Inclusion Criteria:

Arms A, B and C Inclusion Criteria

• Age ≥ 18 years.
• Biopsy-proven relapsed or refractory lymphomas. Relapsed is defined as a relapse that occurred after having a response to the last therapy that lasted > 6 months. Refractory is no response or relapse within 6 months. Previous biopsies < 6 months prior to treatment on this protocol will be acceptable.
  • NOTE: Arms A/B – relapsed or refractory DLBCL within 24 months from the end of anthracycline-based therapy. No prior salvage therapy. Patients can have received radiation therapy as part of initial treatment but not specifically for relapse.
  • NOTE: Arm C patients include relapsed or refractory lymphoma patients of any type for which the recommended treatment includes one of the platinum-based regimens.  Of note, relapsed or refractory double-hit high grade lymphoma patients and relapsed or refractory Hodgkin lymphoma patients will be enrolled in Arm C. There is no limit on the number of prior therapies for Arm C patients. The patient must be eligible for a platinum-based regimen and must not have received the same regimen in the past without responding.
  • Measureable or assessable disease: Measureable disease is defined as measurable by CT (dedicated CT or the CT portion of a PET/CT) or MRI:
    • To be considered measureable, there must be at least one lesion that has a single diameter of ≥ 1.5 cm.
    • NOTE: Skin lesions can be used if the area is ≥ 1.5cm in at least one diameter and photographed with a ruler. Patients with assessable disease by PET are also eligible as long as the assessable disease is biopsy proven lymphoma.
  • Arms A/B – eligible for treatment with ifosfamide, carboplatin, and etoposide (± rituximab).
  • Arm C Eligible for treatment with one of the following standard, every 3 week, platinum-based salvage regimens (with or without monoclonal antibody as appropriate for the disease):
• • ifosfamide/carboplatin/etoposide (ICE) or (RICE);
  • cisplatin, cytosine arabinoside,  dexamethasone (DHAP) or RDHAP;
  • gemcitabine, dexamethasone, cisplatin (GDP) or RGDP;
  • gemcitabine and oxaliplatin (GemOx) or RGemOx;
  • Oxaliplatin, cytosine arabinoside, dexamethasone (OAD) or ROAD.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤ 14 days prior to registration (except creatinine which needs to be obtained ≤ 7 days prior to registration):
  • Hemoglobin ≥ 8.0 g/dL (may transfuse to meet this requirement);
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 75000/mm^3;
  • Total bilirubin ≤ 2 x ULN (if > 2 x ULN direct bilirubin is required and should be ≤ 1.5 x ULN);
  • Alanine aminotransferase (ALT) and Aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Creatinine ≤1.6 mg/dL. If over 1.6 then the Calculated creatinine clearance must be ≥ 55 ml/min using the Cockcroft-Gault formula below:
    • Creatinine clearance for males =    (140 - age)(weight in kg)
    •                                                         ( 72)(serum creatinine in mg/dL);
    • Creatinine clearance for females = (140 - age)(weight in kg)(0.85)
    •                                                         ( 72)(serum creatinine in mg/dL).
• Negative 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.
• HIV test done ≤ 14 days prior to registration.  If positive, the CD4 count must be > 400.
• Provide written informed consent.
• Willingness to have a central venous line (PICC or PORT)    
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research.
• Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to follow the requirements of the intravenous ascorbic acid program schedule.

Arms A, B, and C Exclusion Criteria

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Any therapy ≤ 2 weeks prior to registration.
  • EXCEPTIONS: Patients on ibrutinib or corticosteroids (any dose) may continue therapy up until the new regimen has started at investigator discretion. Corticosteroids can be tapered to lowest possible dose after start of treatment at investigator discretion. Patients can have monoclonal antibodies with steroids prior to registration.
  • EXCEPTION: Palliative radiation is allowed.
• 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.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, pulmonary congestion or pulmonary edema, clinical dehydration, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the lymphoma.
• Other active malignancy than lymphoma.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer that could interfere with this protocol therapy. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria. Patients with non-melanotic skin cancer may enroll.
• History of myocardial infarction ≤ 6 months, or current symptomatic congestive heart failure or LVEF < 40% or with > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure.
• Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal).
• Patients with active CNS lymphoma or active CSF involvement with malignant cells requiring CNS-specific therapy with IV or IT MTX.
  • NOTE: Patients with any prior CNS lymphoma (parenchymalor leptomeningeal) MUST be in CR in those compartments without any maintenance therapy required.
• Patients with uncontrolled or symptomatic kidney stones.
• Known paroxysmal nocturnal hemoglobinuria (PNH).

Arm D Inclusion Criteria

• Patients who had a diagnosis of CCUS with one or more TET2 mutations or TET2 mutations with concurrent splicing genes mutations (SRSF2, U2AF1, SF3B1, and ZRSR2) or epigenetic regulator mutations (DNMT3A, EZH2, IDH1, IDH2). CCUS diagnosis being defined based on the absence of definitive morphologic evidence of hematologic neoplasms from bone marrow biopsy evaluation combined with evidence of pathogenic myeloid somatic mutation with a variant allele frequency (VAF) of at least 2% using our institution’s next generation sequencing (NGS) panel (OncoHeme, Mayo Clinic).
• ECOG Performance Status (PS) 0, 1 or 2.
• Patients must meet at least 1 of these 3 laboratory criteria to be enrolled and the values must be obtained ≤ 7 days prior to registration:
  • Hemoglobin ≤ 10g/dL;
  • Absolute neutrophil count (ANC) ≤ 1000/mm^3;
  • Platelet count ≤ 100,000/mm^3.
• The following laboratory values must be obtained ≤ 7 days prior to registration:
  • Total bilirubin ≤ 2 x ULN (if > 2 x ULN direct bilirubin is required and should be ≤ 1.5 x ULN);
  • Alanine aminotransferase (ALT) and Aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Creatinine ≤ 1.6 mg/dL. If > 1.6, then the Calculated creatinine clearance must be ≥ 55 ml/min using the Cockcroft-Gault formula below:
  • Creatinine clearance for males =     (140 - age)(weight in kg)
  •                                                          ( 72)(serum creatinine in mg/dL);
  • Creatinine clearance for females =  (140 - age)(weight in kg)(0.85)
  •                                                          ( 72)(serum creatinine in mg/dL).
• Negative pregnancy test, 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.
• Provide written informed consent.
• Willingness to have a central venous line (PICC or PORT)   
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to return to enrolling institution (MCR) for follow-up (during the Active Monitoring Phase of the study).
• Willingness to follow the requirements of the intravenous ascorbic acid program schedule.

Arm D Exclusion Criteria

• Bona-fide hematological neoplasm.
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• 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.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, pulmonary congestion or pulmonary edema, clinical dehydration, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• History of myocardial infarction ≤ 6 months, or current symptomatic congestive heart failure or known LVEF < 40% or with > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure.
• Patients with uncontrolled or symptomatic kidney stones.
• Known paroxysmal nocturnal hemoglobinuria (PNH).
• Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal)