Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest may be eligible provided they meet all other inclusion/exclusion criteria

Patients must have follicular lymphoma (grade I, II or IIIa) confirmed at initial diagnosis and at relapse with identifiable fludeoxyglucose F-18 (FDG) avid disease on PET/CT; patients that have involvement with large cell lymphoma are not eligible

Patients with B-lymphoblastic lymphoma (B-LL) are not eligible

Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, high grade B-cell lymphoma not otherwise specified, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

Disease must be anaplastic lymphoma kinase (ALK) positive (defined by local institutional standards)

If the lab abnormality is thought to be due to the lymphoma the patient is eligible and dose adjustments should be made

Patients must have histologically or cytologically confirmed relapsed/refractory CD30 low (< 10%) TCL:\r\n* Peripheral TCL not otherwise specified (PTCL NOS)\r\n* Angioimmunoblastic T cell lymphoma (AITL)\r\n* Hepato-splenic T cell lymphoma (HTCL)\r\n* Adult T cell leukemia/lymphoma (ATLL)\r\n* Enteropathy associated T cell lymphoma (EATL)\r\n* Natural killer (NK) T cell lymphoma (NK/TCL)\r\n* Transformed mycosis fungoides

Pathologically confirmed mantle cell lymphoma (MCL) which is relapsed or refractory to at least one chemotherapy containing regimen\r\n* Presence of cyclin D1 expression and/or t(11;14) by fluorescence in situ hybridization (FISH) or cytogenetics is required

Patients must have histologically confirmed mantle cell lymphoma (MCL)\r\n* Please note: measurable disease is not required, but will be followed if it exists

Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma not-otherwise specified [NOS]) as defined in the World Health Organization (WHO) classification

PARTICIPANTS FROM COLLABORATING SITES PARTICIPATING IN BIOLOGICAL OBJECTIVES ONLY: Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma NOS) as defined in the WHO classification

Histologic diagnosis other than a mature B-cell lymphoma as defined in the WHO classification

Systemic lymphoma

Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS);

Anaplastic large cell lymphoma (ALCL); or

Natural-killer/T-cell lymphoma (NKTL)

Clinical evidence of transformation to a more aggressive subtype of lymphoma

Philadelphia (Ph)-positive ALL, Burkitt’s leukemia/lymphoma, or lymphoblastic lymphoma

Histologically documented CD20-positive lymphoma

Fluorodeoxyglucose (FDG)-avid lymphoma (that is [i.e.], PET-positive lymphoma)

Histologically confirmed, relapsed or refractory, follicular B-cell NHL (follicular lymphoma) Grade 1, 2, and 3a.

Known histological transformation from indolent NHL to diffuse large B-cell lymphoma.

Relapsed or refractory mantle cell lymphoma (MCL) with no adequate therapies.

Subjects with TiNHL are eligible if they have received no prior cytotoxic chemotherapy for lymphoma. Steroids, rituximab, and external beam radiation therapy as prior therapy for indolent lymphoma is allowed.

Biopsy proven plasmablastic lymphomas, or peripheral T cell lymphoma (with the exception of anaplastic lymphoma kinase positive [ALK+] type in first or second complete remission) (timeline 8 months prior to enrollment)

Subjects who have Burkitt's lymphoma or Burkitt-like lymphoma.

Cutaneous T cell Lymphoma (CTCL)

Histologically documented CD20-positive B-cell lymphoma as determined by the local laboratory

fluorodeoxyglucose (FDG)-avid lymphoma (i.e., positron emission tomography (PET)-positive lymphoma)

Grade 3b follicular lymphoma

History of transformation of indolent disease to diffuse large B-cell lymphoma (DLBCL)

NHL SA expansion: Mature B-cell NHL with the following histologies: primary mediastinal lymphoma, DLBCL, and B-cell lymphoma not specified that is R/R to standard therapy and for whom standard treatments are contraindicated or unavailable

Patients must have a histological diagnosis of any of the following (all stages allowed):\r\n* Diffuse large b-cell lymphoma (DLBCL) (including transformation from a previously indolent non-Hodgkin lymphoma [NHL], so long as no prior systemic treatment was given for the indolent NHL)\r\n* B-cell lymphoma, unclassifiable\r\n* Burkitt lymphoma\r\n* MYC+ plasmablastic lymphoma by histology

NOTE: these requirements do not apply to those with marrow involvement of lymphoma (any extent)

Anaplastic large cell lymphoma (ALCL), ALK positive

Angioimmunoblastic T-cell lymphoma (AITL)

Enteropathy-associated T-cell lymphoma

Extranodal natural killer (NK) T-cell lymphoma, nasal type

Hepatosplenic T-cell lymphoma

Peripheral T-cell lymphoma, no otherwise specified (NOS)

Precursor T-cell lymphoma or leukemia

Adult T-cell lymphoma/leukemia (ATLL)

Primary cutaneous type anaplastic large cell lymphoma

Pathologically confirmed relapsed or refractory lymphoma

Histologically confirmed diagnosis of PTCL (using the most recent edition of the World Health Organization [WHO] Classification of Tumors of Hematopoietic and Lymphoid Tissues as guidance) including: \r\n* Anaplastic large cell lymphoma, anaplastic large cell kinase (ALK)-negative \r\n* Angioimmunoblastic T-cell lymphoma \r\n* Enteropathy-type T-cell lymphoma\r\n* Hepatosplenic gamma-delta T-cell lymphoma \r\n* Peripheral T-cell lymphoma, unspecified (not otherwise specified [NOS]) \r\n* Transformed mycosis fungoides\r\n* Subcutaneous panniculitis-like T-cell lymphoma. \r\n* NOTE: patients with adequate archived (well-preserved, formalin-fixed) biopsy tissue remaining will be required to submit a portion for exploratory studies; this is not optional if tissue is available; however, lack of adequate tissue for exploratory studies will not preclude patients from participating

Patients with a diagnosis of any of the following are not eligible:\r\n* Anaplastic large cell lymphoma, ALK-positive \r\n* Adult T-cell lymphoma/leukemia (ATLL)\r\n* Anaplastic large-cell lymphoma, primary cutaneous type\r\n* Precursor T-lymphoblastic lymphoma/leukemia\r\n* Mycosis fungoides/Sezary syndrome (except transformed mycosis fungoides [MF])\r\n* Natural killer (NK)-cell leukemia\r\n* T-cell granular lymphocytic leukemia\r\n* T-cell prolymphocytic leukemia

DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma, composite lymphoma (HL+NHL) or DLBCL transformed from diseases other than indolent NHL.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL)

Histologically-confirmed B-cell non-Hodgkin’s lymphoma (mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone lymphoma, diffuse large B-cell lymphoma, and lymphoplasmacytic lymphoma)

Prior treatment with carfilzomib for lymphoma

Diagnosis of one of the following:\r\n* Relapsed/refractory peripheral T-cell lymphoma of any subtype including mycosis fungoides and Sezary syndrome of advanced stage (IIB-IVB)\r\n** For the expansion cohort: patients must have biopsy-proven T-cell lymphoma and measurable disease\r\n* Relapsed/refractory DLBCL (up to 6 DLBCL patients are allowed in the dose-escalation portion of the study)\r\n* Relapsed/refractory Hodgkin lymphoma (HL)\r\n* Note: extracorporeal photopheresis is NOT considered a systemic therapy for this study

Histologically confirmed CD30-positive, CD20-positive untreated primary mediastinal B-cell lymphoma (any Ann Arbor stage), diffuse large B-cell lymphoma (Ann Arbor stage III or IV), or grey zone lymphoma (any Ann Arbor stage); patients with heterogeneous, weak or equivocal CD30 staining will also be included (no specific cut off percentage for CD30 stain is required)

CNS lymphoma.

Patients with T-cell or B cell lymphoblastic lymphoma confirmed by conventional immature T- or pre B cell markers even if the bone marrow is not involved are also eligible

1. Diffuse Large Cell Lymphoma (NOT primary mediastinal B-cell lymphoma) -2. Burkitt's Lymphoma

3. High Grade B-cell Lymphoma---Burkitt's like.

Patients with newly diagnosed Group A (low risk) lymphoma. Patients with Group B (intermediate risk) if classified as Murphy Stage III/IV and diagnostic LDH > 2 XULN and patients with primary mediastinal B-cell lymphoma (PMBL).

Patients must have histologically or cytologically confirmed non-Hodgkin’s lymphoma for which standard therapies do not exist or are no longer effective; to be eligible for this study, lymphoma patients must have no marrow involvement as documented by routine marrow aspiration and biopsy performed within 30 days of study entry

PROCUREMENT: Diagnosis of Hodgkin’s or non-Hodgkin’s lymphoma:\r\n* GROUP A: \r\n** With active disease \r\n*** In second or subsequent relapse\r\n*** In first relapse for indolent lymphoma after first line therapy for relapse\r\n*** Or first relapse if immunosuppressive chemotherapy contraindicated\r\n*** Primary refractory disease or if persistent disease after first line therapy of relapse\r\n** Or multiply relapsed patients in remission who are at a high risk of relapse or the lymphoma is a second malignancy e.g. a Richter's transformation of chronic lymphocytic leukemia (CLL) after failing frontline therapy OR\r\n* GROUP B:\r\n** After autologous or syngeneic stem cell transplant (SCT) (as adjuvant therapy)

TREATMENT: Diagnosis of Hodgkin’s or non-Hodgkin’s lymphoma:\r\n* GROUP A: \r\n** With active disease \r\n*** In second or subsequent relapse\r\n*** In first relapse for indolent lymphoma after first line therapy for relapse\r\n*** Or first relapse if immunosuppressive chemotherapy contraindicated\r\n*** Primary refractory disease or if persistent disease after first line therapy of relapse\r\n** Or multiply relapsed patients in remission who are at a high risk of relapse or the lymphoma is a second malignancy e.g. a Richter's transformation of CLL after failing frontline therapy OR\r\n* GROUP B:\r\n** After autologous or syngeneic SCT (as adjuvant therapy)

One of the following untreated, histological confirmed lymphoma expressing cluster of differentiation (CD)20 antigen\r\n* DLBCL with disconcordant and/or composite pathology e.g. low grade follicular lymphoma within bone marrow or lymph node are eligible\r\n* DLBCL transformation follicular lymphoma (FL) – untreated with anthracyclines or high dose chemotherapy/autologous stem cell transplantation; patients treated with rituximab alone, non-anthracycline containing regiments and previously observed only are eligible

Receiving any other agent which would be considered as a treatment for the lymphoma

Any patient, regardless of age or sex, with Epstein-Barr virus (EBV)-positive lymphoma, or lymphoepithelioma regardless of the histological subtype or EBV (associated)-T/natural killer (NK)-lymphoproliferative disorder (LPD) all confirmed on any tissue sample\r\n* Primary refractory lymphoma or in second or subsequent relapse including after autologous or syngeneic stem cell transplant OR patients at a high risk for relapse defined as: (i) patients with primary refractory lymphoma or multiply relapsed lymphoma who are in remission but not eligible for autologous stem cell transplant (SCT) or (ii) patients with relapsed lymphoma after autologous SCT who are in remission but not eligible for allogeneic SCT (Group A) OR\r\n* Any patient who has received an allogeneic SCT for EBV lymphoma or EBV (associated)-T/NK-LPD or lymphoepithelioma (Group B)

Patients must have histologically documented metastatic solid tumors which have progressed after one line of therapy, or lymphoma which has progressed after all Food and Drug Administration (FDA)-approved therapy; this trial will enroll a minimum of 5 lymphoma patients

Patients must have histologically confirmed transformed diffuse large B-cell lymphoma (DLBCL), including histologic transformation from any indolent lymphoma (e.g. follicular or marginal zone lymphoma); (patients with Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma are excluded)

Histologically confirmed diagnosis of a histiocyte/dendritic cell neoplasm or relapsed/refractory aggressive lymphoma with at least one of the following features (with review required at a participating study center):\r\n* Diffuse large B cell lymphoma with Epstein-Barr virus (EBV) positive tumor cells (defined as positive EBV-encoded ribonucleic acid [RNA] in tumor cells)\r\n* Plasmablastic lymphoma\r\n* T cell/histiocyte rich diffuse large B-cell lymphoma (DLBCL)\r\n* EBV+ T cell lymphoma of any histology; note, patients with angioimmunoblastic T cell lymphoma will be eligible regardless of EBV status\r\n* Histiocytic sarcoma\r\n* Follicular dendritic cell sarcoma\r\n* Interdigitating dendritic cell sarcoma

Participants with hematologic lymphoma

Participantts with diffuse large B-cell lymphoma (DLBCL) relapsed or refractory to ? 1 course of chemotherapy including an anti-CD20 monoclonal antibody, and not eligible for autologous stem cell transplantation (ASCT) (including due to chemorefractory disease). Participants with transformed FL are eligible, provided DLBCL histology is biopsy-confirmed prior to study entry and a treatment regimen as described above has been administered. The Sponsor retains the option to limit the number of participants enrolled with transformed FL.

Non-Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma (HL) beyond first remission

Prior therapy must include a BTK inhibitor in diseases for which approved therapy includes a BTK inhibitor (i.e., SLL/CLL, WM, and mantle cell lymphoma). Subjects with DLBCL must have failed, refused, or be ineligible for autologous stem cell transplant. Subjects with low grade lymphoma must be progressing and requiring treatment.

Falls under one of the following subtypes of CD52 positive non-Hodgkin lymphoma (defined as >= 50% positive staining by immunohistochemical staining or flow cytometry by local lab):\r\n* High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (DHL)\r\n* DLBCL or high-grade B-cell lymphoma NOS or B-cell lymphoma unclassifiable with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma with MYC and BCL2 protein over-expression by immunohistochemical (IHC) staining as defined by MYC expression in >= 30% of cells and BCL2 positivity >= 50% (DOL)\r\n* Transformed lymphoma with MYC rearrangement by fluorescence in situ hybridization (FISH) or over-expression by IHC, as above\r\n* CD52 positive mature T-cell lymphoproliferative disorder

Histologically confirmed mature peripheral T-cell or natural killer (NK)-cell lymphoma per World Health Organization (WHO) classification, including: \r\n* Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) with international protein index (IPI) of 2 or higher (must have stage III-IV disease)\r\n* ALK-negative ALCL\r\n* PTCL-not otherwise specified (NOS)\r\n* Angioimmunoblastic T-cell lymphoma (AITL)\r\n* Adult T-cell lymphoma/leukemia (ATLL) \r\n* Enteropathy-associated T-cell lymphoma (EATL)\r\n* Hepatosplenic T-cell lymphoma

INCLUSION - PROCUREMENT: Referred patients will initially be consented for procurement of blood for generation of the transduced ATL; eligibility criteria at this stage include:\r\n* Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including angioimmunoblastic T-cell lymphoma [AITL], enteropathy-associated T-cell lymphoma [EATL], monomorphic epitheliotropic intestinal T-cell lymphoma [MEITL], peripheral T-cell lymphoma [PTCL] not otherwise specified [NOS], anaplastic large cell lymphoma [ALCL] adult T-cell leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, extranodal natural killer [NK]/T cell lymphoma, mycosis fungoides/ Sezary syndrome stage IIb or higher)\r\nAND\r\n* suitable for allogeneic hematopoietic stem cell transplant (HSCT)\r\n** with confirmation of an identified eligible allogeneic (allo)-HSCT donor by a Foundation for the Accreditation of Cellular Therapy (FACT) accredited transplant center AND \r\n** with confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission\r\n* For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated

INCLUSION - TREATMENT: Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including angioimmunoblastic T-cell lymphoma [AITL], enteropathy-associated T-cell lymphoma [EATL], monomorphic epitheliotropic intestinal T-cell lymphoma [MEITL], peripheral T-cell lymphoma [PTCL] NOS, anaplastic large cell lymphoma [ALCL], adult T-cell leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, extranodal NK/T cell lymphoma, mycosis fungoides/ Sezary syndrome stage IIB or higher) AND\r\n* suitable for allogeneic hematopoietic stem cell transplant (HSCT) \r\n** with confirmation of an identified eligible allo-HSCT donor by a FACT accredited transplant center AND\r\n** with confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission\r\n* For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated

Participants with small cell lung cancer, lymphoma, or myeloma

INCLUSION - INFUSION: Any patient, regardless of age or sex, with measurable EBV-positive Hodgkin’s or non-Hodgkin’s lymphoma, (regardless of the histological subtype) or EBV (associated)-T/NK- or B cell lymphoproliferative disease\r\n* The first 3 patients enrolled will be adults; patients <18 years of age are eligible if those first 3 patients do not experience dose limiting toxicity considered to be primarily related to the EBVST or nivolumab\r\n* Patients with relapsed or refractory lymphoma who failed or are ineligible for an autologous hematopoietic cell transplantation are also eligible for this study; and\r\n* Hodgkin’s lymphoma patients in second relapse or first relapse and refractory to at least two lines of salvage chemotherapy including brentuximab vedotin or primary refractory disease after at least two lines therapy, or\r\n* Non- Hodgkin’s lymphoma patients in first relapse and/or refractory to at least one salvage chemotherapy or with primary refractory disease after at least two lines of therapy or in second or subsequent relapse, or\r\n* T/NK- or B lymphoproliferative disease in first relapse and/or refractory to at least one salvage chemotherapy or with primary refractory disease after at least two lines of therapy or in second or subsequent relapse

Key Inclusion Criteria:\n\n        -Any of the following as defined by the WHO, 2016 lymphoid neoplasm classifications and\n        histologically confirmed:\n\n          -  Diffuse large B-cell lymphoma (DLBCL), Not Otherwise Specified (NOS): Germinal center\n             B-cell type (GCB), Activated B-cell type (ABC)\n\n          -  High-grade B-cell lymphoma (HGBCL) NOS\n\n          -  HGBCL with MYC and BCL2 and/or BCL6 rearrangements\n\n          -  T-cell histocyte-rich large B-cell lymphoma\n\n          -  EBV+ DLBCL, NOS\n\n          -  HHV8+ DLBCL, NOS\n\n        Relapsed or refractory disease following at least 2 lines (and a maximum of 4 lines) of\n        prior rituximab containing multi-agent chemotherapy which may include an autologous stem\n        cell transplantation unless patients are not considered suitable for intensive second-line\n        chemotherapy or autologous stem cell transplantation. Patients who are ineligible for\n        intensive second line chemotherapy,must have received at least one prior\n        rituximab-containing combination chemotherapy regimen. Patients who are ineligible for\n        intensive second line chemotherapy, must have received at least one prior\n        rituximab-containing combination chemotherapy regimen.\n\n          -  Baseline measurable disease with at least 1 bi dimensional lesion with longest\n             diameter (LDi) >1.5cm on CT scan which is FDG avid on PET scan.\n\n          -  A biopsy (archived or Screening/recent) will be collected at Screening.\n\n          -  At least 18years of age (or ?20 years in Japan).\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.\n\n        Key Exclusion Criteria:\n\n          -  Active central nervous system (CNS) lymphoma.\n\n          -  Prior organ transplantation including prior allogeneic SCT.\n\n          -  Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic\n             T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab,\n             tremelimumab or any other antibody, or drug specifically targeting T cell co\n             stimulatory or immune checkpoint pathways).

TREATMENT INCLUSION: Diagnosis and clinical course falling into one of the following categories:\r\n* Hodgkin lymphoma refractory to second line chemotherapy; relapsed or progressive after high dose therapy/autologous stem cell transplantation; relapsed or progressive after treatment with brentuximab or a checkpoint inhibitor\r\n* Aggressive non-Hodgkin lymphoma refractory to second line chemotherapy; relapsed or progressive after high dose therapy/autologous stem cell transplantation\r\n* ALK-negative anaplastic T cell lymphoma or other peripheral T-cell lymphoma refractory to first line chemotherapy; relapsed after first line therapy (possibly including high dose therapy/autologous stem cell transplantation)\r\n* ALK-positive anaplastic T cell lymphoma refractory to second line therapy; relapsed after second line therapy

Biopsy proven aggressive B-cell Non-Hodgkin Lymphoma (B-NHL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), follicular lymphoma Grade 3B, PMBCL, T-cell rich B-cell lymphoma, or DLBCL that represents transformation of indolent non-Hodgkin's Lymphoma (NHL), (including follicular, marginal zone, and lymphoplasmacytoid lymphoma) excluding chronic lymphocytic leukemia or Hodgkin Lymphoma. The following histologies are not eligible:

Lymphoblastic lymphoma

Burkitt lymphoma

Nodular lymphocyte predominant Hodgkin’s lymphoma subtype

Alanine transaminase (ALT) ? 3 times the ULN, unless determined to be directly due to lymphoma.

Aspartate transaminase (AST) ? 3 times the ULN, unless determined to be directly due to lymphoma

INCLUSION CRITERIA:\n\n          1. Age ?18 years\n\n          2. Histologically confirmed diagnosis, according to the World Health Organization (WHO,\n             2008) classification, of: DLBCL NOS, THRLBCL, EBV-positive DLBCL, composite lymphoma\n             with a DLBCL component with a DLBCL relapse subsequent to DLBCL treatment, disease\n             transformed from an earlier diagnosis of low grade lymphoma (i.e. an indolent\n             pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with a DLBCL\n             relapse subsequent to DLBCL treatment.\n\n          3. Fresh tumour tissue for central pathology review must be provided as an adjunct to\n             participation in this study. Should it not be possible to obtain a fresh tumour tissue\n             sample, archival paraffin embedded tumour tissue acquired ?3 years prior to screening\n             for this protocol must be available for this purpose.\n\n          4. Patients must have:\n\n               1. relapsed or refractory DLBCL\n\n               2. at least one bidimensionally measurable disease site. The lesion must have a\n                  greatest transverse diameter of ?1.5 cm and greatest perpendicular diameter of\n                  ?1.0 cm at baseline. The lesion must be positive on PET scan\n\n               3. received at least one, but no more than three previous systemic therapy lines for\n                  the treatment of DLBCL. At least one previous therapy line must have included a\n                  CD20-targeted.\n\n               4. ECOG 0 to 2\n\n          5. Patients after failure of ASCT or patients considered in the opinion of the\n             investigator currently not eligible for HDC with subsequent ASCT.\n\n          6. Patients must meet the following laboratory criteria at Screening:\n\n               1. ANC ?1.5 × 109/L (unless secondary to bone marrow involvement by DLBCL)\n\n               2. PLTs ?90 × 109/L (unless secondary to bone marrow involvement by DLBCL) and\n                  absence of active bleeding\n\n               3. total serum bilirubin ?2.5 × ULN unless secondary to Gilbert's syndrome (or\n                  pattern consistent with Gilbert's) or documented liver involvement by lymphoma.\n                  Patients with Gilbert's syndrome or documented liver involvement by lymphoma may\n                  be included if their total bilirubin is ?5 x ULN\n\n               4. ALT, AST and AP ?3 × ULN or <5 × ULN in cases of documented liver involvement by\n                  lymphoma\n\n               5. serum creatinine ?2.0 x ULN or creatinine clearance must be ?40 mL/min calculated\n                  using a standard Cockcroft-Gault formula (Cockroft & Gault, 1976)\n\n          7. For a female of childbearing potential (FCBP), a negative pregnancy test must be\n             confirmed before enrolment. An FCBP must commit to take highly effective contraceptive\n             precautions without interruption during the study and for 3, 6 or 12 months after the\n             last dose of MOR00208, BEN or RTX respectively, whichever is later. An FCBP must\n             refrain from breastfeeding and donating blood or oocytes during the course of the\n             study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX\n             respectively, whichever is later. Restrictions concerning blood donations apply as\n             well to females who are not of childbearing potential.\n\n          8. Males must use an effective barrier method of contraception without interruption\n             during the study and for 3, 6 or 12 months after the last dose of MOR00208, BEN or RTX\n             respectively, whichever is later, if the patient is sexually active with an FCBP.\n             Males must refrain from donating blood or sperm during study participation and for 3,\n             6 or 12 months after the last dose of MOR00208, BEN or RTX respectively, whichever is\n             later.\n\n          9. In the opinion of the investigator, the patients must:\n\n               1. be able to comply with all study-related procedures, medication use, and\n                  evaluations\n\n               2. be able to understand and give informed consent\n\n               3. not be considered to be potentially unreliable and/or not cooperative.\n\n        EXCLUSION CRITERIA:\n\n          1. Patients who have: any other histological type of lymphoma including, e.g., primary\n             mediastinal (thymic) large B-cell lymphoma (PMBL) or Burkitt's lymphoma, primary\n             refractory DLBCL, patients with known \double/triple hit\ DLBCL genetics, CNS lymphoma\n             involvement in present or past medical history\n\n          2. Patients who had a major surgery less than 30 days prior to Day 1 dosing\n\n          3. Patients who have, within 14 days prior to Day 1 dosing:\n\n               1. not discontinued CD20-targeted therapy, chemotherapy, radiotherapy,\n                  investigational anticancer therapy or other lymphoma-specific therapy\n\n               2. received live vaccines\n\n               3. required parenteral antimicrobial therapy for active, intercurrent systemic\n                  infections\n\n          4. Patients who:\n\n               1. in the opinion of the investigator, have not recovered sufficiently from the\n                  adverse toxic effects of prior therapies, major surgeries or significant\n                  traumatic injuries\n\n               2. were previously treated with CD19-targeted therapy or BEN\n\n               3. have a history of previous severe allergic reactions to compounds of similar\n                  biological or chemical composition to MOR00208, RTX, murine proteins or BEN, or\n                  the excipients contained in the study drug formulations\n\n               4. have undergone ASCT within a period of ?3 months prior to signing the informed\n                  consent form. Patients who have a more distant history of ASCT must exhibit full\n                  haematological recovery before enrolment into the study.\n\n               5. have undergone previous allogeneic stem cell transplantation\n\n               6. concurrently use other anticancer or experimental treatments\n\n          5. Prior history of malignancies other than DLBCL, unless the patient has been free of\n             the disease for ?3 years prior to Screening. Exceptions to the ?3-year time limit\n             include history of the following:\n\n               1. basal cell carcinoma of the skin\n\n               2. squamous cell carcinoma of the skin\n\n               3. carcinoma in situ of the cervix, breast and bladder\n\n             f) incidental histological finding of prostate cancer (Tumour/Node/Metastasis [TNM]\n             stage of T1a or T1b)\n\n          6. Patients with:\n\n               1. positive hepatitis B and/or C serology\n\n               2. known seropositivity for or history of active viral infection with HIV\n\n               3. evidence of active, severe uncontrolled systemic infections or sepsis\n\n               4. a history or evidence of severely immunocompromised state\n\n               5. a history or evidence of severe hepatic impairment (total serum bilirubin > 3\n                  mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver\n                  involvement by lymphoma\n\n               6. a history or evidence of clinically significant cardiovascular, cerebrovascular,\n                  CNS and/or other disease that, in the investigator's opinion, would preclude\n                  participation in the study or compromise the patient's ability to give informed\n                  consent

Diagnosis of t-FL/DLBCL is allowed. However, other B-cell lymphomas including other transformed indolent lymphomas/DLBCL per the 2008 WHO classification, and Burkitt lymphoma are not eligible.

