Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7)

• ClinicalTrials.gov Identifier: NCT03391466
• Recruitment Status: Active, not recruiting
• First Posted: January 5, 2018
• Results First Posted: March 7, 2024
• Last Update Posted: March 7, 2024
• Sponsor: Kite, A Gilead Company
• Information provided by (Responsible Party): Gilead Sciences ( Kite, A Gilead Company )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
• Interventions: Biological: Axicabtagene Ciloleucel; Drug: Platinum-containing salvage chemotherapy (eg, R-ICE) followed by high dose therapy (eg, BEAM) and autologous stem cell transplant in responders.; Drug: Cyclophosphamide; Drug: Fludarabine
• Enrollment: 359

Participant Flow

Recruitment Details	Participants were enrolled at study sites in the North America, Middle East, Europe, and Australia. The data for participant flow and adverse events are reported up to data cut-off date: 25 January 2023. The data reported for outcome measures 1-13 are complete as per the pre-specified planned analysis in the protocol.
Pre-assignment Details	437 participants were screened.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description	Participants received cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who will respond will get high dose therapy and autologous stem cell transplant up to 60 months.
Period Title: Overall Study
Started	180	179
Completed	0	0
Not Completed	180	179
Reason Not Completed
Death	82	85
Still on study	93	74
Subject withdrawal of consent from further follow-up	0	13
Lost to Follow-up	5	5
Investigator decision	0	1
Other	0	1

Baseline Characteristics

Arm/Group Title		Axicabtagene Ciloleucel	Standard of Care Therapy	Total
Arm/Group Description		Participants received cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.	Total of all reporting groups
Overall Number of Baseline Participants		180	179	359
Baseline Analysis Population Description		The Full Analysis Set (FAS) consisted of all randomized participants.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	180 participants	179 participants	359 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	129 71.7%	121 67.6%	250 69.6%
	>=65 years	51 28.3%	58 32.4%	109 30.4%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	180 participants	179 participants	359 participants
		57 (12.0)	57 (12.2)	57 (12.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	180 participants	179 participants	359 participants
	Female	70 38.9%	52 29.1%	122 34.0%
	Male	110 61.1%	127 70.9%	237 66.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	180 participants	179 participants	359 participants
	Hispanic or Latino	10 5.6%	8 4.5%	18 5.0%
	Not Hispanic or Latino	167 92.8%	169 94.4%	336 93.6%
	Unknown or Not Reported	3 1.7%	2 1.1%	5 1.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	180 participants	179 participants	359 participants
	American Indian or Alaska Native	0 0.0%	1 0.6%	1 0.3%
	Asian	12 6.7%	10 5.6%	22 6.1%
	Native Hawaiian or Other Pacific Islander	2 1.1%	1 0.6%	3 0.8%
	Black or African American	11 6.1%	7 3.9%	18 5.0%
	White	145 80.6%	152 84.9%	297 82.7%
	More than one race	10 5.6%	8 4.5%	18 5.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	180 participants	179 participants	359 participants
United States		130 72.2%	120 67.0%	250 69.6%
United Kingdom		4 2.2%	8 4.5%	12 3.3%
Switzerland		1 0.6%	0 0.0%	1 0.3%
Spain		6 3.3%	9 5.0%	15 4.2%
Canada		10 5.6%	10 5.6%	20 5.6%
Belgium		4 2.2%	3 1.7%	7 1.9%
Netherlands		11 6.1%	14 7.8%	25 7.0%
Sweden		0 0.0%	1 0.6%	1 0.3%
Italy		2 1.1%	1 0.6%	3 0.8%
Israel		4 2.2%	2 1.1%	6 1.7%
Australia		2 1.1%	2 1.1%	4 1.1%
France		4 2.2%	2 1.1%	6 1.7%
Germany		1 0.6%	5 2.8%	6 1.7%
Austria		1 0.6%	2 1.1%	3 0.8%

Outcome Measures

1. Primary Outcome

Title	Event Free Survival (EFS) Per Blinded Central Assessment
Description	EFS:Time from randomization to disease progression (PD), best response of SD up to and including Day 150, commencement of subsequent new anti-lymphoma therapy including stem cell transplant, or death from any cause. PD=score 4 (uptake moderately>liver)/5 (uptake markedly >liver and/or new lesions) with an increase in intensity of uptake from baseline;new fluorodeoxyglucose (FDG)-avid foci consistent with lymphoma at interim/EOT assessment, rather than another etiology or in bone marrow;an individual node/lesion must be abnormal with LDi >1.5 cm, increase by ≥50% from cross-product of LDi and perpendicular diameter nadir, increase in LDi or shortest axis perpendicular to LDi from nadir, splenic length must increase by >50% of extent of its prior increase beyond Baseline. If no prior splenomegaly, increase must be ≥2 cm from baseline;new/recurrent splenomegaly;new/clear progression of pre-existing NMLs;new lesion;new/recurrent bone marrow involvement. KM estimates was used for analysis.
Time Frame	From randomization date up to a median follow-up: 24.9 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: months
	8.3; (4.5 to 15.8)	2.0; (1.6 to 2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	One-sided p-value based on log-rank test stratified by response to first-line therapy and second-line age-adjusted International Prognostic Index (IPI) as data collected on case report forms.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified (randomization factors) log-rank p-value.
	Method	Log Rank
	Comments	Stratified (randomization stratification factors) log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.398
	Confidence Interval	(2-Sided) 95%; 0.308 to 0.514
	Estimation Comments	Hazard ratio (95% confidence interval (CI)), stratified using randomization stratification factors.

