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

• ClinicalTrials.gov Identifier: NCT02228096
• Recruitment Status: Completed
• First Posted: August 28, 2014
• Results First Posted: November 23, 2020
• Last Update Posted: November 23, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: B-cell Acute Lymphoblastic Leukemia; Relapsed B-cell Acute Lymphoblastic Leukemia; Refractory B-cell Acute Lymphoblastic Leukemia
• Intervention: Biological: CTL019 T-cells
• Enrollment: 75

Participant Flow

Recruitment Details	Patients were recruited between 14-Aug-2014 (FPFV) and 22-Sep-2017 (LPFV). At the time of LPLV (24-May-2019), the sponsor had decided to transfer all ongoing patients to a separate long-term follow-up study to complete the planned 15 years of follow-up. These patients are designated with the reason for discontinuation as "terminated by sponsor".
Pre-assignment Details	"Enrolled" means all eligibility criteria were met and apheresis was accepted by the manufacturing facility. Patients could discontinue the trial after enrollment and prior to tisagenlecleucel infusion. Although 75 patients were enrolled, only 64 were infused as 11 discontinued prior to infusion.

Arm/Group Title	Tisagenlecleucel (CTL019) - All Participants
Arm/Group Description	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel
Period Title: Overall Study
Started	75
Enrolled Into Long-term f/u Protocol	31
Enrolled But Not Infused [1]	11
Enrolled and Infused	64
Completed	4 [2]
Not Completed	71
Reason Not Completed
Study terminated by Sponsor	24
Lack of Efficacy	18
Death	12
Physician Decision	3
Subject/guardian decision	2
New therapy for study indication	1
Enrolled, not infused	11
[1] Enrolled means all eligibility criteria were met & apheresis was accepted by manufacturing facility; [2] Completed = study follow-up completed

Baseline Characteristics

Arm/Group Title		Tisagenlecleucel (CTL019) - All Participants	Not Infused	Total
Arm/Group Description		Pediatric participants with r/r B-cell who were infused with tisagenlecleucel	Pediatric patients with r/r B-cell who were enrolled in the study but not infused with tisagenlecleucel	Total of all reporting groups
Overall Number of Baseline Participants		64	11	75
Baseline Analysis Population Description		Enrolled Set: All participants who met all the inclusion/exclusion criteria, and whose apheresis product is received and accepted by the manufacturing facilty
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	64 participants	11 participants	75 participants
		12.4 (5.16)	15.2 (5.44)	12.8 (5.26)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	11 participants	75 participants
	Female	34 53.1%	1 9.1%	35 46.7%
	Male	30 46.9%	10 90.9%	40 53.3%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants
White	Number Analyzed	64 participants	11 participants	75 participants
		52	8	60
Asian	Number Analyzed	64 participants	11 participants	75 participants
		5	1	6
Other	Number Analyzed	64 participants	11 participants	75 participants
		7	2	9
Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	64 participants	11 participants	75 participants
		43.7 (20.10)	86.2 (41.52)	47.3 (25.25)
Karnofsky/Lansky performance status [1] [2]; Measure Type: Count of Participants; Unit of measure: Participants
100	Number Analyzed	64 participants	0 participants	64 participants
		18 28.1%		18 28.1%
90	Number Analyzed	64 participants	0 participants	64 participants
		28 43.8%		28 43.8%
80	Number Analyzed	64 participants	0 participants	64 participants
		13 20.3%		13 20.3%
70	Number Analyzed	64 participants	0 participants	64 participants
		2 3.1%		2 3.1%
60	Number Analyzed	64 participants	0 participants	64 participants
		1 1.6%		1 1.6%
50	Number Analyzed	64 participants	0 participants	64 participants
		2 3.1%		2 3.1%
less than 50	Number Analyzed	64 participants	0 participants	64 participants
		0 0.0%		0 0.0%
		[1] Measure Description: Karnofsky/Lansky performance status helps determine the functional status of a recipient. This status is a critical data field that has been determined to be essential for all outcome-based analyses. Karnofsky Scale: designed for recipients aged 16 years & older; Lansky Scale: designed for recipients 1 year old to less than 16 years old. The Karnofsky/Lansky performances are based from 100 to 0, where 100 is "perfect" health & 0 is death. The scale: Able to carry on normal activity, no special care needed (80- 100); Mild to moderate restriction (50-70); Moderate to severe restriction (10- 40).; [2] Measure Analysis Population Description: FAS = All subjects who received an infusion of tisagenlecleucel

Outcome Measures

1. Primary Outcome

Title	Overall Remission Rate (ORR) Per Independent Review Committee (IRC) (for ALL Participants)
Description	ORR is defined as the percentage of participants with a best overall disease response of complete remission (CR) or Complete remission with incomplete blood count recovery (CRi), where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until the start of new anticancer therapy. Best response was assigned in the following order: CR, CRi, CR or CRi with residual mediastinal disease, No response and Unknown.
Time Frame	within 6 months after CTL019 infusion

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS

Arm/Group Title	Tisagenlecleucel (CTL019) - All Participants
Arm/Group Description:	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel
Overall Number of Participants Analyzed	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	70.3; (57.6 to 81.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tisagenlecleucel (CTL019) - All Participants
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Clopper-Pearson
	Comments	[Not Specified]

2. Primary Outcome

Title	Overall Remission Rate (ORR) Per Local Investigator Assessment (for Lymphoblastic Lymphoma Patients Only)
Description	Overall Remission Rate (ORR), which includes Complete Remission (CR) and Complete Remission with Incomplete Blood Count Recovery (CRi), as determined by assessments of peripheral blood, bone marrow, CNS symptoms, physical exam (PE) and cerebrospinal fluid (CSF). This primary endpoint was based on the local investigator assessment. No participants with lymphoblastic lymphoma were infused in this study.
Time Frame	6 months after CTL019

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS. No patients with Lymphoblastic Lymphoma were enrolled in this trial, hence there is no data to report.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

3. Secondary Outcome

Title	Percentage of Participants With Clinical Response Without Stem Cell Transplantation (SCT) at Month 6 - Per IRC Assessment
Description	Evaluate the percentage of participants who achieved CR or CRi at Month 6 without SCT between tisagenlecleucel infusion and Month 6 response assessment.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS.

Arm/Group Title	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	53.1; (40.2 to 65.7)

4. Secondary Outcome

Title	Percentage of Subjects Who Achieved CR or CRi and Then Proceeded to SCT While in Remission Prior to Month 6 Response - Per IRC Assessment
Description	Evaluate the percentage of subjects who achieved CR or CRi and then proceeded to SCT while in remission prior to Month 6 response assessment.
Time Frame	prior to Month 6

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS.

Arm/Group Title	Tisagenlecleucel (CTL019) - Per IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	7.8; (2.6 to 17.3)

5. Secondary Outcome

Title	Duration of Remission (DOR) Per Local and IRC Assessment
Description	DOR is the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to ALL
Time Frame	From CR or CRi to relapse or death up to 60 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	64	64
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (13.6 to NA)	NA [1]; (13.6 to NA)

[1]

N/A = median DOR was not reached as there were not enough participants with DOR events

6. Secondary Outcome

Title	Percentage of Participants With CR or CRi With Minimum Residual Disease (MRD) Negative Bone Marrow 6 Months After CTL019 Infusion
Description	Percentage of participants with best overall response (BOR) of CR or CRi with MRD negative bone marrow status 6 months after CTL019 infusion among all participants who achieved CR or CRi per Local Investigator & IRC assessment
Time Frame	within 6 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	64	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	67.2; (54.3 to 78.4)	67.2; (54.3 to 78.4)

7. Secondary Outcome

Title	Relapse-free Survival (RFS) for Responders Per Local and IRC Assessment
Description	RFS is the time from achievement of CR or CRi whichever occurs first to relapse or death due to any cause during CR or CRi.
Time Frame	60 Months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	45	45
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (13.6 to NA)	NA [1]; (13.6 to NA)

[1]

N/A = median RFS was not reached as there were not enough participants with RFS events

8. Secondary Outcome

Title	Event-free Survival (EFS) Per Local and IRC Assessment
Description	EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure. Treatment failure is defined as "no response" in the study and discontinuation from the study due to any of the following reasons: death, AE, lack of efficacy, new anticancer therapy.
Time Frame	60 Months

Outcome Measure Data

Analysis Population Description

FAS: All subjects who received an infusion of CTL019

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	64	64
Median (95% Confidence Interval); Unit of Measure: months
	15.6 [1]; (6.4 to NA)	15.6 [1]; (6.4 to NA)

[1]

N/A = not estimable because there were not enough participants who had an EFS event to estimate the upper limit of the median EFS

9. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is the time from date of CTL019 infusion to the date of death due to any reason
Time Frame	60 Months

Outcome Measure Data

Analysis Population Description

FAS: All subjects who received an infusion of CTL019

Arm/Group Title	Tisagenlecleucel (CTL019) - All Participants
Arm/Group Description:	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel
Overall Number of Participants Analyzed	64
Median (95% Confidence Interval); Unit of Measure: months
	29.9; (15.1 to 42.4)

10. Secondary Outcome

Title	Secondary Outcome: Percentage of Participants Attaining CR or CRi With MRD Negative Bone Marrow Status at Day 28 +/- 4 Days After CTL019 Infusion
Description	Percentage of participants attaining CR or CRi with MRD negative bone marrow status at Day 28 +/- 4 days after CTL019 infusion per Local Investigator and IRC assessment. BM MRD were only collected and measured only within responders.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS): A subset of all infused patients who were treated with CTL019 at least 6 months prior to the clinical data cutoff. In the final analysis, it is identical to the FAS. BM MRD were only collected and measured only within responders.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	64	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
With BM MRD -ve: i.e. MRD% < 0.01%	71.9; (59.2 to 82.4)	71.9; (59.2 to 82.4)
With BM 0.01% <= MRD% < 5%	1.6 [1]; (NA to NA)	1.6 [1]; (NA to NA)
With BM MRD% >= 5%	1.6 [2]; (NA to NA)	1.6 [2]; (NA to NA)
BM MRD not available	6.3 [3]; (NA to NA)	6.3 [3]; (NA to NA)

[1]

N/A: only 1 participant with BM MRD to calculate meaningful confidence interval (CI)

[2]

N/A: only 1 participant with BM MRD to calculate meaningful CI

[3]

N/A: few participants with BM MRD to provide meaningful CI

11. Secondary Outcome

Title	CTL019 Transgene Levels by qPCR CTL019 Cells by in qPCR Blood and Bone Marrow
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile (levels,persistence, trafficking) of CTL019 cells in target tissues
Time Frame	Enrollment; D1; D4; D7; D11; D14; D21; D28; M3; M6; M9, M12; M18; M24, M30, M36, M42, M48 for transgene levels in blood; Screening, D28, M3, M6 for transgene levels in bone marrow

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data

Arm/Group Title		CR/CRi	No Response (NR)	Unknown
Arm/Group Description:		Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed		52	6	6
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: copies/ug DNA
Enrollment blood	Number Analyzed	49 participants	6 participants	5 participants
		NA [1]; (NA%)	NA [1]; (NA%)	NA [1]; (NA%)
Day 1 (D1): blood	Number Analyzed	41 participants	4 participants	6 participants
		3680; (344.3%)	3190; (348.6%)	2440; (220.6%)
D4: blood	Number Analyzed	48 participants	6 participants	6 participants
		234; (197.8%)	48.8; (282.4%)	88.0; (71.0%)
D7: blood	Number Analyzed	51 participants	6 participants	6 participants
		4460; (616.2%)	231; (499.1%)	402; (114.7%)
D11: blood	Number Analyzed	34 participants	4 participants	4 participants
		21200; (262.3%)	423; (52.7%)	1920; (8318.1%)
D14: blood	Number Analyzed	49 participants	6 participants	5 participants
		12500; (292.1%)	1600; (337.1%)	42835.8; (9060%)
D21: blood	Number Analyzed	49 participants	6 participants	5 participants
		3720; (480.5%)	7750; (334.5%)	1050; (220743.9%)
D28: blood	Number Analyzed	52 participants	6 participants	3 participants
		1360; (650.3%)	2770; (684.8%)	515; (244650713.9%)
Month 3 (M3): blood	Number Analyzed	49 participants	2 participants	2 participants
		220; (224.3%)	690 [2]; (NA%)	564 [2]; (NA%)
Month M6: blood	Number Analyzed	40 participants	1 participants	1 participants
		146; (157.5%)	NA [3]; (NA%)	127 [2]; (NA%)
Month M9: blood	Number Analyzed	30 participants	0 participants	0 participants
		117; (179.3%)
Month M12: blood	Number Analyzed	30 participants	0 participants	0 participants
		113; (312.4%)
Month M18: blood	Number Analyzed	18 participants	0 participants	0 participants
		87.2; (200.3%)
Month M24: blood	Number Analyzed	15 participants	0 participants	0 participants
		92.7; (160.5%)
Month M30: blood	Number Analyzed	5 participants	0 participants	0 participants
		59.9; (150.0%)
Month M36: blood	Number Analyzed	3 participants	0 participants	0 participants
		10.7; (19.9%)
Month M42: blood	Number Analyzed	2 participants	0 participants	0 participants
		35.3 [2]; (NA%)
Month M48: blood	Number Analyzed	1 participants	0 participants	0 participants
		NA [4]; (NA%)
Screening: Bone marrow (BM)	Number Analyzed	47 participants	6 participants	6 participants
		NA [5]; (NA%)	NA [5]; (NA%)	NA [5]; (NA%)
D28 BM	Number Analyzed	50 participants	4 participants	4 participants
		646; (1009.7%)	969; (166.8%)	615; (4763885.9%)
M3 BM	Number Analyzed	40 participants	0 participants	2 participants
		179; (182.5%)		542 [2]; (NA%)
M6 BM	Number Analyzed	32 participants	1 participants	0 participants
		133; (121.7%)	35.3 [2]; (NA%)

[1]

N/A: No CTL019 was infused at the enrollment

[2]

N/A = not estimable because too few participants to calculate Geometric CV

[3]

N/A = not estimable because too few participants to calculate Geometric CV; also, the geometric mean was not applicable for NR group at Month 6 as the arithmetic mean was zero

[4]

NA = geometric mean is not estimable because the CTL019 transgene level for the only one patient is 0.

[5]

N/A = No CTL019 was infused at screening

12. Secondary Outcome

Title	Humoral Immunogenicity Interpretation by Day 28 Disease Response Per IRC (Anti-CTL019 Antibodies)
Description	Humoral immunogenicity was measured by anti-CTL019 antibodies in human serum using a flow cytometry method. (Prevalence and incidence of immunogenicity to CTL019)
Time Frame	Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24, Month 36

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title	CR/CRi	No Response	Unknown
Arm/Group Description:	Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed	52	6	6
Measure Type: Number; Unit of Measure: Percentage of participants
Baseline: Positive	67.3	66.7	83.3
Day 14: Positive	84.6	100	83.3
Day 28: Positive	80.8	100	50.0
Month 3: Positive	75.0	16.7	33.3
Month 6: Positive	63.5	16.7	16.7
Month 12: Positive	46.2	0	0
Month 24: Positive	11.5	0	0
Month 36: Positive	9.6	0	0

13. Secondary Outcome

Title	ORR by Low Baseline Bone Marrow Burden Within 6 Months Post CTL019 Infusion
Description	ORR within 6 months after infusion of CTL019 per Local & IRC assessment by baseline bone marrow tumor burden presence.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 12 having a low bone marrow tumor burden at enrollment.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	12	12
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	83.3; (51.6 to 97.9)	83.3; (51.6 to 97.9)

14. Secondary Outcome

Title	ORR by High Baseline Bone Marrow Burden Within 6 Months Post CTL019 Infusion
Description	ORR within 6 months after infusion of CTL019 per Local Investigator & IRC assessment by high baseline bone marrow tumor burden presence.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 30 having a high bone marrow tumor burden at enrollment

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	30	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	63.3; (43.9 to 80.1)	63.3; (43.9 to 80.1)

15. Secondary Outcome

Title	ORR by Baseline Extramedullary Disease Presence of Yes Within 6 Months Post CTL019 Infusion
Description	ORR within 6 months after infusion of CTL019 per Local Investigator & IRC assessment by baseline extramedullary disease presence of Yes.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 2 participants having a baseline extramedullary presence.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	2	2
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	100 [1]; (NA to NA)	100 [1]; (NA to NA)

[1]

N/A: no confidence interval for 100% response

16. Secondary Outcome

Title	ORR by Baseline Extramedullary Disease Presence of No Within 6 Months Post CTL019 Infusion
Description	ORR within 6 months after infusion of CTL019 per Local Investigator & IRC assessment by baseline extramedullary disease presence of No.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 40 participants having no baseline extramedullary presence.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	40	40
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	67.5; (50.9 to 81.4)	67.5; (50.9 to 81.4)

17. Secondary Outcome

Title	Bone Marrow (BM) Minimum Residual Disease (MRD) Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by High Baseline Bone Marrow Tumor Burden
Description	BM MRD status was by Local Investigator and IRC assessment within 6 months after infusion of CTL019 by baseline bone marrow tumor burden. BM MRD were collected and measured only within responders.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: A subset of FAS treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on cut-off date of 6-Oct-2017, with only 42 participants and 30 having a high baseline bone marrow tumor burden. BM MRD were collected and measured only within responders

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	30	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Had BOR of CR/CRi with BM MRD -ve (MRD%< 0.01%)	56.7; (37.4 to 74.5)	56.7; (37.4 to 74.5)
Had BOR of CR/CRi with BM 0.01% <= MRD% < 5%	6.7 [1]; (NA to NA)	6.7 [1]; (NA to NA)

[1]

N/A = too few participants to calculate a meaningful CI

18. Secondary Outcome

Title	Bone Marrow MRD Status Was by Flow Cytometry Within 6 Months Post CTL019 Infusion by Low Baseline Bone Marrow Tumor Burden
Description	BM MRD status was per Local Investigator and IRC assessment within 6 months after infusion of CTL019 by low baseline bone marrow tumor burden. BM MRD were collected and measured only within responders.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: A subset of FAS treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on cut-off date of 6-Oct-2017, with only 42 participants and 12 having a high baseline bone marrow tumor burden. BM MRD were collected and measured only within responders

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	12	12
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	83.3; (51.6 to 97.9)	83.3; (51.6 to 97.9)

19. Secondary Outcome

Title	Bone Marrow MRD Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by Baseline Extramedullary Disease Presence: Yes
Description	BM MRD status was by Local Investigator and IRC assessment within 6 months after infusion pf CTL019 by baseline extramedullary disease presence of Yes. BM MRD were collected and measured only within responders.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: A subset of FAS treated with CTL019 at least 6 months prior to the clinical data cutoff. FAS: All subjects who received an infusion of CTL019. Data is based on cut-off date of 6-Oct-2017, with only 42 participants & 2 having a BL extramedullary disease presence of Yes. BM MRD were collected & measured only within responders.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	2	2
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	100; (15.8 to 100)	100; (15.8 to 100)

20. Secondary Outcome

Title	Bone Marrow MRD Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by Baseline Extramedullary Disease Presence: No
Description	BM MRD status WAS per Local Investigator and IRC assessment within 6 months after infusion pf CTL019 by baseline extramedullary disease presence of No. BM MRD were collected and measured only within responders.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: A subset of FAS treated with CTL019 at least 6 months prior to the clinical data cutoff. FAS: All subjects who received an infusion of CTL019. Data is based on cut-off date of 6-Oct-2017, with only 42 participants & 40 having a BL extramedullary disease presence of No. BM MRD were collected & measured only within responders.

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	40	40
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
With BM MRD -ve (MRD%< 0.01%)	62.5; (45.8 to 77.3)	62.5; (45.8 to 77.3)
With bone marrow 0.01% <= MRD% < 5%	5.0 [1]; (NA to NA)	5.0 [1]; (NA to NA)

[1]

N/A = too few participants to calculate CI

21. Secondary Outcome

Title	Duration of Remission (DoR) Censoring Hematopoietic Stem Cell Transplantation (HSCT) by Low Baseline Bone Marrow Tumor Burden
Description	DoR per Local Investigator & IRC assessment by low baseline marrow tumor burden
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 12 having a low baseline marrow tumor burden

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	12	12
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (5.4 to NA)	NA [1]; (5.4 to NA)

[1]

N/A = median DoR was not reached as there were not enough participants with DoR events

22. Secondary Outcome

Title	Duration of Remission (DoR) Censoring HSCT by High Baseline Bone Marrow Tumor Burden
Description	DoR per Local Investigator & IRC assessment by high baseline bone marrow tumor burden
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 30 having a high baseline marrow tumor burden

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	30	30
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (5.3 to NA)	NA [1]; (5.3 to NA)

[1]

N/A = median DoR was not reached as there were not enough participants with DoR events

23. Secondary Outcome

Title	Duration of Remission (DoR) Censoring HSCT by Baseline Extramedullary Disease Presence: Yes
Description	DoR per Local Investigator & IRC assessment by baseline extramedullary disease presence of Yes.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 2 having a baseline extramedullary disease presence of Yes

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	2	2
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (3.4 to NA)	NA [2]; (3.4 to NA)

[1]

N/A = median DoR was not reached as there were not enough participants with D0R events

[2]

N/A = median DoR was not reached as there were not enough participants with DoR events

24. Secondary Outcome

Title	Duration of Remission (DoR) Censoring HSCT by Baseline Extramedullary Disease Presence: No
Description	DoR per Local Investigator & IRC assessment by baseline extramedullary disease presence of No
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

EAS: Efficacy Analysis Set (EAS): A subset of full analysis set (FAS) who were treated with CTL019 at least 6 months prior to the clinical data cutoff FAS: All subjects who received an infusion of CTL019. Data is based on data cut-off date of 6-Oct-2017, with only 42 participants and 40 having a baseline extramedullary disease presence of No

Arm/Group Title	Tisagenlecleucel (CTL019) - Local Assessment	Tisagenlecleucel (CTL019) - IRC Assessment
Arm/Group Description:	Pediatric participants with r/r B-cell ALL	Pediatric participants with r/r B-cell ALL
Overall Number of Participants Analyzed	40	40
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (5.9 to NA)	NA [1]; (5.9 to NA)

[1]

N/A = median DOR was not reached as there were not enough participants with DOR events

25. Secondary Outcome

Title	Participants Achieving Cellular Immunogenicity Net Response by Day 28 Response Per IRC
Description	Activation of T cells in PBMC collected from subjects in response to mCAR19 -derived peptides was used to assess the cellular immunogenicity against tisagenlecleucel. CD4 and CD8 T cell net responses (in %) were calculated for 2 non-overlapping CTL019 peptide pools (i.e., Pool 1 and Pool 2). (Lymphocyte subsets of B and T cells and description of associated safety events)
Time Frame	Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24, Month 36

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		CR/CRi	No Response	Unknown
Arm/Group Description:		Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed		52	6	6
Measure Type: Number; Unit of Measure: Percentage of participants
Baseline: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		92.3	83.3	50.0
Day 14: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	100	50.0
Day 28: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		94.2	100	50.0
Month 3: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	16.7	33.3
Month 6: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		67.3	16.7	57.8
Month 12: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		48.1	0	0
Month 24: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		17.3	0	0
Month 36: Pool 1 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		9.6	0	0
Baseline: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		92.3	83.3	50.0
Day 14: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	100	50.0
Day 28: Pool 2 CD3+ CD4+ IFNg+ )	Number Analyzed	52 participants	6 participants	6 participants
		94.2	100	50.0
Month 3: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	16.7	33.3
Month 6: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		67.3	16.7	16.7
Month 12: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		48.1	0	0
Month 24: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		17.3	0	0
Month 36: Pool 2 CD3+ CD4+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		9.6	0	0
Baseline: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		92.3	83.3	50.0
Day 14: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	100	50.0
Day 28: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	41 participants	6 participants	2 participants
		94.2	100	50.0
Month 3: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	16.7	33.3
Month 6: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		67.3	16.7	16.7
Month 12: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		48.1	0	0
Month 24: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		17.3	0	0
Month 36: Pool 1 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		9.6	0	0
Baseline: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		92.3	83.3	50.0
Day 14: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	100	50.0
Day 28: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		94.2	100	50.0
Month 3: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		82.7	16.7	33.3
Month 6: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		67.3	16.7	16.7
Month 12: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		48.1	0	0
Month 24: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		17.3	0	0
Month 36: Pool 2 CD3+ CD8+ IFNg+	Number Analyzed	52 participants	6 participants	6 participants
		9.6	0	0

26. Secondary Outcome

Title	Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: AUC0-28d and AUC0-84d
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile. AUC0-28d and AUC0-84d is defined as the AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood (% or copies/μg x days). Data was only reported for evaluable PK parameters. The Overall Number of Participants Analyzed represents all participants for which a baseline assessment was collected for this Outcome Measure, and therefore these participants did contribute data to this estimation parameter, whereas the Number Analyzed per Row represents the number of participants with data available at either 28 or 84 days.
Time Frame	0 - 28 days post-infusion for AUC0-28d and 0 - 84 days post-infusion for AUC0-84d

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data.

Arm/Group Title		CR/CRi	No Response (NR)	Unknown
Arm/Group Description:		Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed		52	6	6
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: copies/µg*days
AUC0-28d	Number Analyzed	52 participants	3 participants	1 participants
		261000; (199.8%)	151000; (71.7%)	617000 [1]; (NA%)
AUC0-84d	Number Analyzed	45 participants	2 participants	1 participants
		368000; (182.9%)	443000; (79.9%)	1340000 [1]; (NA%)

[1]

N/A = Too few participants to calculate geometric CV

27. Secondary Outcome

Title	Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Cmax
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile. Cmax is defined as the maximum (peak) observed in peripheral blood drug concentration after single dose administration (% or copies/μg).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data

Arm/Group Title	CR/CRi	No Response (NR)	Unknown
Arm/Group Description:	Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed	52	5	3
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: copies/µg
	28300; (197.0%)	15100; (49.4%)	52500; (91.1%)

28. Secondary Outcome

Title	Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Tmax
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile. Tmax is defined as the time to reach maximum (peak) peripheral blood drug concentration after single dose administration (days)
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data

Arm/Group Title	CR/CRi	No Response (NR)	Unknown
Arm/Group Description:	Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed	52	5	2
Median (Full Range); Unit of Measure: days
	9.84; (6.74 to 54.8)	20.0; (13.9 to 22.8)	11.9; (11.0 to 12.9)

29. Secondary Outcome

Title	Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: T1/2
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile. T1/2 is defined as the half-life associated with the disposition phase slopes (alpha, beta, gamma etc.) of a semi logarithmic concentration-time curve (days) in peripheral blood
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data

Arm/Group Title	CR/CRi	No Response (NR)	Unknown
Arm/Group Description:	Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed	34	2	1
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: days
	31.9; (415.1%)	4.36; (421.2%)	42.1 [1]; (NA%)

[1]

N/A = with only 1 subject, geometric CV could not be calculated

30. Secondary Outcome

Title	Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Clast
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile. Clast is defined as the last observed quantifiable concentration in peripheral blood (% or copies/ug)
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data

Arm/Group Title	CR/CRi	No Response (NR)	Unknown
Arm/Group Description:	Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed	52	5	1
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: copies/µg
	223; (283.4%)	1980; (207.5%)	80.3 [1]; (NA%)

[1]

N/A = with only 1 subject, geometric CV could not be calculated

31. Secondary Outcome

Title	Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Tlast
Description	Characterize the in vivo cellular pharmacokinetic (PK) profile. Tlast is defined as the time of last observed quantifiable concentration in peripheral blood (days)"
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS): A subset of FAS who have at least one sample providing evaluable pharmacokinetic (PK) data

Arm/Group Title	CR/CRi	No Response (NR)	Unknown
Arm/Group Description:	Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed	52	5	1
Median (Full Range); Unit of Measure: days
	179; (17.8 to 921)	26.9; (26.7 to 96.1)	210; (210 to 210)

32. Secondary Outcome

Title	CD19 Status of Bone Marrow/Blood Relapse in FAS Patients Who Achieved CR or CRi and Then Relapsed
Description	The CD19 status of bone marrow/blood relapse was categorized as follows: CD19 positive, CD19 dim, CD19 negative, CD19 positive/negative & CD19 unknown
Time Frame	At time of relapse up to 60 months

Outcome Measure Data

Analysis Population Description

FAS patients who achieved CR & CRi and then relapsed. FAS: All subjects who received an infusion of CTL019

Arm/Group Title	Tisagenlecleucel - FAS Pts Who Achieved CR/CRi & Then Relapsed
Arm/Group Description:	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel and then relapsed
Overall Number of Participants Analyzed	21
Measure Type: Number; Unit of Measure: Percentage of participants
CD19 status of BM/blood relapse:positive	22.2
CD19 status of BM/blood relapse: dim	5.6
CD19 status of BM/blood relapse: negative	16.7
CD19 status of BM/blood relapse: +ve/-ve	16.7
CD19 status of BM/blood relapse: Unknown	55.6

33. Secondary Outcome

Title	Site of Initial Relapse Among FAS Patients Who Achieved CR/CRi and Then Relapsed
Description	This is the site of involvement of initial relapse after achieving a best overall response of CR/CRi.
Time Frame	At time of relapse up to 60 months

Outcome Measure Data

Analysis Population Description

FAS patients who achieved CR & CRi and then relapsed. FAS: All subjects who received an infusion of CTL019

Arm/Group Title	Tisagenlecleucel - FAS Pts Who Achieved CR/CRi & Then Relapsed
Arm/Group Description:	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel and then relapsed
Overall Number of Participants Analyzed	21
Measure Type: Number; Unit of Measure: Percentage of participants
BM/blood relapse	72.2
Extramedullary only	27.8
Unknown	16.7

34. Secondary Outcome

Title	Time to B-cell Recovery in Participants Who Achieved CR or CRi by IRC
Description	Time to B cell recovery was defined as the time from onset of remission to the earliest time when the percentage of CD19+ total B cell among viable WBC is ≥ 1% or among lymphocyte is at least 3%.
Time Frame	during the whole study, up to 60 months

Outcome Measure Data

Analysis Population Description

FAS patients who achieved CR or CRi. FAS: All subjects who received an infusion of CTL019

Arm/Group Title	Tisagenlecleucel (CTL019) - All Participants
Arm/Group Description:	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel
Overall Number of Participants Analyzed	54
Median (95% Confidence Interval); Unit of Measure: Months
	35.5 [1]; (7.6 to NA)

[1]

N/A = not estimable because there were not enough participants who had events to estimate the upper limit of the median

35. Secondary Outcome

Title	Percentage of CD19+ B Cell Levels in Peripheral Blood by Day 28 Disease Response by IRC Assessment
Description	The levels (%) of CD19+ total B cells amongst viable white blood cells (WBC) in peripheral blood
Time Frame	Enrollment/Pre-Chemotherapy; Pre-infusion; Baseline; Day 7; Day 14; Day 21; Day 28; Month 3; Month 6; Month 9; Month 12; Month 24; Month 36

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		CR/CRi	No Response	Unknown
Arm/Group Description:		Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)	No response was defined as failure to attain the criteria needed for any response categories or relapse	unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.
Overall Number of Participants Analyzed		52	6	6
Mean (Standard Deviation); Unit of Measure: Percentage of CD19+ B cell levels
Enrollment/Pre-Chemotherapy	Number Analyzed	50 participants	6 participants	6 participants
		26.8 (28.733)	52.29 (36.758)	32.66 (28.102)
Pre-infusion	Number Analyzed	1 participants	0 participants	1 participants
		0.02 [1] (NA)		46.80 [1] (NA)
Baseline	Number Analyzed	50 participants	6 participants	6 participants
		25.11 (28.584)	52.29 (36.758)	29.50 (24.466)
Day 7	Number Analyzed	45 participants	6 participants	6 participants
		1.06 (3.735)	34.40 (46.922)	23.18 (38.772)
Day 14	Number Analyzed	50 participants	6 participants	5 participants
		0.73 (5.096)	33.76 (45.359)	3.43 (7.520)
Day 21	Number Analyzed	46 participants	6 participants	5 participants
		0.01 (0.017)	19.67 (32.553)	16.13 (35.929)
Day 28	Number Analyzed	48 participants	6 participants	3 participants
		0.02 (0.069)	34.97 (36.648)	0.02 (0.012)
Month 3	Number Analyzed	44 participants	1 participants	2 participants
		0.79 (1.971)	0.57 [1] (NA)	11.26 (15.917)
Month 6	Number Analyzed	37 participants	1 participants	1 participants
		1.86 (7.958)	9.70 [1] (NA)	0.01 [1] (NA)
Month 9	Number Analyzed	27 participants	0 participants	0 participants
		0.63 (2.180)
Month 12	Number Analyzed	27 participants	0 participants	0 participants
		0.85 (2.420)
Month 24	Number Analyzed	14 participants	0 participants	0 participants
		1.74 (3.446)
Month 36	Number Analyzed	6 participants	0 participants	0 participants
		1.10 (2.106)

[1]

N/A = Too few participants to calculate geometric SD

36. Secondary Outcome

Title	Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: C Reactive Protein (CRP)
Description	C-Reactive Protein at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
Time Frame	Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		NO CRS	Grade 1/2	Grade 3	Grade 4	All Participants
Arm/Group Description:		No cytokine release syndrome	Grade 1 and 2 of cytokine release syndrome post tisagenlecleucel infusion	Grade 3 of cytokine release syndrome post tisagenlecleucel infusion	Grade 4 of cytokine release syndrome post tisagenlecleucel infusion	All participants with & without CRS
Overall Number of Participants Analyzed		14	31	8	11	64
Median (Full Range); Unit of Measure: mg/L
Pre-infusion	Number Analyzed	14 participants	29 participants	8 participants	9 participants	60 participants
		9.21; (2.9 to 34.0)	8.27; (2.0 to 1530.0)	7.45; (0.6 to 50.0)	9.00; (2.0 to 153.0)	9.00; (0.6 to 1530.0)
Baseline (BL)	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		9.21; (2.9 to 34.0)	9.04; (2.0 to 1530.0)	7.45; (0.6 to 50.0)	9.00; (2.0 to 153.0)	9.00; (0.6 to 1530.0)
Change from BL Day7	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		0.00; (-15.0 to 25.0)	15.00; (-460.0 to 215.0)	79.55; (-2.0 to 380.0)	108.00; (-125.0 to 255.0)	9.10; (-460.0 to 380.0)
Change from BL Day 14	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		0.00; (-20.0 to 24.0)	0.00; (-1031.0 to 215.0)	10.50; (-42.0 to 199.0)	15.70; (-148.0 to 100.0)	0.00; (-1031.0 to 215.0)
Change from BL Day 21	Number Analyzed	14 participants	28 participants	8 participants	7 participants	57 participants
		0.00; (-14.0 to 29.5)	-0.80; (-1460.0 to 677.0)	2.00; (-42.0 to 37.0)	-3.00; (-57.0 to 73.0)	0.00; (-1460.0 to 677.0)
Change from BL Day 28	Number Analyzed	14 participants	27 participants	8 participants	9 participants	59 participants
		0.00; (-15.0 to 47.0)	-0.70; (-1487.0 to 47.0)	1.50; (-45.0 to 55.0)	-3.00; (-151.0 to 27.0)	0.00; (-1487.0 to 55.0)
Change from BL Month 3	Number Analyzed	11 participants	23 participants	5 participants	7 participants	46 participants
		0.00; (-12.1 to 101.0)	-1.00; (-1501.0 to 7.1)	0.00; (-3.0 to 120.5)	-1.00; (-149.0 to 13.0)	-0.65; (-1501.0 to 120.5)

37. Secondary Outcome

Title	Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Ferritin
Description	Ferritin at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
Time Frame	Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		NO CRS	Grade 1/2	Grade 3	Grade 4	All Participants
Arm/Group Description:		No cytokine release syndrome	Grade 1 and 2 of cytokine release syndrome post tisagenlecleucel infusion	Grade 3 of cytokine release syndrome post tisagenlecleucel infusion	Grade 4 of cytokine release syndrome post tisagenlecleucel infusion	All participants with & without CRS
Overall Number of Participants Analyzed		14	31	8	11	64
Median (Full Range); Unit of Measure: ug/L
Pre-infusion	Number Analyzed	14 participants	26 participants	8 participants	9 participants	54 participants
		1865.20; (459.0 to 5015.0)	2202.22; (230.0 to 18061.0)	1906.95; (357.0 to 4200.0)	2078.40; (487.0 to 13553.9)	1983.90; (230.0 to 18061.0)
Baseline (BL)	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		1865.20; (459.0 to 5015.0)	2202.22; (230.0 to 18061.0)	1906.95; (357.0 to 4200.0)	2078.40; (487.0 to 13553.9)	1983.90; (230.0 to 18061.0)
Change from BL Day7	Number Analyzed	14 participants	29 participants	8 participants	9 participants	60 participants
		-146.50; (-721.4 to 710.0)	377.80; (-1468.0 to 522220.0)	22735.10; (-330.0 to 182380.0)	23788.71; (-161.0 to 269529.0)	358.90; (-1468.0 to 269529.0)
Change from BL Day 14	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		-321.30; (-2035.1 to 520.0)	861.50; (-3483.3 to 59435.9)	10728.40; (1262.0 to 104170.0)	18580.01; (707.0 to 110421.6)	973.00; (-3483.3 to 110421.6)
Change from BL Day 21	Number Analyzed	14 participants	29 participants	8 participants	8 participants	59 participants
		58.00; (-2302.0 to 524.0)	331.00; (-3571.6 to 43336.0)	3299.85; (-600.0 to 121100.0)	3199.00; (-17.0 to 12957.4)	490.00; (-3571.6 to 121100.0)
Change from BL Day 28	Number Analyzed	14 participants	27 participants	8 participants	9 participants	58 participants
		121.10; (-2952.0 to 1510.0)	283.00; (-6443. to 9879.0)	1104.00; (-890.0 to 331000.0)	1211.00; (-606.0 to 12957.4)	280.50; (-6443.7 to 33100.0)
Change from BL Month 3	Number Analyzed	11 participants	23 participants	5 participants	7 participants	46 participants
		-124.90; (-2418.0 to 1985.5)	-358.00; (-5415.0 to 7050.0)	-487.60; (-1500.0 to 8140.0)	-377.00; (-1808.2 to 2641.6)	-330.00; (-5415.0 to 8140.0)

38. Secondary Outcome

Title	Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: INF-gamma
Description	INF-gamma at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
Time Frame	Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		NO CRS	Grade 1/2	Grade 3	Grade 4	All Participants
Arm/Group Description:		No cytokine release syndrome	Grade 1 and 2 of cytokine release syndrome post tisagenlecleucel infusion	Grade 3 of cytokine release syndrome post tisagenlecleucel infusion	Grade 4 of cytokine release syndrome post tisagenlecleucel infusion	All participants with & without CRS
Overall Number of Participants Analyzed		14	31	8	11	64
Median (Full Range); Unit of Measure: pg/mL
Pre-infusion	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		29.63; (1.0 to 283.0)	23.39; (1.0 to 242.8)	15.73; (6.4 to 31.5)	5.79; (2.5 to 34.1)	20.22; (1.0 to 283.0)
Baseline (BL)	Number Analyzed	14 participants	31 participants	8 participants	9 participants	63 participants
		29.63; (1.0 to 283.0)	22.51; (1.0 to 242.8)	15.73; (6.4 to 31.5)	4.77; (1.0 to 34.1)	15.75; (1.0 to 283.0)
Change from BL Day7	Number Analyzed	14 participants	31 participants	8 participants	10 participants	63 participants
		0.47; (-167.9 to 140.6)	52.59; (-201.2 to 39452.4)	3023.82; (-14.7 to 162376.0)	1347.48; (60.2 to 89599.0)	72.09; (-201.2 to 162376.0)
Change from BL Day 14	Number Analyzed	13 participants	30 participants	8 participants	9 participants	60 participants
		-5.10; (-278.3 to 39.2)	-4.44; (-194.8 to 131.1)	58.65; (-14.3 to 1328.7)	102.04; (-2.2 to 8925.9)	1.32; (-278.3 to 8925.9)
Change from BL Day 21	Number Analyzed	13 participants	29 participants	8 participants	8 participants	58 participants
		-4.97; (-264.0 to 58.5)	1.06; (-219.7 to 1384.6)	0.53; (-22.8 to 1048.7)	5.23; (-4.0 to 167.1)	-0.89; (-264.0 to 1384.6)
Change from BL Day 28	Number Analyzed	14 participants	28 participants	8 participants	9 participants	59 participants
		-6.93; (-269.9 to 60.4)	0.20; (-223.6 to 738.8)	-1.19; (-26.1 to 187.7)	0.36; (-4.7 to 138.4)	-0.62; (-269.9 to 738.8)
Change from BL Month 3	Number Analyzed	11 participants	22 participants	6 participants	6 participants	45 participants
		-6.08; (-278.6 to 167.5)	-14.58; (-173.9 to 7.6)	21.25; (-7.7 to 37.2)	-0.67; (-4.4 to 23.1)	-5.71; (-278.6 to 167.5)

39. Secondary Outcome

Title	Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Interleukin-6 (IL-6)
Description	IL-6 at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
Time Frame	Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		NO CRS	Grade 1/2	Grade 3	Grade 4	All Participants
Arm/Group Description:		No cytokine release syndrome	Grade 1 and 2 of cytokine release syndrome post tisagenlecleucel infusion	Grade 3 of cytokine release syndrome post tisagenlecleucel infusion	Grade 4 of cytokine release syndrome post tisagenlecleucel infusion	All participants with & without CRS
Overall Number of Participants Analyzed		14	31	8	11	64
Median (Full Range); Unit of Measure: pg/mL
Pre-infusion	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		2.42; (0.4 to 12.0)	2.89; (0.2 to 19.6)	1.00; (0.8 to 9.4)	2.27; (0.4 to 6.2)	2.27; (0.2 to 19.6)
Baseline (BL)	Number Analyzed	14 participants	31 participants	8 participants	10 participants	63 participants
		2.42; (0.4 to 12.0)	2.83; (0.2 to 19.6)	1.00; (0.8 to 9.4)	1.84; (0.2 to 6.2)	1.99; (0.2 to 19.6)
Change from BL Day7	Number Analyzed	14 participants	31 participants	8 participants	10 participants	63 participants
		-0.23; (-9.6 to 4.3)	2.64; (-13.1 to 61.3)	52.75; (-0.6 to 7201.6)	141.68; (1.3 to 12615.8)	2.64; (-13.1 to 12615.8)
Change from BL Day 14	Number Analyzed	13 participants	30 participants	8 participants	9 participants	60 participants
		-0.36; (-2.3 to 4.1)	-0.67; (-13.4 to 21.5)	8.88; (-0.6 to 30.4)	165.16; (-0.2 to 5734.8)	-0.11; (-13.4 to 5734.8)
Change from BL Day 21	Number Analyzed	13 participants	29 participants	8 participants	8 participants	58 participants
		-0.97; (-5.3 to 5.3)	-0.46; (-15.4 to 103.4)	1.65; (-0.6 to 265.2)	50.75; (-0.2 to 5734.8)	-0.09; (-15.4 to 5734.8)
Change from BL Day 28	Number Analyzed	14 participants	28 participants	8 participants	9 participants	59 participants
		-0.98; (-7.8 to 1.9)	-0.28; (-17.5 to 33.0)	0.91; (-0.6 to 138.6)	38.13; (-0.0 to 2148.4)	-0.03; (-17.5 to 2148.4)
Change from BL Month 3	Number Analyzed	11 participants	22 participants	6 participants	6 participants	45 participants
		0.34; (-10.8 to 22.7)	-0.59; (-8.9 to 1.2)	0.56; (-0.6 to 30.3)	0.40; (-0.9 to 3.2)	-0.19; (-10.8 to 30.3)

40. Secondary Outcome

Title	Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Interleukin-2 (IL-2)
Description	IL-2 at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
Time Frame	Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3

Outcome Measure Data

Analysis Population Description

Safety set: All subjects who received an infusion of tisagenlecleucel

Arm/Group Title		NO CRS	Grade 1/2	Grade 3	Grade 4	All Participants
Arm/Group Description:		No cytokine release syndrome	Grade 1 and 2 of cytokine release syndrome post tisagenlecleucel infusion	Grade 3 of cytokine release syndrome post tisagenlecleucel infusion	Grade 4 of cytokine release syndrome post tisagenlecleucel infusion	All participants with & without CRS
Overall Number of Participants Analyzed		14	31	8	11	64
Median (Full Range); Unit of Measure: pg/mL
Pre-infusion	Number Analyzed	14 participants	30 participants	8 participants	9 participants	61 participants
		2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)
Baseline (BL)	Number Analyzed	14 participants	31 participants	8 participants	10 participants	63 participants
		2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)	2.3; (2.3 to 2.3)
Change from BL Day7	Number Analyzed	14 participants	31 participants	8 participants	10 participants	63 participants
		3.33; (0.0 to 6.7)	3.15; (0.0 to 7.0)	13.14; (5.0 to 63.7)	7.48; (2.9 to 12.1)	5.16; (0.0 to 63.7)
Change from BL Day 14	Number Analyzed	13 participants	30 participants	8 participants	9 participants	60 participants
		NA [1]; (NA to NA)	0.00; (0.00 to 0.00)	NA [1]; (NA to NA)	4.56; (4.56 to 4.6)	0.00; (0.0 to 4.6)
Change from BL Day 21	Number Analyzed	13 participants	29 participants	8 participants	8 participants	58 participants
		NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)
Change from BL Day 28	Number Analyzed	14 participants	28 participants	8 participants	9 participants	59 participants
		NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)
Change from BL Month 3	Number Analyzed	11 participants	22 participants	6 participants	6 participants	45 participants
		NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

N/A = below limit of detection

Adverse Events

Time Frame	Adverse Event (AE) timeframe: Adverse events were collected during the post-infusion period (starting at the day of first infusion until the end of the study), up to maximum duration of 60 months for each patient.
Adverse Event Reporting Description	AE description: Any sign or symptom that occurs during the post-infusion period (starting at the day of first infusion of CTL019 until the end of the study).
Arm/Group Title	Tisagenlecleucel (CTL019) - All Participants
Arm/Group Description	Pediatric participants with r/r B-cell who were infused with tisagenlecleucel
All-Cause Mortality
	Tisagenlecleucel (CTL019) - All Participants
	Affected / at Risk (%)
Total	30/64 (46.88%)
Serious Adverse Events
	Tisagenlecleucel (CTL019) - All Participants
	Affected / at Risk (%)
Total	52/64 (81.25%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation † 1	2/64 (3.13%)
Eosinophilia † 1	1/64 (1.56%)
Febrile neutropenia † 1	23/64 (35.94%)
Neutropenia † 1	3/64 (4.69%)
Cardiac disorders
Atrioventricular block second degree † 1	1/64 (1.56%)
Ventricular tachycardia † 1	1/64 (1.56%)
Eye disorders
Papilloedema † 1	1/64 (1.56%)
Vision blurred † 1	1/64 (1.56%)
Gastrointestinal disorders
Diarrhoea † 1	2/64 (3.13%)
Enterocolitis † 1	1/64 (1.56%)
Intestinal obstruction † 1	1/64 (1.56%)
Pancreatitis † 1	1/64 (1.56%)
Stomatitis † 1	1/64 (1.56%)
Vomiting † 1	1/64 (1.56%)
General disorders
Malaise † 1	1/64 (1.56%)
Physical deconditioning † 1	1/64 (1.56%)
Pyrexia † 1	7/64 (10.94%)
Immune system disorders
Cytokine release syndrome † 1	41/64 (64.06%)
Graft versus host disease in gastrointestinal tract † 1	1/64 (1.56%)
Infections and infestations
Bacterial sepsis † 1	1/64 (1.56%)
Campylobacter infection † 1	1/64 (1.56%)
Catheter site infection † 1	1/64 (1.56%)
Cellulitis of male external genital organ † 1	1/64 (1.56%)
Cholecystitis infective † 1	1/64 (1.56%)
Clostridium difficile colitis † 1	2/64 (3.13%)
Clostridium difficile infection † 1	3/64 (4.69%)
Corona virus infection † 1	1/64 (1.56%)
Enterovirus infection † 1	1/64 (1.56%)
Gastroenteritis † 1	1/64 (1.56%)
Gastroenteritis norovirus † 1	1/64 (1.56%)
Herpes zoster † 1	1/64 (1.56%)
Parainfluenzae virus infection † 1	1/64 (1.56%)
Pneumonia † 1	2/64 (3.13%)
Respiratory syncytial virus infection † 1	1/64 (1.56%)
Respiratory tract infection † 1	1/64 (1.56%)
Respiratory tract infection viral † 1	1/64 (1.56%)
Rhinovirus infection † 1	1/64 (1.56%)
Rotavirus infection † 1	1/64 (1.56%)
Sepsis † 1	1/64 (1.56%)
Septic embolus † 1	1/64 (1.56%)
Staphylococcal infection † 1	1/64 (1.56%)
Upper respiratory tract infection † 1	1/64 (1.56%)
Urinary tract infection † 1	2/64 (3.13%)
Vascular device infection † 1	1/64 (1.56%)
Viral upper respiratory tract infection † 1	1/64 (1.56%)
Vulvovaginal candidiasis † 1	1/64 (1.56%)
Injury, poisoning and procedural complications
Procedural pain † 1	1/64 (1.56%)
Transfusion related complication † 1	1/64 (1.56%)
Investigations
Alanine aminotransferase increased † 1	1/64 (1.56%)
White blood cell count decreased † 1	1/64 (1.56%)
Metabolism and nutrition disorders
Acidosis † 1	1/64 (1.56%)
Decreased appetite † 1	1/64 (1.56%)
Dehydration † 1	1/64 (1.56%)
Tumour lysis syndrome † 1	2/64 (3.13%)
Musculoskeletal and connective tissue disorders
Flank pain † 1	1/64 (1.56%)
Osteonecrosis † 1	1/64 (1.56%)
Pain in extremity † 1	1/64 (1.56%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma multiforme † 1	1/64 (1.56%)
Myelodysplastic syndrome † 1	1/64 (1.56%)
Nervous system disorders
Embolic stroke † 1	1/64 (1.56%)
Encephalopathy † 1	4/64 (6.25%)
Headache † 1	1/64 (1.56%)
Idiopathic intracranial hypertension † 1	1/64 (1.56%)
Seizure † 1	4/64 (6.25%)
Psychiatric disorders
Delirium † 1	1/64 (1.56%)
Renal and urinary disorders
Acute kidney injury † 1	4/64 (6.25%)
Renal failure † 1	1/64 (1.56%)
Reproductive system and breast disorders
Vaginal haemorrhage † 1	1/64 (1.56%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/64 (1.56%)
Hypoxia † 1	4/64 (6.25%)
Pleural effusion † 1	2/64 (3.13%)
Pulmonary oedema † 1	2/64 (3.13%)
Respiratory failure † 1	3/64 (4.69%)
Skin and subcutaneous tissue disorders
Ecchymosis † 1	1/64 (1.56%)
Vascular disorders
Embolism † 1	1/64 (1.56%)
Hypotension † 1	7/64 (10.94%)
1 Term from vocabulary, MedDRA (22.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Tisagenlecleucel (CTL019) - All Participants
	Affected / at Risk (%)
Total	64/64 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	27/64 (42.19%)
Lymphopenia † 1	4/64 (6.25%)
Neutropenia † 1	8/64 (12.50%)
Thrombocytopenia † 1	10/64 (15.63%)
Cardiac disorders
Sinus tachycardia † 1	6/64 (9.38%)
Tachycardia † 1	15/64 (23.44%)
Eye disorders
Periorbital oedema † 1	4/64 (6.25%)
Gastrointestinal disorders
Abdominal pain † 1	11/64 (17.19%)
Constipation † 1	7/64 (10.94%)
Diarrhoea † 1	22/64 (34.38%)
Nausea † 1	25/64 (39.06%)
Vomiting † 1	27/64 (42.19%)
General disorders
Catheter site pain † 1	4/64 (6.25%)
Chills † 1	10/64 (15.63%)
Fatigue † 1	15/64 (23.44%)
Pain † 1	4/64 (6.25%)
Pyrexia † 1	21/64 (32.81%)
Immune system disorders
Cytokine release syndrome † 1	19/64 (29.69%)
Hypogammaglobulinaemia † 1	33/64 (51.56%)
Infections and infestations
Gastroenteritis † 1	4/64 (6.25%)
Influenza † 1	4/64 (6.25%)
Otitis media † 1	4/64 (6.25%)
Rhinovirus infection † 1	4/64 (6.25%)
Sinusitis † 1	4/64 (6.25%)
Upper respiratory tract infection † 1	8/64 (12.50%)
Urinary tract infection † 1	4/64 (6.25%)
Injury, poisoning and procedural complications
Infusion related reaction † 1	4/64 (6.25%)
Procedural pain † 1	5/64 (7.81%)
Investigations
Activated partial thromboplastin time prolonged † 1	5/64 (7.81%)
Alanine aminotransferase increased † 1	21/64 (32.81%)
Aspartate aminotransferase increased † 1	20/64 (31.25%)
Blood bilirubin increased † 1	8/64 (12.50%)
Blood creatinine increased † 1	9/64 (14.06%)
Blood fibrinogen decreased † 1	4/64 (6.25%)
Blood immunoglobulin M decreased † 1	4/64 (6.25%)
International normalised ratio increased † 1	9/64 (14.06%)
Lymphocyte count decreased † 1	16/64 (25.00%)
Neutrophil count decreased † 1	28/64 (43.75%)
Platelet count decreased † 1	20/64 (31.25%)
Prothrombin time prolonged † 1	9/64 (14.06%)
Weight decreased † 1	4/64 (6.25%)
White blood cell count decreased † 1	35/64 (54.69%)
Metabolism and nutrition disorders
Decreased appetite † 1	21/64 (32.81%)
Hypernatraemia † 1	4/64 (6.25%)
Hyperphosphataemia † 1	8/64 (12.50%)
Hypoalbuminaemia † 1	5/64 (7.81%)
Hypokalaemia † 1	19/64 (29.69%)
Hypophosphataemia † 1	10/64 (15.63%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	5/64 (7.81%)
Myalgia † 1	5/64 (7.81%)
Pain in extremity † 1	10/64 (15.63%)
Nervous system disorders
Dizziness † 1	6/64 (9.38%)
Headache † 1	24/64 (37.50%)
Psychiatric disorders
Anxiety † 1	7/64 (10.94%)
Confusional state † 1	6/64 (9.38%)
Renal and urinary disorders
Acute kidney injury † 1	5/64 (7.81%)
Haematuria † 1	5/64 (7.81%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	14/64 (21.88%)
Epistaxis † 1	10/64 (15.63%)
Hypoxia † 1	6/64 (9.38%)
Nasal congestion † 1	5/64 (7.81%)
Oropharyngeal pain † 1	6/64 (9.38%)
Pleural effusion † 1	6/64 (9.38%)
Pulmonary oedema † 1	5/64 (7.81%)
Rhinitis allergic † 1	4/64 (6.25%)
Rhinorrhoea † 1	6/64 (9.38%)
Tachypnoea † 1	5/64 (7.81%)
Skin and subcutaneous tissue disorders
Dry skin † 1	5/64 (7.81%)
Erythema † 1	5/64 (7.81%)
Hyperhidrosis † 1	4/64 (6.25%)
Petechiae † 1	4/64 (6.25%)
Pruritus † 1	4/64 (6.25%)
Rash † 1	8/64 (12.50%)
Rash maculo-papular † 1	5/64 (7.81%)
Vascular disorders
Hypertension † 1	12/64 (18.75%)
Hypotension † 1	9/64 (14.06%)
1 Term from vocabulary, MedDRA (22.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

Safety data reported is based on all the 64 infused patients with data cutoff of 24May2019.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: novartis.email@novartis.com

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

Laetsch TW, Maude SL, Balduzzi A, Rives S, Bittencourt H, Boyer MW, Buechner J, De Moerloose B, Qayed M, Phillips CL, Pulsipher MA, Hiramatsu H, Tiwari R, Grupp SA. Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2022 Jun;36(6):1508-1515. doi: 10.1038/s41375-022-01550-z. Epub 2022 Apr 14.

Thudium Mueller K, Grupp SA, Maude SL, Levine JE, Pulsipher MA, Boyer MW, August KJ, Myers GD, Tam CS, Jaeger U, Foley SR, Borchmann P, Schuster SJ, Waller EK, Awasthi R, Potthoff B, Warren A, Waldron ER, McBlane F, Chassot-Agostinho A, Laetsch TW. Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Blood Adv. 2021 Dec 14;5(23):4980-4991. doi: 10.1182/bloodadvances.2020003844.

Levine JE, Grupp SA, Pulsipher MA, Dietz AC, Rives S, Myers GD, August KJ, Verneris MR, Buechner J, Laetsch TW, Bittencourt H, Baruchel A, Boyer MW, De Moerloose B, Qayed M, Davies SM, Phillips CL, Driscoll TA, Bader P, Schlis K, Wood PA, Mody R, Yi L, Leung M, Eldjerou LK, June CH, Maude SL. Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J Immunother Cancer. 2021 Aug;9(8). pii: e002287. doi: 10.1136/jitc-2020-002287.

Buechner J, Grupp SA, Hiramatsu H, Teachey DT, Rives S, Laetsch TW, Yanik GA, Wood P, Awasthi R, Yi L, Chassot-Agostinho A, Eldjerou LK, De Moerloose B. Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy. Blood Adv. 2021 Jan 26;5(2):593-601. doi: 10.1182/bloodadvances.2020002757.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT02228096
• Other Study ID Numbers: CCTL019B2205J; 2015-003736-13 ( EudraCT Number )
• First Submitted: August 26, 2014
• First Posted: August 28, 2014
• Results First Submitted: November 22, 2019
• Results First Posted: November 23, 2020
• Last Update Posted: November 23, 2020