Patients must have a diagnosis of mantle cell lymphoma confirmed at diagnosis by one of the following:\r\n* t(11;14) detected by fluorescence in situ hybridization (FISH), conventional cytogenetics, or other molecular evaluation\r\n* Expression of cyclin D1 confirmed by immunohistochemistry

lymphoma

Diagnosis of follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL) (meeting International Workshop on Chronic Lymphocytic Leukemia [IWCLL] Criteria 2008), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), or non-germinal center B-cell lymphoma (GCB) diffuse large B-cell lymphoma (DLBCL) as documented by medical records on WHO criteria

History or diagnosis of mantle cell lymphoma or anaplastic large cell lymphoma.

Diffuse large B cell lymphoma (DLBCL). Histology based upon bone marrow biopsies and/or fine needle aspirates as the sole means of diagnosis are not acceptable.

Histologically confirmed relapsed (response to last treatment >= 6 months duration) or refractory (no response to last treatment or response duration < 6 months) indolent/low grade B cell NHL; NOTE: if patient has received previous anti-PD-1 or anti-PDL-1 consult with study chair\r\n* Follicular lymphoma, grades 1, 2 and 3\r\n* Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type\r\n* Splenic and nodal marginal zone lymphoma\r\n* Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia;

Pathology confirmed relapsed or refractory T-cell lymphoma (PTCL and stage > IB CTCL) at treating institution

A histologically confirmed diagnosis of mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL) de novo or in the setting of transformation from an indolent lymphoma (including DLBCL not otherwise specified) according to the World Health Organization criteria for diagnosis of NHL; AND

Patients with lymphoblastic lymphoma are also eligible

Patients must have histologically determined indolent NHL that is relapsed or primary refractory after initial therapy; indolent NHL includes the morphologic and clinical variants:\r\n* Follicular lymphoma, grades 1-3a\r\n* Marginal zone lymphoma (extranodal, nodal, or splenic)\r\n** All nodal marginal zone lymphomas are eligible\r\n** Extranodal marginal zone lymphomas of the stomach (gastric mucosa associated lymphoid tissue [MALT] lymphomas) may not be candidates for cure with antibiotics or local radiotherapy; patients who have failed antibiotics or local therapy are eligible for the protocol as long as they have measurable disease\r\n** Splenic marginal zone lymphoma patients may have received prior splenectomy as long as they have measurable disease\r\n* Re-biopsy is not mandated at relapse unless there is clinical suspicion about an alternate diagnosis

Patients must have histologically confirmed diffuse large B-cell lymphoma (DLBCL); patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are eligible only if they have not previously been treated for indolent lymphoma; for the Phase II study, patients must have non-GC DLBCL as determined by Hans Algorithm

Patients must not have been previously treated with chemotherapy or radiation for diagnosis of lymphoma; brief (< 15 days) treatment with glucocorticoids is acceptable

Patients with T-cell lymphoma (untreated, relapsed or refractory) (Phase II)

Untreated ALK+ anaplastic large cell lymphoma (ALCL)

Patients with large cell transformation of cutaneous T cell lymphoma are eligible

Patients with systemic T cell lymphoma of any stage and any subtypes; patient must have had at least one standard chemotherapy and measurable disease at the time of enrollment

Chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma or follicular lymphoma that have progressed after at least two different prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant; these patients must be presented at primary care center (PCC) prior to enrollment, given potential competing eligibility on autotransplant protocols

Histologically confirmed relapsed or refractory extranodal NK/T-cell lymphoma (ENKTL), nasal type, or EBV-associated diffuse large B cell lymphomas

Patients with histological confirmation of relapsed/refractory non-GCB type (using Hans algorithm) diffuse large B cell lymphoma (DLBCL) or relapsed/refractory primary CNS lymphoma (PCNSL) with at least one of the following characteristics:\r\n* Definition of refractory disease: progression of disease based on Cheson criteria for DLBCL or international primary CNS lymphoma cooperative group for PCNSL either with nonresponse or progression within 3 months of prior therapy\r\n* Definition of relapsed disease: progression of disease based on Cheson criteria for DLBCL or International primary CNS lymphoma cooperative group for PCNSL at least 3 months after prior therapy\r\n* Definition of non-GCB subtype (Hans algorithm): cases will be subclassified based on immunohistochemical staining with CD10, BCL-6 and MUM-1 as previously described.\r\n* Patients should have exhausted (or be ineligible for) approved therapies known to provide clinical benefit for DLBCL or PCNSL (e.g. high dose chemotherapy with autologous stem cell transplant, chimeric antigen receptor-transduced [CAR-T] therapy, etc.).

Absolute neutrophil count >= 1000/mm^3 within 45 days prior to initiation of therapy. (Patients with documented marrow involvement (with lymphoma) or hypersplenism secondary to involvement of the spleen by lymphoma at the time of randomization are not required to meet the parameter).

Platelet count >= 75K /mm^3 within 45 days prior to initiation of therapy. (Patients with documented marrow involvement (with lymphoma) or hypersplenism secondary to involvement of the spleen by lymphoma at the time of randomization are not required to meet the parameter).

Total bilirubin =< 1.5 mg/dL within 45 days prior to initiation of therapy. (Patients with documented marrow involvement (with lymphoma) or hypersplenism secondary to involvement of the spleen by lymphoma at the time of randomization are not required to meet the parameter).

Histologically-confirmed diagnosis of Follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia(CLL), or diffuse large B-cell lymphoma (DLBCL) a. Subjects must have disease that has relapsed or is refractory to 2 or more prior regimens and in need of treatment due to progressive disease

Known histological transformation to an aggressive lymphoma

Pathologically proven diffuse large B-cell lymphoma

No prior systemic therapy for lymphoma

Cohort #1: histologically confirmed CD20-positive, relapsed or refractory DLBCL, including de novo and transformed DLBCL (from follicular or marginal zone lymphoma); this includes patients with DLBCL who are found to have small cell infiltration of the bone marrow or other diagnostic material (representing a discordant lymphoma)

The patient’s lymphoma must be CD19 positive, either by immunohistochemistry or flow cytometry analysis on the last biopsy available.

Biopsy confirmed low-grade B-cell lymphoma, including grade 1, 2, or 3A follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, or indolent mantle cell lymphoma; patients may be newly diagnosed or previously treated

Patients with large cell transformation of cutaneous T cell lymphoma are eligible

AST (SGOT) and ALT (SGPT) =< 5 x ULN in patients with documented hepatic involvement by lymphoma

Diagnosis of Non-Hodgkin's Lymphoma including Diffuse Large B-cell Lymphoma, Follicular, Small Lymphocytic and Marginal Zone Lymphoma

Histologically or cytologically confirmed relapsed cluster of differentiation (CD)19+ non-Hodgkin lymphoma (NHL) (included in this category are follicular grade I, II, III, marginal zone, mantle cell, gray zone, primary mediastinal, Burkitt's, diffuse large B cell, small lymphocytic lymphoma)

Patients with relapsed/refractory CD19+ non-Hodgkin’s lymphoma of the following subtypes: \r\n* Diffuse large B-cell lymphoma (DLBCL) \r\n* Mantle cell lymphoma (MCL)\r\n* Follicular lymphoma (FL)\r\n* Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL)\r\n* Burkitt’s Lymphoma

Confirmed diagnosis of Marginal Zone Lymphoma or Waldenstroms Macroglobulinemia

Histologically confirmed diagnosis of rel/ref DLBCL, or diffuse large B cell lymphoma transformed from an indolent lymphoma\r\n* Since the endpoint of the phase I portion is safety, any B-cell NHL can be enrolled; however, the progression-free survival (PFS) endpoint varies greatly amongst different types of lymphoma; in order to accurately interpret the survival data, a homogeneous cohort of patients with DLBCL will be evaluated; DLBCL is the most aggressive B-NHL with limited options; other B-NHL’s are generally more indolent and have more options available to them

Patients must have relapsed (first or greater relapse) or refractory lymphoma with:\r\n* Lymphoblastic lymphoma or peripheral T-cell lymphoma\r\n* Histologic verification of disease at original diagnosis or subsequent relapse\r\n* Evaluable or measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry\r\n* Patient may have CNS 2 status if other sites of leukemia or lymphoma involvement are present

Adults with histologically proven solid malignancy, high-grade lymphoma or low-grade lymphoma

Transformed lymphoma

Histologically confirmed mantle cell lymphoma (confirmation of cyclin D1 positivity on diagnostic biopsy)

Histologically confirmed NHL: diffuse large B-cell lymphoma and follicular lymphoma (Grade 1-3A) that has progressed following at least 1 line of prior anticancer therapy.

Patients with peripheral T-cell lymphoma (including but not limited to peripheral T-cell lymphoma, not otherwise specified [PTCL-NOS], angioimmunoblastic T-cell lymphoma, anaplastic large T-cell lymphoma). Patients with mycosis fungoides with large cell transformation with measurable disease is eligible.

Subjects with ALK+, anaplastic large cell lymphoma (ALCL) should have been treated with, be ineligible for, or have refuse chemotherapy and brentuximab prior to enrollment on the current study.

Patients must have B-cell non-Hodgkin lymphoma, including mantle cell, follicular, lymphoplasmacytic, marginal zone, transformed indolent B cell lymphoma (including transformed chromic lymphoid leukemia [CLL]), or diffuse large B cell lymphoma that has relapsed after a response to at least one prior therapy regimen or is refractory to prior therapy; patients with de novo diffuse large B-cell lymphoma (DLBCL) must meet one of the following criteria:\r\n* Biopsy-proven refractory disease after a frontline regimen containing both an anthracycline and rituximab or other anti-CD20 antibody (i.e. “primary refractory”), where any disease recurring within 6 months of completion of the regimen is considered refractory\r\n* Relapsed or refractory disease after at least one of the following:\r\n** At least 2 lines of therapy (including at least one with an anthracycline and anti-CD20 antibody)\r\n** Autologous stem cell transplant\r\n** Allogeneic stem cell transplant

Waldenstrom's macroglobulinemia (WM) or marginal zone lymphoma (MZL) based on institutional pathology review; patients may have either previously untreated or relapsed/refractory disease

Patients must have a diagnosis of B-cell lymphoma confirmed by Laboratory of Pathology, National Cancer Institute (NCI), that is relapsed from or refractory to prior therapy as follows:\r\n* Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone lymphoma or GZL)\r\n* Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the specified extranodal sites (i.e., extranodal DLBCL); the following subtypes are included (they do not have to be confirmed as non-germinal center B-cell [GCB] subtype for study entry):\r\n** Primary central nervous system (CNS) lymphoma (PCNSL)\r\n** Primary testicular lymphoma (PTL)\r\n** Primary breast lymphoma (PBL)\r\n** Primary cutaneous DLBCL, leg-type\r\n** Intravascular large B-cell lymphoma (IVBCL)\r\n** Diffuse large B-cell, not otherwise specified (NOS), activated B-cell type, involving 1 or more extranodal site\r\n* NOTE: For GZL, diagnosis will be in accordance with the 2016 World Health Organization classification of lymphoid malignancies; patients diagnosed with other extranodal DLBCL subtypes or that are not otherwise specified (NOS) must involved at least 1 extranodal site and must be considered non-GCB by local immunohistochemistry algorithms; cases that are non-GCB by the Hans criteria are considered eligible as well as cases of DLBCL that are both CD10+ and MUM1+

For DLBCL\r\n* Histologically confirmed aggressive B cell non-Hodgkin lymphoma (NHL) including the following types defined by World Health Organization (WHO) 2008: \r\n** DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein Barr virus (EBV)+ DLBCL of the elderly; OR \r\n** Primary mediastinal (thymic) large B cell lymphoma \r\n** Transformation of follicular lymphoma, marginal zone lymphoma or chronic lymphocytic leukemia to DLBCL will also be included\r\n* Subjects with DLBCL must have progressed, had stable disease (SD), or recurred after initial treatment regimens that include an anthracycline and an anti CD20 monoclonal antibody; subjects who relapse >= 12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant

Patients must have histologically or cytologically confirmed relapsed and/or refractory B-cell lymphoma confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), as follows:\r\n* Aggressive B-cell lymphoma: includes diffuse large B-cell lymphoma (DLBCL) and subtypes, transformed lymphoma, Burkitt lymphoma, as well as high-grade B-cell lymphoma with MYC and/or BCL2 and/or BCL6 rearrangement(s)\r\n* Indolent B-cell lymphoma:\r\n** Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is excluded\r\n** Mantle cell lymphoma (MCL) is excluded\r\n* NOTE: patients with known active central nervous system (CNS) lymphoma are not eligible

Relapsed and/or refractory disease on at least 1 prior treatment regimen, as follows:\r\n* Aggressive B-cell lymphoma: relapsed after and/or refractory to at least 1 prior doxorubicin-containing regimen\r\n* Indolent B-cell lymphoma: relapsed after and/or refractory to at least 1 prior rituximab-containing regimen

Previously untreated, histologically confirmed indolent non-Hodgkin’s lymphoma as follows:\r\n* Follicular lymphoma (World Health Organization [WHO] classification grade 1, 2, or 3a)\r\n* Marginal zone lymphoma including:\r\n** Nodal and splenic marginal zone lymphoma (MZL) who have an indication for systemic therapy\r\n** Extranodal MZL:\r\n*** Nongastric/noncutaneous MZL requiring systemic therapy\r\n*** Cutaneous MZL will be eligible only if they have pathologically confirmed extra-cutaneous disease\r\n*** Gastric MZL only if stage IIIE/IV defined as lymph node involvement on both sides of the diaphragm or with disseminated extranodal disease such as bone marrow or additional extra nodal sites

Histologically confirmed CD30-positive lymphoma with cutaneous presentation

Grade 3B FL or evidence of transformation of FL to a more aggressive lymphoma

Lymphoma that is not amenable for mandatory pre- and cycle 2 day 15 (C2D15) post-treatment biopsy

Have a histologically confirmed diagnosis of follicular lymphoma, diffuse large B-cell lymphoma, or classical Hodgkin lymphoma according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution\r\n* FL: grade 1, 2, 3A, or 3B are eligible\r\n* DBLCL: transformed indolent lymphomas (TIL), primary mediastinal large B-cell lymphoma (PMBCL), and aggressive B-cell lymphoma unclassified (BCL-U) are eligible\r\n* HL: all classical HL subtypes are eligible except for nodular lymphocyte predominant Hodgkin lymphoma, which is excluded

Phase 1 Part: Patients with pathologically confirmed advanced stage B-cell NHL (Ann Arbor stage 3 or 4) for whom R-CHOP is considered appropriate therapy; newly diagnosed DLBCL, newly diagnosed low grade B cell NHL, and previously treated low grade B cell NHL patients in first relapse after a prior treatment with non-anthracycline containing chemotherapy are allowed; double hit and transformed diffuse large B cell lymphoma are allowed\r\n* Allowed low grade B cell lymphomas will include follicular lymphoma any grade, marginal zone lymphoma including mucosa-associated lymphoid tissue (MALT) lymphoma, indolent mantle cell lymphoma and Waldenstrom's macroglobulinemia

Phase 2 Part: Patients with pathologically confirmed newly diagnosed diffuse large B cell lymphoma (Ann Arbor stage 3 or 4); newly diagnosed double hit and transformed diffuse large B cell lymphoma are allowed

Histologically documented (by history of present illness [HPI] or pathology report) iNHL as defined by follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/Waldenstrom disease (LPL/WM) and small lymphocytic lymphoma (SLL) or tiNHL as defined by large B cell transformation of any of the above entities including chronic lymphocytic leukemia (CLL)

Patients with de novo diffuse large B-cell lymphoma

Mature B-cell lymphoma\r\n* Follicular lymphoma and other indolent lymphoma\r\n** In >= second CR2/PR2\r\n* Diffuse large B-cell lymphoma\r\n** In >= CR2 or >= PR1\r\n** A high intermediate or high international prognostic index (IPI) (>= 2 for age-adjusted IPI or >= 3 for IPI) at diagnosis and double-hit or triple-hit lymphoma will be eligible in first CR\r\n** Transformed lymphoma from follicular lymphoma (FL) (or other indolent lymphoma) or chronic lymphocytic leukemia will be eligible if chemosensitive and bone marrow is negative\r\n* Mantle cell lymphoma\r\n** In first or greater CR or PR\r\n* Burkitt’s/Burkitt’s like\r\n** All patients except localized lymphoma will be eligible any time after initial therapy (after achievement of first complete remission), or in partial remission if they fail to achieve CR\r\n** Patients with localized (stage I or Ziegler stage A) will be eligible only if they fail to achieve CR1 or after relapse

Diagnosis of R/R B-cell NHL or ALL as defined below:\r\n* Relapsed or refractory B-cell NHL meeting all of the following criteria:\r\n** Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; LBCL transformed from any indolent histology; or primary mediastinal B-cell lymphoma (PMBCL)\r\n** Prior treatment with an anthracycline and rituximab or another CD20-targeted agent (unless the disease is CD20-negative); transformed DLBCL (tDLBCL) must have failed treatment for DLBCL\r\n** At least one of the following:\r\n*** Refractory disease after frontline chemo-immunotherapy\r\n*** Not eligible for autologous hematopoietic stem cell transplant (auto-HSCT)\r\n*** Relapsed or refractory disease after at least 2 lines of therapy or after auto-HSCT\r\n*** Relapsed or refractory disease after allogeneic hematopoietic stem cell transplant (allo-HSCT)\r\n* Relapsed or refractory B-cell ALL (patients with Burkitt’s lymphoma/leukemia are not eligible)\r\n* All B-ALL patients must have detectable disease by morphology, flow cytometry, cytogenetic analysis (e.g. polymerase chain reaction [PCR], fluorescence in situ hybridization [FISH], karyotyping) or imaging (positron emission tomography [PET]-computed tomography [CT])\r\n** Refractory: failure to achieve complete response (CR) (minimal residual disease [MRD]-negative) at the end of induction\r\n** Relapsed: recurrence of disease after achieving CR

Patients must have CD19+ B cell malignancy with relapsed or refractory disease, defined as below:\r\n* Patients with chronic lymphocytic leukemia (CLL):\r\n** Refractory to or relapsed after at least 2 prior chemo or chemoimmunotherapy (e.g. fludarabine, cyclophosphamide, rituximab [FCR], bendamustine plus rituximab [BR]) requiring further treatment \r\n** Refractory to or relapsed after at least 1 prior biologic agent (e.g. ibrutinib, idelalisib, venetoclax, except a single agent anti-CD20 monoclonal antibody) requiring further treatment\r\n* Patients with indolent non-Hodgkin lymphoma (iNHL) (follicular lymphoma [FL], marginal zone lymphoma [MZL], Waldenstrom macroglobulinemia [WM]):\r\n** Refractory or relapsed after at least 2 lines of chemoimmunotherapy (including at least one course of anti-CD20 antibody)\r\n** Refractory or relapsed after at least 1 prior biologic agent (e.g. lenalidomide, ibrutinib, idelalisib)\r\n** Patients must have measurable disease (for WM patients, measurable disease is demonstrable monoclonal paraprotein and bone marrow involvement)\r\n* Patients with diffuse large B cell lymphoma (DLBCL), transformed B cell lymphoma, or high grade B cell lymphoma:\r\n** Refractory to or relapsed after 1 or more prior chemoimmunotherapies with at least one containing an anthracycline and CD20 directed therapy\r\n** Transplant ineligible\r\n** Biopsy proven relapsed disease\r\n* Patients with acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) in lymphoid blast crisis or Burkitt‘s lymphoma:\r\n** Refractory to at least 1 prior induction chemotherapy\r\n** Relapsed after at least 1 prior multiagent systemic chemotherapy that included induction and consolidation\r\n** Patients with Philadelphia chromosome-positive ALL must have failed a second generation tyrosine kinase inhibitor

Must have a diagnosis of a solid tumor (except primary brain tumors), acute myeloid leukemia (AML), or non-Hodgkin lymphoma (NHL); NHL may be of any subtype for Dose Escalation but is limited to diffuse large B-cell lymphoma (DLBCL) for those enrolled to the cohort evaluating the combination of ABBV-621 and venetoclax. Subjects in the Dose Optimization solid tumor cohorts must have either colorectal cancer with documented KRAS mutations (as determined by local testing), or pancreatic cancer (irrespective of mutational status).

Relapsed or refractory T-cell lymphoma (TCL) biopsy-proven =< 6 months prior to registration, including the following subtypes:\r\n* Peripheral T-cell lymphoma, not otherwise specified\r\n* Anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK) negative, primary systemic type\r\n* Angioimmunoblastic T-cell lymphoma\r\n* Extranodal natural killer (NK)/T-cell lymphoma, nasal type\r\n* Adult T-cell lymphoma/leukemia (human T-lymphotropic virus 1 [HTLV1]+)\r\n* Blastic NK-cell lymphoma\r\n* Enteropathy-associated T-cell lymphoma\r\n* Hepatosplenic gamma delta T-cell lymphoma\r\n* Transformed mycosis fungoides\r\n* T/NK-cell lymphoma, unclassifiable

Histologically confirmed diagnosis of CD19 positive diffuse large B-cell lymphoma (DLBCL) or transformed large cell lymphoma from low grade lymphoma

Patients must have Hodgkin lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, gray zone lymphoma, enteropathy-associated T-cell lymphoma, or extranodal natural killer (NK)/T-cell lymphoma, nasal type

Clinical evidence of transformation to a more aggressive subtype of lymphoma or Grade 3B FL.

For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma belonging to one of the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms\r\n* For the purposes of stratification, diagnoses are grouped into 2 categories:\r\n** Category A\r\n*** Burkitt lymphoma\r\n*** Burkitt-like lymphoma with 11q aberration\r\n*** High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements\r\n*** High-grade B-cell lymphoma, not otherwise specified (NOS)\r\n** Category B\r\n*** Diffuse large B-cell lymphoma (DLBCL), NOS\r\n*** Diffuse large B-cell lymphoma (DLBCL), NOS; germinal center B-cell type\r\n*** Diffuse large B-cell lymphoma (DLBCL), NOS; activated B-cell type\r\n*** Large B-cell lymphoma with IRF4 rearrangement\r\n*** T-cell/histiocyte-rich large B-cell lymphoma\r\n*** Primary DLBCL of the central nervous system (CNS)\r\n*** Primary cutaneous DLBCL, leg type\r\n*** Epstein-Barr virus (EBV)+ DLBCL, NOS\r\n*** EBV+ mucocutaneous ulcer\r\n*** DLBCL associated with chronic inflammation\r\n*** Lymphomatoid granulomatosis\r\n*** Primary mediastinal (thymic) large B-cell lymphoma\r\n*** Intravascular large B-cell lymphoma\r\n*** ALK+ large B-cell lymphoma\r\n*** Plasmablastic lymphoma\r\n*** Primary effusion lymphoma\r\n*** Human herpesvirus (HHV)-8+ DLBCL, NOS\r\n*** B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Histological confirmation of biopsy-proven non-Hodgkin lymphoma, excluding chronic lymphocytic leukemia, primary central nervous system (CNS) lymphoma and Burkitt’s lymphoma; Note: small lymphocytic lymphoma (SLL) is allowed

Patients with indolent non-Hodgkin lymphoma (NHL) must have had >= 1 regimen of rituximab-containing regimen; Note: this includes follicular lymphoma (FL), marginal lymphoma and mucosa-associated lymphoid tissue (MALT)

Patients with a histology of lymphoma and myeloma histologies

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), or high-grade lymphomas (Burkitt’s lymphoma/lymphoblastic lymphoma)

Histologically proven DLBCL, including transformation from follicular lymphoma

Previously untreated participants with cluster of differentiation 20 (CD20)-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms: DLBCL, not otherwise specified (NOS) including germinal center B-cell type, activated B-cell type; T-cell/histiocyte-rich large B-cell lymphoma; Epstein-Barr virus-positive DLBCL, NOS; anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma; human herpesvirus-8 (HHV8)-positive DLBCL, NOS; High-grade B-cell lymphoma with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma); High-grade B-cell lymphoma, NOS

History of indolent lymphoma

History of follicular lymphoma grade 3B

B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma)

Primary mediastinal (thymic) large B-cell lymphoma

Burkitt lymphoma

Participants must have histologically (via at least a core or ideally, incisional or excisional biopsy) documented CD20 positive or negative diffuse large B-cell lymphoma (DLBCL)

DLBCL cohort: DLBCL, not otherwise specified (NOS; includes transformed DLBCL from indolent histology [tDLBCL]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (Swerdlow 2016), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma Grade 3B. Subjects must have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have relapsed or refractory disease after at least 2 lines of therapy or after auto-HSCT.

Diagnosed with relapsed or refractory de novo DLBCL or follicular lymphoma transformed to DLBCL to one previous line of anthracycline-containing chemotherapy

Patients with B-cell lymphoma who are candidates to autologous stem-cell transplantation: \r\n* Primary refractory or relapsed diffuse large B-cell lymphoma in response to salvage treatment\r\n* Primary refractory or relapsed follicular lymphoma or other indolent B-cell histology in response to salvage treatment\r\n* Chemosensitive mantle-cell lymphoma in first or later line of treatment

Relapsed or refractory:\r\n* Multiple myeloma (MM) previously treated with an immunomodulatory drug (IMID), a proteosome inhibitor and an alkylating agent; OR\r\n* Acute myeloid leukemia (AML), excluding acute promyelocytic leukemia (PML-RARA rearranged- AML-M3); either primary refractory or relapsed/refractory disease after at least two front line chemotherapy regimens (note: induction and consolidation chemotherapy is considered one line of therapy); diagnosis based on 2008 World Health Organization (WHO) criteria; OR\r\n* Relapsed T-cell lymphoma (TCL) or the following types: peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell (ALCL), and cutaneous TCL (CTCL) of mycosis fungoides (MF); patients should have failed standard therapy and in the case of PTCL-NOS, AITL, and ALCL either have failed or be ineligible for high-dose therapy with autologous stem cell transplant

PHASE I: Histologically confirmed B-cell NHL with any of the following subtypes: DLBCL, mantle cell lymphoma (MCL), FL, marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LL/WM), Burkitt’s lymphoma (BL); patients with histological transformation to DLBCL from indolent lymphoma, primary mediastinal lymphoma and grey zone lymphoma are eligible

CUTANEOUS T-CELL LYMPHOMA (CTCL) ONLY

PERIPHERAL T-CELL LYMPHOMA (PTCL) ONLY

Phase I portion of the study: The following types of NHL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO):\r\n* Mantle cell lymphoma (MCL)\r\n* Follicular lymphoma (FL) - grades 1-3a\r\n* Lymphoplasmacytic lymphoma (LPL)\r\n* Marginal zone lymphoma (MZL)\r\n* CLL in Richter’s transformation\r\n* B-cell prolymphocytic leukemia

Refractory to chemotherapy lymphoma

Histologically confirmed B-cell non-Hodgkin’s lymphoma (NHL) of any of the following subtypes recognized by the World Health Organization (WHO) classification: Burkitt lymphoma, B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, or follicular lymphoma; patients with evidence of histological transformation to diffuse large B-cell lymphoma from indolent NHL are eligible

Patients with indolent lymphoma must have an indication for treatment in the opinion of the investigator

Cohort A will enroll 10 patients with a diagnosis of diffuse large B-cell lymphoma; B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (double hit lymphoma), Burkitt lymphoma, and transformed lymphoma

Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma that is chemotherapy sensitive and has failed or ineligible for an autologous transplant

Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless bulky disease and an estimated tumor doubling time of less than one month

Lymphoplasmacytic lymphoma is eligible after initial therapy if chemotherapy sensitive

Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy

Follicular Lymphoma I, II, IIIA

Marginal zone lymphoma (extranodal, nodal or splenic). Subjects with gastric mucosa-associated lymphoid tissue must have progressed after Helicobacter pylori therapy and radiation. Subjects with splenic marginal zone lymphoma must have prior splenectomy.

Lymphoplasmocytic lymphoma

Mantle cell lymphoma ([MCL] with the exception of aggressive MCL, defined as Ki67 > 30%, or blastoid histology)

Small lymphocytic lymphoma

PART I: Histologically confirmed B-cell NHL with any of the following subtypes: diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LL/WM), Burkitt’s lymphoma (BL); patients with histological transformation to DLBCL from indolent lymphoma, primary mediastinal lymphoma and grey zone lymphoma are eligible

PART IB: Histologically confirmed B-cell NHL:\r\n* Group 1: with only de novo DLBCL,\r\n* Group 2: with only FL of grade 1, 2 or 3a\r\n* Group 3: with only MCL with t(11;14) or overexpression of cyclin D1\r\n* Group 4: all other NHL including MZL, LL, WM, BL, primary mediastinal B cell lymphoma (PMBCL), gray zone lymphoma (GZL) and patients with histological transformation to DLBCL from indolent lymphoma are eligible

Primary disease of hematologic origin, lymphoma, or small cell cancer

Biopsy-confirmed grade 1 or 2, or 3A follicular lymphoma; mantle cell lymphoma; or marginal zone lymphoma; subjects must have relapsed from or are refractory to prior therapy

Other histologic types of prostate cancers such as ductal, sarcomatous, lymphoma, small cell, and neuroendocrine tumors

Primary effusion lymphoma (PEL), including extracavitary variant, and KSHV-associated large cell lymphoma that is pathologically confirmed by the National Cancer Institute (NCI) Laboratory of Pathology

Measurable or assessable lymphoma

Phase I or II patients who have received prior dose-adjusted EPOCH for treatment for PEL or KSHV-associated large cell lymphoma

Phase II patients who have received any prior therapy for PEL or KSHV-associated large cell lymphoma

Parenchymal brain involvement with lymphoma

Patients with a diagnosis of chronic lymphocytic leukemia (CLL) or other B-cell neoplasms including small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and follicular B-cell non-Hodgkin's lymphoma (FL) who have no available approved therapies.

Patients must have histologically confirmed, low-grade B-lymphocyte non-Hodgkin lymphoma (NHL) by the World Health Organization classification:\r\n* Follicular lymphoma grades 1, 2, and 3a\r\n* Marginal zone B-cell lymphoma, including extranodal (mucosa-associated lymphoid tissue [MALT]), nodal and splenic\r\n* Excluding:\r\n** Small lymphocytic lymphoma\r\n** Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (WM)

Histologically confirmed diffuse large B-cell lymphoma (DLBCL) or transformed DLBCL

Patients with a low grade lymphoma or CLL and a concurrent high grade lymphoma transformed from the low grade lymphoma or CLL will be eligible

Histologically or cytologically-proven T- or B-cell lymphoma

Subjects must have histologically determined B cell NHL that is relapsed or primary refractory after initial therapy\r\n* Follicular lymphoma of any grade\r\n* Marginal zone lymphoma (extranodal, nodal, or splenic); patients with gastric mucosa-associated lymphoid tissue (MALT) must have progressed after Helicobacter pylori (H. pylori) therapy and radiation; patients with splenic marginal zone lymphoma (MZL) must have prior splenectomy

Patients with histologically-confirmed Low Tumor Burden Follicular Lymphoma, without B symptoms, Ann Arbor stage II to IVA NHL (CD20+ FL of Grades 1, 2, or 3a)

Transformation to high-grade lymphoma secondary to previously untreated low-grade lymphoma.

Primary small cell lung cancer, myeloma, lymphoma, leukemia, or other histologies not optimally treated with SRS

Patients with relapsed/refractory stage IIB-IV cutaneous T cell lymphoma who have received at least one standard systemic treatment such as extracorporeal photopheresis, bexarotene, or interferon

Subjects must have a diagnosis of relapsed or refractory mantle cell lymphoma as follows:\r\n* Diagnosis of mantle cell lymphoma (MCL) must include morphology and expression of either cyclin D1 in association with other relevant markers (eg, CD19, CD20, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR)\r\n* Relapsed or refractory disease is defined as no response or progressive disease to prior treatment if the prior treatment comprised any of the following:\r\n** 1 regimen containing an anti-CD20 antibody administered for >= 2 doses, and/or\r\n** >= 1 regimen containing 1 cytotoxic agent (e.g., bendamustine, chlorambucil, cyclophosphamide, cytarabine, doxorubicin) administered for 2 cycles

Patients must have a diagnosis of prior treated diffuse large b-cell lymphoma, mantle cell lymphoma, transformed lymphoma, follicular lymphoma (any grade), small lymphocytic lymphoma, marginal zone lymphoma, or Hodgkin lymphoma who do not have curative treatment options

Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma which have progressed within 12 months of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless bulky disease and an estimated tumor doubling time of less than one month

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive

Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; primary mediastinal B-cell lymphoma (PMBCL); or DLBCL transformed from indolent histology with one of the following:\r\n* Persistent disease after first-line chemo-immunotherapy\r\n* Relapse after first-line chemo-immunotherapy and not eligible for autologous hematopoietic stem cell transplant (HCT)\r\n* Relapse or persistent disease after at least two lines of therapy or after autologous HCT

Mantle cell lymphoma patients who are beyond first remission and previously treated with chemoimmunotherapy; patients who have relapsed following autologous hematopoietic cell transplant (HCT) are eligible

Patients must have been refractory or relapsed following front line therapy for adult T-cell leukemia (ATL); those with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) who have CD30+ disease must have progressed during or after treatment with brentuximab vedotin, or are unable to receive treatment due to allergy or intolerance

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone b-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for de-bulking chemotherapy before transplant

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia, natural killer (NK) cell malignancies are eligible after initial therapy in CR1+ or partial remission (PR1+)

No prior treatment for lymphoma

Malignancy criteria:\r\n* Patients with the following malignancies are potentially eligible: any B-cell lymphoma and chronic lymphocytic leukemia (CLL); patients with indolent malignancies that have transformed to diffuse large B-cell lymphoma are eligible\r\n* Clear CD19 expression must be uniformly detected on 75% or more of malignant cells from either bone marrow or a leukemia or lymphoma mass by flow cytometry or immunohistochemistry; these assays must be performed at the National Institutes of Health; it is preferable but not required that the specimen used for CD19 determination comes from a sample that was obtained after the patient’s most recent treatment; if paraffin embedded unstained samples of bone marrow involved with malignancy or a lymphoma mass are available, these can be shipped to the National Institutes of Health (NIH) for CD19 staining; otherwise, new biopsies will need to be performed for determination of CD19 expression\r\n* Diffused large B-cell lymphoma (DLBCL) patients must have received at least two prior chemotherapy-containing regimens at least one of which must have contained doxorubicin and a monoclonal antibody; follicular lymphoma patients must have received at least 2 prior regimens including at least 1 regimen with chemotherapy; all other lymphoma and leukemia patients must have had at least 1 prior chemotherapy-containing regimen; all patients with CLL or small lymphocytic lymphoma must have had prior treatment with ibrutinib or another signal transduction inhibitor\r\n* Patients must have measurable malignancy as defined by at least one of the criteria below\r\n** Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter) by computed tomography (CT) scan is required for all diagnoses except CLL; all masses must be less than 10 cm in the largest diameter\r\n** For a lymphoma mass to count as measurable malignancy, it must have abnormally increased metabolic activity when assessed by positron emission tomography (PET) scan\r\n** For CLL and lymphoma with only bone marrow involvement no mass is necessary, but if a mass is not present, bone marrow malignancy must be detectable by flow cytometry in lymphoma and CLL

Patients must meet one of the following disease criteria within 24 months of registration; salvage therapy is allowed between the patient meeting one of the below criterion and registration; patients will be considered eligible regardless of their current disease status (i.e. complete remission, partial remission, stable disease, progressive disease) unless otherwise noted below as long as one of the below criterion has been met within the previous 24 months :\r\n* Relapsed/refractory Hodgkin lymphoma after autologous stem cell transplant (ASCT)\r\n* Relapsed/refractory Hodgkin lymphoma, deemed ineligible for ASCT due to refractory disease\r\n* Relapsed/refractory diffuse large B cell lymphoma after ASCT (history of transformed lymphoma is acceptable); disease must be in at least complete remission or partial remission with the use of salvage therapy before study treatment commences\r\n* Relapsed/refractory diffuse large B cell lymphoma, deemed ineligible for ASCT due to refractory disease (history of transformed lymphoma is acceptable); disease must be in at least complete remission or partial remission with the use of salvage therapy before study treatment commences\r\n* Relapsed/refractory T cell lymphoma relapsed after at least 1 prior line of therapy\r\n* Relapsed/refractory follicular lymphoma relapsed after at least 1 prior line of therapy\r\n* Relapsed/refractory mantle cell lymphoma relapsed after at least 1 prior line of therapy\r\n* Relapsed/refractory small lymphocytic lymphoma/chronic lymphocytic leukemia relapsed after at least 1 prior line of therapy\r\n* Relapsed/refractory non-Hodgkin lymphoma, if not specified above, relapsed after at least 1 prior line of therapy

For an indolent lymphoma histology (follicular lymphoma, small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL]) or mantle cell lymphoma, the patient should not have an HLA-matched sibling, who would be an eligible donor, available

Histologically confirmed follicular lymphoma grade 1-3A, diffuse large B cell lymphoma, and mantle cell lymphoma by World Health Organization (WHO) 2009 classification

Relapsed/refractory lymphoma after CTL019

Follicular lymphoma G1-2-3a

Small lymphocytic lymphoma with absolute lymphocyte count <5x10E9/L at study entry

Marginal zone lymphoma (splenic, nodal, or extranodal)

Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia.

Patients with ABC (determined by immunohistochemistry using the Hans algorithm) diffuse large B-cell lymphoma (DLBCL) with primary refractory disease, relapse < 12 months after initial therapy, secondary International Prognostic Index (IPI) > 1, less than partial response to salvage treatment or exposure to > 3 salvage regimens

Large cell transformation

Previously untreated diffuse large B-cell lymphoma or grade 3B follicular lymphoma (of any stage); subjects must be planned to receive full course (6 cycles) of RCHOP chemoimmunotherapy as per clinical standard of care; patients may have de novo DLBCL, and /or any of the following:\r\n* Composite lymphomas, which include both diffuse DLBCL and another histology (most commonly follicular lymphoma) in the same lymph node\r\n* Transformed lymphoma with DLBCL histology, as long as the patient has not received prior therapy for lymphoma\r\n* Discordant presentations, such as DLBCL in a lymph node  and low-grade lymphoma such as follicular lymphoma in the bone marrow

Diagnosis of either cutaneous T-cell lymphoma; T-prolymphocytic leukemia; T-large granulocytic leukemia; T-lymphoblastic leukemia/lymphoma; or peripheral T-cell lymphoma, natural killer/T-cell lymphoma for whom allogeneic stem cell transplantation is indicated

Participants with primary mediastinal B-cell lymphoma (PMBCL)

Only 1 line of previous anti-lymphoma therapy is allowed and not currently receiving any other agent that would be considered as a treatment for the lymphoma; patients must be >= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed

Pathologic diagnosis of one of the following:\r\n* For dose escalation:\r\n** Confirmed diagnosis of peripheral T-cell lymphoma (PTCL) or angioimmunoblastic T-cell lymphoma (AITL) that is refractory to at least one line of therapy; anaplastic large cell lymphoma (ALCL) and natural killer T-cell lymphoma nasal type (NKTCL) are excluded\r\n** Advanced stage cutaneous T-cell lymphoma (CTCL), specifically CTCL NOS, small/medium T-cell lymphoma (SMTCL) and mycosis fungoides (MF) stage IB, IIA, IIB, III and IV that have relapsed after at least one specific prior therapy (e.g. interferon, photopheresis, denileukin difitox, bexarotene, etc); anaplastic cutaneous large cell lymphoma (ACLCL) and lymphomatoid papulopsis are excluded\r\n** Follicular lymphoma grade 1, 2 or 3A that meets the following criteria: \r\n*** Relapsed or refractory to at least 2 lines of therapy AND\r\n*** Relapsed or refractory post autologous cell transplantation (HCT)\r\n* For dose expansion/dose confirmation phase: \r\n** Patients with confirmed diagnosis of peripheral T-cell lymphoma (PTCL) follicular type or angioimmunoblastic T-cell lymphoma (AITL) that is refractory to at least one line of therapy

All cancer diagnoses, except lymphoma, will be eligible

Diagnosis of lymphoma

Inclusion Criteria:\n\n        -- Age ?18 years\n\n          -  Histologically confirmed Follicular Lymphoma (Grade 1, 2 or 3a), Marginal Zone\n             Lymphoma, or Mantle Cell Lymphoma\n\n          -  Must have documented relapsed, refractory or Progressive Disease after last treatment\n             with systemic therapy\n\n          -  Bi-dimensionally measurable disease\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance status ? 2\n\n          -  Adequate bone marrow function\n\n          -  Willingness to follow pregnancy precautions\n\n        Exclusion Criteria:\n\n          -  Histology other than follicular or marginal zone lymphoma or clinical evidence of\n             transformation or Grade 3b follicular lymphoma\n\n          -  Any medical condition (other than the underlying lymphoma) that requires chronic\n             steroid use\n\n          -  Subjects taking corticosteroids during the last 1 week prior treatment, unless\n             administered at a dose equivalent to < 20 mg/day of prednisone\n\n          -  Systemic anti-lymphoma therapy within 28 days or use of antibody agents within 8 weeks\n             use of radioimmunotherapy within 3 months\n\n          -  Known seropositive for or active viral infection with hepatitis B virus (HBV),\n             hepatitis C virus (HCV), human immunodeficiency virus (HIV)\n\n          -  Known sensitivity or allergy to murine products\n\n          -  Presence or history of central nervous system involvement by lymphoma. Subjects who\n             are at a risk for a thromboembolic event and are not willing to take prophylaxis for\n             it.\n\n          -  Any condition that places the subject at unacceptable risk if he/she were to\n             participate in the study or that confounds the ability to interpret data from the\n             study.

Patients with stage I-IV indolent B cell lymphoma, including mucosa-associated lymphoid tissue (MALT) and follicular grade I/II; patients with mantle cell lymphoma will also be included in this study, as mantle cell lymphoma is also radiosensitive, despite it not being an indolent B cell lymphoma; patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are ineligible

Patients must have measurable disease within the orbit, either clinically and/or radiographically after biopsy confirmation of B cell lymphoma

Patients treated with chemotherapy for lymphoma within 4 weeks of protocol enrollment (including Rituxan)

Patients with aggressive B cell lymphoma histology, including diffuse large B cell lymphoma (DLBCL) and grade 3 follicular lymphoma

Patients must have histologically confirmed relapsed/refractory or previously untreated mantle cell lymphoma (any stage)

Patients must have a histologically confirmed diagnosis of lymphoma expressing the CD20 antigen and generally must have failed at least one prior standard systemic therapy; the exception will be mantle cell lymphoma (MCL) patients, who may be enrolled while in first complete remission (CR) as well as other select high-risk lymphomas (e.g., Burkitt’s, double hit diffuse large B-cell lymphoma [DLBCL], transformed indolent B-cell non-Hodgkin lymphoma [B-NHL], etc.) in accordance with current transplant standard of care for these patients

Patient has a confirmed diagnosis of mantle cell lymphoma with B-lymphocyte antigen cluster of differentiation (CD)20 (CD20) positivity in tissue biopsy

Burkitt’s leukemia or lymphoma, T-cell ALL or lymphoblastic lymphoma

Known secondary HPS that is otherwise treatable (e.g. non-Hodgkin’s lymphoma)

Patients must have newly diagnosed, previously untreated diffuse large B-cell lymphoma, mantle cell lymphoma, grade 3B follicular lymphoma, Burkitt lymphoma, peripheral T cell lymphoma not otherwise specified (NOS), natural killer (NK)/T cell lymphoma, or transformed lymphoma

Follicular lymphoma(FL) grade1-2-3a

Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)

Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia

Follicular lymphoma, marginal zone lymphomas (splenic, nodal, or extranodal/mucosa-associated lymphoid tissue [MALT] type)\r\n* Primary refractory disease\r\n* Relapse after >= 2 prior regimens\r\n* Relapse/progression after autologous HSCT

Diffuse large B-cell lymphoma, follicular large cell lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma\r\n* Primary refractory disease\r\n* Relapse/progression after autologous HSCT\r\n* Non-CR after salvage regimen

Central nervous system (CNS) lymphoma: CNS involvement by lymphoma, including parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease prior to registration

Patients must have a diagnosis of one of the following B-NHL malignancies: chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom macroglobulinemia (WM)/ lymphoplasmacytic lymphoma (LPL); patients with mucosa associated lymphoid tissue (MALT) subtype of MZL may have relapsed or refractory disease after a course of antibiotic therapy; otherwise, patients will not have received standard systemic treatment for their B-NHL before the time of study enrollment; standard systemic therapy is defined by including any of the following agents, representing a comprehensive list of recommended front-line agents used in the treatment of B-NHL: cytotoxic chemotherapies (bendamustine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, cytarabine, gemcitabine, platinum drugs, etoposide); anti-CD20 antibodies (obinutuzumab, ofatumumab, rituximab); lenalidomide; ibritumomab tiuxetan; proteasome inhibitors (bortezomib, carfilzomib); tyrosine kinase inhibitors (ibrutinib, acalabrutinib, idelalisib); alemtuzumab; corticosteroids unless given for an indication other than treating the B-NHL; or other therapy as determined by the principal investigator (PI)\r\n* Disease: CLL/SLL; Criteria for diagnosis: histopathologic or flow cytometric confirmation\r\n* Disease: FL; Criteria for diagnosis: histopathologic confirmation\r\n* Disease: MZL; Criteria for diagnosis: histopathologic confirmation\r\n* Disease: MCL; Criteria for diagnosis: histopathologic confirmation\r\n* Disease: WM/LPL; Criteria for diagnosis: Per World Health Organization (WHO) criteria

STEP 1: Within 30 days of study entry: T cell leukemia or lymphoma

COH pathology review confirms that research participant’s diagnostic material is consistent with recurrent/progressive/residual B cell lymphoproliferative neoplasms as listed below AND the research participant is not eligible for or declines COH IRB Protocol No. 13277; additionally, CD19 positivity must be documented in a pathology report if the research participant previously received CD19-targeted therapy; however, it is not a requirement that the CD19 testing be performed by a COH pathologist\r\n* Disease stratum 1 (NHL): Unclassifiable high grade lymphoma, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) and all its subtypes, Burkitt lymphoma (BL), marginal zone B-cell lymphoma, hairy cell leukemia, lymphoplasmacytic lymphoma, B cell lymphoma unclassifiable with features intermediate between DLBCL and BL, B cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, and those research participants who either declined or were not eligible for COH IRB Protocol No. 13277, or who collected autologous T cells for COH IRB Protocol No. 13277 but then became ineligible for autologous hematopoietic stem cell transplant (HSCT) or participants who have relapsed following prior T cell therapy on either COH IRB Protocol No. 09174 or 12224 may be enrolled on this study\r\n* Disease stratum 2 (CLL/PLL/SLL): chronic lymphocytic leukemia (CLL), and B-cell prolymphocytic leukemia (PLL), and small lymphocytic lymphoma (SLL)

Patients must have histologic or cytologic diagnosis of hematologic malignancies with an indication for allogeneic hematopoietic progenitor cell transplantation, who are ineligible to receive a full ablative conditioning regimen as part of their transplantation, including:\r\n* Acute myeloid leukemia (AML)\r\n** As post-remission therapy in patients with intermediate and high risk cytogenetic and molecular abnormalities, including therapy-related leukemia\r\n** Patients refractory to induction chemotherapy\r\n** Relapsed after complete remission\r\n* Acute lymphocytic leukemia (ALL)\r\n** As post remission therapy in Philadelphia chromosome positive (Ph+) and Philadelphia chromosome negative (Ph-) ALL in complete remission, with or without minimal residual disease in patients older than 55 years of age and those younger than 55 years but ineligible for treatment with fully ablative conditioning regimens\r\n** Relapsed or refractory after prior therapy\r\n* Non Hodgkin lymphoma\r\n** Aggressive lymphoma (Burkitt, diffuse large B cell lymphoma, plasmablastic lymphoma, mantle cell lymphoma) relapsed after autologous hematopoietic progenitor transplantation or patients ineligible to receive autologous hematopoietic progenitor transplantation because of mobilization failure or persistent bone marrow involvement by lymphoma\r\n** Indolent lymphoma (follicular, marginal zone lymphoma, mantle cell lymphoma, etc.) patients are eligible if they have received at least two lines of therapy and have remission of their extramedullary disease\r\n** Indolent and aggressive lymphoma patients with refractory disease to at least two lines of therapy\r\n* Hodgkin lymphoma\r\n** Patients relapsed after autologous hematopoietic progenitor transplantation with remission of at least their extramedullary disease after salvage therapy\r\n** Patients with refractory disease to at least 2 lines of chemotherapy\r\n* Multiple myeloma\r\n** Patients who have presented with relapsed or refractory disease after second line therapy\r\n* Myelodysplastic syndrome\r\n** Patients with International Prognostic Score System Risk rating of: intermediate – 2 and higher, ineligible to receive a fully ablative conditioning regimen for allogeneic hematopoietic progenitor cell transplantation\r\n* Chronic lymphocytic leukemia\r\n** Patients with disease relapsed or refractory after 2 or more lines of therapy, ineligible to receive fully ablative conditioning regimens for allogeneic hematopoietic progenitor cell transplantation\r\n** Patients with disease transformed to aggressive lymphoma (Richter transformation) who have received induction therapy for their aggressive disease\r\n* Chronic myeloid leukemia:\r\n** In chronic phase that has failed therapy with at least 3 different tyrosine kinase inhibitors or has progressed to accelerated or blast phase\r\n** In accelerated or blast crisis\r\n* Myeloproliferative syndromes including myelofibrosis\r\n* Complete remission is not necessary for enrollment in this protocol, however Hodgkin and non Hodgkin lymphoma must have had remission of all extramedullary disease to be eligible to participate in this trial

Patients must have a previously documented histologic diagnosis of multiple myeloma (MM) Hodgkin’s Disease (HD) or non-Hodgkin’s lymphoma (NHL), and be eligible to undergo autologous PBSC transplantation on institutional protocols\r\n* Multiple myeloma should be in first or second partial response or better, as defined by International Myeloma Working Group criteria\r\n* Hodgkin’s Disease should be primary refractory or relapsed (either chemosensitive or refractory)\r\n* Non-Hodgkin’s lymphoma must be in either first or second partial response or better and have any one of the following histologies:\r\n** Diffuse large B cell lymphoma\r\n** Transformed lymphoma\r\n** Mantle cell lymphoma\r\n** Follicular lymphoma (any grade)\r\n** Peripheral T cell lymphoma

Follicular lymphoma, previously identified as CD19+\r\n* At least 2 prior chemotherapy or immunochemotherapy regimens (not including single agent monoclonal antibody therapy)\r\n* Patients who progress within 2 years after second or higher line of therapy will be eligible; for instance, patients who have progression of lymphoma < 2 years after second or greater line therapy, but who have responded to their most recent treatment (3rd line or higher) will be eligible; patients may have progression, stable disease or responding disease at the time of enrollment\r\n* Patients with a history of large cell transformation are eligible

Diffuse large B cell lymphoma, previously identified as CD19+\r\n* Residual disease after primary therapy and not eligible for autologous SCT\r\n* Relapsed or persistent disease after prior autologous SCT\r\n* Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT\r\n* Patients with an antecedent history of follicular lymphoma or chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are eligible

Patients will be ineligible if they have a lymphoma diagnosis

A diagnosis of small lymphocytic lymphoma, follicular lymphoma (grades 1-3a), or marginal zone lymphoma

Biopsy-confirmed low-grade B-cell or cutaneous T cell lymphoma; specifically, follicular grade 1, 2, or 3A, marginal zone or small lymphocytic lymphoma, or mycosis fungoides of any initial stage; patients in cohort A must have had no prior systemic therapy and patients in cohort B must be relapsed/refractory after at least one prior systemic therapy

Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell lymphoma; network sites must submit slides to Roswell Park for central review and confirmation

Autologous patients can be included anytime within 6 months post-transplant, if they had no signs of progression and meet one of the following criteria: i. leukemia; ii. lymphoma (all types of B and T cell lymphoma); iii. multiple myeloma

Relapsed/refractory MCL: Confirmed diagnosis of mantle cell lymphoma with cluster of differentiation (CD)20 and cyclin D1 through cyclin D3 positivity in tissue biopsy

PROCUREMENT INCLUSION CRITERIA\r\n* Diagnosis of recurrent aggressive or indolent B-cell lymphoma or CLL, or newly diagnosed patients unable to receive or complete standard therapy OR diagnosis of relapsed/refractory aggressive B-cell lymphoma with a treatment plan that will include high dose therapy and autologous stem cell transplantation\r\n* CD19-positive tumor (result can be pending at this time)\r\n* Hemoglobin (Hgb) > 8.0\r\n* If pheresis required to collect blood:\r\n** Creatinine < 1.5 × upper limit normal\r\n** Aspartate aminotransferase (AST) < 1.5 × upper limit normal\r\n** Prothrombin time (PT) and activated partial thromboplastin time (APTT) < 1.5 × upper limit normal\r\n* Informed consent explained to, understood by and signed by patient/guardian (and donor, where applicable); patient/guardian given copy of informed consent

Diagnosis of recurrent aggressive or indolent B-cell lymphoma or CLL, or newly diagnosed patients unable to receive or complete standard therapy OR diagnosis of relapsed/refractory aggressive B-cell lymphoma with a treatment plan that will include high dose therapy and autologous stem cell transplantation

Any primary is eligible with exception of small cell lung cancer, lymphoma, and germ cell histologies

Small cell lung cancer, lymphoma, and germ cell histologies

Histologically or cytologically confirmed relapsed cluster of differentiation (CD)20+ non-Hodgkin's lymphoma (NHL) (included in this category are follicular grade I, II, III, marginal zone, mantle cell, diffuse large B cell, small lymphocytic lymphoma) for which standard curative therapy does not exist or is no longer effective; this includes patients who have failed or are not eligible for autologous transplants

Patients with histologically confirmed B-cell NHL including marginal zone lymphoma, follicular lymphoma, or mantle cell lymphoma by WHO criteria.

Previously untreated primary mediastinal diffuse large B-cell lymphoma, CD20 positive.

No prior treatment for mantle cell lymphoma with the exception of corticosteroids for 7 days or less, or 1 course of involved-field radiation

Patients must have a histologically confirmed diagnosis of aggressive B-cell lymphoma (diffuse large B-cell lymphoma [DLBCL], Burkitt lymphoma [BL], etc.) expressing the CD20 antigen and have failed at least one prior standard systemic therapy

1) Transformed FL 2) Small lymphocytic lymphoma 3) Histological Grade 3b FL 4) Subject will have undergone autologous transplant within 6 weeks of planned leukapheresis or has undergone allogeneic transplant. 5) Subject has evidence of involvement of the heart by lymphoma or requirement for urgent therapy due to ongoing or impending oncologic emergency (e.g. mass effect, tumor lysis syndrome, etc.)

Patients with primary tumors including germ cell tumor, or lymphoma/leukemia

Pathologically confirmed T-cell lymphomas at the enrolling institution, including stage >= Ib cutaneous T-cell lymphoma (CTCL), which has relapsed or progressed after at least one systemic therapy

Receiving systemic therapy for another primary malignancy (other than T-cell lymphoma);\r\n* Patients with more than one type of lymphoma may be enrolled after discussion with the MSK principal investigator\r\n* Adjuvant or maintenance therapy to reduce the risk of recurrence of other malignancy (other than T-cell lymphoma) is permissible after discussion with the MSK principal investigator

(Monotherapy - Parts A, B, C, D, G, H, J, and K) -- Histologically confirmed advanced malignancy, either: (a) Metastatic or unresectable solid malignancy; or (b) Classical Hodgkin lymphoma (HL), or diffuse large B-cell lymphoma (DLBCL), or indolent lymphoma (including follicular lymphoma [FL])

The following histologies will need to be confirmed at Memorial Sloan-Kettering Cancer Center (MSK) or locally for participating sites in order to be considered for HDT-ASCT and post-transplant maintenance romidepsin:\r\n* Peripheral T-cell lymphoma (PTCL)\r\n* Angioimmunoblastic T-cell lymphoma (AITL)\r\n* Anaplastic large-cell lymphoma (ALCL)\r\n* Enteropathy-associated T-cell lymphoma (EaTCL)\r\n* Hepatosplenic gamma delta T-cell lymphoma\r\n* Adult T-cell leukemia/lymphoma\r\n* Primary cutaneous gamma/delta T-cell lymphoma\r\n* Extranodal natural killer (NK)/T-cell lymphoma, nasal type\r\n* Primary cutaneous anaplastic large cell lymphoma\r\n* Subcutaneous panniculitis-like T-cell lymphoma\r\n* Mycosis fungoides/Sezary syndrome

Ph-positive ALL, Burkitt’s leukemia or lymphoma, T-cell ALL or lymphoblastic lymphoma

Patients with small cell lung cancer and lymphoma are ineligible

Low-grade non-Hodgkin lymphoma (including small lymphocytic lymphoma [SLL] and chronic lymphocytic leukemia [CLL]) or plasma cell neoplasm that has progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or in the case of lymphoma undergone histologic conversion; patients with transformed lymphomas must have stable disease or better

Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy:\r\n* Natural killer (NK) or NK-T cell lymphoma, peripheral T-cell lymphoma (including angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitic T-cell lymphoma, and other variants), T-cell prolymphocytic leukemia, or blastic/blastoid variant of mantle cell lymphoma; or\r\n* Hodgkin or aggressive non-Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended; eligible subtypes of aggressive non-Hodgkin lymphoma include: mantle cell lymphoma; follicular grade 3 lymphoma; diffuse large B-cell lymphoma or its subtypes, excluding primary central nervous system (CNS) lymphoma; primary mediastinal large B-cell lymphoma; large B-cell lymphoma, unspecified; anaplastic large cell lymphoma, excluding skin-only disease; Burkitt’s lymphoma or atypical Burkitt’s lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt’s), in complete remission

Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan)

Histologically proven non-Hodgkin’s lymphoma

Radiation sensitive histology such as lymphoma, myeloma, or plasmacytoma are not allowed

Follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, and indolent T-cell lymphomas: Must have progressed with the most recent remission duration being < 6 months; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless they have bulky disease and an estimated tumor doubling time of less than one month

Lymphoma\r\n* Relapsed lymphoma with residual disease that appears to be chemo-sensitive and non-bulky (< 5 cm at largest diameter)

Patients must have the following CD19+ B cell leukemia or lymphoma either with relapsed or chemotherapy-refractory disease or with evidence of residual disease following therapy; in all cases, patient’s disease must be confirmed at Memorial Sloan-Kettering Cancer Center (MSKCC)\r\n* Chronic lymphocytic leukemia (CLL): Patients must have a diagnosis of CLL as evidenced by flow cytometry, bone marrow histology, and/or cytogenetics\r\n* Other low grade B-cell neoplasms are eligible for study, such as small lymphocytic lymphoma (SLL), follicular lymphoma, Waldenstrom’s macroglobulinemia, hairy cell leukemia, marginal zone lymphomas, and mantle cell lymphomas

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive

Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on salvage therapy; stable disease is acceptable to move forward provided it is non-bulky

Aggressive CD20 positive diffuse large B-cell lymphoma confirmed by Laboratory of Pathology, National Cancer Institute (NCI)

Primary CNS lymphoma

Any stage for mediastinal gray zone lymphoma (MGZL) and primary mediastinal B cell lymphoma (PMBL)

Absolute neutrophil count (ANC) > 1000 unless impairment is due to lymphoma or immune-mediated mechanism caused by lymphoma

Platelets > 100,000 unless impairment is due to lymphoma or immune-mediated mechanism caused by lymphoma

Have histologically confirmed Diffuse Large B Cell Lymphoma that is either:

Richter's transformation (DLBCL arising in the setting of prior chronic lymphocytic leukemia) or Primary Mediastinal B cell Lymphoma (PMBCL)

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or first partial remission (PR1+)

Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy

Patients with relapsed/refractory, biopsy-proven primary cutaneous T-cell lymphoma who have received at least two previous standard systemic therapies and, if MF/SS, is stage IB IVB at study entry.

Histologically confirmed diagnosis of B-cell follicular lymphoma (FL), and grade limited to 1, 2, or 3a based on criteria established by the WHO 2008 classification of tumors of hematopoietic and lymphoid tissues

History of lymphoid malignancy other than FL (eg, diffuse large B-cell lymphoma)

Documented history of immunohistochemistry (IHC)-confirmed CD20-positive (with no subsequent history of CD20-negativity) B-cell, NHL, including diffuse large B cell (DLBCL), mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B cell lymphoma

Confirmed diagnosis of low tumour burden, CD20+ follicular lymphoma

Inclusion Criteria:\n\n        Each participant must meet all of the following inclusion criteria to be enrolled in the\n        study:\n\n          1. Male or female participants 18 years or older.\n\n          2. To be enrolled to the dose escalation (Part A), participants must have\n\n               1. histologically or cytologically confirmed diagnosis of metastatic and/or advanced\n                  solid tumor malignancy or lymphoma, for which no effective standard treatment is\n                  available. However, participants with primary brain tumors or WM will be\n                  excluded.\n\n               2. Radiographically or clinically measurable or nonmeasurable (but evaluable)\n                  disease. Radiographically measurable disease is determined by RECIST (version\n                  1.1) for solid tumors or by International Working Group (IWG) criteria for\n                  malignant lymphoma (2007 IWG).\n\n          3. To be enrolled to the dose expansion cohorts (Part B), participants must meet the\n             following criteria:\n\n               1. Diagnosis of CLL that meets International Workshop on Chronic Lymphocytic\n                  Leukemia (IWCLL) 2008 criteria for Cohort 1; pathologically confirmed diagnosis\n                  of DLBCL for Cohort 2; histologically confirmed diagnosis of B-cell NHL\n                  (follicular lymphoma [FL] [Grade 1, 2, or 3a], small lymphocytic lymphoma (SLL),\n                  lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), marginal zone\n                  lymphoma (MZL) [splenic, nodal, or extra-nodal]) for Cohort 3; histologically\n                  confirmed diagnosis of MCL for Cohort 4; and histologically confirmed diagnosis\n                  of PTLD (early lesion, polymorphic, monomorphic, classical Hodgkin lymphoma-type,\n                  Epstein-Barr virus (EBV) -positive DLBCL of the elderly, DLBCL associated with\n                  chronic inflammation; along with documented or documentable Epstein-Barr\n                  virus-encoded small RNA (EBER) status by tissue in situ hybridization [ISH]) for\n                  Cohort 5; histologically confirmed DLBCL (de novo or transformed disease from\n                  iNHL) for Cohort 6.\n\n               2. Must have received greater than or equal to (>=) 1 prior therapy (excluding\n                  radiation); documented PD (MCL); either treatment naïve to, relapsed/refractory\n                  to, or treatment failure due to other reasons with ibrutinib, idelalisib, or any\n                  other investigational B-cell receptor (BCR) in pathway inhibitors not directly\n                  targeting Spleen tyrosine kinase (SYK); considered not appropriate for treatment\n                  or retreatment with purine analog-based therapy (CLL); or considered ineligible\n                  for at least 1 prior therapy (PTLD); or relapsed or refractory to >= 2 prior\n                  lines of chemotherapy (including standard first line therapy including Rituximab\n                  and an anthracycline [or equivalent if contraindicated] and one additional\n                  systemic multiagent chemotherapy as second-line salvage therapy that may have\n                  included autologous stem cell transplant (ASCT) [unless ineligible for salvage\n                  therapy and ASCT]) and should not have failed more than 4 prior lines of therapy\n                  (DLBCL Cohort 6).\n\n               3. Radiographically or clinically measurable and/or evaluable disease as specified\n                  in the protocol.\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.\n\n          5. Participants must have adequate organ function, including bone marrow reserve,\n             hepatic, renal, pancreatic function and controlled blood pressure as described in the\n             protocol.\n\n          6. Female participants who are postmenopausal for at least 1 year, are surgically\n             sterile, or if of childbearing potential who agree to use 2 effective method(s) of\n             contraception during the study treatment period through 6 months after the last dose\n             of study drug or practice true abstinence.\n\n             Male participants, even if surgically sterilized, who agree to practice effective\n             barrier contraception during the study treatment period through 6 months after the\n             last dose of study drug or practice true abstinence.\n\n          7. Voluntary written consent must be given before performance of any study related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the participant at any time without prejudice to future medical care.\n\n          8. Participants must have recovered from the reversible effects of prior anticancer\n             therapy (to Grade less than or equal to (<=) 1).\n\n        Exclusion Criteria:\n\n        Participants meeting any of the following exclusion criteria are not to be enrolled in the\n        study.\n\n          1. Participants with brain metastasis, or participants with central nervous system (CNS)\n             lymphoma or participants with another malignancy within two years of study start, with\n             exceptions as described in the protocol.\n\n          2. Any serious medical or psychiatric illness, including drug or alcohol abuse, that\n             could, in the investigator's opinion, potentially interfere with the completion of\n             treatment according to this protocol.\n\n          3. Life-threatening illness unrelated to cancer; major surgery within 14 days before the\n             first dose of study drug; systemic infection requiring intravenous (IV) antibiotic\n             therapy or other serious infection (bacterial, fungal, or viral) within 21 days before\n             the first dose of study drug.\n\n          4. Female participants who are pregnant or lactating.\n\n          5. Any immunotherapy, chemotherapy, radiotherapy, or investigational therapy within 3-4\n             weeks before the first dose of study treatment, as detailed in the protocol.\n\n          6. For escalation cohort or expansion cohorts excluding PTLD, ASCT within 6 months before\n             Day 1 of Cycle 1, or prior ASCT at any time without full hematopoietic recovery before\n             Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time.\n\n          7. Treatment with high dose corticosteroids (> daily dose equivalent to 10 milligram (mg)\n             oral prednisone) for anticancer purposes within 7 days before the first dose of\n             TAK-659.\n\n          8. Known human immunodeficiency virus (HIV) positive; known hepatitis B surface\n             antigen-positive; or known or suspected active hepatitis C infection (testing not\n             required).\n\n          9. Evidence of currently uncontrolled cardiovascular conditions as listed in the\n             protocol.\n\n         10. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral\n             absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea >\n             Grade 1 despite supportive therapy.\n\n         11. Lack of suitable venous access for required blood sampling.\n\n         12. Use or consumption of P-glycoprotein (P-gp) inducers/inhibitors and/or strong CYP3A\n             inducers/inhibitors as described in the protocol, and grapefruit-containing food or\n             beverages as described in the protocol.

Men and women with recurrent surface immunoglobulin positive B cell non-Hodgkin's lymphoma (NHL) according to WHO classification (including, but not limited to, CLL/SLL, Waldenström's macroglobulinemia [WM], mantle cell lymphoma [MCL], and diffuse large B cell lymphoma [DLBCL) who have met requirements for roll over from their parent protocol and want to continue study drug.

103 Biopsy proven B-NHL (biopsy proven at least at primary diagnosis), including DLBCL that represents transformation of indolent NHL (including follicular, marginal zone, and lymphoplasmacytic lymphoma excluding chronic lymphocytic leukemia or Hodgkin Lymphoma), FL, and MCL. Presentations of these histologies with substantial occurrence of malignant cells into the bloodstream (lymphocyte count ? 7 x 10^9/L) including all leukemic presentations are excluded. Subjects with transformation of indolent lymphoma must have received therapy after a diagnosis of transformation that is appropriate for aggressive histology as described in 105. The following histologies are not eligible: Lymphoblastic lymphoma, Burkitt lymphoma. Any histologies not specifically mentioned must be discussed with the medical monitor.

104 For Part 2 (Expansion in patients with DLBCL): only biopsy proven DLBCL (biopsy proven at least at primary diagnosis), including DLBCL that represents transformation of indolent NHL (including follicular, marginal zone, and lymphoplasmacytic lymphoma excluding chronic lymphocytic leukemia or Hodgkin Lymphoma) are eligible. Presentations of these histologies with substantial occurrence of malignant cells into the bloodstream (lymphocyte count ? 7 x 10^9/L) including all leukemic presentations are excluded. Subjects with transformation of indolent lymphoma must have received therapy after a diagnosis of transformation that is appropriate for aggressive histology as described in 105. Other histologies are not eligible.

Patients must have a histopathologically confirmed diagnosis of diffuse large B-cell lymphoma (DBLCL) or primary mediastinal large B-cell lymphoma

Any high grade B-cell lymphoma

Confirmation of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma of the following histology at relapse: diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; de novo or transformed follicular lymphoma [tFL]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple hit lymphoma [DHL/THL]), and follicular lymphoma Grade 3B per WHO 2016 classification

History of treatment with venetoclax or another B-Cell Lymphoma (BCL)-2 inhibitor or pomalidomide.

Histologically confirmed peripheral T-cell lymphoma (PTCL) as defined by the World Health Organization (WHO) criteria 2016, excluding cutaneous T-cell lymphoma (CTCL); transformed mycosis fungoides is allowed

COHORT 1: patients undergoing high dose chemotherapy with autologous stem cell rescue and “high-risk” disease as defined below:\r\n* Diffuse large cell lymphoma or peripheral T cell lymphoma (including specified World Health Organization [WHO] subtypes) not in computed tomography (CT)-positron emission tomography (PET) complete remission at time of high dose therapy\r\n* Diffuse large cell lymphoma with “double hit” or “double expressor” features\r\n* Diffuse large cell lymphoma or peripheral T cell lymphoma (including WHO specified subtypes) refractory to standard induction therapy OR relapsing within 1 year of treatment OR in greater that second complete remission (CR)\r\n* Mantle cell lymphoma not in CR1\r\n* Multiple myeloma with ONE (or more) of the following high risk features:\r\n** Less than very good partial remission at time of high dose therapy \r\n** High Revised-International Staging System (R-ISS) (stage III – 2 microglobulin >= 5.5 plus lactate dehydrogenase [LDH] > upper limit of normal [ULN] and/or del17p, t(4;14), t(14;16)) at time of diagnosis\r\n** Cytogenetics or fluorescent in situ hybridization (FISH) del17p

Patients with B-cell lymphoma who are candidates to autologous stem-cell transplantation, including: 1. Primary refractory or relapsed diffuse large B-cell lymphoma in response to salvage treatment. 2. Primary refractory or relapsed follicular lymphoma or other indolent B-cell histology in response to salvage treatment. 3. Chemosensitive mantle-cell lymphoma in first or later line of treatment. 4. Patients with B cell lymphoma (all CD19+ NHL) with progressive or refractory disease who would otherwise not be candidates for autologous stem cell transplantation

Dose escalation cohort:\r\n* Histologically or flow cytometry confirmed diagnosis of B-CLL/small lymphocytic lymphoma (SLL) according to National Cancer Institute–sponsored Working Group (NCI-WG) 1996 guidelines\r\n* The following types of NHL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO):\r\n** Mantle cell lymphoma (MCL)\r\n** Follicular lymphoma (FL) - grades 1-3a\r\n** Lymphoplasmacytic lymphoma (LPL)\r\n** Marginal zone lymphoma (MZL)\r\n** CLL in Richter’s transformation\r\n** B-cell prolymphocytic leukemia (B-PLL)\r\n** Diffuse large B-cell lymphoma (DLBCL)

Histologically confirmed follicular lymphoma, grade 1-3a.

Known current or previous histologic transformation from indolent non-Hodgkin lymphoma to diffuse large B-cell lymphoma or other aggressive lymphoma histology.

Aspartate transaminase (AST) =< 3 X ULN unless due to direct lymphoma involvement, and then =< 5 X ULN

DLBCL Phase 2 cohort: De novo or transformed diffuse large B-cell lymphoma (DLBCL), relapsed or refractory to frontline or second line treatment or autologous hematopoietic cell transplantation

Indolent lymphoma Phase 2 cohort: Marginal zone or follicular lymphoma, relapsed or refractory to standard approved therapies

Patients must have a histologically documented (either primary or metastatic site) diagnosis of advanced solid tumor cancer (stage IV or unresectable) or aggressive lymphoma (diffuse large B cell lymphoma, mantle cell lymphoma, T cell lymphoma, and natural killer [NK] cell lymphoma)\r\n* NOTE: The following histologies will be excluded: non-small cell lung cancer, squamous cell carcinoma of head and neck, melanoma, renal cell carcinoma, bladder cancer, Hodgkin’s lymphoma, Merkel cell carcinoma, and high-frequency microsatellite instability (MSI-H) colorectal cancer\r\n* NOTE: Patients with deleterious BRCA 1/2 mutated ovarian cancer will be excluded

Have a histologically or cytologically confirmed relapsed/refractory mature T-cell lymphoma that has progressed after a minimum of 1 systemic therapy with any of the following T-cell histologies: peripheral T-cell non-Hodgkin lymphoma (NHL), not otherwise specified (PTCL, NOS); anaplastic large cell T-cell lymphoma (ALCL) anaplastic lymphoma kinase positive or negative; angioimmunoblastic T-cell lymphoma; subcutaneous panniculitis like T-cell lymphoma; primary cutaneous gamma-delta T cell lymphoma; enteropathy associated T-cell lymphoma; hepatosplenic T-cell lymphoma; extranodal NK/T-cell lymphoma, nasal type; adult T-cell leukemia/lymphoma; unclassifiable PTCL; and transformed cutaneous T-cell lymphoma (CTCL) to PTCL with systemic involvement (not local skin transformation)

Relapsed or refractory primary central nervous system (CNS) diffuse large B cell lymphoma (PCNSDLBCL) with a CNS lesion, with cerebrospinal fluid (CSF) relapse with positive CSF cytology, or with ocular relapse with positive ocular tissue biopsy; NOTE: tissue biopsy is not absolutely necessary for CNS tumor unless clinical and radiologic findings strongly suggest other etiologies as per treating physician; initial diagnosis must be made by tissue biopsy; NOTE: patients with B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma are also eligible for the protocol as long as they meet other criteria; patients with typical Burkitt lymphoma are not eligible

Patients with chemorefractory non-Hodgkin’s or Hodgkin’s lymphoma or multiple myeloma\r\n* Criteria for consideration of enrollment will include:\r\n** Primary refractory or refractory relapsed disease for which autologous hematopoietic cell transplantation (HCT) is unlikely to be beneficial\r\n** Relapse after autologous HCT\r\n** Ineligibility for standard myeloablative or nonmyeloablative allogeneic (allo)-HCT because of either lack of a donor or patient considerations\r\n*** Non-Hodgkin’s lymphoma, or Hodgkin’s lymphoma: primary refractory or refractory relapse\r\n*** Multiple myeloma; primary refractory or refractory relapse\r\n*** Patients with the above malignancies who have had a previous autologous or allogeneic bone marrow or stem cell transplant

Subjects must have histologically confirmed relapsed or refractory non-Hodgkin lymphoma that is not a candidate for standard curative therapy; non-Hodgkin lymphoma (NHL) subtypes include: diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, plasmablastic lymphomas, peripheral T-cell lymphomas, and follicular lymphoma of any grade; cutaneous T-cell and B-cell lymphomas will also be eligible in the dose-escalation phase only

Patients must have histologically or cytologically confirmed primary central nervous system diffuse large B-cell lymphoma; only patients with relapsed or refractory disease are eligible; patients with PCNSL that is only extracranial will not be eligible

HIV-1 seropositive at or before the time of lymphoma diagnosis

Biopsy proven NHL, including plasmablastic lymphoma and primary effusion lymphoma but not T-cell lymphoma; tissue histology will be reviewed at City of Hope (COH); patients who have been in remission for >= 1 year post Hodgkin's lymphoma chemotherapy are also considered eligible

Phase I: Pathologically confirmed relapsed or refractory B cell lymphoma; must have relapsed after initial therapy; no restriction in number of prior lines of therapy

Indolent non-Hodgkin’s lymphoma, which may include the following:\r\n* Nodal marginal zone lymphoma\r\n* Extranodal marginal zone lymphoma mucosa-associated lymphoid tissue (MALT)\r\n* Splenic marginal zone lymphoma\r\n* Follicular lymphoma grade 1-3a with low tumor burden, Follicular Lymphoma International Prognostic Index (FLIPI) 2 risk category of either low (i.e. no risk factors) or intermediate (1-2 risk factors), and with no B symptoms. B symptoms are defined as:\r\n** Fever (i.e., temperature > 38 degree Celsius (C) [> 100.4 degree Fahrenheit (F)]) for 3 consecutive days\r\n** Weight loss exceeding 10% of body weight in 6 months\r\n** Drenching night sweats\r\n* Lymphoplasmacytic lymphoma\r\n*** Low tumor burden is defined as normal lactate dehydrogenase, largest nodal or extranodal mass less than 7 cm, up to three nodal sites containing nodes with a diameter greater than 3 cm, no clinically significant serous effusions detectable by physical examination or positron emission tomography (PET)/computed tomography (CT) scan, and spleen enlargement up to 16 cm by CT without any evidence of portal hypertension

Prior chemotherapy for lymphoma

Follicular lymphoma with large cell transformation

Biopsy proven lymphoma for which rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (R-EPOCH) is appropriate frontline therapy, e.g., Burkitt lymphoma or diffuse large B-cell lymphoma (DLBCL) NHL, including plasmablastic lymphoma and primary effusion lymphoma but not T-cell lymphoma; tissue histology will be reviewed at the treating institution

Patients must have histologically or cytologically confirmed Hodgkin lymphoma, Burkitt’s lymphoma, double-hit lymphoma, other c-Myc positive B-cell lymphoma, diffuse large-B cell lymphoma including those patients with history of transformed follicular lymphoma, mantle cell lymphoma, or peripheral T-cell lymphoma

Patient with newly diagnosed, histologically confirmed, group B or C Burkitt lymphoma or leukemia (acute lymphoblastic leukemia, L3 subtype); diffuse large B-cell lymphoma; or primary mediastinal B-cell lymphoma; patients with group B/C post transplant lymphoproliferative disorder are eligible for the study regardless of whether disease is newly diagnosed

Patients with relapsed diffuse large B-cell lymphoma (DLBCL) or HL that have achieved a positron emission tomography (PET)-negative CR following first salvage chemotherapy

Participants with histologically or cytologically documented diffuse large B-cell lymphoma (DLBCL) must meet at least 1 of the following risk criteria:\r\n* Age-adjusted International Prognostic Index (IPI) score: 2-3 \r\n* Ki-67 >= 80%\r\n* Histologically, or cytologically documented activated B-cell-like (ABC, also known as post-GCB) subtype \r\n* Double hit variant, defined as having v-myc avian myelocytomatosis viral oncogene homolog (MYC) gene rearrangement in the presence of B-cell chronic lymphocytic leukemia (CLL)/lymphoma (BCL) 2 or BCL6 gene rearrangement \r\n** Other aggressive non-DLBCL non-Burkitt non-Hodgkin B-cell lymphoma variants as defined by the 2008 World Health Organization (WHO) classification, including rare CD20 negative B-cell lymphomas (i.e. plasmablastic lymphoma, and primary effusion lymphoma) are also eligible; grade 3B follicular lymphoma is also eligible as long as one the above risk criteria is met

Diagnosis of non-Hodgkin’s lymphoma, transformed B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell or T-cell lymphoma, and deemed a candidate for autologous transplant

30-120 days post ASCT for non-Hodgkin’s lymphoma

* Phase 1 (Part A1) - COMPLETE: Patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (excluding patients with primary or metastatic central nervous system [CNS] tumors or patients with primary cutaneous ALCL)

Recurrent B cell lymphoma or leukemia (ALL or CLL), or newly diagnosed patients unable to receive or complete standard therapy OR diagnosis of relapsed/refractory intermediate B cell lymphoma with a treatment plan that will include high dose therapy and autologous stem cell transplantation; if the patient is less than age 18, the lymphoma/leukemia is highly aggressive (i.e. lymphoblastic, Burkitt, ALL)

Mantle cell lymphoma\r\n* All patients will be eligible in first or greater CR or PR

Mature T-cell lymphoma\r\n* T-cell lymphomas including primary T-cell not otherwise specified, angioimmunoblastic, and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell, will be eligible after initial therapy, whether or not CR is achieved\r\n* Mycosis fungoides/Sezary syndrome will be eligible in >= CR2/PR2

Pathologically confirmed diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL; including de novo and transformed DLBCL) or Grade 3b follicular lymphoma

Previous history of indolent lymphoma treated with more than 1 multi-agent chemotherapy regimen or previous cancer therapy for recurrent DLBCL or Grade 3b follicular lymphoma

Histologically proven Diffuse Large B-Cell Lymphoma of the Activated B-Cell type

Diagnosis of lymphoma histologies other than Diffuse Large B-Cell Lymphoma

History of malignancies, other than Diffuse Large B-Cell Lymphoma, unless the patient has been disease free for 5 years or more

Patients must have biopsy-proven de-novo diffuse large B-cell lymphoma (DLBCL) \r\n* Patients with primary mediastinal lymphoma or testicular lymphoma are not eligible\r\n* Patients with prior or simultaneous diagnosis of indolent lymphoma are not eligible\r\n* Post-transplant lymphoproliferative disorder with DLBCL morphology is ineligible

Diagnosis of relapsed or refractory primary mediastinal large B-cell lymphoma AND

Diagnosis of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) as documented by medical records and with histology based on criteria established by The World Health Organization (WHO):

If the subjects has transformed DLBCL, the diagnosis is confirmed by biopsy and is immunohistologically characterized as transformation to DLBCL from indolent lymphoma (eg, follicular lymphoma).

Relapsed/refractory diffuse large B cell lymphoma (DLBCL), relapsed/refractory peripheral T cell lymphoma (PTCL) (all subtypes excluding anaplastic large cell lymphoma), relapsed/refractory Cutaneous T cell lymphoma (CTCL) mycosis fungoides/sezary syndrome (MF/SS), relapsed/refractory primary mediastinal B lymphoma (PMBL), and relapsed/refractory mediastinal gray zone lymphoma (MGZL)

Phase 2 subjects with known lymphoma: >=1000 cells/mm3 (>750 cell/mm3 for subjects with lymphoma in bone marrow)

Phase 2 subjects with known lymphoma: >= 50,000 cells/mm3; >=25,000 cells/mm3 for subjects with lymphoma in bone marrow

Inclusion Criteria:\n\n        Phase 1 Specific Patient at least 18yrs of age with histologically confirmed CLL/SLL or\n        B-cell Non-Hodgkin lymphoma (DLBCL, FL, MCL, MZL, lymphoplasmacytic lymphoma).\n\n        Phase 2a Inclusion\n\n          -  Histological evidence: FL Grade 1-3A/iNHL, with relapsed or refractory disease (iNHL\n             includes LPL/WM, MZL); aNHL, defined as DLBCL, FL Grade 3B, MCL, and transformed NHL\n             with relapsed disease; CLL/SLL, PTCL, or CTCL (with MF/SS) with relapsed or\n             refractory.\n\n          -  Received BCR and/or BCL2 inhibitors were intolerant or had relapsed/refractory disease\n             afterwards.\n\n          -  Prior treatment for lymphoid malignancy for progressive /refractory disease\n\n          -  ? 1 prior regimen (min 2 cycles) with antibody conjugate, cytotoxic chemotherapy, or\n             TKI alone or in combination.\n\n          -  Measureable disease defined as: ? 1 lesion ? 1.5 cm single dimension via CT, CT/PET\n             with nodal or mass lesions; Quantifiable circulating tumor cells; or for Waldenström's\n             macroglobulinemia presence of IgM l > 2X ULN; For CTCL: mSWAT > 0\n\n          -  Ability to provide diagnostic reports\n\n        General Inclusion\n\n          -  ECOG Score of 0 or 1.\n\n          -  Hematologic ANC > 1000/uL and platelet > 75,000/uL,\n\n          -  Serum creatinine of < 1.5 ULN or calculated CrCl of > 50 mL/min\n\n          -  Bilirubin < 20.0mg/dL (if Gilberts then < 2.5 mg/dL) and AST/AST < 2.5 ULN\n\n        Exclusion Criteria:\n\n          -  Richter's syndrome, Burkitt's lymphoma, or Burkitt-like Lymphoma (transformed DLBCL\n             from Follicular NHL are eligible).\n\n          -  Prior transplant with stem cell infusion 90 days or active graft-versus-host treatment\n             within 8 weeks of Day 1.\n\n          -  Prior therapy with SYK inhibitors.\n\n          -  Chronic treatment with strong CYP3A4 inhibitor/ inducer, acid reducing agent, Proton\n             pump inhibitors\n\n          -  Known lymphomatous involvement of the CNS.\n\n          -  Persistent, unresolved NCI CTCAE v4.0 ? Grade 2, previous drug-related toxicity\n             (except alopecia, erectile impotence, hot flashes, libido, neuropathy).\n\n          -  Prior monoclonal antibody, radioimmunoconjugate, antibody drug conjugate,\n             phototherapy, radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or\n             any test agent within 3 weeks or for alemtuzumab 8 weeks of Day 1.\n\n          -  For CTCL: (TSEBT) within 12 weeks, or initiation of topical steroid, nitrogen mustard,\n             or topical retinoid within 2 weeks. (Stable topical ? 4 weeks prior to Day 1 allowed).\n\n          -  Known carrier or infection for HIV/Hep B or C. HCV ab+ must be PCR-. HBV ab+ must be\n             HBsAg- or undetectable DNA\n\n          -  Active infection requiring systemic treatment,\n\n          -  Significant GI disease, previous major gastric/bowel surgery, difficulty swallowing or\n             malabsorption syndrome.\n\n          -  Major surgery within 4 weeks\n\n          -  Previous malignancies within 2 yrs. unless relapse risk is small (< 5%).\n\n          -  Current use of systemic steroids >20 mg QD prednisone (or equivalent)\n\n          -  Breastfeeding or pregnant (intention to become) females or participation in other\n             clinical trials

Phase 1 (Cohort T2): Participants with diffuse large B-cell lymphoma (DLBCL), regardless of PIK3CA mutation status

T-cell lymphoma

Has confirmed diagnosis of relapse or refractory Multiple Myeloma (enrollment completed), Primary mediastinal Large B cell Lymphoma, non-Hodgkin lymphoma (NHL), Follicular Lymphoma, Diffuse Large B cell lymphoma (enrollment discontinued), Hodgkin lymphoma or Myelodysplastic syndrome (enrollment completed).

Has histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or histologically and/or cytologically confirmed advanced or metastatic solid tumor and have relapsed or refractory disease following at least two lines of prior standard therapy, including alkylator/anthracycline (unless anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy (R-CHOP; rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone or prednisone, or equivalent) AND must be considered unable to benefit from intensification treatment with autologous hematopoietic stem cell transplantation (ASCT), as defined by meeting at least one of the following criteria:

Histologically documented, CD20-positive, relapsed or refractory (defined as having relapsed within 6 months to the previous treatment) FL or DLBCL (including primary mediastinal large B-cell lymphoma [PMLBCL])

Known central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation from an indolent lymphoma to a high-grade or DLBCL

Grade 3b FL, small lymphocytic lymphoma (SLL), or Waldenström's macroglobulinemia (WM) or other lymphoma subtypes except as stated in the inclusion criteria

Histologically confirmed DLBCL expressing CD20 antigen; patients with transformed lymphoma are excluded; in this regard, patients with composite lymphoma in the diagnostic tissue (concomitant DLBCL and follicular or other low-grade lymphoma component) are excluded; however, patients with DLBCL in primary diagnostic tissue but a bone marrow that shows low grade or indeterminate lymphoma are eligible; patients with known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; similarly, patients with known c-myc translocation (by fluorescence in situ hybridization) positive DLBCL are encouraged to participate in trials specifically designed for these patients; however patients with known c-myc DLBC positive are NOT excluded from this study; c-myc testing prior to study enrollment is NOT required

Patients must have Burkitt lymphoma; effective with Amendment J (version date: 06/24/2014), the following histologies were removed: B-cell lymphoma: unclassifiable with features intermediate between diffuse large B–cell lymphoma and Burkitt lymphoma; c-MYC + DLBCL and c-MYC+ plasmablastic lymphoma\r\n* If questions arise related to diagnosis, please contact the National Cancer Institute (NCI) principle investigator, Dr. Mark Roschewski or the NCI study coordinator, A. Nicole Lucas

Primary mediastinal (thymic) large B-cell lymphoma.

Treatment-naive patients with histologically confirmed systemic de novo or transformed diffuse large B-cell lymphoma (DLBCL) (from follicular or marginal zone lymphoma), or follicular lymphoma (FL) Grade 3b;

Previous history of treated indolent lymphoma

Histologically documented CD20-positive lymphoma as determined by the local laboratory

Fluorodeoxyglucose-avid lymphoma (i.e., PET-positive lymphoma)

Grade 3b follicular lymphoma

History of transformation of indolent disease to diffuse large B-cell lymphoma (DLBCL)

other histological type of lymphoma

Histologically confirmed previously untreated DLBCL or Grade 3B FL, [double-positive for BCL2 and c-MYC] or transformed lymphoma. Transformed lymphoma from FL or marginal zone lymphoma, but not chronic lymphocytic leukemia (CLL) [Richter Transformation] are allowed as long as no prior anti-lymphoma therapy of any kind has been administered.

Prior history of malignancies, other than diffuse large B-cell lymphoma, unless the subject has been free of the disease for ? 5 years from the signing of the ICD. Exceptions to the ? 5 year time limit include history of the following:

Primary mediastinal B-cell lymphoma

Known active cerebral/meningeal lymphoma

STRATUM III: \r\n* Any patients with MDD >= 1% and MRD positive (>= 0.01%) on day 8 in T-lymphoblastic lymphoma

For Primary Central Nervous System (CNS) Lymphoma (PCNSL): Subjects must have disease that is objectively measurable by International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary CNS Lymphoma, Cerebrospinal Fluid (CSF) cytology (in case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal photographs (in case of ocular lymphoma).

Previously untreated, histologically confirmed indolent lymphoma including follicle cell lymphoma, World Health Organization (WHO) classification, grade I or II, and marginal zone lymphoma; bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable

Any prior treatment for non-Hodgkin’s lymphoma

Patients must have histological documented or cytological confirmed mantle cell lymphoma; cyclin D1 must be present as evidenced by either fluorescence in situ hybridization (FISH) or immunohistochemical staining

A diagnosis of follicular lymphoma (grades 1, 2, or 3a), untreated

Follicular lymphoma with evidence of diffuse large B-cell transformation

Grade 3b follicular lymphoma

Subject who has histologically confirmed and documented B-cell lymphoma (eg, follicular, diffuse large B-cell, mantle cell, small lymphocytic, or Hodgkin lymphoma) and chronic lymphocytic leukemia.

Histologically documented cluster of differentiation 20 (CD20) positive lymphoma

Fluorodeoxyglucose-avid lymphoma

Current or history of CNS lymphoma

Patients with known cerebral or meningeal involvement by lymphoma are excluded

Patient has histologically confirmed diagnosis of diffuse large B cell lymphoma or follicular lymphoma harboring mutations in CREB binding protein (CREBBP) or E1A binding protein p300 (EP300) with relapsed or refractory disease

Patients with either diffuse large B cell lymphoma or follicular lymphoma will be allowed to enroll after receiving only 1 prior therapy if they are felt to not be a candidate for further systemic chemotherapy

Patients with histologically confirmed aggressive hematologic malignancies with chemotherapy-refractory disease; chemotherapy refractory disease is defined as one or more of the following: stable disease or progressive disease as best response to most recent chemotherapy containing regimen or disease progression or recurrence within 12 months of prior autologous or allogeneic stem cell transplant; subjects must have received adequate prior therapy including at a minimum: anti-cluster of differentiation (CD)20 monoclonal antibody unless tumor is CD20-negative, an anthracycline containing chemotherapy regimen; subjects with transformed follicular lymphoma (FL) must have received prior chemotherapy for follicular lymphoma and subsequently have chemo-refractory disease after transformation to diffuse large B-cell lymphoma (DLBCL)

Participants must have previously untreated cluster of differentiation (CD) 20-positive diffuse large, B-cell lymphoma

Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL) Expansion Portion of the Study:

Participants with transformed lymphoma

EXCLUDING: Burkitt's lymphoma and precursor B lymphoblastic leukemia/lymphoma

Histologically confirmed marginal zone lymphoma or follicular lymphoma (grade 1, 2 or 3a; CD20+ by flow cytometry or histochemistry).

Histology other than follicular or marginal zone lymphoma or clinical evidence of transformation or Grade 3b follicular lymphoma.

Prior history of malignancies, other than follicular or marginal zone lymphoma, unless the subject has been free of the disease for ? 5 years.

Patients who have undergone high-dose therapy and autologous PBSCT for treatment of CD20+; NOTE: Based on historical experience of the Indiana University (IU) Bone Marrow and Stem Cell Transplantation Program, it is expected that the vast majority of patients will have been transplanted for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, or mantle cell lymphoma; however, any patient transplanted for CD20+ lymphoma will be considered potentially eligible

Active CNS lymphoma.

Part II: Subjects must have relapsed or refractory aggressive B cell NHL including follicular lymphoma (FL) grade 3, diffuse large B cell lymphoma (DLBCL), transformed NHL, mantle cell lymphoma (MCL), or other aggressive B cell NHL histology as per the World Health Organization (WHO) 2008 criteria

Histologically confirmed untreated mantle cell lymphoma, with documented cyclin D1 (BCL1) by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescent in situ hybridization (FISH)

Previous systemic anti-cancer therapy for T-cell lymphoma must have been discontinued at least 2 weeks prior to treatment;\r\n* Glucocorticoids aimed at controlling lymphoma-related symptoms are allowed as long as they are tapered down to 20 mg or less by the time of ruxolitinib initiation\r\n* Topical steroids for CTCL are permitted

Platelets >= 100 x 10^9/L or >= 50 x 10^9/L (if related to lymphoma)

Receiving systemic therapy for another primary malignancy (other than T-cell lymphoma)\r\n* Patients with more than one type of lymphoma may be enrolled after discussion with the Memorial Sloan-Kettering (MSK) principal investigator\r\n* Adjuvant or maintenance therapy to reduce the risk of recurrence of other malignancy (other than T-cell lymphoma) is permissible after discussion with the MSK principal investigator

Disease that is measurable by standard imaging techniques per RECIST and immune-related response criteria (irRC; all tumor types except lymphoma) or International Working Group (IWG) revised response criteria for malignant lymphoma (lymphoma only). For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that disease site subsequent to radiation.

Transformed DLBCL or DLBCL with coexistent histologies (eg, follicular or mucosa-associated lymphoid tissue lymphoma).

Primary mediastinal (thymic) large B-cell lymphoma.

Histologically confirmed diagnosis with review of the diagnostic pathology specimen at one of the participating institutions; eligible histologies are:\r\n* For Arm A: diffuse large B cell lymphoma; patients with a prior history of indolent B-cell non-Hodgkin lymphoma (NHL) are eligible, as long as they have histologically confirmed diffuse large B cell lymphoma (DLBCL) prior to their pretransplant salvage treatment; patients with mediastinal large B cell lymphoma are also eligible\r\n* For Arm B: classical Hodgkin lymphoma (patients with nodular lymphocyte predominant Hodgkin lymphoma [NLPHL] are NOT eligible)\r\nFor Arm C: peripheral T cell lymphoma – eligible subtypes will include peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS); angioimmunoblastic T cell lymphoma (AITL); ALK-negative anaplastic large cell lymphoma (ALCL); enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL); and extranodal NK/T-cell lymphoma (ENKTL); patients with other PTCL histologies, including ALK-positive PTCL, and cutaneous T-cell lymphoma will not be eligible

CD20+Diffuse Large B-Cell Lymphoma.

No prior anti-lymphoma treatment.

Diagnosis of lymphoma other than Diffuse Large B-Cell Lymphoma.

Composite lymphoma or transformed lymphoma.

Patient has histologically confirmed diagnosis of R/R mantle cell lymphoma, follicular lymphoma or diffuse large B cell lymphoma\r\n* Diffuse large B cell lymphoma patients has received at least 1 prior regimen and received, declined, or is ineligible for autologous or allogeneic stem cell transplant\r\n* Follicular lymphoma patients have received at least 2 lines of therapy\r\n* Mantle cell lymphoma patients has received at least 1 line of therapy\r\n* Allogeneic stem cell transplant recipients be greater than 6 months post transplant, not on immunosuppression for prevention of graft versus host disease for > 3 months and without active graft versus host disease are eligible\r\n* Autologous stem cell transplant recipients must have adequate bone marrow recovery and transfusion independent\r\n* Transformed histologies are permitted

Histologically documented CD20-positive lymphoma and fluorodeoxyglucose (FDG)-avid lymphoma (that is PET-positive lymphoma) with at least one bi-dimensionally measurable lesion

Grade 3b follicular lymphoma

Known CD20-negative status at relapse or progression; CNS lymphoma or leptomeningeal infiltration

Histologically confirmed mantle cell lymphoma with documented expression of cyclin D1 (BCL1) by immunohistochemical stains and/or t (11; 14) by cytogenetics or fluorescence in situ hybridization (FISH)

Total bilirubin =< 2 x institutional upper limit of normal (IULN) except when, in the opinion of the treating physician, is due to direct involvement of lymphoma (e.g., hepatic infiltration or biliary obstruction due to lymphoma) or Gilbert’s disease

Any previous chemotherapy or radiation for mantle cell lymphoma; short course of steroids for symptom relief prior to presentation is permissible

Symptomatic meningeal or parenchymal brain lymphoma

Histologically confirmed new diagnosis of stage II, III and IV peripheral T-cell non-Hodgkin’s lymphoma not otherwise specified (NOS), anaplastic large cell lymphoma (ALK negative) (ALK positive if IPI 3, 4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma

Histologically confirmed CD20+ follicular lymphoma, grade 1, 2, or 3a or marginal zone lymphoma

Have had no prior systemic treatment for lymphoma

Evidence of diffuse large B-cell transformation

Histologically confirmed de novo DLBCL by the 4th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues published in 2008; patients with a history of indolent lymphoma excluded; patients with known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; patients with known c-v-myc avian myelocytomatosis viral oncogene homolog (c-myc) translocation (by fluorescence in situ hybridization) positive DLBCL are eligible for enrollment; c-myc testing prior to study enrollment is not required; availability of diagnostic biopsy samples in encouraged for the exploratory analysis but not required for enrollment; patients with \double-hit\ or \triple-hit\ lymphoma are eligible for enrollment

Prior history of low grade lymphoma with transformation to DLBCL; if a patient has a composite diagnosis of DLBCL and low grade without a prior history of lymphoma, they will not be considered ineligible

Patients with non-T-cell-based lymphoma of any type or hairy cell leukemia are eligible on the condition that they do not receive active systemic treatment for their hematologic disease and are in complete remission as evidenced by PET/CT scans and bone marrow biopsies for at least 3 months.

Phase 1 and Phase 2: confirmed diagnosis of previously treated relapsed and/or refractory mantle cell lymphoma, diffuse large B-cell lymphoma and/or transformed large cell lymphoma (TLCL)

Pathologically documented relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL)

Primary CNS lymphoma or evidence of CNS involvement by lymphoma

Follicular lymphoma (FL) grade 1-2-3a.

Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal).

Pathologically confirmed B- or T-cell lymphomas at the enrolling institution, including stage >= Ib cutaneous T-cell lymphoma (CTCL), which has relapsed or progressed after at least one systemic therapy\r\n* Hodgkin lymphoma is allowed and will be classified as a B-cell lymphoma in the phase IIA portion

Cohort B-2: 1) B- cell follicular lymphoma Grade 1, 2, or 3a (WHO criteria) 2) Relapsed/refractory disease >= 2 lines separated by Progression, prior treatment (or not eligible for receiving) CD20 antibody 3) Measurable disease (IWG -Lugano 2014)

Patients must have a confirmed diagnosis of mantle cell lymphoma with positivity in tissue biopsy

Disease status: all the patients need to have scan or biopsy proven active disease at the time of clinical trial\r\n* Multiple myeloma: patient must have failed at least one line of therapy\r\n* Chronic lymphocytic leukemia (CLL): status post (S/P) at least one line of therapy\r\n* Hodgkin’s lymphoma: S/P at least two lines of therapy\r\n* Follicular lymphoma: S/P at least one line of therapy\r\n* Mantle cell lymphoma: S/P at least one line of therapy\r\n* Diffuse large B cell lymphoma: S/P at least two lines of therapy

Known central nervous system (CNS) disease (NHL, diffuse large B cell lymphoma [DLBCL])

All patients must have a pathologic diagnosis of one of the following malignancies:\r\n* Non-Hodgkin’s lymphoma, including B- and T-cell lymphoma\r\n* Multiple myeloma or another plasma cell dyscrasia (Waldenstrom, Amyloidosis)

Research participants enrolled are patients with an indication to be considered for HSCT, who are diagnosed with intermediate or high grade B-cell non-Hodgkin lymphoma (NHL) (e.g. diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], or transformed NHL), and that have either (1) recurrence/progression following prior therapy, or (2) verification of high-risk disease in first or subsequent remission

Patients must have histologically confirmed B-cell NHL; acceptable subtypes of B-cell NHL include follicular lymphoma (grades 1, 2, or 3a), marginal zone lymphoma, or lymphoplasmacytic lymphoma/Waldenstrom‘s macroglobulinemia; patients with mantle cell lymphoma must have a documented t(11;14) or overexpression of cyclin D1 by immunohistochemical evaluation; patients with diffuse large B cell lymphoma must have activated B cell subtype as defined by the Hans criteria; however, patients with a history of large cell transformation are eligible provided that there is no current clinical evidence of active transformed lymphoma

Known anaplastic lymphoma kinase (ALK) translocations

Confirmation of relapsed or refractory DLBCL or transformed lymphoma (TL)

Exploratory Cohort: Patients with histologically confirmed relapsed or refractory germinal center (GC)-derived B-Cell lymphoma (diffuse large B-cell [DLBCL] and follicular lymphoma [FL]) defined by the WHO and Hans criteria with no accepted curative options

Histologically confirmed diagnosis of B-cell indolent Non-Hodgkin lymphoma with histological subtype limited to follicular lymphoma or marginal zone lymphoma, at initial diagnosis and without evidence of pathological transformation or clinical signs suggesting transformation

Histologically documented relapsed or refractory (defined as having relapsed within 6 months to the previous treatment) follicular lymphoma grade I-IIIA

Histologically confirmed mantle cell lymphoma (MCL)

Relapse or progression after at least one systemic therapy for mantle cell lymphoma

Diagnosis of lymphoma

Histologically confirmed B-cell non-Hodgkin’s lymphoma (NHL) of any of the following subtypes recognized by the World Health Organization (WHO) classification: diffuse large B-cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, or follicular lymphoma; patients with evidence of histological transformation to diffuse large B-cell lymphoma from indolent NHL are eligible

Curative therapy must have been exhausted or not feasible to administer; patients with diffuse large B-cell lymphoma, germinal center subtype should only enroll on the study if there are no other potentially effective therapeutic options

Grade 3B FL and/or clinical evidence of transformation to a more aggressive subtype of lymphoma.

No prior treatment for diffuse B-cell lymphoma (DLBCL)

Prior history of indolent lymphoma

Patients with aggressive B-cell non-Hodgkin lymphoma subtypes including, relapsed or refractory diffused large B-cell lymphoma (DLBCL) and transformed follicular lymphoma meeting at least one of the following criteria:\r\n* Bone marrow involvement at the time of relapse or refractory disease and not appropriate for allogeneic transplantation\r\n* Positron emission tomography (PET) positive disease outside of one radiation port, unless single-port disease treated with prior radiotherapy within the port, following >= 2 cycles of salvage chemotherapy, per 1999 International Working Group (IWG) criteria

Patients with other aggressive B-cell malignancies including, but not limited to: Burkitt lymphoma, transformed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and transformed marginal zone lymphoma that are not included above in the inclusion criteria

Diagnosis of islet cell tumor, lymphoma, metastatic lesion, acinar cell (or other atypical pathologic malignancy)

Pathology confirmed lymphoma or multiple myeloma\r\n* Hodgkin lymphoma is eligible for either phase and will be considered a B-cell lymphoma in the phase IIa study\r\n* Phase IIa portion, subjects must have B-cell lymphoma, T-cell lymphoma, or multiple myeloma

Participants must have histologically confirmed Hodgkin lymphoma or non-Hodgkin lymphoma, (including, but not limited to, diffuse large B-cell lymphoma [DLBCL] or primary mediastinal B-cell lymphoma [PMBCL], Ann Arbor stage I-II disease, or stage III-IV disease with a dominant presenting mass within the mediastinum); pathology must be reviewed and confirmed at Massachusetts General Hospital (MGH) or other Dana-Farber (DF)/Harvard Cancer Center (HCC) institution

Patients must have previously treated relapsed and/or refractory MCL, follicular lymphoma grade 1-3, marginal zone lymphoma, or non-germinal center B-cell diffuse large B-cell lymphoma with 1-4 prior lines of therapy; (prior anthracycline, rituximab or stem cell transplant [autologous (auto) or allogeneic (allo)] are acceptable)

Previous treatment with cytotoxic chemotherapy, immunotherapy, radiotherapy or other lymphoma specific therapy within 14 days before the screening visit or patient has not recovered from side effects of previous lymphoma-specific therapy.

Histologically confirmed diagnosis of follicular lymphoma (FL) grades 1, 2 or 3a, marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue [MALT] lymphoma), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL).

Histologically confirmed diagnosis of grade 3b follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma (DLBCL), mediastinal large B-cell lymphoma, mantle cell lymphoma (MCL), peripheral T-cell lymphoma unspecified, or anaplastic large cell lymphoma primary systemic type, or angioimmunoblastic T cell lymphoma.

Indolent B-cell NHL lymphoma (study part B):

Follicular lymphoma (FL) grade 1-2-3a

Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)

Follicular lymphoma, Mucosa-Associated Lymphoid Tissue (MALT) and nodular marginal zone are not included into this therapeutic study

Subject has been diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma or mantle cell lymphoma (MCL).

Subject has refractory diffuse large B-cell lymphoma, defined as meeting any of the following criteria:

Male or female participants 18 years or older with diagnosis of mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL)

Diagnosis of refractory or relapsed biopsy-proven CD20+ diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma

Presence of disease transformation from a previously diagnosed low-grade lymphoma

Patients with Hodgkin’s lymphoma may have one of the following World Health Organization subtypes:\r\n* Nodular sclerosis Hodgkin’s lymphoma\r\n* Lymphocyte-rich Hodgkin’s lymphoma\r\n* Mixed cellularity Hodgkin’s lymphoma\r\n* Lymphocyte depletion Hodgkin’s lymphoma\r\n* Nodular lymphocyte predominant Hodgkin’s lymphoma

No active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating mantle cell lymphoma at the time of registration to this study is not an exclusion for study enrollment

No prior radiation therapy for mantle cell lymphoma

Histologically or cytologically proven B-cell malignancies, either Burkitt lymphoma or B-AL (=Burkitt leukaemia = L3-AL) or diffuse large B-cell NHL or aggressive mature B-cell NHL non other specified or specifiable.

Follicular lymphoma, MALT and nodular marginal zone are not included into this therapeutic study

Diagnosis of primary central nervous system (CNS) diffuse large B-cell lymphoma confirmed by one of the following:\r\n* Brain biopsy or resection\r\n* Cerebrospinal fluid\r\n* Vitreous fluid

Patients with the following cluster of differentiation (CD)20+ lymphoid malignancies who are eligible for allogeneic transplantation:\r\n* Relapsed or refractory follicular lymphoma\r\n* Relapsed or refractory or high risk mantle cell lymphoma (hi ki67; blastic)\r\n* Recurrent or refractory marginal zone\r\n* Recurrent or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma\r\n* Double-hit lymphoma\r\n* Diffuse large B cell lymphoma\r\n* Richter's patients\r\n* Refractory or recurrent Burkitts

Have no prior systemic treatment for lymphoma

Symptomatic follicular lymphoma requiring treatment.

Clinical evidence of transformed lymphoma or Grade 3b follicular lymphoma.

Patients with documented marrow involvement by lymphoma at the time of registration are not required to meet the above hematologic parameters

Patients with histologically confirmed aggressive B-cell lymphoid malignancy, such as diffuse large B cell lymphoma (DLBCL), including primary mediastinal large B cell lymphoma, T cell rich B cell lymphoma, \double hit\ DLBCL, mantle cell lymphoma, any transformed low grade B cell lymphomas or grade 3 follicular lymphoma (grade 3a or 3b) who were refractory to rituximab-cyclophosphamide-hydroxydaunorubicin (doxorubicin hydrochloride)-Oncovin (vincristine sulfate)-prednisone (R-CHOP)-like or any anthracycline based chemotherapy or relapsed after at least one prior combination chemotherapeutic regimen and who are deemed candidates for a salvage type chemotherapy\r\n* Relapsed disease:\r\n** Progressive disease after a CR for at least 28 days; progression will be defined according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007)\r\n* Refractory disease:\r\n** Subjects must meet one of the following criteria:\r\n*** Persistent or progressive lymphoma with a CR of < 28 days duration or with a PR of any duration; subjects must have received at least 3 cycles of RCHOP-like or any anthracycline base chemotherapy or at least 2 full cycles of hyperfractionated cyclophosphamide-vincristine sulfate-Adriamycin (doxorubicin hydrochloride)-dexamethasone (HyperCVAD)-like chemotherapy\r\n*** Persistent lymphoma and stable disease after at least 2 cycles of RCHOP-like or any anthracycline base chemotherapy or at least 1 full cycle of HyperCVAD-like chemotherapy (part A and B)\r\n*** Progressive disease despite at least 1 cycle of RCHOP-like or any anthracycline base chemotherapy or at least 1 cycle (part A or A and B) of HyperCVAD-like chemotherapy

Cluster of differentiation 20 (CD20)-positive indolent B-cell non-Hodgkin's lymphoma (follicular lymphoma or splenic, nodal or extranodal marginal zone lymphoma)

Central nervous system lymphoma, leptomeningeal lymphoma, or histological evidence of transformation to a high-grade or diffuse large B-cell lymphoma

Grade 3b follicular lymphoma, small lymphocytic lymphoma or Waldenström's macroglobulinaemia

For participants with non-follicular lymphoma: prior treatment with chemotherapy or immunotherapy

Diagnosis of DLBCL (de novo DLBCL, or transformed from indolent lymphoma) or follicular grade 3 lymphoma on the basis of tissue biopsy.

Patients with de novo DLBCL must have received 1-3 treatment regimens for DLBCL. Patients with follicular grade 3 lymphoma must have received 1-3 treatment regimens for follicular lymphoma (any grade). Patients with DLBCL transformed from indolent lymphoma must have received at least 1-4 treatment regimens for NHL.

Patients with DLBCL transformed from indolent lymphoma must have had a complete or partial response to a therapy for NHL lasting at least 12 weeks.

Primary refractory de novo DLBCL or primary refractory follicular grade 3 lymphoma, defined as documented progression within 12 weeks of the last cycle of the first-line multi-agent regimen.

The following disease types are eligible: transformed lymphomas: diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma grade III; precursor B lymphoblastic leukemia/lymphoma; mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma/leukemia; precursor T-lymphoblastic leukemia/lymphoma; primary cutaneous anaplastic large cell lymphoma; anaplastic large cell lymphoma – primary systemic type; small lymphocytic lymphoma/chronic lymphocytic leukemia; follicular lymphoma, grades 1, 2; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type; nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma; peripheral T cell lymphoma, unspecified; anaplastic large cell lymphoma (T and null cell type); lymphoplasmacytic lymphoma (Waldenstrom Macroglobulinemia); CNS lymphoma; post transplant lymphoproliferative disorders; mycosis fungoides/Sezary syndrome; primary effusion lymphoma; blastic natural killer (NK)-cell lymphoma; adult T-cell leukemia/lymphoma; extranodal NK/T-cell lymphoma, nasal type; enteropathy-type T-cell lymphoma; hepatosplenic T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma – primary cutaneous type; T-cell prolymphocytic lymphoma

Histologic documentation of diffuse large B-cell lymphoma, or any of its variants as defined in the World Health Organization (WHO) classification, including but not limited to any of the following:\r\n* Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS)\r\n* Primary mediastinal DLBCL\r\n* T cell/histiocyte-rich large B-cell lymphoma

Have confirmed mantle cell lymphoma diagnosis.

Histologically confirmed marginal zone lymphoma, including extranodal, nodal, and splenic subtypes.

Evidence of diffuse large B-cell transformation.

More than one prior line of any systemic chemoimmunotherapy for follicular lymphoma

Transformed lymphoma

Prior treatment for follicular lymphoma

Patients must have one of the following relapsed/ refractory lymphoid malignancies: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or B-prolymphocytic leukemia which has been previously treated with a purine analog, and are not candidates for higher priority clinical studies; follicular lymphoma, mantle cell lymphoma, lymphoplasmacytoid lymphoma or marginal zone lymphoma which has been previously treated with autologous or allogeneic stem cell transplantation; T-cell prolymphocytic leukemia, large granular lymphocyte leukemia, mycosis fungoides / Sezary syndrome or peripheral T-cell lymphoma which has been previously treated with at least one line of chemotherapy or monoclonal antibody therapy; T-cell or B-cell acute lymphoblastic leukemia (ALL) which has been previously treated with at least one line of chemotherapy

Indolent lymphoma including Grades 1-3a follicular, small lymphocytic, lymphoplasmacytic, and marginal zone lymphoma; Stages III-IV, or bulky disease, Stage II. Tumor verified CD20+ and CT imaging done at screening verifying disease

Indolent lymphoma including grades 1-3a follicular, small lymphocytic, lymphoplasmacytic, and marginal zone lymphoma; stages III-IV, or bulky disease stage II (i.e. as any single mass > 5 cm in any direction)

Grade 3b follicular lymphoma or evidence that the indolent lymphoma has transformed to aggressive lymphoma

Central nervous system lymphoma or prior diffuse large B-cell lymphoma (DLBCL), histological evidence of transformation to high grade or diffuse large B-cell lymphoma

Persistent, or relapsed non-Hodgkin's lymphoma (NHL) (any histology) that is chemo-resistant (< a partial response [PR]), subjects who have received >= 3 prior chemotherapy regimens, or subjects with lymphomas that have a high relapse rate following autologous or syngeneic stem cell transplantation (transformed NHL, peripheral T-cell lymphoma [PTCL], mantle cell lymphoma, anaplastic lymphoma kinase [ALK]-negative anaplastic large cell lymphoma [ALCL, alk neg]), intermediate International Prognostic Index (IPI) or high risk IPI or subjects with a positive positron emission tomography (PET) scan prior to transplant, and otherwise eligible for transplantation with adequate end-organ function

Chemosensitive NHL, except subjects receiving >= 3 prior chemotherapy regimens, or subjects having transformed NHL, PTCL, mantle cell lymphoma (MCL) or ALCL, alk neg

Diagnosis Arm A: CLL (including SLL), DLBCL, or FL; SLL, DLBCL, and FL must be histologically confirmed Arm B: Histologically confirmed SLL or previous confirmation of B-cell CLL with a characteristic immunophenotype by flow cytometry Arm C: Histologically confirmed aggressive B-cell DLBCL, including FL transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL, according to the World Health Organization (WHO)/American Joint Committee on Cancer (AJCC) criteria Arm D: Histologically confirmed anti-CD20-refractory (defined as any subject with less than a PR to any prior anti-CD20-based therapy or progression within 6 months after completing therapy with any anti-CD20-based regimen, including maintenance rituximab) aggressive B-cell DLBCL, including FL transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL, according to the WHO/AJCC criteria

Patient must have a CD19-expressing B cell lymphoma; patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab

Follicular lymphoma, marginal zone lymphomas (splenic, nodal, or extranodal/mucosa-associated lymphoid tissue [MALT] type)\r\n* Chemotherapy-refractory disease\r\n* Relapse after >= 2 prior regimens\r\n* Relapse/progression after autologous HSCT

Diffuse large B-cell lymphoma, follicular large cell lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma\r\n* Primary refractory disease\r\n* Relapse/progression after autologous HSCT after autologous HSCT\r\n* Stable disease or better response to last therapy

T-cell neoplasm: adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma, and enteropathy associated T-cell lymphoma\r\n* First CR\r\n* Chemotherapy-refractory disease\r\n* Relapse after greater than or equal to 1 prior regimen

For patient with NK cell neoplasms: 1) patients with high risk natural killer cell neoplasms including myeloid/NK cell precursor acute leukemia, blastic NK-cell lymphoma, aggressive NK-cell leukemia and nasal-type extranodal NK-cell lymphoma in first complete remission; 2) all NK cell neoplasms can be transplanted in: a) primary induction failure or b) second or greater complete remission

For patients with T-cell neoplasms including adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma and enteropathy associated T-cell lymphoma\r\n* First CR\r\n* Chemotherapy-refractory disease\r\n* Relapse after greater than or equal to 1 prior regimen

For patients with non-Hodgkin’s lymphoma, they must be determined to have at least stable disease to last therapy

TIER I SUBJECTS: Histologically confirmed follicular lymphoma (grade 1, 2 or 3) by the World Health Organization (WHO) classification; all pathology must be confirmed at either Brigham and Women's Hospital or Massachusetts General Hospital; a repeat biopsy confirming the above histologies must be performed prior to enrollment if there is clinical suspicion that the patient has transformed to a more aggressive lymphoma

TIER II SUBJECTS: Histologically confirmed follicular lymphoma (grade 1, 2 or 3) by the WHO classification; all pathology must be confirmed at either Brigham and Women's Hospital or Massachusetts General Hospital; a repeat biopsy confirming the above histologies must be performed prior to enrollment if there is clinical suspicion that the patient has transformed to a more aggressive lymphoma

Lymphoma accessible for sampling or existing cryopreserved lymphoma tumor judged suitable for preparation of vaccine

Any component of transformed follicular lymphoma

Histologically proven non-Hodgkin’s lymphoma

Inclusion Criteria:\n\n        Patients must fulfill all of the following criteria to be eligible for study participation\n        and have:\n\n          -  Histologically confirmed PTCL not otherwise specified, angioimmunoblastic T-cell\n             lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy- type\n             T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous ?? T-cell\n             lymphoma (excludes mycosis fungoides or Sezary syndrome), transformed mycosis\n             fungoides, hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL;\n             anaplastic lymphoma kinase [ALK]-1 negative), or patients with ALK 1 expressing ALCL\n             (ALK-1 positive) who have relapsed disease after autologous stem cell transplant\n             (ASCT);\n\n          -  Age ?18 years;\n\n          -  Written informed consent;\n\n          -  Progressive disease following at least one systemic therapy or refractory to at least\n             one prior systemic therapy;\n\n          -  Measurable disease according to the International Workshop Response (IWC) criteria\n             and/or measurable cutaneous disease;\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;\n\n          -  Serum potassium ?3.8 mmol/L and magnesium ?0.85 mmol/L (electrolyte abnormalities can\n             be corrected with supplementation to meet inclusion criteria);\n\n          -  Negative urine or serum pregnancy test on females of childbearing potential; and\n\n          -  All women of childbearing potential must use an effective barrier method of\n             contraception (either an intrauterine contraceptive device [IUCD] or double barrier\n             method using condoms or a diaphragm plus spermicide) during the treatment period and\n             for at least 1 month thereafter. Male patients should use a barrier method of\n             contraception during the treatment period and for at least 1 month thereafter.\n             Hormonal methods of contraception such as the contraceptive pill or patch\n             (particularly those containing ethinyl-estradiol) should be avoided due to a potential\n             drug interaction.\n\n        Exclusion Criteria:\n\n        Patients are ineligible for entry if any of the following criteria are met:\n\n          -  Known central nervous system (CNS) lymphoma [computed tomography (CT) or magnetic\n             resonance imaging (MRI) scans are required only if brain metastasis is suspected\n             clinically];\n\n          -  Chemotherapy or immunotherapy within 4 weeks of study entry (6 weeks if nitrosoureas\n             given);\n\n          -  Initiation of corticosteroids during study (defined as 7 days prior to Cycle 1 Day\n             1[C1D1] until study drug discontinuation)\n\n               -  Patients treated with a pulse of steroids were to discontinue steroid use 7 days\n                  prior to C1D1 and have a repeat CT scan and disease assessment after\n                  discontinuation of corticosteroids and before starting romidepsin;\n\n          -  Concomitant use of any other anti-cancer therapy;\n\n          -  Concomitant use of any investigational agent;\n\n          -  Use of any investigational agent within 4 weeks of study entry;\n\n          -  Any known cardiac abnormalities such as:\n\n               -  Congenital long QT syndrome;\n\n               -  QTc interval >480 milliseconds (msec);\n\n               -  A myocardial infarction within 6 months of C1D1. Patients with a history of\n                  myocardial infraction between 6 and 12 months prior to C1D1 who are asymptomatic\n                  and have had a negative cardiac risk assessment (treadmill stress test, nuclear\n                  medicine stress test, or stress echocardiogram) since the event may participate;\n\n               -  Other significant electrocardiogram (ECG) abnormalities including 2nd degree\n                  atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia\n                  (ventricular rate less than 50 beats/min).\n\n               -  Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV. In\n                  any patient in whom there is doubt, the patient should be referred to a\n                  cardiologist for evaluation;\n\n               -  An ECG recorded at screening showing significant ST depression (ST depression of\n                  ?2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the\n                  end of the QRS complex). If in any doubt, the patient should have a stress\n                  imaging study and, if abnormal, angiography to define whether or not CAD is\n                  present;\n\n               -  Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class\n                  II to IV definitions and/or ejection fraction <40% by MUGA scan or <50% by\n                  echocardiogram and/or MRI;\n\n               -  A known history of sustained ventricular tachycardia (VT), ventricular\n                  fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently\n                  addressed with an automatic implantable cardioverter defibrillator (AICD);\n\n               -  Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or\n                  other causes (if in doubt, see ejection fraction criteria above);\n\n               -  Uncontrolled hypertension, i.e., blood pressure (BP) of ?160/95; patients who\n                  have a history of hypertension controlled by medication must be on a stable dose\n                  (for at least one month) and meet all other inclusion criteria;\n\n               -  Any cardiac arrhythmia requiring anti-arrhythmic medication;\n\n          -  Serum potassium <3.8 mmol/L or serum magnesium <0.85 mmol/L (electrolyte abnormalities\n             can be corrected with supplementation to meet inclusion criteria);\n\n          -  Concomitant use of drugs that may cause a significant prolongation of the QTc;\n\n          -  Concomitant use of CYP3A4 significant or moderate inhibitors;\n\n          -  Concomitant use of therapeutic warfarin or another anticoagulant due to a potential\n             drug interaction. Use of a small dose of a anticoagulant to maintain patency of venous\n             access port and cannulas is permitted;\n\n          -  Clinically significant active infection;\n\n          -  Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;\n\n          -  Previous extensive radiotherapy involving ?30% of bone marrow (e.g., whole pelvis,\n             half spine), excluding patients who have had total body irradiation as part of a\n             conditioning regimen for ASCT;\n\n          -  Major surgery within 2 weeks of study entry;\n\n          -  Previous allogeneic stem cell transplant;\n\n          -  Inadequate bone marrow or other organ function as evidenced by:\n\n               -  Hemoglobin <9 g/dL (transfusions and/or erythropoietin are permitted);\n\n               -  Absolute neutrophil count (ANC) ?1.0 × 10^9 cells/L [patients with neutropenia\n                  (ANC 1-1.5 10^9 cells/L) as a function of their disease may be supported with\n                  granulocyte-colony stimulating factor (G-CSF)];\n\n               -  Platelet count <100 × 10^9 cells/L or platelet count <75 × 10^9 cells/L if bone\n                  marrow disease involvement is documented;\n\n               -  Total bilirubin >2.0 × upper limit of normal (ULN) or >3.0 × ULN in the presence\n                  of demonstrable liver metastases;\n\n               -  Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and\n                  alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) >2.0 × ULN or\n                  >3.0 × ULN in the presence of demonstrable liver metastases; or\n\n               -  Serum creatinine >2.0 × ULN;\n\n          -  Patients who are pregnant or breast-feeding;\n\n          -  Coexistent second malignancy or history of prior solid organ malignancy within\n             previous 3 years (excluding basal or squamous cell carcinoma of the skin, and in situ\n             carcinoma of the cervix (CIN 1) that has been treated curatively);\n\n          -  Any prior history of a hematologic malignancy (other than T-cell lymphoma);\n\n          -  Any significant medical or psychiatric condition that might prevent the patient from\n             complying with all study procedures; or\n\n          -  Prior exposure to romidepsin (other histone deacetylase inhibitors are allowed).

Diagnosis of mantle cell lymphoma (confirmed at National Cancer Institute [NCI]); all variants are eligible

Platelets > 75,000 unless impairment due to organ involvement by lymphoma

Has diagnosis and prior treatment for each non-hodgkin's lymphoma (NHL) subtype as defined below: Mantle cell lymphoma (MCL): pathologically verified diagnosis of MCL based on local pathology report, relapsed or refractory disease after at least 2 prior lines of therapy, including at least 1 cycle of Bruton's tyrosine kinase (BTK) inhibitor therapy and documented progressive disease (PD) during or after BTK inhibitor treatment or participants who could not tolerate BTK inhibitor [ie, discontinued BTK inhibitor due to adverse events (AEs)], b) Diffuse large B cell lymphoma (DLBCL): pathologically confirmed diagnosis of non-transformed DLBCL, and relapsed or refractory disease; for those participants who have not received HDT/ASCT are not eligible for HDT/ASCT due to comorbidities, c) Follicular lymphoma (FL): pathologically confirmed diagnosis of FL of Grade 1, 2, or 3a according to World Health Organization (WHO) criteria without pathological evidence of transformation, and relapsed disease after at least two prior systemic therapies including one anti-CD20 containing combination regimen

CD30 detectable B lineage relapsed refractory NHL including the following histologies: \r\n* Aggressive lymphomas: diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, grey zone lymphomas, high grade B cell lymphomas, and transformed indolent lymphomas\r\n* Indolent lymphoma: follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma; indolent lymphoma patients eligible for this trial should have high tumor burden and high risk disease, as defined by:\t\r\n** The Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria\r\n** Intermediate or high risk by Follicular Lymphoma International Prognostic Index (FLIPI) score or elevated lactose dehydrogenase (LDH)/ beta-2 microglobulin (B2M)

Prior use of bendamustine for indolent lymphoma allowed if > 2 years, CR to bendamustine and well tolerated with no residual > grade 1 toxicity; no prior use of bendamustine for aggressive lymphoma allowed

Patients with CD30 positive Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) that have undergone allogeneic or haploidentical stem cell transplant (SCT) in the past 60 days (matched related or matched unrelated donors only)

Follicular lymphoma (FL) Grade 1, 2, or 3a

Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)

Histologically or cytologically documented newly diagnosed (stages II, III or IV) Myc-positive diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, or high-grade unclassifiable with features intermediate between DLBCL and Burkitt lymphoma (per the 2008 World Health Organization [WHO] classification of lymphoid neoplasm) OR histologically or cytologically-documented newly diagnosed (stages II, III or IV) DLBCL not otherwise specified (NOS) or high-grade B-cell lymphoma with Myc and B-cell lymphoma 2 (Bcl2) and/or B-cell lymphoma 6 (Bcl6) (per the 2016 revision of the WHO classification of lymphoid neoplasms)

Prior radiotherapy is allowed if it was given for low-grade lymphoma before transformation in those with transformed NHL and as long as no chemotherapy was administered in conjunction with radiation

Hodgkin's variant of Richter's lymphoma, accelerated CLL, composite lymphoma, interdigitating dendritic cell sarcoma, sarcoma, EBV-associated lymphoma or prolymphocytic transformation.

Patients with cluster of differentiation (CD)20 positive diffuse large B-cell lymphoma as confirmed by a pathological biopsy report

High-grade transformation from earlier diagnosis of low-grade lymphoma; patients with “de novo” transformed diffuse large B-cell lymphoma (DLBCL), defined as DLBCL only on lymph node biopsy and a discordant marrow with para-trabecular small cells at first diagnosis of lymphoma, are eligible if adherent to all other selection criteria

Double hit lymphoma is defined as B-cell lymphoma with genetic abnormalities involving A) and in addition, B) and/or C): A) v-myc myelocytomatosis viral oncogene homolog (avian) (C-MYC) arrangement or amplification by fluorescence in situ hybridization (FISH) study; B) B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL2) rearrangement or amplification by FISH study; C) BCL6 rearrangement or amplification by FISH study

Biopsy confirmed low-grade B-cell lymphoma, specifically, follicular grade 1 or 2, or 3A marginal zone or small lymphocytic lymphoma; patients must have relapsed from or are refractory to prior therapy

Clinical evidence of other indolent forms of lymphoma (e.g., marginal zone lymphoma [MZL], small lymphocytic lymphoma [SLL])

Transformation to a more aggressive subtype of lymphoma or grade 3b FL

Patients must have histologically proven T-cell lymphoma, including the following subtypes:\r\n* Peripheral T-cell lymphoma, not otherwise specified\r\n* Angioimmunoblastic T-cell lymphoma\r\n* Anaplastic large cell lymphoma, anaplastic lymphoma receptor tyrosine kinase (ALK) positive\r\n* Anaplastic large cell lymphoma, ALK negative\r\n* Mycosis fungoides\r\n* Sezary syndrome

Richter's transformation, arising in the setting of prior CLL, documented by histologically confirmed lymphoma, including large B-cell and immunoblastic variants.

Lung adenocarcinoma with an Anaplastic Lymphoma Kinase (ALK) gene rearrangement

Cerebrospinal fluid (CSF) cytology for lymphoma or monoclonal lymphocyte population as defined by cell surface markers.

T-cell primary CNS lymphoma.

Known HIV infection and histologically confirmed B-cell non-Hodgkin lymphoma or B-cell lymphoproliferative disease as follows, as defined by the World Health Organization classification:\r\n* Active B-cell non-Hodgkin lymphoma (cluster of differentiation [CD]20 positive or negative), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), or multiple myeloma that has relapsed, progressed, or been refractory to at least one regimen\r\n* Note: Patients with CLL, SLL, or mantle cell lymphoma (MCL) may only be enrolled in Stratum C

Germinal Center B cell Diffuse large B cell lymphoma (GCB-DLBCL) relapsed or refractory to at least one prior regimen (e.g., rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]) AND not a candidate for standard salvage regimens or autologous or allogeneic stem cell transplant. Local confirmation of lymphoma subtype (e.g. GCB-DLBCL) is allowed for enrollment but must be confirmed through central laboratory testing.

Confirmed diagnosis of mantle cell lymphoma

Treatment-naive patients with systemic de novo or transformed diffuse large B cell lymphoma (DLBCL) or follicular non-Hodgkin lymphoma (NHL) grade 3b

Previous history of treated indolent lymphoma

Confirmed diagnosis of PTCL expressing CD30 receptor; diagnosis will be based on identification of PTCL in biopsy specimens characterized 0 (negative) to 79% (positive) immunohistochemistry staining with CD30 in the malignant cell population; following PTCL subtypes will be eligible: \r\n* Peripheral T-cell lymphoma, not otherwise specified (NOS) \r\n* Angioimmunoblastic T-cell lymphoma \r\n* Subcutaneous panniculitis like T-cell lymphoma \r\n* Hepatosplenic gamma/delta T-cell lymphoma \r\n* Extranodal natural killer (NK) T-cell lymphoma, nasal type \r\n* Enteropathy-associated T-cell lymphoma \r\n* Adult T-cell leukemia/lymphoma \r\n* T-cell prolymphocytic leukemia \r\n* Primary cutaneous gamma-delta T-cell lymphoma \r\n* Aggressive NK cell leukemia \r\n* Aggressive subtype of T cell large granular lymphocyte (LGL) leukemia or transformed LGL leukemia\r\n* Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders of childhood \r\n* Transformed mycosis fungoides who have progressed following treatment with at least one systemic therapy\r\n* Sezary syndrome \r\nImmunophenotyping of lymphomas will be performed with panels of monoclonal antibodies targeting surface markers and assisting in differential diagnosis of PTCL according to National Comprehensive Cancer Network (NCCN) guidelines version (V)2 2012; CD2, CD5, CD7, CD4, CD8, CD10, CD25, CD30, CD56, beta-Framework 1 (F1), activin receptor-like kinase-1 (ALK-1), Epstein-Barr virus encoded ribonucleic acid (RNA) (EBER), TIA1 cytotoxic granule-associated RNA binding protein (Tia-1), granzyme B, cartesian genetic programming (CGP), perforin, CD21, B-cell chronic lymphocytic leukemia/lymphoma 6 (bcl-6), programmed cell death 1 (PD-1); proliferation index will also be evaluated using antibodies against mindbomb E3 ubiquitin protein ligase 1 (Mib-1)/ marker of proliferation Ki-67 (Ki-67); clonality studies with T-cell receptor (TCR) gene rearrangement of beta and gamma genes will also be included; pathology sample must be adequate for a complete immunohistochemical analysis

Anaplastic lymphoma kinase (ALK) translocations

Biopsy-confirmed relapsed, refractory, or progressive NHL or HL, including cutaneous T-cell lymphoma (CTCL)

Patient has one of the following peripheral T-cell lymphoma (PTCL) subtypes confirmed by an independent central pathology reviewer, using the Revised European American Lymphoma World Health Organization disease classification:

T/natural killer (NK)-cell leukemia/lymphoma

Anaplastic large cell lymphoma (ALCL), primary systemic type, excluding anaplastic lymphoma kinase positive (ALK+) with International Prognostic Index (IPI) score less than 2 at initial diagnosis and complete response (CR) after CHOP-based therapy

Enteropathy-type intestinal lymphoma

Extranodal T/NK-cell lymphoma nasal or nasal type

Previously treated CLL or other B-cell neoplasm including small lymphocytic lymphoma, hairy cell leukemia, follicular lymphoma, Waldenstrom’s macroglobulinemia, marginal zone lymphomas, mantle cell lymphomas, lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma; patients with composite lymphoma and transformed disease will be included; immunophenotypic (or immunohistochemical) analysis of the malignant lymphocytes should demonstrate that the cells are B-cells

Patients must have had prior cytotoxic therapy for their disease; patients with diffuse large B-cell lymphoma must have been treated with at least 2 prior cytotoxic therapies

Histological confirmation of biopsy-proven B-cell non-Hodgkin’s lymphoma, excluding chronic lymphocytic leukemia/small lymphocytic lymphoma, primary central nervous system (CNS) lymphoma and Burkitt’s lymphoma

CD20+ B-cell primary central nervous system lymphoma (PCNSL) confirmed at the time of diagnosis by histology, cytology, or immunocytochemistry from cerebrospinal fluid (CSF); diagnosis must be documented by pathology report

Diffuse Large B Cell Lymphoma (DLBCL)

Primary Mediastinal Large B Cell Lymphoma (PMBCL)

Transformation Follicular Lymphoma (TFL)

High grade B-cell lymphoma (HGBCL)

for subjects with transformed FL must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to DLBCL

Relapsed/refractory Hodgkin lymphoma or NHL patients (e.g. histologies include: any subtype of Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), any subtype of marginal zone, follicular [grades 1, 2 or 3], diffuse large B-cell lymphoma (DLBCL) [including any morphological variants], transformed lymphoma, mantle cell, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma (PTCL) [but excluding cutaneous T-cell, precursor T-cell or B-cell lymphoma, or Burkitt lymphoma]), who have relapsed or are refractory after receiving a minimum of two prior systemic therapies (i.e., excludes patients who have involved field radiation therapy for limited stage disease); patients who have undergone prior autologous (but not allogeneic) stem cell transplantation are eligible for this study as long as they meet all other required inclusion/exclusion criteria

Non-Hodgkin’s Lymphoma subjects that have received at least one prior treatment (Antibodies and / or chemotherapy); subjects must have one of the following subtypes according to the World Health Organization (WHO)/Revised European American Lymphoma (REAL) Classification(1):\r\n* Follicular lymphoma, diffuse large cell lymphoma, mantle cell lymphoma and small lymphocytic lymphoma / chronic lymphocytic lymphoma

Any T cell lymphoma

\Indolent lymphoma\ is included, and refers to small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (SLL/CLL); lymphoplasmacytic lymphoma (with or without Waldenstrom’s macroglobulinemia); hairy cell leukemia; follicular lymphoma (FL) of any grade; marginal zone B-cell lymphoma; or mantle cell lymphoma

In addition, cutaneous B and T cell lymphoma are permitted; cutaneous T cell lymphoma must be refractory to 1 prior systemic therapy (topical therapy, photophoresis, radiation are not considered systemic therapy); transformed B and T cell cutaneous lymphoma are also permitted

Relapsed/refractory diffuse large B cell lymphoma (DLBCL) is allowed if the patient is not eligible for, or refuses, hematopoietic stem cell transplant

Relapsed/refractory nodal, leukemic, and extranodal T cell lymphomas are eligible; subtypes eligible include anaplastic large cell lymphoma, angioimmunoblastic T cell lymphoma, peripheral T-cell lymphoma-not-otherwise specified (PTCL-NOS), nasal or disseminated extranodal T/natural killer (NK) lymphoma, enteropathy-associated T cell lymphoma, hepatosplenic gamma/delta T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, T-prolymphocytic leukemia, adult T-cell leukemia/lymphoma, large granular lymphocytic leukemia, aggressive NK leukemia

DISEASE CHARACTERISTICS:\n\n          -  Histologically confirmed indolent non-Hodgkin's lymphoma (NHL), including 1 of the\n             following histologic subtypes:\n\n               -  Grade1 or 2 follicular lymphoma\n\n               -  Small lymphocytic lymphoma (SLL)\n\n               -  Marginal zone B-cell lymphoma\n\n          -  CD20-positive disease confirmed by immunohistochemistry or flow cytometry\n\n          -  Bidimensionally measurable disease\n\n               -  At least 1 lesion measuring ? 2.0 cm in a single dimension by CT scan\n\n          -  Less than 25% bone marrow involvement with lymphoma by bilateral iliac crest bone\n             marrow aspiration and biopsy within the past 6 weeks\n\n          -  No clinically significant impaired bone marrow reserve as evidenced by any of the\n             following:\n\n               -  Hypocellular marrow, as evidenced by 1 of the following:\n\n                    -  ? 15% cellularity\n\n                    -  Marked reduction in bone marrow precursors\n\n               -  Platelet count < 100,000/mm^3\n\n               -  Absolute neutrophil count < 1,500/mm^3\n\n               -  History of failed stem cell collection\n\n               -  Prior myeloablative therapy\n\n          -  No greater than 5,000/mm^3 circulating tumor cells in peripheral blood\n\n          -  Requires antilymphoma therapy, as indicated by any of the following:\n\n               -  Systemic symptoms\n\n               -  B symptoms\n\n               -  Cytopenias\n\n               -  Malaise\n\n               -  Organ compromise\n\n               -  Discomfort\n\n               -  Pain\n\n               -  Disfigurement\n\n               -  Rapidly progressive disease\n\n               -  Undue anxiety related to not receiving treatment\n\n          -  No transformation to intermediate or high-grade NHL\n\n          -  No known brain metastases or CNS involvement by lymphoma NOTE: A new classification\n             scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of\n             \indolent\ or \aggressive\ lymphoma will replace the former terminology of \low\,\n             \intermediate\, or \high\ grade lymphoma. However, this protocol uses the former\n             terminology.\n\n        PATIENT CHARACTERISTICS:\n\n        Age\n\n          -  Over 18\n\n        Performance status\n\n          -  ECOG 0-2 OR\n\n          -  WHO 0-2 OR\n\n          -  Karnofsky 70-100%\n\n        Life expectancy\n\n          -  More than 3 months\n\n        Hematopoietic\n\n          -  See Disease Characteristics\n\n          -  WBC ? 3,000/mm^3\n\n          -  Absolute neutrophil count ? 1,500/mm^3\n\n          -  Platelet count ? 100,000/mm^3\n\n          -  Lymphocyte count < 5,000/mm^3 (for patients with SLL )\n\n        Hepatic\n\n          -  Bilirubin ? 2.0 mg/dL\n\n          -  AST and ALT ? 2.5 times upper limit of normal\n\n        Renal\n\n          -  Creatinine ? 2.0 mg/dL OR\n\n          -  Creatinine clearance > 60 mL/min\n\n        Cardiovascular\n\n          -  No symptomatic congestive heart failure\n\n          -  No unstable angina pectoris\n\n          -  No cardiac arrhythmia\n\n        Immunologic\n\n          -  No anti-murine antibody reactivity (in patients with prior exposure to murine\n             antibodies or proteins)\n\n          -  No ongoing or active infection\n\n          -  No history of allergic reaction attributed to compounds of similar chemical or\n             biologic composition to yttrium Y 90 ibritumomab tiuxetan\n\n        Other\n\n          -  Not pregnant or nursing\n\n          -  Negative pregnancy test\n\n          -  Fertile patients must use effective contraception during and for at least 1 year after\n             study treatment\n\n          -  No other active malignancy except non-melanoma skin cancer\n\n          -  No other serious nonmalignant disease that would preclude study participation\n\n          -  No psychiatric illness or social situation that would preclude study compliance\n\n          -  No other uncontrolled illness\n\n        PRIOR CONCURRENT THERAPY:\n\n        Biologic therapy\n\n          -  More than 4 weeks since prior pegfilgrastim\n\n          -  More than 2 weeks since prior filgrastim (G-CSF) or sargramostim (GM-CSF)\n\n        Chemotherapy\n\n          -  No prior chemotherapy\n\n        Endocrine therapy\n\n          -  Not specified\n\n        Radiotherapy\n\n          -  No prior external beam radiotherapy to > 25% of active bone marrow (involved field or\n             regional)\n\n        Surgery\n\n          -  More than 4 weeks since prior major surgery except diagnostic surgery\n\n        Other\n\n          -  No prior systemic antilymphoma therapy\n\n          -  No concurrent combination antiretroviral therapy for HIV-positive patients\n\n          -  No other concurrent anticancer therapy\n\n          -  No other concurrent investigational agents\n\n          -  No other concurrent antilymphoma therapy

Co-existent diffuse large B-cell lymphoma (Richter's transformation)

Metastatic renal cell carcinoma, mantle cell lymphoma, or diffuse large B-cell lymphoma including Grade 3b follicular lymphoma

Relapsed or refractory Primary Central Nervous System Lymphoma (PCNSL) demonstrated by cranial MRI.

Diagnosis of mantle or diffuse large-cell lymphoma, Grade 3B follicular lymphoma [Harris, Swerdlow et al. 2008] or gastric mucosa-associated lymphoid tissue (MALT) lymphoma

Received any prior therapy for lymphoma

Confirmed diagnosis of low tumor burden, CD20-positive follicular lymphoma

Evidence of transformation to a high grade or diffuse large B-cell lymphoma

Follicular lymphoma (FL)

Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)

Known histological transformation from iNHL to diffuse large B-cell lymphoma.

Enteropathy-Associated T cell Lymphoma (EATL)

Diagnosis of Primary Mediastinal Large B-cell Lymphoma

Group 3: Individuals with lymphoma are limited to diffuse large B-cell lymphoma and peripheral T-cell lymphoma that are refractory to or intolerant of standard therapy or for which no standard therapy is available

Diagnosis of CD20+, follicular lymphoma that has not been treated

CD20-immunophenotyping of tumor to document B-cell follicular lymphoma

Clinical evidence of transformation to a more aggressive subtype of lymphoma or grade 3B follicular lymphoma

Primary disease of hematologic origin, lymphoma, or small cell cancer

Patients must have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL) of non-GCB subtype, established according to the World Health Organization (WHO) criteria that has been tested for the MyD88 L265P mutation.

Participants must have histologically confirmed follicular lymphoma (FL) of Grade 1, 2, or 3a

Patients with non-Hodgkin’s lymphoma and one or more of the following: \r\n* Diffuse large B-cell lymphoma with one or more of the following: \r\n** Primary refractory disease\r\n** Relapse within 12 months of completion of first-line therapy\r\n** Secondary International Prognostic Index (IPI) > 1\r\n** Less than partial remission (PR) to first-line salvage chemotherapy\r\n** Kinetic failure after salvage chemotherapy\r\n** Prior treatment with 3 or more lines of therapy\r\n** Patients with double-hit or triple-hit non-Hodgkin lymphoma (NHL), in any state of the disease\r\n* Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in any stage of the disease\r\n* Angioimmunoblastic T-cell lymphoma (AITL) in any stage of the disease\r\n* Refractory or recurrent Burkitt¹s lymphoma\r\n* Any other lymphoma that is refractory or relapsed and that does not qualify for treatment protocols of higher priority

Medically apparent CNS lymphoma or leptomeningeal disease

Expansion phase only: Subjects with advanced, histologically or cytologically confirmed gastric cancer, triple negative breast cancer (TNBC), or diffuse large B-cell lymphoma (DLBCL), who were refractory to or had exhausted all available therapies. Subjects had to have evaluable or measurable disease (as per RECIST 1.1 or Cheson 2007 criteria).

Patients with mantle cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma within 6 months post autologous transplantation and without relapse

Participants must have histologically confirmed peripheral T-cell lymphoma, with the diagnostic specimen reviewed at one of the Dana-Farber Harvard Cancer Center (DFHCC) hematopathology laboratories; eligible histologies include:\r\n* PTCL-not otherwise specified (NOS)\r\n* Systemic T cell/null anaplastic large cell lymphoma (ALCL), regardless of anaplastic lymphoma kinase (Alk)-status\r\n* Angioimmunoblastic T-cell lymphoma (AITL)\r\n* Hepatosplenic (alpha-beta or gamma-delta) lymphoma (HSL)\r\n* Enteropathy-associated T-cell lymphoma (EATL)\r\n* Adult T-cell leukemia/lymphoma (ATLL), lymphomatous subtype\r\n* Subcutaneous panniculitis-like T-cell lymphoma\r\n* T-cell prolymphocytic leukemia (T-PLL)\r\n* Natural killer (NK) cell lymphoma/leukemia

Participants must have relapsed or progressed after at least 1 prior course of anti-lymphoma therapy

Patients with extranodal NK T-cell lymphoma

Patients with CD20-expressing B-cell NHL that is relapsed or refractory to standard therapy. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with peripheral blood leukemia/lymphoma cells and high-grade lymphomas are excluded

Diffuse DLBCL with activating mutations in CD79 (A or B subunits) or ABC-subtype DLBCL (CD79 wildtype or CD79 mutant). DLBCL that arose from transformed indolent lymphoma is allowed.

Has enlarged lymph node(s) highly suspicious of lymphoma; or has been diagnosed with lymphoma but is untreated; or has persistent recurrent, or progressive lymphoma

Patients must have histologically proven relapsed or refractory B-cell NHL of the following World Health Organization (WHO) classification subtypes: follicular lymphoma (FL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (LPL/WM), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma (BL), and B-cell lymphoma with features unclassifiable between Burkitt’s and large cell lymphoma; alternatively, patients with histologically proven, newly diagnosed transformed non-Hodgkin’s lymphoma (tNHL) are eligible

Pathologically confirmed diagnosis of mantle cell lymphoma, follicular lymphoma Grade 3, diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology, Burkitt lymphoma, or B-lineage lymphoblastic lymphoma

Relapsed, refractory, or progressive disease following at least 1 prior systemic therapy. Patients with DLBCL or follicular lymphoma Grade 3 must have also received intensive salvage therapy.

Clinical diagnosis of relapsed/refractory B-cell Malignancies (B-Non-Hodgkins Lymphoma (NHL)) per International Workshop Group (IWG)

Subjects in Expansion cohorts are restricted to relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or Follicular Lymphoma (FL) subjects who are either relapsed or refractory to prior rituximab or ritxumab-containing chemotherapy regimens

Follicular Lymphoma (FL) must have at least 1 lesion that can be biopsied at screening and on treatment

Patient has a histologically confirmed diagnosis of mantle cell lymphoma, follicular lymphoma, or diffuse large B cell lymphoma.

Patients must have biopsy confirmed, cluster of differentiation (CD)20 positive diffuse large B-cell lymphoma, mantel cell, high grade-B-cell or anaplastic large B cell non-Hodgkin lymphoma (NHL); AND bone marrow must show =< 20% CD20+ B-cells with >= 15% cellularity within 42 days of study registration

Primary or secondary CNS lymphoma

B-cell lymphoma with comprehensive immunohistochemistry (IHC) panel establishing lineage (cluster of differentiation [CD]20, CD3) and cell of origin (CD10, B-cell chronic lymphocytic leukemia [CLL]/lymphoma 6 [BCL6] and melanoma associated antigen [mutated] 1 [MUM1]) in addition to proliferative/prognostic markers (proliferation-related Ki-67 antigen [Ki-67], C-myc and B-cell CLL/lymphoma 2 [BCL2]); DHL will be identified using cytogenetics and/or immunohistochemistry as detailed in DHL defined below

Prior therapy for lymphoma

Known primary CNS lymphoma

Expansion cohort only: Advanced lymphoma confirmed by histopathology

Relapsed or refractory NHL including tumor types: Follicular lymphoma (FL), marginal zone lymphoma (MZL)/mucosa-associated lymphoid tissue (MALT), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL).

Diagnosis of systemic anaplastic large-cell lymphoma (sALCL), or HL for which standard, curative, life-prolonging, or palliative treatment does not exist or is no longer effective

Participants with sALCL must have documented anaplastic lymphoma kinase (ALK) status and must be beyond first remission or refractory to front-line chemotherapy

Participants diagnosed with any relapsed or refractory CD30+ hematologic malignancy (e.g., primary mediastinal B-cell lymphoma) may be included in phase 1 of the study

Histological diagnosis of Diffuse Large B Cell Lymphoma (de novo or transformed) expressing CD19 by immunohistochemistry or flow cytometry analysis (>30% positivity), based on recent (less than 6 months) or new biopsy.

Relapsed, refractory, or progressive aggressive non-Hodgkin’s lymphoma (including mantle cell lymphoma), with partial response (PR) or better prior to transplantation, and autologous BMT is not recommended;\r\n* Note: Patients with Burkitt’s, atypical Burkitt’s, or acute lymphoblastic lymphoma must be in complete remission (CR)

One of the following poor-risk lymphomas or plasma cell neoplasms, in PR or better prior to transplantation:\r\n* Transformed lymphoma\r\n* T-cell prolymphocytic leukemia (PLL)\r\n* Peripheral T-cell lymphoma\r\n* Natural killer (NK) or NK/T-cell lymphoma\r\n* Blastic/blastoid mantle cell lymphoma\r\n* Plasma cell leukemia

Untreated, histological diagnosis of CD20-positive diffuse large B-cell lymphoma

ALL or lymphoblastic lymphoma patients in first or higher relapse

Treatment-naive CD30-positive mature T-cell and NK-cell neoplasms, including systemic anaplastic large cell lymphoma

Current diagnosis of primary cutaneous anaplastic large cell lymphoma, mycosis fungoides, Sezary syndrome or other primary cutaneous lymphomas; extranodal NK/T-cell lymphoma, nasal type

Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, and follicular lymphoma; Grades 1, 2 and 3a, defined according to World Health organization (WHO) guidelines. [Tefferi, 2008]

Histologically confirmed cancer with 1-4 brain metastases (except lymphoma or small cell histologies)

Follicular lymphoma Grades 1, 2, 3 A

Marginal zone lymphoma

Lymphoplasmacytic lymphoma

One or more of the following lymphoma-related symptoms:

splenic marginal zone B-cell lymphoma

extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tumor (MALT) type

nodal marginal zone B-cell lymphoma

mantle cell lymphoma

Meets one of the following need-for-treatment criteria (with the exception of mantle cell lymphoma for which treatment is indicated):

presence of lymphoma-related complications, including narrowing of ureters or bile ducts, tumor-related compression of a vital organ, lymphoma-induced pain, cytopenias related to lymphoma/leukemia, splenomegaly, pleural effusions, or ascites

Adequate hematologic function (unless abnormalities related to lymphoma infiltration of the bone marrow or hypersplenism due to lymphoma) as follows:

Chronic lymphocytic leukemia, small lymphocytic lymphoma (SLL), or grade 3 follicular lymphoma

Corticosteroids for treatment of lymphoma within 28 days of study entry Chronically administered low-dose corticosteroids (e.g., prednisone ?20 mg/day) for indications other than lymphoma or lymphoma-related complications are permitted

Documented anaplastic lymphoma kinase (ALK) status.

Inclusion Criteria:\n\n          1. Previously untreated stage IV indolent B-cell lymphoma [Amendment May 2001:\n             eligibility restricted to follicular lymphoma]\n\n          2. Age <76\n\n        Exclusion Criteria:

Patients must be newly diagnosed with mantle cell lymphoma, have an accessible disease site for excisional biopsy or have sufficient peripheral blood tumor to leukapheresis at least 1.5 x 10^9 lymphoma cells in a single session

Grade 3b FL, small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), or other lymphoma subtypes except as stated in the inclusion criteria

Documentation of diagnosis as evidenced by one or more clinical features consistent with mycosis fungoides cutaneous T-cell lymphoma

Histologically confirmed relapsed or refractory CD20+ DLBCL, transformed indolent lymphoma (follicular or other), or primary mediastinal large B-cell lymphoma;

Burkitt, mantle cell, follicular, or mucosa-associated lymphoid tissue lymphoma

Inclusion Criteria: -\n\n        Subject must have either • Relapsed or refractory Chronic Lymphocytic Leukemia/Small\n        Lymphocytic Lymphoma (for Waves 2 or 3)\n\n          -  Subject has evaluable disease and requires treatment in the opinion of the\n             investigator.\n\n          -  Subject must have relapsed following or be refractory to ? 1 standard treatments such\n             as fludarabine based regimens (F, FC, FR, FCR), alkylator (chlorambucil, bendamustine)\n             based regimens, or Bruton's Tyrosine Kinase inhibitor (Ibrutinib).\n\n        Or\n\n        • Relapsed or refractory indolent Non-Hodgkin Lymphoma or aggressive Non-Hodgkin Lymphoma\n        (for Waves 1, 2, or 3, unless otherwise indicated)\n\n          -  Subject must have histologically documented diagnosis of a Follicular Lymphoma or\n             Marginal Zone Lymphoma.\n\n          -  Subject must have histologically documented diagnosis of a Diffuse Large B-cell\n             Lymphoma (excluding Richter's Transformation), Non-cutaneous T-Cell Lymphoma, or\n             Mantle Cell Lymphoma (MCL) (MCL Wave 3 only)\n\n          -  Subject has evaluable disease and requires treatment in the opinion of the\n             investigator.\n\n          -  Subject must have relapsed following or be refractory to ? 1 standard treatments such\n             as R-CHOP, R-CVP, bendamustine, lenalidomide-rituximab, or fludarabine-based regimens.\n\n               -  Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of\n                  less than or equal to 2.\n\n               -  Subject must have adequate bone marrow independent of growth factor support per\n                  local laboratory reference range at Screening.\n\n               -  Subject must have adequate coagulation, renal, and hepatic function, per\n                  laboratory reference range at Screening.\n\n               -  NHL subjects who have a history of an autologous stem cell transplant (e.g., bone\n                  marrow) must be > 6 months post-transplant (prior to the first dose of study\n                  drug) and must not require any growth factor support.\n\n        Exclusion Criteria:\n\n          -  Subject has been previously treated with a Bcl-2 or PI3K inhibitor.\n\n          -  Subject is a candidate to receive another second-line therapy approved for usage by\n             the local Health Authority.\n\n          -  Subject is appropriate for a stem cell transplant or has undergone an allogeneic stem\n             cell transplant.\n\n          -  Subject has received any of the following within 14 days or 5 drug half-lives\n             (whichever is shortest) prior to the first dose of duvelisib or venetoclax, or has not\n             recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of\n             the previous therapy:\n\n               -  Any anti-cancer therapy including chemotherapy or radiotherapy;\n\n               -  Investigational therapy, including targeted small molecule agents.\n\n          -  Subject has received biologic agents (e.g., monoclonal antibodies) for anti-neoplastic\n             treatment within 30 days prior to first dose of duvelisib or venetoclax.\n\n          -  Subject has received live or live attenuated vaccines within 6 weeks prior to first\n             dose of duvelisib or venetoclax.\n\n          -  Subject has received the following within 7 days prior to the first dose of duvelisib\n             or venetoclax:\n\n               -  Steroid therapy for anti-neoplastic treatment;\n\n               -  Strong and Moderate CYP3A inhibitors;\n\n               -  Strong and Moderate CYP3A inducers;\n\n               -  Chronic immunosuppressants, other than corticosteroids given at daily dose < 20\n                  mg prednisone equivalent for ITP or AIHA.

Aggressive B-cell lymphoma, including DLBCL and follicular lymphoma (FL) or other indolent or low grade malignancy transforming to DLBCL, grade III FL, Burkitt lymphoma, and unclassifiable B-cell lymphoma with features of Burkitt and DLBCL according to the World Health Organization, with biopsy confirmation of disease which has relapsed after or refractory to a standard cytotoxic chemotherapy combination including rituximab and doxorubicin, for whom an autologous stem cell transplant is planned

Patients with an Alk+ relapsed/refractory hematologic malignancy including but not limited to ALK+ ALCL or ALK+ large B cell lymphoma

PHASE II: Histological confirmation of transformation of FL lymphoma to diffuse large B cell lymphoma or aggressive lymphoma

Aspartate transaminase (AST) =< 3 x ULN unless due to direct lymphoma involvement, and then =< 5x ULN

Platelets >= 75,000/?L unless due to marrow involvement by lymphoma

No prior chemotherapy for lymphoma

Patients with follicular, grade 1 or 2 non-Hodgkin lymphoma with a FLIPI (Follicular Lymphoma International Prognostic Index) score of 0-2, with no anticipated need for treatment within the next 5 months are considered eligible for this study, regardless of previous treatment history

Survivors of mediastinal lymphoma (either non-Hodgkin’s lymphoma or Hodgkin’s lymphoma) with no active malignancy

Inclusion Criteria:\n\n        Each of the following criteria must be met in order for a patient to be considered eligible\n        for registration:\n\n          -  Biopsy proven (with hematopathology review at one of the participating sites to\n             confirm correct histology in accordance with World Health Organization) indolent\n             lymphoma to include the following diagnoses:\n\n               -  Grade 1, 2, or 3a follicular lymphoma\n\n               -  Small lymphocytic lymphoma (CLL excluded)\n\n               -  Marginal zone lymphoma (nodal or splenic)\n\n               -  Mucosal-associated lymphoid tissue\n\n          -  Measurable disease defined by Lugano criteria\n\n          -  No prior anti-lymphoma systemic therapy; prior radiation therapy allowed\n\n          -  Age 18 or over\n\n          -  Ann Arbor stages II, III or IV\n\n          -  Patients with follicular lymphoma must have PET FDG-avid lymphoma and fulfill Low\n             tumor burden by Groupe D'Etude des Lymphomes Folliculaires (GELF) criteria:\n\n               -  No mass > 7 cm\n\n               -  < 3 distinct masses of greater than 3 cm\n\n               -  No B symptoms\n\n               -  No splenomegaly > 16 cm by computed tomography (CT) scan\n\n               -  No risk of vital organ compression\n\n               -  No leukemic phase > 5000/µl circulating lymphocytes (except for in patients with\n                  splenic marginal zone diagnosis)\n\n               -  No cytopenias (platelets < 100,000/µl, hemoglobin < 10 g/dl, or absolute\n                  neutrophil count < 1500/µl)\n\n        Exclusion Criteria:\n\n        The following criteria will prevent inclusion of an inappropriate subject into the trial:\n\n          -  Osteoporosis requiring prescription treatment\n\n          -  Known symptomatic primary hyperparathyroidism\n\n          -  Hypercalcemia defined as above the institutional normal range (corrected for albumin\n             when albumin levels are below normal)\n\n          -  History of calcium-related kidney stones\n\n          -  Creatinine > 1.5X above upper limit of normal\n\n          -  Women who are known to be pregnant or who plan to become pregnant while on rituximab\n             treatment

Active relapse of ALL or lymphoblastic lymphoma

Currently enrolled on any therapeutic research study for the treatment of ALL or lymphoblastic lymphoma

Within 2 years post-treatment completion for lymphoma

=< 30 days post diagnosis of a solid tumor or lymphoma

Patients with a histology of lymphoma, myeloma and small cell lung cancer histologies

Histologic diagnosis of malignancy of a solid organ or lymphoma

Previously untreated mantle cell lymphoma patients (at least clinical stage 2)

Platelet count >= 100,000, unless felt to be secondary to underlying mantle cell lymphoma

Confirmed diagnosis of B-cell Non-Hodgkin's lymphoma limited to follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), primary mediastinal B-cell lymphoma (PMBL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has progressed and for which standard curative measures do not exist or are no longer effective. Prior therapy must have included a rituximab-based regimen.

Histologically documented PCNSL or histologically documented systemic diffuse large B-cell lymphoma (DLBCL)

Prior use of brentuximab vedotin for GVHD is not allowed; prior use of brentuximab vedotin for the treatment of malignancy, i.e. Hodgkin lymphoma, anaplastic large cell lymphoma, etc. is allowed

Patients with mantle cell lymphoma (MCL) with stage 1 or 2 disease

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-Cell lymphoma, follicular lymphoma, which have progressed within 12 months of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive

Subjects with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B cell, Hodgkin's lymphoma, or mantle cell lymphoma must have chemosensitive disease at time of transplant.

Subjects with a diagnosis of lymphoma falling into the following categories:\r\n* Diffuse large B-cell lymphoma (DLBCL) who have received 1 cycle of anthracycline-based chemotherapy\r\n* DLBCL in complete remission and within 12 months after completion of anthracycline-based chemotherapy\r\n* Chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) receiving ibrutinib for at least 1 month\r\n* Follicular lymphoma (FL) in remission and on surveillance for 6 or more months\r\n* Aggressive peripheral T-cell lymphoma (PTCL) who have received 1 cycle of chemotherapy

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin lymphoma, or mantle cell lymphoma with chemosensitive disease at time of transplantation; all types of lymphoma are eligible

Patients with transformed lymphoma (e.g., Richter's transformation arising in follicular lymphoma or chronic lymphocytic leukemia)

Patients with aggressive non-Hodgkin’s lymphoma (NHL), including diffuse large cell lymphoma, mediastinal B-cell lymphoma, transformed lymphoma, mantle cell lymphoma, and peripheral T cell lymphoma, who also have one of the following criteria:\r\n* Failure to achieve complete remission to primary induction therapy\r\n* Relapsed and refractory to at least one line of salvage systemic therapy\r\n* Failed stem cell collection

Non-Hodgkin lymphoma (NHL) subjects with anaplastic lymphoma kinase (ALK) negative CD30+ anaplastic large-cell lymphomas (ALCL), CD30+ ALCL regardless of ALK status, with chemotherapy-sensitive relapse, CD30+ high-risk diffuse large B-cell lymphoma (DLBCL), CD30+ cutaneous T cell lymphoma, or CD30+ mycosis fungoides who are otherwise eligible for transplant, are eligible for this study

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of achieving a partial or complete remission; patients who had remissions lasting > 12 months are eligible after at least two prior therapies; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month

Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive

Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy

Hematologic malignancies with the exception of lymphoma

Part 2/Other BCMA positive Hematologic Malignancies cohort: Subject with one of the following lymphomas: Diffuse Large B-cell Lymphoma (DLBCL) or follicular lymphoma (FL) that exhibits positive BCMA expression on tumor cells as determined by a central laboratory using a validated Immunohistochemistry (IHC) assay. Eligible subjects with BCMA positive malignancies must also fulfill the prior treatment requirements as follows: DLBCL: at least 2 prior lines of systemic therapy containing at least one line of chemo-immunotherapy with anti-CD20 antibody, and either has undergone stem cell transplant or is considered transplant ineligible. FL: at least 2 prior lines of systemic therapy.

Chemo-refractory DLBCL (including transformed low grade lymphoma)

Lenalidomide exposed: relapsed or refractory CD20-positive follicular lymphoma (Grade 1, 2, or 3a) previously treated with at least two cycles of lenalidomide-containing regimen (FL-2 cohort), either as a single agent or in combination

Study 1 - Aggressive lymphoma\r\n* Newly diagnosed de-novo DLBCL or primary mediastinal B-cell lymphoma that will be treated with an anthracycline-containing regimen (rituximab-cyclophosphamide, doxorubicin hydrochloride, prednisone [R-CHOP] or equivalent) \r\n* Patients with composite lymphomas (low grade and large cell; marginal and large cell; nodular lymphocyte predominant [LP] Hodgkin and large cell, etc) at the time of original diagnosis can also be enrolled as long as they have large cell component and will be treated with an anthracycline\r\n* Patients with high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (formerly DLBCL with double or triple hit), high-grade B-cell lymphoma, not otherwise specified (NOS), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma, and post-transplant DLBCL are also eligible as long as they meet other criteria and are receiving RCHOP-based therapy\r\n** NOTE: patients can be enrolled up through day 1 of cycle 3 of therapy; the patient is permitted to participate in any other therapeutic therapy for their disease as long as it does not concern vitamin D; patients can begin their chemotherapy while awaiting vitamin D results and treatment arm assignment or\r\n* Newly diagnosed untreated peripheral T-cell non-Hodgkin lymphoma (NHL) that will be treated with chemotherapy; NOTE: patients can be enrolled up through day 1 of cycle 3 of therapy; this includes the following disease types:\r\n** Peripheral T cell lymphoma, unspecified\r\n** Anaplastic large cell lymphoma (T and null cell type)\r\n** Extranodal NK/T-cell lymphoma, nasal type\r\n** Enteropathy-type T-cell lymphoma\r\n** Hepatosplenic T-cell lymphoma\r\n** Subcutaneous panniculitis-like T-cell lymphoma\r\n** Angioimmunoblastic T-cell lymphoma\r\n** Anaplastic large cell lymphoma – primary cutaneous type and\r\n* Willing to provide tissue for correlative research purposes

Patients who previously had indolent lymphoma and now at a separate episode have large cell NHL (i.e. transformation)

Diffuse large B-cell lymphoma (DLBCL) Not otherwise specified (NOS) including transformed indolent Non-Hodgkin lymphoma (NHL)

Follicular lymphoma Grade 3B

T cell/histiocyte-rich large B-cell lymphoma

Primary mediastinal (thymic) large B-cell lymphoma

High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma)

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma; follicular, marginal zone, diffuse large B-cell or mantle cell lymphoma with chemo-sensitive disease at time of transplant

Patients with transformed lymphoma (e.g., Richter's transformation arising in follicular lymphoma or chronic lymphocytic leukemia)

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin's Lymphoma,or mantle cell lymphoma with chemosensitive disease at time of transplantation

Patients with transformed lymphoma (e.g., Richters transformation arising in follicular lymphoma or chronic lymphocytic leukemia)

New diagnosis of lymphoma and scheduled to undergo doxorubicin hydrochloride (DOX)-based chemotherapy

Immunocompetent patients with newly diagnosed or recurrent non-Hodgkins lymphoma involving the brain (primary or secondary), as demonstrated by magnetic resonance imaging (MRI) and histologic confirmation either by positive cerebrospinal fluid (CSF) cytology for lymphoma or a monoclonal lymphocyte population defined by cell surface markers, vitreous or uvea biopsy or brain biopsy

History of lymphoma

Histologically confirmed aggressive B-cell DLBCL, including follicular lymphoma (FL) transforming to DLBCL

No concurrent, active malignancy, other than non-metastatic skin cancer of any type, superficial bladder cancer, or early stage chronic lymphocytic leukemia (well-differentiated small cell lymphocytic lymphoma) or < stage IV follicular lymphoma; if a prior malignancy is in remission for >= 3 years then the patient is eligible

Known histological transformation from iNHL to diffuse large B-cell lymphoma or Richter’s transformation for CLL

For the Dose Escalation phase, participants must have histologically confirmed diagnosis of advanced NHL of any histology (with the exception of participants with mantle cell lymphoma [MCL] or chronic lymphoma leukemia [CLL]).

For the expansion phase, participants must have histologically confirmed diagnosis of advanced DLBCL or follicular lymphoma FL.

Diffuse Large B Cell Lymphoma (DLBCL)