Hypertensive patients are permitted if their blood pressure is controlled to =\< grade 1 by hypertensive medications
* Female patients must meet at least one of the following criteria:

  * Are postmenopausal with last menstrual period at least 1 year before registration OR
  * Are surgically sterile, OR
  * If they are of childbearing potential

    * Agree to practice 1 highly effective method of contraception and one additional effective (barrier) method at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or
    * Agree to practice true abstinence, when is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together
    * Agree not to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug
* Male patients, even if surgically sterilized (i.e., status post-vasectomy), must:

  * Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or
  * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception. Female and male condoms should not be used together.)
  * Agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug
* Female of childbearing potential (FOCBP) must have a negative pregnancy test =\< 7 days prior to registration on study
* Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
* Patients must have the ability to swallow oral medication
* Patients must be willing and able to complete study-required procedures

Exclusion Criteria:

* Patients with exposure to chemotherapy or immunotherapy =\< 30 days prior to starting study treatment are not eligible

  * NOTE: Patients may receive at most 1 cycle of R-CHOP, rituximab, or systemic corticosteroids within this timeframe
  * NOTE: If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration
* Patients with prior exposure to a SYK inhibitor are not eligible

  * NOTE: Examples of SYK inhibitors include fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659
* Patients with untreated brain metastases or leptomeningeal metastases are not eligible
* Patients with known hypersensitivity (e.g. anaphylactic and anaphylactoid reactions) to TAK-659 or components of R-CHOP are not eligible
* Patients with history of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening imaging are not eligible

  * NOTE: A history of radiation pneumonitis in the radiation field (fibrosis) is permitted
* Patients with known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection are not eligible
* Patients who are known to be human immunodeficiency virus (HIV) positive are not eligible
* Patients must not have had autologous stem cell transplant within 6 months prior to registration
* Patients must have not had allogeneic stem cell transplant at any time
* Patients who have received systemic anticancer treatment (including investigational agents) or radiotherapy less than 3 weeks before the first dose of study treatment (=\< 5 times half-life for large molecule agents or =\< 4 weeks with evidence of disease progression if 5 times half-life is \> 4 weeks) are not eligible

  * NOTE: Patients may receive R-CHOP cycle 1
  * NOTE: If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration
* Use or consumption of the following substances is not permitted:

  * Medications or supplements that are known to be inhibitors of P-gp and/or strong reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known), or within 7 days (if a reasonable half-life estimate is unknown), before the first dose of study drug. The use of these agents is not permitted during the study
  * Medications or supplements that are known to be strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days, or within 5 times the inhibitor or inducer half-life (whichever is longer), before the first dose of study drug. The use of these agents is not permitted during the study
  * Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are prohibited during the study
* Patients who have major surgery, per principal investigator (PI) discretion, =\< 14 days before the first dose of study drug and those who have not recovered fully from any complications from surgery are not eligible
* Patients who have systemic infection requiring parenteral antibiotic therapy or other serious infection (bacterial, fungal or viral) =\< 21 days before the first dose of study drug are not eligible

  * NOTE: Patients who are at substantial risk of developing an infection may receive prophylaxis at the start of study treatment per investigator?s discretion
* Patients with an active secondary malignancy that requires treatment are not eligible

  * NOTE: Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are considered disease-free at the time of registration
* Patients with known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 are not eligible (this may include difficulty swallowing tablets or diarrhea \> grade 1 despite supportive therapy)
* Patients who received treatment with high-dose corticosteroids for anticancer purposes =\< 7 days before the first dose of TAK-659 are not eligible

  * NOTE: Prednisone and other steroids given as part of the R-CHOP regimen and as pre-medications are exceptions throughout the study. Patients may also receive steroids prior to starting chemotherapy to improve performance status. In other contexts, daily dose equivalent to 10 mg oral prednisone or less is permitted. Corticosteroids for topical use or in nasal spray or inhalers are allowed
* Patients who have known central nervous system (CNS) lymphomatous involvement are not eligible
* Patients who have an uncontrolled intercurrent illness, in the opinion of the investigator, including, but not limited to any of the following, are not eligible:

  * Uncontrolled pulmonary disease
  * Active CNS disease that would interfere with study participation
  * Active infection requiring parenteral systemic treatment
  * Psychiatric illness/social situations that would limit compliance with study requirements
  * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient?s safety or study endpoints
* Patients with any of the following cardiovascular conditions are excluded:

  * Acute myocardial infarction within 6 months before starting study drug
  * Current or history of New York Heart Association class III or IV heart failure
  * Evidence of current, uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  * Fridericia corrected QT interval (QTcF) \> 450 milliseconds (msec) (men) or \> 475 msec (women) on a 12-lead electrocardiography (ECG) during the screening period
  * Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that, in the opinion of the investigator, are considered to be clinically significant
  * Abnormal left ventricular function (ejection fraction \[EF\] \< 50%, as indicated by baseline echocardiography \[ECHO\])
* Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of TAK-659