Ascorbic Acid and Combination Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma or CCUS

Study Overview
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Brief Summary
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This phase II trial studies the effect of ascorbic acid and combination chemotherapy in treating patients with lymphoma that has come back (recurrent) or does not respond to therapy (refractory) or clonal cytopenia of undetermined significance. Ascorbic acid may make cancer cells more sensitive to chemotherapy. Drugs used in chemotherapy, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ascorbic acid and combination chemotherapy may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the overall response rate (ORR) at the end of 2 cycles for intravenous (IV) ascorbic acid (AA) added to standard salvage therapy compared to standard salvage therapy plus normal saline in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have relapsed within the first 24 months of end of their therapy. (Arms A versus [vs] B) II. To determine the ORR at the end of 2 cycles of AA plus standard salvage chemotherapy in patients with other types of relapsed/refractory lymphomas not eligible for Arms A/B (peripheral T-cell lymphoma [PTCL], double-hit high grade, and Hodgkin lymphoma [HL]). (Arm C) III. To assess the hematological response rate to treatment with high dose intravenous ascorbic acid (IV AA) for clonal cytopenia of undetermined significance (CCUS) patients. (Arm D) SECONDARY OBJECTIVES: I. To compare the adverse event profile of IV AA added to salvage therapy versus salvage therapy plus IV saline in patients with DLBCL using both the Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes (PRO)-CTCAE. (Arms A and B) II. To compare the progression-free survival, overall survival, clinical benefit rate (those not progressing), and percentage (%) transplant eligible patients proceeding to transplant of AA added to salvage therapy versus salvage therapy plus IV saline in patients with DLBCL. (Arms A and B) III. To compare the ORR at the end of 4 cycles for those with minor response/stable disease at the end of cycle 2 who proceed to receive the additional 2 cycles of rituximab, dexamethasone, cytarabine and cisplatin (RDHAP) with either AA or normal saline (NS) as previously assigned. (Arms A and B) IV. To evaluate the adverse event profile, rate of febrile neutropenia, overall survival, progression-free survival, and clinical benefit rate of AA added to salvage therapy in patients with relapsed/refractory lymphoma. (Arm C) V. To assess safety/tolerability, transfusion dependency (TD), progression-free survival (PFS), and overall survival (OS) for CCUS patients receiving high dose IV AA. EXPLORATORY OBJECTIVES: I. Will include baseline AA levels (at Mayo Clinic Research [MCR]) and staining of pre/post treatment biopsies for markers of oxidative stress generation and deoxyribonucleic acid (DNA) methylation. (Arms A, B, and C Correlative Research on blood and tumor tissue) IIa. To assess TET2 activity at baseline, weeks 12, 20, and 52. (Arm D correlative research) IIb. To assess the association between using AA and the hydroxymethylation and methylation status (gene-specific and global changes in 5mC/5hmC level) at baseline and weeks 20 and 52. (Arm D correlative research) IIc. To assess the association between using IV AA and endothelial dysfunction (at baseline, weeks 20, and 52). (Arm D correlative research) IId. To assess the association between using IV AA and the inflammation markers. (Arm D correlative research) IIe. To assess the association between using IV AA and molecular response including clonal dynamics (new mutations and variant allele frequency [VAF]) (at baseline, weeks 20, and 52). (Arm D correlative research) OUTLINE: Patients with DLBCL are randomized to Arms A or B. Patients with other lymphomas are assigned to Arm C. Patients with CCUS are assigned to Arm D. Arm A: Patients receive ascorbic acid IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19, and rituximab intravenously (IV), ifosfamide IV, carboplatin IV and etoposide IV on days 1-3. Patients who achieve minor response (MR) or stable disease (SD) after 2 cycles may receive rituximab IV or PO, cisplatin IV or PO, cytarabine IV or PO, and dexamethasone IV or PO. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive placebo (normal saline) IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19, and rituximab intravenously IV, ifosfamide IV, carboplatin IV and etoposide IV on days 1-3. Patients who achieve MR or SD after 2 cycles may receive rituximab IV or PO, cisplatin IV or PO, cytarabine IV or PO, and dexamethasone IV or PO. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive ascorbic acid IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19. Patients also receive ifosfamide, carboplatin, and etoposide IV or PO, or cisplatin, cytarabine, and dexamethasone IV or PO, or gemcitabine hydrochloride, dexamethasone, and cisplatin IV or PO, or gemcitabine hydrochloride and oxaliplatin IV or PO, or oxaliplatin, cytarabine, and dexamethasone IV or PO according to standard regimen schedule. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve MR or SD after 2 cycles may switch to an alternative chemotherapy regimen. ARM D: Patients receive ascorbic acid IV three times a week (TIW). Treatments repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. In Arms A, B, and C, patients who achieve complete response (CR), partial response (PR) or MR may undergo stem cell transplantation. After completion of study treatment, patients are followed up every 3 months, then every 6 months after progressive disease for up to 2 years.

