Please select the eligibility criteria that correspond to the clinical trial below.
Title: Pilot Study of Redirected Autologous T Cells Transduced to Express A CD20-Specific Chimeric Immunoreceptor in Patient With Chemotherapy Resistant or Refractory CD20+ Leukemia and Lymphoma
Brief Summary: RATIONALE: Placing a gene that has been created in the laboratory into white blood cells may make the body build an immune response to kill cancer cells.

PURPOSE: This clinical trial is studying genetically engineered lymphocyte therapy in treating patients with B-cell leukemia or lymphoma that is resistant or refractory to chemotherapy.


Options:
A: Inclusion Criteria:

* Age ≥ 18 years at the time of consent
* Relapsed or refractory B-cell NHL of the following histologies: diffuse large B cell lymphoma (DLBCL) not otherwise specified; includes biopsy-confirmed transformed DLBCL from indolent histologies, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, 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 systemic lines of therapy for DLBCL or after auto-HSCT.
* Positron-emission tomography-positive disease by Lugano Classification
* Eastern Cooperative Oncology Group performance status of 0 to 1
* Adequate bone marrow, renal, hepatic, pulmonary, cardiac organ function
* Adequate vascular access for leukapheresis procedure
* Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy
* Subjects must agree to use appropriate contraception.

Exclusion Criteria:

* Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study)
* History of prior allogeneic hematopoietic stem cell transplant
* Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis
* History of another primary malignancy that has not been in remission for at least 2 years.The following are examples of exceptions from the 2-year limit: nonmelanoma skin cancer, definitively-treated stage 1 solid tumor with a low risk of recurrence, curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on a Papanicolau smear.
* Active hepatitis B or hepatitis C infection at the time of screening
* History of or active human immunodeficiency virus infection at the time of screening
* Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate anti-infection treatment at the time of leukapheresis or lisocabtagene maraleucel administration
* Presence of acute or chronic graft-versus-host disease
* History of clinically significant cardiac conditions within the past 6 months
* History or presence of clinically relevant CNS pathology such as epilepsy/seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
* Pregnant or nursing women
* Subject does not meet protocol-specified washout periods for certain prior treatments
* Prior CAR T-cell or other genetically modified T-cell therapy
* Progressive vascular tumor invasion, thrombosis, or embolism
* Venous thrombosis or embolism not managed on stable regimen of anticoagulation
* Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol
B: Inclusion Criteria:

1. Relapsed or refractory pediatric B-cell ALL
2. Adequate organ function
3. For relapsed patients, documentation of CD19 tumor expression within 3 months of study entry.
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
5. Life expectancy \> 12 weeks.
6. Karnofsky (age ≥16 years) or Lansky (age \< 16 years) performance status ≥ 50 at screening
7. Signed written informed consent and assent forms
8. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, store leukapheresis product
9. Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.
10. Cohort 1 only:

    1. First relapse AND hypodiploid cytogenetics OR
    2. First relapse AND t(17;19) with defined TCF3-HLF fusion OR
    3. First relapse with any cytogenetics provided the relapse occurred ≤ 36 months of initial diagnosis AND MRD at end of reinduction therapy is ≥0.01% by flow cytometry (local assessment)

Exclusion Criteria

1. Isolated extra-medullary disease relapse
2. Patients with concomitant genetic syndrome: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.
3. Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell \[sIg positive and kappa or lambda restricted positivity\] ALL, with FAB L3 morphology and /or a MYC translocation)
4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
5. Treatment with any prior gene therapy product
6. Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
7. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
8. Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
9. Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).
10. Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines.
11. Patient has an investigational medicinal product within the last 30 days prior to screening.
12. Pregnant or nursing (lactating) women.
13. Women of child-bearing potential, defined as physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception for at least 12 months after the CTL019 infusion and after CAR T-cells are no longer present by qPCR on two consecutive tests
14. Sexually active males must use a condom during intercourse at least 12 months after the CTL019 infusion after CAR T-cells are no longer present by qPCR on two consecutive tests
C: Inclusion Criteria:

* •Male and female subjects with CD20+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to \< 2 year survival) with currently available therapies will be enrolled

