Trial Outcomes & Findings for Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients (NCT NCT02435849)

Last Updated: 2024-02-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

80 participants

Primary outcome timeframe

during the 3 months after tisagenlecleucel administration

Results posted on

2024-02-13

Participant Flow

98 patients met the eligibility criteria and apheresis was accepted by the manufacturing facility, 80 patients were infused in this study: 79 in the Main Cohort and 1 in Cohort 1. No patients were infused in Cohort 2. Patients could discontinue the trial after meeting the eligibility criteria and prior to tisagenlecleucel infusion.

This study was conducted in 11 countries with 23 sites.

Participant milestones

Participant milestones
Measure	Main Cohort: Single Dose of CTL019 Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Overall Study STARTED	79	1
Overall Study Enrolled and Infused	79	1
Overall Study Discontinued Study Follow-up	48	1
Overall Study COMPLETED	31	0
Overall Study NOT COMPLETED	48	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Main Cohort: Single Dose of CTL019 Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Overall Study Death	23	0
Overall Study Lack of Efficacy	10	0
Overall Study New therapy for study indication	8	0
Overall Study Subject/guardian decision	5	1
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	1	0

Baseline Characteristics

Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.	Total n=80 Participants Total of all reporting groups
Age, Continuous	12 Years STANDARD_DEVIATION 5.38 • n=93 Participants	4 Years STANDARD_DEVIATION NA • n=4 Participants	11.9 Years STANDARD_DEVIATION 5.42 • n=27 Participants
Sex: Female, Male Female	34 Participants n=93 Participants	0 Participants n=4 Participants	34 Participants n=27 Participants
Sex: Female, Male Male	45 Participants n=93 Participants	1 Participants n=4 Participants	46 Participants n=27 Participants
Race/Ethnicity, Customized White	58 Participants n=93 Participants	1 Participants n=4 Participants	59 Participants n=27 Participants
Race/Ethnicity, Customized Asian	10 Participants n=93 Participants	0 Participants n=4 Participants	10 Participants n=27 Participants
Race/Ethnicity, Customized Other	11 Participants n=93 Participants	0 Participants n=4 Participants	11 Participants n=27 Participants

PRIMARY outcome

Timeframe: during the 3 months after tisagenlecleucel administration

Population: Full Analysis Set (FAS): The Full analysis set comprised all patients who received infusion of tisagenlecleucel in the Main Cohort.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.	82.3 Percentage of participants Interval 72.1 to 90.0	100.0 Percentage of participants NA: Confidence Interval could not be calculated for only 1 participant.

SECONDARY outcome

Timeframe: 3 months after tisagenlecleucel administration

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel from US manufacturing facilities.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=67 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary)	82.1 Percentage of participants Interval 70.8 to 90.4	—

SECONDARY outcome

Timeframe: 3 months after tisagenlecleucel administration

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel from US manufacturing facilities.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=67 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
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)	82.1 Percentage of participants Interval 70.8 to 90.4	—

SECONDARY outcome

Timeframe: 3 months after tisagenlecleucel administration

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel from all manufacturing facilities.

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%

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
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)	81.0 Percentage of participants Interval 70.6 to 89.0	—

SECONDARY outcome

Timeframe: 6 months after tisagenlecleucel administration

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel.

These are the participants who achieved CR or CRi without HSCT between tisagenlecleucel (CTL019) infusion and Month 6 response assessment.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT)	60.8 Percentage of participants Interval 49.1 to 71.6	100.0 Percentage of participants NA: Confidence Interval could not be calculated for only 1 participant.

SECONDARY outcome

Timeframe: 6 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel.

These are the participants who achieved CR or CRi and then proceeded to HSCT while in remission prior to Month 6 response assessment

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
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	7.6 Percentage of Participants Interval 2.8 to 15.8	0.0 Percentage of Participants NA: Confidence Interval could not be calculated for only 1 participant.

SECONDARY outcome

Timeframe: up to 6 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel.

These are the participants who achieved CR or CRi and then proceeded to SCT after being infused by tisagenlecleucel.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion	18 Participants	0 Participants

SECONDARY outcome

Timeframe: 60 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel and who achieved CR or CRi.

DOR is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=66 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Duration of Remission (DOR)	46.8 months Interval 17.8 to NA: more than 50% were either censored or in remission at time of analysis.	NA months NA: The patient did not relapse at the time of discontinuation.

SECONDARY outcome

Timeframe: 60 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel and who achieved CR or CRi. Achieving CR or CRi" requireb confirmation but for this analysis, all patients with one CR/CRi, regardless of confirmation were included.

