Ruxolitinib in Combination With CHOP Chemotherapy for the Treatment of Untreated Nodal T-Follicular Helper Cell Lymphomas

Inclusion Criteria:

* Ability to understand and willingness to sign a written informed consent document
* Documented informed consent of the participant and/or legally authorized representative.

  * Assent, when appropriate, will be obtained per institutional guidelines
* Be ≥ 18 years of age on day of signing informed consent
* Have a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) scale (PS) at time of enrollment. Patients with a performance status of 2 on the ECOG scale due to lymphoma may be eligible with principal investigator (PI) approval
* Histologically confirmed nodal T-follicular helper (TFH) cell lymphomas. Nodal TFH cell lymphomas include encompasses three subtypes:

  * Angioimmunoblastic T-cell lymphoma (AITL)(World Health Organization \[WHO\]4R)/follicular helper T-cell lymphoma (TFH lymphoma), angioimmunoblastic type (ICC)/nodal TFH cell lymphoma, angioimmunoblastic-type (WHO5)
  * Nodal peripheral T-cell lymphoma (PTCL) with TFH phenotype (nodal PTCL, TFH)(WHO4R)/TFH lymphoma, NOS (ICC)/nodal TFH cell lymphoma, not otherwise specified (NOS) (WHO5)
  * Follicular T-cell lymphoma (FTCL)(WHO4R)/TFH lymphoma, follicular type (ICC)/ nodal TFH cell lymphoma, follicular-type (WHO5)
* Must be planned to receive full course (6 cycles) chemoimmunotherapy as per clinical standard of care for untreated nodal TFH cell lymphoma
* Have measurable disease, including at least 1 nodal site measuring 1.5 cm or 1 extranodal site measuring 1.0 cm in longest dimension on CT or FDG-PET or marrow-only disease (disease only found on bone marrow biopsy)
* Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
* Absolute neutrophil count (ANC) ≥ 1,000/mm\^3
* Hemoglobin ≥ 8 g/dL
* Platelets ≥ 100,000/mm\^3 (≥ 50,000/mm\^3 in cases of marrow infiltration by lymphoma or hypersplenism per investigator assessment)
* Measured or calculated creatinine clearance ≥ 60 mL/min (glomerular filtration rate \[GFR\] can also be used in place of creatinine clearance \[CrCl\])

  * Creatinine clearance should be calculated per institutional standard
* Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN)

  * (Patients with documented liver or pancreatic involvement with lymphoma may be enrolled if total bilirubin ≤ 3.0 x ULN. Patients with documented Gilbert disease may be enrolled if total bilirubin ≤ 5.0 x ULN) OR direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3.0 x ULN OR ≤ 5 x ULN for patients with liver involvement
* International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN

  * Note: unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, or patient is shown to have an antiphospholipid antibody on workup
* Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN

  * Note: unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, or patient is shown to have an antiphospholipid antibody on workup
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of ≤ 1% per year during the treatment period and for at least 4 months after the last dose of study treatment. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≤ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of ≤ 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
* For women of childbearing potential, a negative serum pregnancy test result during screening period. Women who are considered not to be of childbearing potential are not required to have a pregnancy test
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 4 months after the last treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. Male patients considering preservation of fertility should bank sperm before study treatment
* TO BE ASSESSED UPON COMPLETION OF PART A FOR CONSIDERATION FOR PART B ONLY: Completion of first-line multi-agent chemotherapy with ruxolitinib with CHOP
* TO BE ASSESSED UPON COMPLETION OF PART A FOR CONSIDERATION FOR PART B ONLY: Documentation of response (PR or CR) per Lugano criteria within the previous 3 months
* TO BE ASSESSED UPON COMPLETION OF PART A FOR CONSIDERATION FOR PART B ONLY: Ineligible for or decline consolidative autologous stem cell transplantation. Ineligibility is defined by:

  * Patient deemed ineligible for high-dose chemotherapy and ASCT based on physician's assessment
  * AND at least one of the following criteria:

    * Age ≥ 65 years or
    * Age ≥ 18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥ 3
* TO BE ASSESSED UPON COMPLETION OF PART A FOR CONSIDERATION FOR PART B ONLY: Recovery to ≤ grade 1 or baseline for any toxicities due to prior treatments, with the exception of peripheral neuropathy (recovery to ≤ grade 2) or alopecia

Exclusion Criteria:

* Contraindication to any of the individual components of CHOP, or if receiving an additional 6 cycles of anthracycline would place patient over the anthracycline lifetime cumulative dose (450 mg/m\^2)
* Prior systemic treatment or radiation for T-cell lymphoma except for patients who require lymphoma symptom control during screening may receive steroids in the following manner:

  * Up to 30 mg/day of prednisone or equivalent may be used for lymphoma symptom control during screening, including prior to finalization of staging (not included as part of pre-phase treatment). If glucocorticoid treatment is urgently required at higher doses for lymphoma symptom control prior to the start of study treatment, tumor assessments must be completed prior to initiation of \> 30-100 mg/day of prednisone or equivalent. Prednisone \> 30-100 mg/day or equivalent may be given for a maximum of 7 days as a pre-phase treatment. If patients exceed the allowed dosing of corticosteroids, patients may still be eligible for the study provided that baseline imaging is performed (or repeated) after completion of the course of higher dose of steroids. Allowed corticosteroid dosing resets from the point of imaging forward and patients who do not exceed the allowed corticosteroid dosing from the point of imaging until initiation of study treatment may enroll
* Prior organ transplantation
* Known history of cirrhosis
* Current grade \> 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
* History of other malignancy that could affect compliance with the protocol or interpretation of results except with permission of the principal investigator. The following are eligible without a specific waiver:

  * Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible
  * Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible
  * Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
* Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
* History of thrombosis, such as stroke or pulmonary embolism/deep vein thrombosis, within the last 6 months
* Recent major surgery (within 4 weeks prior to the start of cycle 1), other than for diagnosis
* History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction in the last 6 months
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) which requires systemic treatment. Patients may proceed with screening during treatment for infection, but systemic treatment must be completed by cycle 1 day 1

  * If a patient has signs/symptoms suggestive of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the patient must have a negative molecular (e.g., polymerase chain reaction \[PCR\]) test or 2 negative antigen test results at least 24 hours apart. Patients who do not meet SARS-CoV-2 infection eligibility criteria must be screen-failed and may only be rescreened if the following have been met:
  * At least 10 days since first positive test result have passed in asymptomatic patients or at least 10 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms
* Current and/or history of active tuberculosis or latent tuberculosis
* Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology):

  * Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated by institutional standard
* Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing)

  * Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
* History of uncontrolled HIV

  * Patients with known diagnosis of HIV must have undetectable viral load and be on anti-retroviral therapy
* Known human T cell lymphotropic virus (HTLV) 1/2
* Untreated latent tuberculosis
* Patients with known active central nervous system lymphoma
* Pregnancy or lactation or intending to become pregnant during study
* Symptomatic inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, 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 (ruxolitinib) and/or predispose the subject to an increased risk of gastrointestinal toxicity
* Use of medications or consumption of foods that are strong inducers or inhibitors of cytochrome P450 (CYP)3A must be discontinued at least 2 weeks prior to study intervention. Patients who (after enrollment) require use of a strong CYP3A4 inhibitor to treat a fungal/mold infection will require dose reductions
* Participants who are receiving other investigational agents
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)