  * CD20+ leukemia or lymphoma
  * ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor
  * Follicular lymphoma, previously identified as CD20+:
  * At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy
  * Stage III-IV disease
  * Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval \< 1 year)
  * Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)
  * CLL:
  * At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior
  * Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval \< 2 years)
  * Not eligible or appropriate for conventional allogeneic SCT
  * Patients who achieve only a partial response to FCR as initial therapy will be eligible.
  * Mantle cell lymphoma:
  * Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT
  * Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)
  * Relapsed after prior autologous SCT
  * B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT
  * Diffuse large cell lymphoma, previously identified as CD20+:
  * Residual disease after primary therapy and not eligible for autologous SCT
  * Relapsed after prior autologous SCT
  * Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT
  * Expected survival \> 12 weeks
  * Creatinine \< 2.5 mg/dl
  * ALT/AST \< 3x normal
  * Bilirubin \< 2.0 mg/dl
  * Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy
  * Adequate venous access for apheresis, and no other contraindications for leukapheresis
  * Voluntary informed consent is given

Exclusion Criteria:

* •Pregnant or lactating women

  * The safety of this therapy on unborn children is not known
  * Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
  * Uncontrolled active infection
  * Active hepatitis B or hepatitis C infection
  * Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
  * Previously treatment with any gene therapy products
  * Feasibility assessment during screening demonstrates \< 30% transduction of target lymphocytes, or insufficient expansion (\< 5-fold) in response to CD3/CD28 costimulation
  * Any uncontrolled active medical disorder that would preclude participation as outlined
  * HIV infection
D: Inclusion Criteria:

1. Male and female subjects with CD19 expressing B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin Lymphoma (NHL) with BM involvement and one of the following:

   i. Patients in 2nd or subsequent relapse, after at least one standard frontline chemotherapy and one salvage regimen, with BM involvement ii. Relapse after allogeneic HSCT, if at least 100 days post-transplant, if there is no evidence of active GVHD and if the patient is no longer taking immunosuppressive agents for at least 30 days prior to enrollment iii. MRD \> 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL
2. Measurable or evaluable disease at the time of enrollment, which may include any evidence of disease, including MRD detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
3. Age: 6 months - 25 years.
4. Voluntary informed consent is given. For subjects \< 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
5. Clinical performance status: Patients \> 16 years of age: Karnofsky greater than or equal to 60%; Patients \< 16 years of age: Lansky scale greater than or equal to 60%.
6. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
7. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.

Exclusion Criteria:

1. Pregnant or lactating women
2. Severe, uncontrolled active intercurrent infections
3. HIV, or active HCV and/or HBV infection
4. Life-expectancy \< 6 weeks
5. Hepatic function: Inadequate liver function defined as total bilirubin \> 4x upper limit of normal (ULN) or transaminase (ALT and AST) \> 6 x ULN
6. Renal function: serum creatinine \> 3x ULN for age.
7. Blood oxygen saturation \< 90%.
8. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO.
9. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject.
10. BM blasts \> 50% pre-infusion.
11. Hyperleukocytosis (greater than or equal to 20,000 blasts/microliter) or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy
12. Active CNS disease as documented by the presence of blasts in the CSF or by MRI. This criterion could be revised once that, after the phase I portion of the study, absence of life-threatening (i.e. grade IV) neurological toxicity will be documented.
13. Presence of active, grade 2-4 acute or extensive chronic GvHD
14. Recurrent or refractory ALL with testicular involvement
15. Concurrent or recent prior therapies, before infusion:

    i. Systemic steroids (at a dose \> 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary.

    ii. Systemic chemotherapy in the 2 weeks preceding infusion. iii. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) in the 4 weeks preceding infusion.

    iv. Immunosuppressive agents in the 2 weeks preceding infusion. v. Radiation therapy must have been completed at least 3 weeks prior to enrollment.

    vi. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy);

    vii. Exceptions:
    1. There is no time restriction with respect to prior intrathecal chemotherapy, provided that there is complete recovery from any acute toxic effects of such;
    2. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided that they meet all other eligibility criteria;
    3. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided that there has been no increase in dose for at least 2 weeks prior to starting apheresis;
16. Patient-derived CD19-CART01 production failure

Answer: C