Anatomical location of relapse in participants who achieved prior CR/CRi subsequent to tisagenlecleucel infusion.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=71 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Site of Involvement of Subsequent Relapse BM and/or blood relapse	23 Participants	—
Site of Involvement of Subsequent Relapse Extramedullary only	2 Participants	—
Site of Involvement of Subsequent Relapse Unknown	4 Participants	—

SECONDARY outcome

Timeframe: 60 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=66 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Relapse-free Survival Per IRC Assessment	46.8 months Interval 17.8 to NA: more than 50% were either censored or in remission at time of analysis.	NA months NA: The patient did not relapse at the time of discontinuation.

SECONDARY outcome

Timeframe: 60 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel

EFS is the time from date of tisagenlecleucel infusion to the earliest of death, relapse or treatment failure.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Event-free Survival Per IRC Assessment	23.7 months Interval 9.2 to NA: more than 50% were either censored or without failure event at time of analysis.	NA months NA: The patient did not have an EFS event at the time of discontinuation.

SECONDARY outcome

Timeframe: 60 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel

OS, is the time from date of tisagenlecleucel infusion to the date of death due to any reason.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Overall Survival (OS)	NA months Interval 45.6 to NA: median was not reached, simply because more than 50% of patients remained alive at end of study, or data was otherwise censored.	NA months NA: The patient was still alive at the time of discontinuation.

SECONDARY outcome

Timeframe: 1 month

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel.

These are participants who had a day 28 response (CR or CRi response) by IRC assessment.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment	78.5 Percentage of participants Interval 67.8 to 86.9	100 Percentage of participants NA: Confidence Interval could not be calculated for only 1 participant.

SECONDARY outcome

Timeframe: 3 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel with a baseline tumor burden assessment.

Percentage of participants who achieved BOR of CR or CRi by flow cytometry as a function of baseline bone marrow tumor burden.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only Baseline bone marrow tumor burden: Low (<50%)	96.0 Percentage of participants Interval 79.6 to 99.9	100.0 Percentage of participants NA: 95% CI could not be calculated as there was only 1 participant who had low baseline tumor burden
Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only Baseline bone marrow tumor burden: High (>=50%)	75.9 Percentage of participants Interval 62.4 to 86.5	—

SECONDARY outcome

Timeframe: 28 days

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel

Percentage of participants who achieved CR or CRi response with bone marrow MRD negative (MRD \< 0.01%) after tisagenlecleucel infusion by flow cytometry.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment	75.9 Percentage of participants Interval 65.0 to 84.9	100.0 Percentage of participants NA: Confidence Interval could not be calculated for only1 participant.

SECONDARY outcome

Timeframe: Month 60

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel. Analysis of this particular outcome included a subset of PAS who had evaluation data of the parameter at the specific timepoint. Therefore, no participants in Cohort 1 had at least one blood sample providing evaluable cellular kinetic data for tisagenlecleucel at tis time point, so no data was collected for Cohort 1.

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in peripheral blood.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=20 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment	207 copies/ug DNA Geometric Coefficient of Variation 95.5	—

SECONDARY outcome

Timeframe: Month 6

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in bone marrow.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=39 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment	210 copies/ug DNA Geometric Coefficient of Variation 138.1	NA copies/ug DNA Geometric Coefficient of Variation NA NA: Geometric mean/Geometric Coefficient of Variation could not be calculated for only 1 participant

SECONDARY outcome

Timeframe: Month 60

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel parameter under investigation. Analysis of this particular outcome included a subset of PAS who had evaluation data of the parameter at the specific timepoint. Therefore, no participants in Cohort 1 had at least one blood sample providing evaluable cellular kinetic data for tisagenlecleucel at tis time point, so no data was collected for Cohort 1.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=17 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment	0.253 Percentage of CD3+/CTL019+ cells Geometric Coefficient of Variation 67.4	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=49 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment	0.519 Percentage of CD3+/CTL019+ cells Geometric Coefficient of Variation 185.8	0.1 Percentage of CD3+/CTL019+ cells Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for only 1 participant.

SECONDARY outcome

Timeframe: 60 months

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=75 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC CR/CRi	37200 copies/ug Geometric Coefficient of Variation 154.2	2690 copies/ug Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for 1 participant.
Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC NR	31700 copies/ug Geometric Coefficient of Variation 87.4	—
Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC Unknown	67700 copies/ug Geometric Coefficient of Variation 132.5	—
Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC All Participants	39200 copies/ug Geometric Coefficient of Variation 148.8	2690 copies/ug Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for 1 participant.

SECONDARY outcome

Timeframe: 60 months

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=75 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC CR/CRi	9.87 days Interval 5.7 to 27.8	8.55 days Interval 8.55 to 8.55
Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC NR	20.9 days Interval 12.6 to 62.7	—
Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC Unknown	13.4 days Interval 8.73 to 19.9	—
Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC All Participants	9.98 days Interval 5.7 to 62.7	8.55 days Interval 8.55 to 8.55

SECONDARY outcome

Timeframe: 0 to 84 days after infusion

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel.

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).

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=75 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC0-28d: CR/CRi	310000 copies/ug*days Geometric Coefficient of Variation 192.2	31500 copies/ug*days Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for 1 participant.
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC0-28d: NR	301000 copies/ug*days Geometric Coefficient of Variation 116.9	—
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC0-28d: Unknown	768000 copies/ug*days Geometric Coefficient of Variation 177.4	—
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC0-28d: All Participants	341000 copies/ug*days Geometric Coefficient of Variation 190.9	31500 copies/ug*days Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for 1 participant.
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC 0-84d: CR/CRi	462000 copies/ug*days Geometric Coefficient of Variation 230.1	74700 copies/ug*days Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for 1 participant.
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC 0-84d: NR	1130000 copies/ug*days Geometric Coefficient of Variation 75.5	—
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC 0-84d: Unknown	984000 copies/ug*days Geometric Coefficient of Variation 202.4	—
Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC AUC 0-84d: All Participants	521000 copies/ug*days Geometric Coefficient of Variation 225.3	74700 copies/ug*days Geometric Coefficient of Variation NA NA: Geo-CV could not be calculated for 1 participant.

SECONDARY outcome

Timeframe: 60 months

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=76 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC Tlast CR/CRi	232 days Interval 19.8 to 1860.0	89.7 days Interval 89.7 to 89.7
Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC Tlast NR	48.5 days Interval 13.9 to 888.0	—
Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC Tlast Unknown	220 days Interval 64.0 to 1460.0	—
Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC Tlast All Participants	179 days Interval 13.9 to 1860.0	89.7 days Interval 89.7 to 89.7

SECONDARY outcome

Timeframe: At any time post-baseline, up to a max. of 60 months

Population: Safety Set: The Safety set comprised all patients who received tisagenlecleucel infusion in the Main Cohort. No participants in Cohort 1 had immunogenicity data providing evaluable cellular kinetic data for tisagenlecleucel at this time point, so no data was collected for Cohort 1.

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. .

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019) CR/CRi positive	61 Participants	—
Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019) NR positive	6 Participants	—
Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019) Unknown positive	11 Participants	—
Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019) All Patients positive	78 Participants	—

SECONDARY outcome

Timeframe: Month 3, M6, M12, M24, M60

Population: FAS: the Full analysis set comprised all patients who received infusion of tisagenlecleucel and who had evaluable results at the measured time points. This analysis included a subset of FAS who had any data of the particular questionnaire at the specific timepoint. Therefore, no participants in Cohort 1 had questionnaire data for tisagenlecleucel at the measured time points, so no data was collected for Cohort 1.

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).

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=39 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M3 change from baseline - Emotional	14.5 Scores on a scale Standard Error 17.98	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M6 change from baseline - Emotional	15.9 Scores on a scale Standard Error 18.96	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M12 change from baseline - Emotional	24.6 Scores on a scale Standard Error 23.74	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M24 change from baseline - Emotional	27.02 Scores on a scale Standard Error 21.85	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M60 change from baseline - Emotional	21.4 Scores on a scale Standard Error 24.53	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M3 change from baseline - Social	7.6 Scores on a scale Standard Error 13.90	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M6 change from baseline - Social	8.4 Scores on a scale Standard Error 17.04	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M12 change from baseline - Social	14.8 Scores on a scale Standard Error 16.68	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M24 change from baseline - Social	17.3 Scores on a scale Standard Error 15.85	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M60 change from baseline - Social	17.9 Scores on a scale Standard Error 14.77	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M3 change from baseline - School	8.9 Scores on a scale Standard Error 14.35	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M6 change from baseline - School	10.0 Scores on a scale Standard Error 16.58	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M12 change from baseline - School	19.0 Scores on a scale Standard Error 19.97	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M24 change from baseline - School	13.9 Scores on a scale Standard Error 23.98	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M60 change from baseline - School	17.7 Scores on a scale Standard Error 24.46	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M3 change from baseline - Physical	17.5 Scores on a scale Standard Error 18.36	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M6 change from baseline - Physical	21.6 Scores on a scale Standard Error 25.81	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M12 change from baseline - Physical	31.1 Scores on a scale Standard Error 28.57	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M24 change from baseline - Physical	37.4 Scores on a scale Standard Error 25.12	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M60 change from baseline - Physical	37.1 Scores on a scale Standard Error 24.90	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M3 change from baseline - Psychosocial health	10.4 Scores on a scale Standard Error 12.38	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M6 change from baseline - Psychosocial health	11.0 Scores on a scale Standard Error 14.08	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M12 change from baseline - Psychosocial health	19.8 Scores on a scale Standard Error 16.80	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M24 change from baseline - Psychosocial health	20.1 Scores on a scale Standard Error 16.34	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M60 change from baseline - Psychosocial health	18.9 Scores on a scale Standard Error 15.15	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M3 change from baseline - Total score	13.0 Scores on a scale Standard Error 13.28	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M6 change from baseline - Total score	14.8 Scores on a scale Standard Error 17.00	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M12 change from baseline - Total score	2.8 Scores on a scale Standard Error 19.56	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M24 change from baseline - Total score	26.2 Scores on a scale Standard Error 16.70	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire M60 change from baseline - Total score	25.3 Scores on a scale Standard Error 15.45	—

SECONDARY outcome

Timeframe: Month 60

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel and who had evaluable results at the measured time points. This analysis included a subset of FAS who had any data of the particular questionnaire at the measured timepoints. Therefore, no participants in Cohort 1 had questionnaire data for tisagenlecleucel at the measured time points, so no data was collected for Cohort 1.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=16 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Mobility - No problems	15 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Mobility - Some problems	1 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Mobility - Severe problems	0 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Self-care - No problems	16 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Self-care - Severe problems	0 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Usual activities - No problems	15 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Usual activities - Some problems	0 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Usual activities - Severe problems	1 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Pain/discomfort - No problems	14 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Pain/discomfort - Some problems	2 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Pain/discomfort - Severe problems	0 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Anxiety/depression - Some problems	4 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Anxiety/depression - Severe problems	0 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Self-care - Some problems	0 Participants	—
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire M60: Anxiety/depression - No problems	12 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: This objective was not associated with any data collection from participants. The original plan was to mathematically derive a score from other endpoints measures (e.g., a score combing age, value of CRP, Ferritin, Interferon gamma, etc.). Those potential biomarkers were used to derive the scores that are already reported in other tables. None of the biomarkers analyzed proved to be prognostic for the onset or severity of CRS, hence finally no score was derived and no data for this objective.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Maximum post-baseline (approx. 60 months)

Population: Safety Set: The Safety set comprised all patients who received tisagenlecleucel infusion with evaluable data. This analysis included a subset of Safety set who had any data of the particular biomarker at the specific timepoint. Therefore, no participants in Cohort 1 had biomarker data at this time point, so no data was collected for Cohort 1.

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).

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=21 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin) C Reactive Protein: Fold-change from BL Grade 4 CRS	9.33 fold-change from baseline Geometric Coefficient of Variation 303.9	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin) Ferritin: Fold-change from BL Grade 4 CRS	36.62 fold-change from baseline Geometric Coefficient of Variation 164.6	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=21 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 2: Fold-change from BL Grade 4 CRS	337.86 fold-change from baseline Geometric Coefficient of Variation 161.1	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 4: Fold-change from BL Grade 4 CRS	170.21 fold-change from baseline Geometric Coefficient of Variation 163.3	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 6: Fold-change from BL Grade 4 CRS	1435.85 fold-change from baseline Geometric Coefficient of Variation 221.6	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 8: Fold-change from BL Grade 4 CRS	139.40 fold-change from baseline Geometric Coefficient of Variation 246.9	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interferon gamma: Fold-change from BL Grade 4 CRS	2745.92 fold-change from baseline Geometric Coefficient of Variation 1186.3	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 10: Fold-change from BL Grade 4 CRS	179.49 fold-change from baseline Geometric Coefficient of Variation 966.7	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 12p70: Fold-change from BL Grade 4 CRS	93.50 fold-change from baseline Geometric Coefficient of Variation 261.0	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 13: Fold-change from BL Grade 4 CRS	49.21 fold-change from baseline Geometric Coefficient of Variation 124.0	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Interleukin 1 beta: Fold-change from BL Grade 4 CRS	16.75 fold-change from baseline Geometric Coefficient of Variation 127.7	—
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers) Tumor necrosis factor alpha: Fold-change from BL Grade 4 CRS	27.13 fold-change from baseline Geometric Coefficient of Variation 223.7	—

SECONDARY outcome

Timeframe: Month 3, Month 12, Maximum post-baseline (approx. 60 months)

Population: Safety Set: The Safety set comprised all patients who received tisagenlecleucel infusion.

Levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion Maximum post-BL: (B cell) CR/CRi	-21.25 percentage change from baseline Standard Deviation 37.618	6.06 percentage change from baseline Standard Deviation NA NA: not enough participants to analyze the Standard Deviation.
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion Maximum post-BL: (B cell) NR	2.10 percentage change from baseline Standard Deviation 66.398	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion Maximum post-BL: (B cell) Unknown	7.98 percentage change from baseline Standard Deviation 29.536	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion Maximum post-BL: (B cell) All participants	-15.60 percentage change from baseline Standard Deviation 40.336	6.06 percentage change from baseline Standard Deviation NA NA: not enough participants to analyze the Standard Deviation.
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M12: % change from BL - (T cell) All participants	-1.68 percentage change from baseline Standard Deviation 36.228	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M3: % change from BL - (T cell) All participants	-11.91 percentage change from baseline Standard Deviation 32.333	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion Maximum post-BL: (T cell) All participants	34.12 percentage change from baseline Standard Deviation 29.450	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M3: % change from BL - (B cell) CR/CRi	-25.37 percentage change from baseline Standard Deviation 31.693	-0.51 percentage change from baseline Standard Deviation NA NA: not enough participants to analyze the Standard Deviation.
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M3: % change from BL - (B cell) NR	-37.93 percentage change from baseline Standard Deviation 35.882	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M3: % change from BL - (B cell) Unknown	-11.01 percentage change from baseline Standard Deviation 6.649	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M3: % change from BL - (B cell) All participants	-24.23 percentage change from baseline Standard Deviation 30.215	-0.51 percentage change from baseline Standard Deviation NA NA: not enough participants to analyze the Standard Deviation.
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M12: % change from BL - (B cell) CR/CRi	-18.55 percentage change from baseline Standard Deviation 27.144	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M12: % change from BL - (B cell) NR	-55.21 percentage change from baseline Standard Deviation NA NA: not enough participants to analyze the Standard Deviation.	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M12: % change from BL - (B cell) Unknown	-12.04 percentage change from baseline Standard Deviation 5.995	—
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion M12 % change from BL -: (B cell) All Participants	-19.00 percentage change from baseline Standard Deviation 26.432	—

SECONDARY outcome

Timeframe: 60 months

Population: FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel from Fraunhofer Institue Manufacturing Facility. Participants in Cohort 1 were from the Fraunhofer Institute manufacturing facility and not the US where the data was collected from, so no data was collected for this Cohort.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=12 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility	83.3 Percentage of participants Interval 51.6 to 97.9	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=12 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
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	75.0 Percentage of participants Interval 42.8 to 94.5	—

SECONDARY outcome

Timeframe: Month 60

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel from Fraunhofer Institue Manufacturing Facility. Participants in Cohort 1 were from the Fraunhofer Institute manufacturing facility and not the US where the data was collected from, so no data was collected for this Cohort.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=10 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute	42800 copies/ug Geometric Coefficient of Variation 117.7	—

SECONDARY outcome

Timeframe: Month 3

Population: PAS: The PAS consisted of patients in the FAS who had at least one sample providing evaluable cellular kinetic data for tisagenlecleucel. Participants in Cohort 1 were from the Fraunhofer Institute manufacturing facility and not the US where the data was collected from, so no data was collected for this Cohort.

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.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=7 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 Pediatric B-ALL patients who are very high risk at first relapse.
Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute	855 copies/ug Geometric Coefficient of Variation 792.6	—

POST_HOC outcome

Timeframe: On-treatment deaths: Up to 60 months; Post-treatment survival follow-up deaths: Up to approx. 60 months

Population: Clinical Database Population: all infused participants in the Main cohort

On-treatment deaths, which include post-treatment survival follow-up deaths, were collected during the post-infusion period (starting at the day of first infusion) until the end of the study, approx. 60 months. All deaths refers to the sum of on-treatment deaths and post-treatment survival follow-up deaths up to approx. 60 months.

Outcome measures

Outcome measures
Measure	Main Cohort: Single Dose of CTL019 n=79 Participants Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Cohort 1: Single Dose of CTL019 n=1 Participants Pediatric B-ALL patients who are very high risk at first relapse.
All Collected Deaths On-treatment deaths include post-treatment survival follow-up deaths	33 Participants	0 Participants
All Collected Deaths All deaths	33 Participants	0 Participants

Adverse Events

Main Cohort (On-treatment + Post-treatment Survival Follow-up Deaths)

Serious events: 63 serious events

Other events: 79 other events

Deaths: 33 deaths

Cohort 1 (On-treatment + Post-treatment Survival Follow-up Deaths)

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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 pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER