Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy (TRANSCEND-PILOT-017006)

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multicenter study to determine the efficacy and safety of lisocabtagene maraleucel (JCAR017) in adult subjects who have relapsed from, or are refractory to, a single line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) and are ineligible for hematopoietic stem cell transplant (based on age, performance status, and/or comorbidities). Subjects will receive treatment with lisocabtagene maraleucel and will be followed for 2 years for safety, pharmacokinetics and biomarkers, disease status, quality of life, and survival.

Official Title
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A Phase 2 Study of Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy in Adult Patients With Aggressive B-cell NHL (017006)

Conditions
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Lymphoma, Non-Hodgkin, Lymphoma, Nonhodgkin, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Biological: lisocabtagene maraleucel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Previous treatment must include treatment with a single line of chemoimmunotherapy containing an anthracycline and a CD20-targeted agent Subjects must be deemed ineligible for both high-dose chemotherapy and hematopoietic stem cell transplant (based on age, performance status and/or comorbidities) while also having adequate organ function for CAR T cell treatment. Positron emission tomography (PET)-positive disease Histological confirmation of diagnosis at last relapse. Enough tumor material must be available for central confirmation of diagnosis, otherwise a new tumor biopsy is mandated. ECOG performance status of 0, or 1, or 2 Adequate vascular access for leukapheresis procedure (either peripheral line or surgically-placed line) Subjects must agree to use appropriate contraception Subjects must agree to not donate blood, organs, semen, and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy Exclusion Criteria: Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study) History of another primary malignancy that has not been in remission for at least 2 years. Previous treatment with CD19-targeted therapy, with the exception of prior lisocabtagene maraleucel treatment in this protocol for subjects receiving retreatment Active hepatitis B or hepatitis C infection at the time of screening History of or active human immunodeficiency virus (HIV) infection at the time of screening Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or lisocabtagene maraleucel administration History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease History or presence of clinically relevant CNS pathology Pregnant or nursing women Subject does not meet protocol-specified washout periods for prior treatments Prior hematopoietic stem cell transplant 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Lisocabtagene maraleucel at a dose of 100×10^6 CAR+ T cells (50×10^6 CD8+ CAR+ T cells and 50×10^6 CD4+ CAR+ T cells), will be given IV in a single-dose schedule on Day 1 (between 2 and 7 days following the completion of lymphodepleting chemotherapy). | Biological: lisocabtagene maraleucel<br>* lisocabtagene maraleucel will be administered as a single dose intravenous (IV) injection<br>* Other names: liso-cel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate is the percent of participants with a best overall response (BOR) of either complete response (CR) or partial reasons (PR) based on the Independent Review Committee (IRC) assessment recorded from the time of JCAR017 treatment until disease progression, end of study, the start of another anticancer therapy or JCAR017 retreatment. CR = Score 1, 2, or 3 with or without a residual mass on the positron emission tomography 5-point scale (PET 5PS). A score of 3 in many patients indicates a good prognosis with standard treatment. PR = Score 4 or 5b with reduced uptake compared with baseline and residual mass(es) of any size. PET 5PS = 1- no uptake above background; 2- uptake ≤ mediastinum; 3- uptake > mediastinum but ≤ liver; 4- uptake moderately > liver; 5- uptake markedly higher than liver and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma. | From first dose to disease progression, end of study, the start of another anticancer therapy, or hematopoietic stem cell transplantation (up to approximately 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Treatment-Emergent Adverse Events (TEAEs) | A TEAE was defined as an adverse event that started any time from initiation of product administration through and including 90 days following product administration. AEs that occurred after the initiation of subsequent anticancer therapy or product retreatment were not considered as product TEAE. AEs are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) (NCI CTCAE) guidelines where Grade 3= Severe, Grade 4= Life-threatening, and 5 = Death. | From first dose to 90 days following first dose (up to approximately 90 days) | 
| Change From Baseline of Hematology Laboratory Results: Hemoglobin | Change from baseline in Hematology laboratory analysis. Includes Hemoglobin. Baseline is the last observation collected prior to or on the date of product infusion. | Baseline and Day 29 | 
| Change From Baseline of Hematology Laboratory Results: Leukocytes, Lymphocytes, Neutrophils, Platelets | Change from baseline in Hematology laboratory analysis. Includes Leukocytes, Lymphocytes, Neutrophils, and Platelets. Baseline is the last observation collected prior to or on the date of product infusion. | Baseline and Day 29 | 
| Change From Baseline of Chemistry Laboratory Results: Albumin | Change from baseline in Chemistry laboratory analysis. Includes Albumin. Baseline is the last observation collected prior to or on the date of product infusion. | Baseline and Day 29 | 
| Change From Baseline of Chemistry Laboratory Results: Alanine Aminotransferase, Aspartate Aminotransferase, Lactate Dehydrogenase | Change from baseline in Chemistry laboratory analysis. Includes Alanine Aminotransferase, Aspartate Aminotransferase, and Lactate Dehydrogenase. Baseline is the last observation collected prior to or on the date of product infusion. | Baseline and Day 29 | 
| Change From Baseline of Chemistry Laboratory Results: Bilirubin, Creatinine, Direct Bilirubin, Urate | Change from baseline in Chemistry laboratory analysis. Includes Bilirubin, Creatinine, Direct Bilirubin, and Urate. Baseline is the last observation collected prior to or on the date of product infusion. | Baseline and Day 29 | 
| Change From Baseline of Chemistry Laboratory Results: Calcium Corrected, Magnesium, Phosphate, Potassium, Sodium | Change from baseline in Chemistry laboratory analysis. Includes Calcium Corrected, Magnesium, Phosphate, Potassium, and Sodium. Baseline is the last observation collected prior to or on the date of product infusion. | Baseline and Day 29 | 
| Complete Response (CR) Rate | Complete response rate (CRR) was defined as the percent of participants with a best overall response (BOR) of complete response (CR) based on the Independent Review Committee (IRC) assessment recorded from the time of JCAR017 treatment until disease progression, end of study, the start of another anticancer therapy or JCAR017 retreatment. CR = Score 1, 2, or 3 with or without a residual mass on the positron emission tomography 5-point scale (PET 5PS). A score of 3 in many patients indicates a good prognosis with standard treatment. PET 5PS = 1- no uptake above background; 2- uptake ≤ mediastinum; 3- uptake > mediastinum but ≤ liver; 4- uptake moderately > liver; 5- uptake markedly higher than liver and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma. | From first dose to disease progression, end of study, the start of another anticancer therapy, or hematopoietic stem cell transplant (up to approximately 24 months) | 
| Duration of Response (DOR) | Duration of response (DOR) is defined as the time from first complete response(CR) or partial response (PR) to progressive disease (PD) or death, whichever occurred first. CR = Score 1, 2, or 3 on the positron emission tomography 5-point scale (PET 5PS). A score of 3 indicates a good prognosis with standard treatment. PR = Score 4 or 5b with reduced uptake compared with baseline and residual mass(es) of any size. PD = Score 4 or 5b on PET 5PS with an increase in intensity of uptake from baseline and/or new fluorodeoxyglucose-avid foci consistent with lymphoma at interim or end-of-treatment assessment. PET 5PS = 1-no uptake above background; 2-uptake ≤ mediastinum; 3-uptake > mediastinum but ≤ liver; 4-uptake moderately > liver; 5-uptake markedly higher than liver and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma. | From first dose to up to approximately 24 months | 
| Duration of Response (DOR) in Participants With Complete Response (CR) | DOR for participants with a best overall response of CR was defined as the time from documentation of first response (or CR) to progressive disease (PD) or death, whichever occurred first. The first documentation of CR/PR is the latest of all dates of required measurements to establish the response. The progression date is the earliest date of all assessments that led to a response assessment of PD. CR = Score 1, 2, or 3 on the positron emission tomography 5-point scale (PET 5PS). A score of 3 indicates a good prognosis with standard treatment. PD = Score 4 or 5b on PET 5PS with an increase in intensity of uptake from baseline and/or new fluorodeoxyglucose-avid foci consistent with lymphoma at interim or end-of-treatment assessment. PET 5PS = 1-no uptake above background; 2-uptake ≤ mediastinum; 3-uptake > mediastinum but ≤ liver; 4-uptake moderately > liver; 5-uptake markedly higher than liver and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma. | From first dose to up to approximately 24 months | 
| Progression-Free Survival (PFS) | PFS is defined as the time from JCAR017 infusion to progressive disease (PD) or death. Kaplan-Meier (KM) methodology will be used to analyze PFS. PD = Score 4 or 5b on the positron emission tomography 5-point scale (PET 5PS) with an increase in intensity of uptake from baseline and/or new fluorodeoxyglucose-avid foci consistent with lymphoma at interim or end-of-treatment assessment. PET 5PS = 1- no uptake above background; 2- uptake ≤ mediastinum; 3- uptake > mediastinum but ≤ liver; 4- uptake moderately > liver; 5- uptake markedly higher than liver and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma. | From first dose to progressive disease (PD) or death (up to approximately 24 months) | 
| Event-Free Survival (EFS) | EFS is defined as the time from JCAR017 infusion to the earliest of the following events: death from any cause, progressive disease (PD), or starting a new anticancer therapy. Kaplan-Meier (KM) methodology will be used to analyze EFS. PD = Score 4 or 5b on PET 5PS with an increase in intensity of uptake from baseline and/or new fluorodeoxyglucose-avid foci consistent with lymphoma at interim or end-of-treatment assessment. PET 5PS = 1-no uptake above background; 2-uptake ≤ mediastinum; 3-uptake > mediastinum but ≤ liver; 4-uptake moderately > liver; 5-uptake markedly higher than liver and/or new lesions; X- new areas of uptake unlikely to be related to lymphoma. | From first dose to death from any cause, progressive disease (PD), or starting a new anticancer therapy (up to approximately 24 months) | 
| Overall Survival (OS) | OS is defined as the time from JCAR017 infusion to the date of death. Kaplan-Meier (KM) methodology will be used to analyze OS. | From first dose to date of death (up to approximately 24 months) | 
| PK Parameters of JCAR017 in Blood as Assessed by qPCR: Cmax | Pharmacokinetic (PK) analyses were based on quantitative polymerase chain reaction (qPCR). Cmax = Maximum observed blood concentration. | From first dose to up to 24 months | 
| PK Parameters of JCAR017 in Blood as Assessed by qPCR: Tmax | Pharmacokinetic (PK) analyses were based on quantitative polymerase chain reaction (qPCR). Tmax = Time of maximum observed blood concentration. | From first dose to up to 24 months | 
| PK Parameters of JCAR017 in Blood as Assessed by qPCR: AUC (0-28) | Pharmacokinetic (PK) analyses were based on quantitative polymerase chain reaction (qPCR). AUC (0-28) = Area under the curve for concentration. | From first dose to up to 24 months | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health/QoL Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea/Vomiting Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Symptom scale/item higher score represents a high level of symptomatic problem. | Baseline and Day 29 | 
| Mean Score in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties Subscale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. | Baseline and Day 29 | 
| Health-Related Quality of Life (HRQoL) Assessed by the FACT-Lym Subscale | The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) consists of the FACT-General scale and a 15-item lymphoma-specific additional concerns subscale (LYM). This scale addresses symptoms and functional limitations that are important to lymphoma patients. The LYM items are scored on a 0 (Not at all) to 4 (Very much) response scale. Items are aggregated to a single score on a 0-60 scale. | Baseline and Day 29 | 
| Health-Related Quality of Life (HRQoL) Assessed by the EuroQol Instrument EQ-5D-5L | The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. These health states are converted to a single index value using the crosswalk method to the EQ-5D-3L value set from the United Kingdom (UK). The EQ-5D-5L health states ranged from -.594 for the worst (55555) to 1 for the best (11111) for UK value set with an optimal health state is assigned a score of 1.00, death is assigned a score of 0.00 and negative values representing values as worse than dead. A change of .08 is considered to be a clinically meaningful change in health utility. | Baseline and Day 29 | 
| Numbers of Intensive Care Unit (ICU) Inpatient Days | The numbers of ICU inpatient days. | From first dose after JCAR017 infusion to up to approximately 24 months | 
| Numbers of Non-intensive Care Unit (ICU) Inpatient Days | Number of non-ICU inpatient days. | From first dose after JCAR017 infusion to up to approximately 24 months | 
| The Number of Participants That Were Hospitalized For Adverse Events, Prophylaxis, Other | Length of hospitalization stay was reported for up to 24 months post liso-cel infusion. Reasons for hospitalization include adverse events, prophylaxis, and other. Adverse events were reported for up to 90 days post liso-cel infusion. | From first dose after JCAR017 infusion to up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JCAR017, lisocabtagene maraleucel, NHL, chimeric antigen receptor, CAR, CAR T cell, autologous T cell therapy, immunotherapy, cell therapy, liso-cel