Official Title
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LS1781: Phase 2 Trial of High Dose Intravenous Ascorbic Acid as an Adjunct to Salvage Chemotherapy in Relapsed / Refractory Lymphoma and Patients With Clonal Cytopenia of Undetermined Significance

Conditions
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Clonal Cytopenia of Undetermined Significance, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Hodgkin Lymphoma, Recurrent Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Lymphoma

Intervention / Treatment
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* Dietary Supplement: Ascorbic Acid
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Etoposide
* Drug: Gemcitabine Hydrochloride
* Drug: Ifosfamide
* Other: Laboratory Biomarker Analysis
* Drug: Oxaliplatin
* Other: Placebo Administration
* Other: Questionnaire Administration
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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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 Measurable or assessable disease: measurable disease is defined as measurable by computed tomography (CT) (dedicated CT or the CT portion of a positron emission tomography [PET]/CT) or magnetic resonance imaging (MRI): to be considered measurable, 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 >= 1.5 cm 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 rituximab/ifosfamide/carboplatin/etoposide (RICE); Cisplatin, cytarabine (cytosine arabinoside), dexamethasone (DHAP) or RDHAP; Gemcitabine hydrochloride (gemcitabine), dexamethasone, cisplatin (GDP) or rituximab, gemcitabine, dexamethasone, cisplatin (RGDP); Gemcitabine and oxaliplatin (GemOx) or rituximab, gemcitabine and oxaliplatin (RGemOx); Oxaliplatin, cytosine arabinoside, dexamethasone (OAD) or rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Hemoglobin >= 8.0 g/dL (may transfuse to meet this requirement), obtained =< 14 days prior to registration Absolute neutrophil count (ANC) >= 1500/mm^3, obtained =< 14 days prior to registration Platelet count >= 75000/mm^3, obtained =< 14 days prior to registration Total bilirubin =< 2 x upper limit of normal (ULN) (if > 2 x ULN direct bilirubin is required and should be =< 1.5 x ULN), obtained =< 14 days prior to registration Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement), obtained =< 14 days prior to registration Creatinine =< 1.6 mg/dL; if over 1.6 then the calculated creatinine clearance must be >= 55 ml/min using the Cockcroft-Gault formula, obtained =< 7 days prior to registration 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 Human immunodeficiency virus (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 (peripherally inserted central catheter [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 ARM D: 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) ARM D: ECOG performance status (PS) 0, 1 or 2 ARM D: Patients must meet at least 1 of these 3 laboratory criteria to be enrolled: Hemoglobin =< 10g/dL (obtained =< 7 days prior to registration) Absolute neutrophil count (ANC) =< 1000/mm^3 (obtained =< 7 days prior to registration) Platelet count =< 100,000/mm^ 3 (obtained =< 7 days prior to registration) ARM D: Total bilirubin =< 2 x ULN (if > 2 x ULN direct bilirubin is required and should be =< 1.5 x ULN) (obtained =<7 days prior to registration) ARM D: Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement) (obtained =<7 days prior to registration) ARM D: Creatinine =< 1.6 mg/dL (obtained =<7 days prior to registration). If > 1.6, then the Calculated creatinine clearance must be >= 55 ml/min using the Cockcroft-Gault formula ARM D: Negative pregnancy test, for persons of childbearing potential only (obtained =< 7 days prior to registration). NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. ARM D: Provide written informed consent ARM D: Willingness to have a central venous line (PICC or PORT) ARM D: Willingness to provide mandatory blood specimens for correlative research ARM D: Willingness to return to enrolling institution (MCR) for follow-up (during the active monitoring phase of the study) ARM D: Willingness to follow the requirements of the intravenous ascorbic acid program schedule Exclusion Criteria: Any of the following: Pregnant persons Nursing persons Persons of childbearing potential who are unwilling to employ adequate contraception Any therapy =< 2 weeks prior to registration; NOTE: Exception: 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. 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 left ventricular ejection fraction (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 central nervous system (CNS) lymphoma or active cerebrospinal fluid (CSF) involvement with malignant cells requiring CNS-specific therapy with IV or intrathecal (IT) methotrexate (MTX); Note: Patients with any prior CNS lymphoma (parenchymal or leptomeningeal) MUST be in complete remission (CR) in those compartments without any maintenance therapy required Patients with uncontrolled or symptomatic kidney stones Known paroxysmal nocturnal hemoglobinuria (PNH) ARM D: Bona-fide hematological neoplasm ARM D: 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 ARM D: 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 ARM D: 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 ARM D: 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 ARM D: Patients with uncontrolled or symptomatic kidney stones ARM D: Known paroxysmal nocturnal hemoglobinuria (PNH) ARM D: Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (ascorbic acid, combination chemotherapy)<br>Patients receive ascorbic acid IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19, and rituximab intravenously IV, ifosfamide IV, carboplatin IV and etoposide IV on days 1-3. Patients who achieve MR or SD after 2 cycles may receive rituximab IV or PO, cisplatin IV or PO, cytarabine IV or PO, and dexamethasone IV or PO. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. | Dietary Supplement: Ascorbic Acid<br>* Given IV<br>* Other names: Vitamin-C;Drug: Carboplatin<br>* Given IV or PO<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV or PO<br>* Other names: Platosin;Drug: Cytarabine<br>* Given IV or PO<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV or PO<br>* Other names: VP16;Drug: Ifosfamide<br>* Given IV or PO<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Active Comparator: Arm B (placebo, combination chemotherapy)<br>Patients receive placebo (normal saline) IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19, and rituximab intravenously IV, ifosfamide IV, carboplatin IV and etoposide IV on days 1-3. Patients who achieve MR or SD after 2 cycles may receive rituximab IV or PO, cisplatin IV or PO, cytarabine IV or PO, and dexamethasone IV or PO. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV or PO<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV or PO<br>* Other names: Platosin;Drug: Cytarabine<br>* Given IV or PO<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV or PO<br>* Other names: VP16;Drug: Ifosfamide<br>* Given IV or PO<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given normal saline IV<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Arm C (ascorbic acid and combination chemotherapy)<br>Patients receive ascorbic acid IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19. Patients also receive ifosfamide, carboplatin, and etoposide IV or PO, or cisplatin, cytarabine, and dexamethasone IV or PO, or gemcitabine hydrochloride, dexamethasone, and cisplatin IV or PO, or gemcitabine hydrochloride and oxaliplatin IV or PO, or oxaliplatin, cytarabine, and dexamethasone IV or PO according to standard regimen schedule. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve MR or SD after 2 cycles may switch to an alternative chemotherapy regimen. | Dietary Supplement: Ascorbic Acid<br>* Given IV<br>* Other names: Vitamin-C;Drug: Carboplatin<br>* Given IV or PO<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV or PO<br>* Other names: Platosin;Drug: Cytarabine<br>* Given IV or PO<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV or PO<br>* Other names: VP16;Drug: Gemcitabine Hydrochloride<br>* Given IV or PO<br>* Other names: LY188011;Drug: Ifosfamide<br>* Given IV or PO<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Oxaliplatin<br>* Given IV or PO<br>* Other names: SR-96669;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm D (ascorbic acid)<br>Patients receive ascorbic acid IV TIW. Treatments repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. | Dietary Supplement: Ascorbic Acid<br>* Given IV<br>* Other names: Vitamin-C;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) (Arms A and B) | Defined as an objective status of complete response (CR) or partial response (PR) evaluated by Response Evaluation Criteria in Lymphoma (RECIL) criteria after 2 courses of treatment in all arms. Will be compared between the two arms. The proportion of successes will be estimated in each arm by the number of successes divided by the total number of evaluable patients. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. For the diffuse large B-cell lymphoma (DLBCL) arms, comparison of overall response rates between the two treatment groups will be performed using a one-sided chi-square test at significance level 0.10. | Up to 2 years | 
| ORR (Arm C) | Defined as an objective status of CR or PR evaluated by RECIL criteria after 2 cycles of treatment. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. | Up to 2 years | 
| Hematologic response (HI) rate (Arm D) | Defined as an objective status of HI-E (minor or major response), HI-P, or HI-N evaluated by Myelodysplastic Syndrome International Working Group 2018 criteria at 20 weeks. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. | At 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate (Arms A, B, and C) | Will be estimated in each arm by the number of patients who achieve a CR, PR, minor response (MR), or stable disease (SD) on the cycle 2 response assessment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated. The clinical benefit rate will be compared between the DLBCL arms using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse). | Up to 2 years | 
| Overall survival | The distribution of overall survival will be estimated in each arm using the method of Kaplan-Meier. In the DLBCL arms, the comparison of overall survival between the two treatment arms will be based on the log-rank test. | From registration to death due to any cause, assessed up to 2 years | 
| Progression-free survival | The distribution of progression-free survival will be estimated in each arm using the method of Kaplan-Meier. In the DLBCL arms, the comparison of progression-free survival between the two treatment arms will be based on the log-rank test. | From date of first treatment to the earliest date of documentation of disease progression or death due to any cause, assessed up to 2 years | 
| Percent of transplant eligible patients proceeding to transplant (Arms A, B and C) | Will be estimated in each arm by the number of patients proceeding to transplant divided by the total number of patients who were considered transplant eligible. Exact binomial 95% confidence intervals for the true success rate will be calculated. The rate will be compared between the DLBCL arms using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse). | Up to 2 years | 
| Transfusion dependency (Arm D) | Transfusion dependency will be summarized descriptively. The number of patients transfusion dependent at baseline and during follow-up will be summarized. | Up to 2 years | 
| Incidence of adverse events | Assessed using Common Terminology Criteria for Adverse Events (CTCAE). The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. In the DLBCL arms, the overall adverse event rates for Grade 3 or higher hematologic and non-hematologic adverse events at least possibly related to treatment will be compared between the two treatment groups using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse). The rate of febrile neutropenia will be evaluated in each arm. | Up to 2 years | 
| Incidence of adverse events | Assessed using Patient Reported Outcomes (PRO)-CTCAE (Arms A and B). PRO-CTCAE scores range from 0-4, with corresponding response choices for frequency (Never / Rarely / Occasionally / Frequently / Almost constantly), for severity (None / Mild / Moderate / Severe / Very severe) and interference (Not at all / A little bit / Somewhat / Quite a bit / Very much). The scores for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. PRO-CTCAE scores will be compared between the two treatment groups using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse). | Up to 2 years | 
| Continued salvage therapy beyond cycle 2 (Arm A, B and C) | Will be assessed by evaluating the number of patients who achieve an improved response after cycle 4 compared to the cycle 2 assessment in patients who received additional cycles of ascorbic acid/placebo added to salvage therapy beyond cycle 2. In addition, the number of patients who changed salvage therapies after cycle 2 will be assessed. This analysis will be primarily descriptive. | Up to 2 years |