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Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients (ELIANA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02435849
Recruitment Status : Completed
First Posted : May 6, 2015
Results First Posted : November 22, 2021
Last Update Posted : February 13, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL.

Condition or disease Intervention/treatment Phase
B-cell Acute Lymphoblastic Leukemia Biological: CTL019 Phase 2

Detailed Description:

This was a initially a one cohort, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL. This main cohort completed enrollment. Two new cohorts were added via an amendment, Cohort 1 for high risk B-cell ALL patients at first relapse, and Cohort 2 for feasibility and safety of CTL019 in high risk B-cell ALL in patients that relapsed <6 months post allo-HSCT. Due to lack of recruitment, Cohort 1 and Cohort 2 halted recruitment. This decision was not related to any safety issue.

The study had the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Primary Follow-up, Secondary Follow-up (if applicable) and Survival Follow-up. The total duration of the study is 5 years from CTL019 cell infusion.

Efficacy analyses were performed only on the Main Cohort (n=79) who were infused with tisagenlecleucel. However, the data on disposition and demographics presented in this section includes all patients enrolled to the study (98) and all infused patients (80) (Main Cohort + Cohort 1). No patients were enrolled in Cohort 2.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 80 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia
Actual Study Start Date : April 8, 2015
Actual Primary Completion Date : January 21, 2020
Actual Study Completion Date : November 17, 2022


Arm Intervention/treatment
Experimental: Single dose of CTL019
Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).
Biological: CTL019
Tisagenlecleucel was administered as a single iv infusion. Dose: 2.0 to 5.0x10^6 tisagenlecleucel per kg body weight (for patients ≤ 50 kg) or 1.0 to 2.5x10^8 tisagenlecleucel (for patients >50 kg).




Primary Outcome Measures :
  1. Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment. [ Time Frame: during the 3 months after tisagenlecleucel administration ]

    Evaluating the efficacy of tisagenlecleucel therapy from all manufacturing facilities as measured by overall remission rate (ORR) during the 3 months after tisagenlecleucel administration. ORR included complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by an Independent Review Committee assessment. Per response criteria defined by National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH) and International Working Group (IWG) guidelines.

    CR is defined as:

    Bone marrow <5% blasts, Peripheral blood: Neutrophils >1.0 x 10^9/L, and Platelets >100 x 10^9/L and Circulating blasts <1% and No evidence of extramedullary disease, at least 7 days transfusion independency.

    CRi is defined as all the prior criteria being met, except that the following exists: Neutrophils ≤1.0 x 10^9/L, and/or Platelets ≤100 x 10^9/L, and/or Platelet and/or neutrophil transfusions ≤7 days before the date of the peripheral blood sample for disease assessment.



Secondary Outcome Measures :
  1. Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary) [ Time Frame: 3 months after tisagenlecleucel administration ]
    These are the percentage of participants with ORR who achieved overall remission rate which includes complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by IRC assessment after having been infused with tisagenlecleucel from US manufacturing facilities.

  2. Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From US Manufacturing Facility as Per IRC in the Main Cohort Only (Key Secondary) [ Time Frame: 3 months after tisagenlecleucel administration ]
    These are the percentage of participants who achieved Best Overall Response (BOR) of complete response (CR) or complete response with incomplete blood count recovery (CRi) with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from US manufacturing facilities only, by IRC assessment.

  3. Percentage of Participants With Best Overall Response (BOR) of CR or CRi With MRD Negative Bone Marrow by Flow Cytometry From All Manufacturing Facilities as Per IRC in the Main Cohort Only (Key Secondary) [ Time Frame: 3 months after tisagenlecleucel administration ]
    These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from all manufacturing facilities by IRC assessment. MRD negative = MRD% < 0.01%

  4. Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT) [ Time Frame: 6 months after tisagenlecleucel administration ]
    These are the participants who achieved CR or CRi without HSCT between tisagenlecleucel (CTL019) infusion and Month 6 response assessment.

  5. Percentage of Participants Who Achieved CR or CRi and Then Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) While in Remission Prior to Month 6 Resoonse [ Time Frame: 6 months ]
    These are the participants who achieved CR or CRi and then proceeded to HSCT while in remission prior to Month 6 response assessment

  6. Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion [ Time Frame: up to 6 months ]
    These are the participants who achieved CR or CRi and then proceeded to SCT after being infused by tisagenlecleucel.

  7. Duration of Remission (DOR) [ Time Frame: 60 months ]
    DOR is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death.

  8. Site of Involvement of Subsequent Relapse [ Time Frame: 60 months ]
    Anatomical location of relapse in participants who achieved prior CR/CRi subsequent to tisagenlecleucel infusion.

  9. Relapse-free Survival Per IRC Assessment [ Time Frame: 60 months ]
    RFS is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death due to any cause during CR or CRi.

  10. Event-free Survival Per IRC Assessment [ Time Frame: 60 months ]
    EFS is the time from date of tisagenlecleucel infusion to the earliest of death, relapse or treatment failure.

  11. Overall Survival (OS) [ Time Frame: 60 months ]
    OS, is the time from date of tisagenlecleucel infusion to the date of death due to any reason.

  12. Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment [ Time Frame: 1 month ]
    These are participants who had a day 28 response (CR or CRi response) by IRC assessment.

  13. Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only [ Time Frame: 3 months ]
    Percentage of participants who achieved BOR of CR or CRi by flow cytometry as a function of baseline bone marrow tumor burden.

  14. Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment [ Time Frame: 28 days ]
    Percentage of participants who achieved CR or CRi response with bone marrow MRD negative (MRD < 0.01%) after tisagenlecleucel infusion by flow cytometry.

  15. Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment [ Time Frame: Month 60 ]
    This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in peripheral blood.

  16. Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment [ Time Frame: Month 6 ]
    This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in bone marrow.

  17. Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment [ Time Frame: Month 60 ]
    This is the summary cellular kinetic concentrations for CTL019 by flow cytometry in peripheral blood. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 60 for peripheral blood.

  18. Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment [ Time Frame: Month 6 ]
    This is the summary cellular kinetic concentrations for CTL019 by flow cytometry. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 6 for bone marrow.

  19. Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC [ Time Frame: 60 months ]
    Cmax is the maximum (peak) observed in peripheral blood drug concentration after single dose administration reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment. The reported Cmax is the summary of maximum level observed based on the data from each patient and based on all the data that's been collected for up to 60 months in a patient.

  20. Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC [ Time Frame: 60 months ]
    Tmax is the time to reach maximum (peak) peripheral blood drug concentration after single dose administration (days)", reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment. The time frame of 60 months refers to the duration for which the data were reviewed to identify the time of Cmax for this measure.

  21. Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC [ Time Frame: 0 to 84 days after infusion ]
    AUC (area under curve) from day of infusion to day 28 or other disease assessment days, in peripheral blood (% or copies/μg x days), reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas 84 days is the actual timepoint for endpoint assessment. : AUC is defined based on the time window i.e., AUC from 0 to 84 days after infusion. Therefore, the time frame specifies the maximum time for up to which the data are used for estimation of AUC (84 days for AUC84d).

  22. Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC [ Time Frame: 60 months ]
    Persistence is defined as the time corresponding to last quantifiable transgene level in peripheral blood (Tlast), reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment.

  23. Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019) [ Time Frame: At any time post-baseline, up to a max. of 60 months ]
    This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by CR/CRi, no response (NR), Unknown and by All participants. .

  24. Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire [ Time Frame: Month 3, M6, M12, M24, M60 ]
    The PedsQL questionnaire was for patients ≥ 8-years-old who achieved BOR as CR or CRi within 3 months and the questionnaire was on emotional, social, school, physical, and psychosocial health. Scores are transformed on a scale from 0 to 100, with the sum of all the items over the number of items answered on all the scales. The total scale score is the averaged value of scores of subscales, which means for each subscale and the total scale, the allowed ranges are 0-100. Higher scores on the PedsQL questionnaire for these subscales indicate consistent improvement of health-related quality of life (HRQol).

  25. Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire [ Time Frame: Month 60 ]
    Results from the EQ-5D questionnaire is for number of participants who achieved CR or CRi at month 60. The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain & discomfort, anxiety & depression. Respondents are asked to choose the statement in each dimension that best describes their health status on the day surveyed. Their responses are coded as a number (1, 2, or 3) that corresponds to the respective level of severity: 1 indicates no problems, 2 some problems, and 3 severe problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes the patient's health state. The scores are then normalized to a value from 0-100 where higher scores = better HRQOL & fewer problems or symptoms.

  26. Develop a Score Utilizing Clinical and Biomarker Data and Assess Its Ability for Early Prediction of Cytokine Release Syndrome (CRS) [ Time Frame: 3 months ]
    Derivation of a score to predict cytokine release syndrome. Considering the complexity and challenges of building a scoring system based on limited data from the trial, this analysis was not performed.

  27. Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin) [ Time Frame: Maximum post-baseline (approx. 60 months) ]
    Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).

  28. Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) [ Time Frame: Maximum post-baseline (approx. 60 months) ]
    Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).

  29. Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion [ Time Frame: Month 3, Month 12, Maximum post-baseline (approx. 60 months) ]
    Levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring

  30. Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility [ Time Frame: 60 months ]
    These are the percentage of participants with ORR who achieved overall remission rate which includes complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by IRC assessment after having been infused with tisagenlecleucel from Fraunhofer Institute manufacturing facility.

  31. Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From Fraunhofer Institute Manufacturing Facility as Per IRC [ Time Frame: 3 months ]
    These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from Fraunhofer Institute manufacturing facilities only, by IRC assessment.

  32. Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute [ Time Frame: Month 60 ]
    This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR, by disease response in blood by IRC assessment. The assessment of the efficacy, safety and in vivo cellular pharmacokinetics are for patients infused with tisagenlecleucel manufactured by Fraunhofer Institute.

  33. Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute [ Time Frame: Month 3 ]
    This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR, by disease response in bone marrow by IRC assessment. The assessment of the efficacy, safety and in vivo cellular pharmacokinetics are for patients infused with tisagenlecleucel manufactured by Fraunhofer Institute.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02435849


Locations
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United States, California
Childrens Hospital Los Angeles SC CTL019
Los Angeles, California, United States, 90027
Stanford Universtiy Medical Center SC - CTL019B2205J - B2206
Stanford, California, United States, 94304
United States, Georgia
Children's Healthcare of Atlanta SC CTL019
Atlanta, Georgia, United States, 30342
United States, Michigan
University of Michigan .
Ann Arbor, Michigan, United States, 48109-2800
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Children s Mercy Hospital SC - CTL019B2205J
Kansas City, Missouri, United States, 64108
United States, North Carolina
Duke Unversity Medical Center .
Durham, North Carolina, United States, 27705
United States, Oregon
Oregon Health and Science University Doernbecher Children's Hosp.
Portland, Oregon, United States, 97239-3098
United States, Pennsylvania
The Childrens Hospital of Philadelphia CHOP
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas Southwestern Medical Center .
Dallas, Texas, United States, 75235
United States, Utah
University of Utah Clinical Trials Office SC - CTL019B2205J
Salt Lake City, Utah, United States, 84108
Australia, Victoria
Novartis Investigative Site
Parkville, Victoria, Australia, 3052
Austria
Novartis Investigative Site
Wien, Austria, A 1090
Belgium
Novartis Investigative Site
Gent, Belgium, 9000
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H3T 1C5
France
Novartis Investigative Site
Paris 10, Cedex 10, France, 75475
Novartis Investigative Site
Paris, France, 75019
Germany
Novartis Investigative Site
Frankfurt, Germany, 60590
Italy
Novartis Investigative Site
Monza, MB, Italy, 20900
Japan
Novartis Investigative Site
Kyoto, Japan, 606 8507
Norway
Novartis Investigative Site
Oslo, Norway, 0424
Spain
Novartis Investigative Site
Esplugues De Llobregat, Barcelona, Spain, 08950
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] October 26, 2020
Statistical Analysis Plan  [PDF] November 28, 2022

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02435849    
Other Study ID Numbers: CCTL019B2202
2013-003205-25 ( EudraCT Number )
First Posted: May 6, 2015    Key Record Dates
Results First Posted: November 22, 2021
Last Update Posted: February 13, 2024
Last Verified: December 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Pediatric
ALL
Cell therapy
Lymphoblastic Leukemia
Acute
High Risk
Childhood
CTL019
tisagenlecleucel
Pediatric patients
r/r B-cell ALL
high risk B-cell ALL at first relapse
high risk B-cell ALL that relapsed < 6 months post allo-HSCT
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Tisagenlecleucel
Antineoplastic Agents, Immunological
Antineoplastic Agents