2. Secondary Outcome

Title	Objective Response Rate (ORR) Per Blinded Central Assessment
Description	ORR: Percentage of participants with CR [CMR;CRR] or PR [partial metabolic response (PMR); partial radiologic response (PRR)].CMR: PET 5PS scores of 1 (no uptake above background, 2(uptake≤mediastinum), 3(uptake>mediastinum but≤liver) with/without a residual mass;no new lesions; no evidence of FDG-avid disease in BM. CRR:target nodes/nodal masses regressed to ≤ 1.5 cm in LDi;no extralymphatic sites of disease;absent non-measured lesions (NMLs);organ enlargement regress to normal;no new sites;bone marrow morphology normal. PMR:scores 4 (uptake moderately>liver),5(uptake markedly > liver, new lesions) with reduced uptake compared with baseline and residual mass;no new lesions;responding disease at interim/residual disease at end of treatment (EOT).PRR: ≥50% decrease in sum of the product of perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites;absent/normal, regressed, but no increase of NMLs;spleen regressed by >50% in length beyond normal;no new sites.
Time Frame	From randomization date up to a median follow-up: 24.9 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy, ifosfamide 5 g/m^2 24hour (hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg, etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy, dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum, cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: percentage of participants
	83; (77.1 to 88.5)	50; (42.7 to 57.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	One-sided p-value based on CMH test, one-sided tailed test, stratified by response to first-line therapy and second-line age-adjusted IPI as data collected on case report forms.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified (randomization factor) CMH test p-value.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified (randomization factor) CMH test.
Method of Estimation	Estimation Parameter	Difference in ORR
	Estimated Value	33.1
	Confidence Interval	(2-Sided) 95%; 23.2 to 42.1
	Estimation Comments	Difference in ORR (95% CI)

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as the time from randomization to death from any cause. Kaplan-Meier (KM) estimates was used for analysis.
Time Frame	From randomization date up to a median follow-up: 47.2 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (28.6 to NA)	31.1 [2]; (17.1 to NA)

[1]

Median and upper limit of CI were not reached due to insufficient number of events.

[2]

Median and upper limit of CI were not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	One-sided p-value based on log-rank test stratified by response to first-line therapy and second-line age-adjusted IPI as data collected on case report forms.
Statistical Test of Hypothesis	P-Value	0.0168
	Comments	Stratified log-rank (randomization factor) p-value.
	Method	Log Rank
	Comments	Stratified (randomization factor) log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.726
	Confidence Interval	(2-Sided) 95%; 0.540 to 0.977
	Estimation Comments	Hazard ratio (95% CI), stratified using randomization stratification factors.
Other Statistical Analysis		The Rho family spending function with parameter (Rho = 6) was used to allocate alpha between the interim and primary OS analysis. Given that fewer than the anticipated 210 events were observed at the data cutoff date for the primary OS analysis (25 January 2023), the efficacy boundary for the primary OS analysis was recalculated using the Rho family spending function based on the actual observed event numbers (177 deaths) resulting in an efficacy boundary at 1-sided significance level of 0.0249.

4. Secondary Outcome

Title	Duration of Response (DOR) Per Blinded Central Assessments
Description	DOR is defined only for participants who experience an objective response after axicabtagene ciloleucel infusion and is the time from the first objective response per Lugano classification to disease progression or death from any cause. Objective response is defined in outcome measure 2 and disease progression is defined in outcome measure 1. KM estimates were used for analysis.
Time Frame	From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (Up to 37.8 months)

Outcome Measure Data

Analysis Population Description

Participants in FAS with response were analyzed. Participants not meeting the criteria by the analysis data cut-off date were censored at their last evaluable disease assessment date prior to the data cut-off date or new lymphoma therapy start date (including stem cell transplant in the axicabtagene ciloleucel arm or retreatment of axicabtagene ciloleucel), whichever was earlier.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	150	90
Median (95% Confidence Interval); Unit of Measure: months
	26.9 [1]; (13.6 to NA)	8.9 [1]; (5.7 to NA)

[1]

The upper limit of CI were not reached due to insufficient number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	One-sided p-value based on log-rank test stratified by response to first-line therapy and second-line age-adjusted IPI as data collected on case report forms.
Statistical Test of Hypothesis	P-Value	0.0695
	Comments	Stratified (randomization stratification factors) log-rank test.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.736
	Confidence Interval	(2-Sided) 95%; 0.488 to 1.108
	Estimation Comments	Hazard ratio (95% CI), stratified using randomization stratification factors.

5. Secondary Outcome

Title	Modified Event Free Survival (mEFS) Per Blinded Central Assessment
Description	Modified event free survival is defined the same way as EFS, except that a best response of SD up to and including Day 150 assessment post randomization was not considered an event. KM estimates were used for analysis.
Time Frame	From randomization date up to a median follow-up: 24.9 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: months
	10.3; (5.0 to 21.5)	2.0; (1.6 to 2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value based on log-rank test stratified by response to first-line therapy and second-line age-adjusted IPI as data collected on case report forms.
	Method	Log Rank
	Comments	Stratified (randomization stratification factors) log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.376
	Confidence Interval	(2-Sided) 95%; 0.290 to 0.487
	Estimation Comments	Hazard ratio (95% CI), stratified using randomization stratification factors.

6. Secondary Outcome

Title	Event Free Survival Per Investigator Disease Assessments
Description	EFS was defined as the time from randomization to the earliest date of disease progression per the IWG Lugano Classification, best response of stable disease (SD) up to and including Day 150, commencement of new lymphoma therapy, or death from any cause. Disease progression is defined in outcome measure 1.
Time Frame	From randomization date up to a median follow-up: 47.2 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: months
	10.8; (5.0 to 25.5)	2.3; (1.7 to 3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.422
	Confidence Interval	(2-Sided) 95%; 0.327 to 0.545
	Estimation Comments	Hazard ratio (95% CI), stratified using randomization stratification factors.

7. Secondary Outcome

Title	Progression-Free Survival (PFS) Per Investigator Disease Assessments
Description	PFS is defined as the time from the randomization date to the date of disease progression per Lugano classification or death from any cause. Disease progression is defined in outcome measure 1. KM estimates was used for analysis.
Time Frame	From randomization date up to a median follow-up: 47.2 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: months
	14.7; (5.4 to 43.5)	3.7; (2.9 to 5.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.506
	Confidence Interval	(2-Sided) 95%; 0.383 to 0.669
	Estimation Comments	Hazard ratio (95% CI), stratified using randomization stratification factors.

8. Secondary Outcome

Title	Modified Event Free Survival (mEFS) Per Investigator Assessment
Description	Modified event free survival is defined the same way as EFS, except that a best response of SD up to and including Day 150 assessment post randomization was not considered an event. KM estimates were used for analysis.
Time Frame	From randomization date up to a median follow-up: 47.2 months

Outcome Measure Data

Analysis Population Description

Participants in FAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed	180	179
Median (95% Confidence Interval); Unit of Measure: months
	12.6; (5.0 to 29.1)	2.3; (1.7 to 3.1)

9. Secondary Outcome

Title	Change From Baseline in Global Health Status Scores
Description	Global health status was measured using European Organization for Research and Treatment of Cancer (EORTC) Quality Life Questionnaire (QLQ) C-30. This health related quality of life (HRQoL) questionnaire was comprised of 15 questions on functional scales, 13 questions on symptom scales and 2 on global health status scale. Global Health Status used a 7 point Likert-type scale of 1 (Very poor) to 7 (Excellent). All scores were transformed to 0-100. Higher scores for Global Health Status indicated better HRQoL.
Time Frame	Baseline, Days 50, 100, and 150; Months 9, 12, 15, 18, 21 and 24

Outcome Measure Data

Analysis Population Description

The QoL analysis set is defined as the subset of participants in the FAS who have a baseline and Day 150 post-randomization QoL assessment. Participants in QoL analysis set with data available at given timepoint were analyzed.

Arm/Group Title		Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:		Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed		165	130
Mean (Standard Deviation); Unit of Measure: Score on scale
Score at Baseline	Number Analyzed	165 participants	130 participants
		68.6 (19.9)	70.1 (23.1)
Change from Baseline at Study Day 50	Number Analyzed	163 participants	124 participants
		-7.4 (20.2)	-8.5 (22.7)
Change from Baseline at Study Day 100	Number Analyzed	146 participants	62 participants
		1.3 (19.6)	-15.3 (22.7)
Change from Baseline at Study Day 150	Number Analyzed	110 participants	56 participants
		5.9 (24.9)	-4.2 (23.7)
Change from Baseline at Study Month 9	Number Analyzed	88 participants	40 participants
		8.0 (22.7)	3.5 (23.7)
Change from Baseline at Study Month 12	Number Analyzed	79 participants	33 participants
		8.6 (24.9)	9.1 (20.2)
Change from Baseline at Study Month 15	Number Analyzed	67 participants	26 participants
		9.0 (22.3)	9.9 (18.9)
Change from Baseline at Study Month 18	Number Analyzed	71 participants	23 participants
		10.2 (20.9)	6.5 (21.3)
Change from Baseline at Study Month 21	Number Analyzed	45 participants	20 participants
		10.0 (21.5)	15.0 (19.6)
Change from Baseline at Study Month 24	Number Analyzed	32 participants	12 participants
		8.6 (21.0)	13.2 (17.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 100.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	False Discovery Rate Methodology
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	18.1
	Confidence Interval	(2-Sided) 95%; 12.3 to 23.9
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 150.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0124
	Comments	False Discovery Rate Methodology
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	9.8
	Confidence Interval	(2-Sided) 95%; 2.6 to 17.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Month 9.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2655
	Comments	False Discovery Rate Methodology
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; -3.3 to 12.0
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Change From Baseline in EORTC QLQ-C30 Physical Functioning Score
Description	The EORTC QLQ-C30 is composed of global health status/QoL scale; five functional domains (physical, role, emotional, cognitive, and social); three symptom domains (fatigue, nausea and vomiting, and pain); and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The Physical Functioning domain includes 5 questions in which participants were asked to rate their overall health and overall quality of life as it relates to physical functioning during the past week on a scale from 1 (very poor) to 7 (excellent). The 5 scores were transformed to a scale from 0 to 100, where a high score indicated better QoL. A positive change from baseline indicates better QoL.
Time Frame	Baseline, Days 50, 100, 150, Months 9, 12, 15, 18, 21 and 24

Outcome Measure Data

Analysis Population Description

Participants in QoL analysis set with data available at given timepoint were analyzed.

Arm/Group Title		Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:		Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed		164	131
Mean (Standard Deviation); Unit of Measure: Score on scale
Score at Baseline	Number Analyzed	164 participants	131 participants
		83.5 (17.7)	85.3 (18.9)
Change from Baseline at Study Day 50	Number Analyzed	162 participants	126 participants
		-12.9 (21.7)	-8.3 (17.5)
Change from Baseline at Study Day 100	Number Analyzed	146 participants	64 participants
		-1.8 (17.8)	-15.0 (19.1)
Change from Baseline at Study Day 150	Number Analyzed	109 participants	56 participants
		1.3 (18.9)	-5.2 (21.3)
Change from Baseline at Study Month 9	Number Analyzed	88 participants	40 participants
		4.1 (17.1)	-2.4 (23.5)
Change from Baseline at Study Month 12	Number Analyzed	79 participants	33 participants
		3.4 (20.8)	0.4 (20.3)
Change from Baseline at Study Month 15	Number Analyzed	67 participants	26 participants
		3.9 (19.3)	1.6 (16.1)
Change from Baseline at Study Month 18	Number Analyzed	71 participants	23 participants
		5.0 (15.1)	3.2 (17.9)
Change from Baseline at Study Month 21	Number Analyzed	45 participants	20 participants
		6.0 (16.1)	4.3 (21.4)
Change from Baseline at Study Month 24	Number Analyzed	32 participants	12 participants
		3.7 (16.5)	5.6 (8.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 100.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	False Discovery Rate Methodology.
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	13.1
	Confidence Interval	(2-Sided) 95%; 8.0 to 18.2
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 150.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1253
	Comments	False Discovery Rate Methodology.
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; -0.9 to 11.0
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Changes From Baseline in the European Quality of Life Five Dimensions Five Levels Scale (EQ-5D-5L) Index Score
Description	The Euro-QOL, Five Dimensions, Five Levels (EQ-5D-5L) questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L comprises 2 components: a questionnaire covering 5 dimensions and a tariff of values based upon direct valuations of health states using a visual analog scale (VAS). The total score for EQ-5D-5L index- is presented on a range from 0 to 1 where higher scores indicate better outcome. A positive change from Baseline indicates improvement.
Time Frame	Baseline, Days 50, 100, 150; Months 9, 12, 15, 18, 21 and 24

Outcome Measure Data

Analysis Population Description

Participants in QoL analysis set with data available at given timepoint were analyzed.

Arm/Group Title		Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:		Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed		165	131
Mean (Standard Deviation); Unit of Measure: Score on scale
Score at Baseline	Number Analyzed	165 participants	131 participants
		0.803 (0.210)	0.799 (0.250)
Change from Baseline at Study Day 50	Number Analyzed	163 participants	123 participants
		-0.049 (0.205)	-0.003 (0.198)
Change from Baseline at Study Day 100	Number Analyzed	146 participants	65 participants
		0.012 (0.191)	-0.068 (0.246)
Change from Baseline at Study Day 150	Number Analyzed	109 participants	56 participants
		0.050 (0.212)	0.014 (0.208)
Change from Baseline at Study Month 9	Number Analyzed	88 participants	39 participants
		0.064 (0.190)	0.015 (0.197)
Change from Baseline at Study Month 12	Number Analyzed	79 participants	32 participants
		0.072 (0.241)	0.051 (0.200)
Change from Baseline at Study Month 15	Number Analyzed	67 participants	26 participants
		0.051 (0.209)	0.080 (0.125)
Change from Baseline at Study Month 18	Number Analyzed	71 participants	22 participants
		0.094 (0.180)	0.072 (0.188)
Change from Baseline at Study Month 21	Number Analyzed	45 participants	20 participants
		0.089 (0.235)	0.110 (0.177)
Change from Baseline at Study Month 24	Number Analyzed	33 participants	12 participants
		0.051 (0.239)	0.117 (0.138)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 100.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0112
	Comments	False Discovery Rate Methodology.
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	0.081
	Confidence Interval	(2-Sided) 95%; 0.024 to 0.138
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 150.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3703
	Comments	False Discovery Rate Methodology.
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95%; -0.034 to 0.091
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Baseline in EQ-5D-5L VAS Scale Score
Description	The EQ-5D-5L VAS is a 20-cm VAS for recording self-rated current HRQoL state and is used to describe the participants' health status on the day of the assessment. The EQ-5D-5L VAS score is recorded by each participant for his or her current HRQoL state and scored 0 ("the worst health you can imagine") to 100 ("the best health you can imagine"). The value 100 indicates improvement.
Time Frame	Baseline, Days 50, 100, 150; Months 9, 12, 18, 21 and 24

Outcome Measure Data

Analysis Population Description

Participants in QoL analysis set with data available at given timepoint were analyzed.

Arm/Group Title		Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description:		Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
Overall Number of Participants Analyzed		165	129
Mean (Standard Deviation); Unit of Measure: Score on scale
Score at Baseline	Number Analyzed	165 participants	129 participants
		72.4 (18.7)	74.4 (20.1)
Change from Baseline at Study Day 50	Number Analyzed	163 participants	124 participants
		-1.9 (18.7)	-4.4 (16.7)
Change from Baseline at Study Day 100	Number Analyzed	145 participants	64 participants
		4.0 (18.4)	-8.2 (19.8)
Change from Baseline at Study Day 150	Number Analyzed	110 participants	54 participants
		9.1 (19.4)	-2.2 (22.2)
Change from Baseline at Study Month 9	Number Analyzed	88 participants	39 participants
		11.4 (19.9)	4.4 (19.0)
Change from Baseline at Study Month 12	Number Analyzed	80 participants	31 participants
		10.1 (19.9)	6.6 (17.8)
Change from Baseline at Study Month 15	Number Analyzed	67 participants	26 participants
		10.7 (20.7)	8.2 (13.7)
Change from Baseline at Study Month 18	Number Analyzed	70 participants	23 participants
		15.1 (17.1)	9.3 (13.6)
Change from Baseline at Study Month 21	Number Analyzed	45 participants	20 participants
		14.0 (17.2)	10.1 (14.3)
Change from Baseline at Study Month 24	Number Analyzed	33 participants	12 participants
		10.9 (18.8)	12.2 (15.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 100.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	False Discovery Rate Methodology
	Method	Mixed Model with Repeated Measures
	Comments	Mixed Model with Repeated Measures Differences in Change from Baseline.
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	13.7
	Confidence Interval	(2-Sided) 95%; 8.5 to 18.8
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Day 150.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	False Discovery Rate Methodology
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	11.3
	Confidence Interval	(2-Sided) 95%; 5.4 to 17.1
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Axicabtagene Ciloleucel, Standard of Care Therapy
	Comments	Difference in mean change of scores from Baseline at Month 9.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2549
	Comments	False Discovery Rate Methodology.
	Method	Mixed Model with Repeated Measures
	Comments	Mixed Model with Repeated Measures Differences in Change from Baseline.
Method of Estimation	Estimation Parameter	Mixed Model with Repeated Measures
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; -2.3 to 10.0
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Number of Participants With Anti-Axicabtagene Ciloleucel Antibodies
Description	[Not Specified]
Time Frame	From first dose of axicabtagene up to a median follow-up: 24 months

Outcome Measure Data

Analysis Population Description

Participants in SAS were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received conditioning chemotherapy regimen consisting of fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day (day -5 to day -3) for 3 days followed by 2 rest days (day -2 & day -1) and then received a single infusion of axicabtagene ciloleucel administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg on treatment Day 0.
Overall Number of Participants Analyzed	170
Measure Type: Count of Participants; Unit of Measure: Participants
	0

14. Secondary Outcome

Title	Percentage of Participants Experiencing Treatment-emergent Adverse Events
Description	A TEAE is defined as any AE that begins on or after the first dose of study treatment (axicabtagene ciloleucel infusion or SOC), excluding bridging therapy. Participant incidence rates of TEAEs, including all, serious, fatal, CTCAE Grade 3 or higher, and treatment related AEs reported will be tabulated by preferred term and system organ class coded with the Medical Dictionary for Regulatory Activities (MedDRA).
Time Frame	Up to 5 years

Outcome Measure Data Not Reported

15. Secondary Outcome

Title	Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs
Description	Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.
Time Frame	Up to 5 years

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Up to 59.3 months
Adverse Event Reporting Description	All-Cause Mortality: The Full Analysis Set consisted of all randomized participants. Adverse Events: The Safety Analysis Set is defined as the subset of all randomized participants who received at least 1 dose of axicabtagene ciloleucel as protocol therapy or SOC chemotherapy as protocol therapy.
Arm/Group Title	Axicabtagene Ciloleucel	Standard of Care Therapy
Arm/Group Description	Participants received cyclophosphamide 500 mg/m^2/day IV and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation antigen (CD) 19 CAR transduced autologous T cells/kg on Day 0.	Participants received 2 or 3 21-day cycles of second-line chemotherapy regimen; R-ICE: rituximab 375 mg/m^2 before chemotherapy,ifosfamide 5 g/m^2 24hour(hr) infusion on Day 2+mesna,carboplatin area under the curve (AUC) 5 on Day 2, maximum dose 800 mg,etoposide 100 mg/ m^2/day on Days 1-3; R-ESHAP: rituximab 375 mg/m^2 Day 1,etoposide 40 mg/m^2/day IV on Days 1-4,methylprednisolone 500 mg/day IV on Days 1-4 or 5,cisplatin at 25 mg/m^2/day Days 1-4,cytarabine 2 g/m^2 on Day 5; R-GDP: rituximab 375 mg/m^2 Day 1(or Day 8),gemcitabine 1g/m^2 on Days 1 and 8,dexamethasone 40 mg on Days 1-4,cisplatin 75mg/m^2 on Day 1 or carboplatin AUC=5; or R-DHAP: Rituximab 375 mg/ m^2 before chemotherapy,dexamethasone 40 mg/day on Days 1-4,highdose cytarabine 2 g/m^2 every 12 hours for 2 doses on Day 2 following/platinum,cisplatin 100 mg/m^2 24hr infusion on Day 1 or oxaliplatin 100 mg/m^2. Participants who responded got high dose therapy and autologous stem cell transplant up to 60 months.
All-Cause Mortality
	Axicabtagene Ciloleucel	Standard of Care Therapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	82/180 (45.56%)	95/179 (53.07%)
Serious Adverse Events
	Axicabtagene Ciloleucel	Standard of Care Therapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	95/170 (55.88%)	78/168 (46.43%)
Blood and lymphatic system disorders
Anaemia † 1	2/170 (1.18%)	3/168 (1.79%)
Coagulopathy † 1	1/170 (0.59%)	0/168 (0.00%)
Febrile neutropenia † 1	6/170 (3.53%)	22/168 (13.10%)
Leukopenia † 1	0/170 (0.00%)	1/168 (0.60%)
Neutropenia † 1	4/170 (2.35%)	1/168 (0.60%)
Thrombocytopenia † 1	0/170 (0.00%)	1/168 (0.60%)
Cardiac disorders
Acute myocardial infarction † 1	0/170 (0.00%)	1/168 (0.60%)
Atrial fibrillation † 1	5/170 (2.94%)	2/168 (1.19%)
Cardiac arrest † 1	1/170 (0.59%)	1/168 (0.60%)
Cardiac failure † 1	1/170 (0.59%)	1/168 (0.60%)
Cardiomyopathy † 1	1/170 (0.59%)	0/168 (0.00%)
Myocardial infarction † 1	1/170 (0.59%)	0/168 (0.00%)
Pericardial effusion † 1	1/170 (0.59%)	0/168 (0.00%)
Sinus tachycardia † 1	2/170 (1.18%)	2/168 (1.19%)
Tachycardia † 1	2/170 (1.18%)	0/168 (0.00%)
Ventricular tachycardia † 1	1/170 (0.59%)	0/168 (0.00%)
Eye disorders
Vision blurred † 1	1/170 (0.59%)	0/168 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	3/170 (1.76%)	2/168 (1.19%)
Colitis † 1	0/170 (0.00%)	1/168 (0.60%)
Diarrhoea † 1	0/170 (0.00%)	1/168 (0.60%)
Dysphagia † 1	0/170 (0.00%)	1/168 (0.60%)
Enterocolitis † 1	0/170 (0.00%)	1/168 (0.60%)
Enterovesical fistula † 1	1/170 (0.59%)	0/168 (0.00%)
Food poisoning † 1	1/170 (0.59%)	0/168 (0.00%)
Gastric ulcer perforation † 1	0/170 (0.00%)	1/168 (0.60%)
Gastrointestinal haemorrhage † 1	0/170 (0.00%)	1/168 (0.60%)
Ileus † 1	0/170 (0.00%)	1/168 (0.60%)
Intestinal obstruction † 1	0/170 (0.00%)	1/168 (0.60%)
Lower gastrointestinal haemorrhage † 1	0/170 (0.00%)	1/168 (0.60%)
Nausea † 1	1/170 (0.59%)	2/168 (1.19%)
Oesophageal fistula † 1	1/170 (0.59%)	0/168 (0.00%)
Oral disorder † 1	1/170 (0.59%)	0/168 (0.00%)
Pancreatitis acute † 1	0/170 (0.00%)	1/168 (0.60%)
Stomatitis † 1	1/170 (0.59%)	0/168 (0.00%)
Vomiting † 1	1/170 (0.59%)	1/168 (0.60%)
General disorders
Chest pain † 1	0/170 (0.00%)	1/168 (0.60%)
Chills † 1	1/170 (0.59%)	0/168 (0.00%)
Fatigue † 1	3/170 (1.76%)	0/168 (0.00%)
Incarcerated hernia † 1	1/170 (0.59%)	0/168 (0.00%)
Influenza like illness † 1	0/170 (0.00%)	1/168 (0.60%)
Malaise † 1	2/170 (1.18%)	1/168 (0.60%)
Mucosal inflammation † 1	0/170 (0.00%)	1/168 (0.60%)
Pyrexia † 1	27/170 (15.88%)	8/168 (4.76%)
Hepatobiliary disorders
Cholangitis † 1	1/170 (0.59%)	0/168 (0.00%)
Cholelithiasis † 1	0/170 (0.00%)	1/168 (0.60%)
Infections and infestations
Anal abscess † 1	0/170 (0.00%)	1/168 (0.60%)
Arthritis infective † 1	0/170 (0.00%)	1/168 (0.60%)
Bacteraemia † 1	0/170 (0.00%)	1/168 (0.60%)
Clostridium difficile infection † 1	0/170 (0.00%)	1/168 (0.60%)
Covid-19 † 1	6/170 (3.53%)	1/168 (0.60%)
Covid-19 pneumonia † 1	2/170 (1.18%)	0/168 (0.00%)
Cytomegalovirus infection † 1	1/170 (0.59%)	0/168 (0.00%)
Device related infection † 1	0/170 (0.00%)	1/168 (0.60%)
Fungal cystitis † 1	1/170 (0.59%)	0/168 (0.00%)
Gastrointestinal infection † 1	1/170 (0.59%)	0/168 (0.00%)
Hepatitis B reactivation † 1	1/170 (0.59%)	0/168 (0.00%)
Herpes zoster † 1	0/170 (0.00%)	2/168 (1.19%)
Influenza † 1	1/170 (0.59%)	0/168 (0.00%)
Metapneumovirus infection † 1	1/170 (0.59%)	0/168 (0.00%)
Parainfluenzae virus infection † 1	0/170 (0.00%)	1/168 (0.60%)
Pelvic abscess † 1	1/170 (0.59%)	0/168 (0.00%)
Pneumococcal sepsis † 1	0/170 (0.00%)	1/168 (0.60%)
Pneumocystis jirovecii pneumonia † 1	1/170 (0.59%)	1/168 (0.60%)
Pneumonia † 1	11/170 (6.47%)	4/168 (2.38%)
Pneumonia legionella † 1	0/170 (0.00%)	1/168 (0.60%)
Pneumonia staphylococcal † 1	1/170 (0.59%)	0/168 (0.00%)
Progressive multifocal leukoencephalopathy † 1	1/170 (0.59%)	0/168 (0.00%)
Pseudomonal sepsis † 1	1/170 (0.59%)	0/168 (0.00%)
Pyelonephritis † 1	1/170 (0.59%)	0/168 (0.00%)
Respiratory tract infection † 1	1/170 (0.59%)	0/168 (0.00%)
Rhinovirus infection † 1	1/170 (0.59%)	0/168 (0.00%)
Salmonella bacteraemia † 1	1/170 (0.59%)	0/168 (0.00%)
Sepsis † 1	4/170 (2.35%)	4/168 (2.38%)
Sinusitis † 1	1/170 (0.59%)	0/168 (0.00%)
Staphylococcal infection † 1	0/170 (0.00%)	1/168 (0.60%)
Upper respiratory tract infection † 1	2/170 (1.18%)	0/168 (0.00%)
Urinary tract infection † 1	2/170 (1.18%)	0/168 (0.00%)
Urosepsis † 1	1/170 (0.59%)	1/168 (0.60%)
Wound infection † 1	1/170 (0.59%)	0/168 (0.00%)
Injury, poisoning and procedural complications
Blood stem cell harvest failure † 1	0/170 (0.00%)	1/168 (0.60%)
Fall † 1	2/170 (1.18%)	0/168 (0.00%)
Femoral neck fracture † 1	1/170 (0.59%)	0/168 (0.00%)
Hip fracture † 1	0/170 (0.00%)	1/168 (0.60%)
Infusion related reaction † 1	0/170 (0.00%)	1/168 (0.60%)
Subdural haematoma † 1	1/170 (0.59%)	0/168 (0.00%)
Vascular access complication † 1	0/170 (0.00%)	1/168 (0.60%)
Investigations
Aspartate aminotransferase increased † 1	1/170 (0.59%)	0/168 (0.00%)
Blood creatinine increased † 1	0/170 (0.00%)	1/168 (0.60%)
Blood fibrinogen decreased † 1	1/170 (0.59%)	0/168 (0.00%)
Neutrophil count decreased † 1	3/170 (1.76%)	3/168 (1.79%)
Platelet count decreased † 1	0/170 (0.00%)	5/168 (2.98%)
Troponin I increased † 1	1/170 (0.59%)	0/168 (0.00%)
Weight decreased † 1	0/170 (0.00%)	1/168 (0.60%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/170 (0.59%)	3/168 (1.79%)
Dehydration † 1	0/170 (0.00%)	3/168 (1.79%)
Hypercalcaemia † 1	0/170 (0.00%)	1/168 (0.60%)
Hyperglycaemia † 1	0/170 (0.00%)	1/168 (0.60%)
Hypokalaemia † 1	0/170 (0.00%)	2/168 (1.19%)
Hypomagnesaemia † 1	0/170 (0.00%)	1/168 (0.60%)
Hyponatraemia † 1	2/170 (1.18%)	1/168 (0.60%)
Musculoskeletal and connective tissue disorders
Back pain † 1	1/170 (0.59%)	2/168 (1.19%)
Flank pain † 1	1/170 (0.59%)	0/168 (0.00%)
Muscular weakness † 1	3/170 (1.76%)	0/168 (0.00%)
Pain in extremity † 1	0/170 (0.00%)	1/168 (0.60%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia † 1	1/170 (0.59%)	0/168 (0.00%)
Adenocarcinoma of colon † 1	1/170 (0.59%)	0/168 (0.00%)
Anal squamous cell carcinoma † 1	1/170 (0.59%)	0/168 (0.00%)
B-cell lymphoma † 1	7/170 (4.12%)	5/168 (2.98%)
Bladder transitional cell carcinoma † 1	0/170 (0.00%)	1/168 (0.60%)
Ductal adenocarcinoma of pancreas † 1	0/170 (0.00%)	1/168 (0.60%)
Hepatocellular carcinoma † 1	1/170 (0.59%)	0/168 (0.00%)
Lung adenocarcinoma † 1	1/170 (0.59%)	0/168 (0.00%)
Metastatic malignant melanoma † 1	0/170 (0.00%)	1/168 (0.60%)
Myelodysplastic syndrome † 1	2/170 (1.18%)	0/168 (0.00%)
Plasma cell myeloma † 1	1/170 (0.59%)	0/168 (0.00%)
Spindle cell sarcoma † 1	1/170 (0.59%)	0/168 (0.00%)
Nervous system disorders
Aphasia † 1	9/170 (5.29%)	0/168 (0.00%)
Ataxia † 1	1/170 (0.59%)	0/168 (0.00%)
Cerebrovascular accident † 1	1/170 (0.59%)	0/168 (0.00%)
Cognitive disorder † 1	1/170 (0.59%)	0/168 (0.00%)
Depressed level of consciousness † 1	1/170 (0.59%)	0/168 (0.00%)
Dysarthria † 1	1/170 (0.59%)	0/168 (0.00%)
Dyspraxia † 1	1/170 (0.59%)	0/168 (0.00%)
Encephalopathy † 1	17/170 (10.00%)	1/168 (0.60%)
Facial paralysis † 1	1/170 (0.59%)	0/168 (0.00%)
Guillain-Barre syndrome † 1	0/170 (0.00%)	1/168 (0.60%)
Headache † 1	4/170 (2.35%)	1/168 (0.60%)
Hemiparesis † 1	1/170 (0.59%)	0/168 (0.00%)
Hypoaesthesia † 1	2/170 (1.18%)	0/168 (0.00%)
Ischaemic stroke † 1	0/170 (0.00%)	1/168 (0.60%)
Lethargy † 1	1/170 (0.59%)	0/168 (0.00%)
Memory impairment † 1	1/170 (0.59%)	0/168 (0.00%)
Paraesthesia † 1	1/170 (0.59%)	0/168 (0.00%)
Seizure † 1	1/170 (0.59%)	0/168 (0.00%)
Somnolence † 1	5/170 (2.94%)	0/168 (0.00%)
Spinal cord compression † 1	0/170 (0.00%)	1/168 (0.60%)
Syncope † 1	1/170 (0.59%)	3/168 (1.79%)
Tremor † 1	5/170 (2.94%)	0/168 (0.00%)
Psychiatric disorders
Agitation † 1	2/170 (1.18%)	0/168 (0.00%)
Bradyphrenia † 1	1/170 (0.59%)	0/168 (0.00%)
Confusional state † 1	6/170 (3.53%)	0/168 (0.00%)
Delirium † 1	1/170 (0.59%)	0/168 (0.00%)
Mental status changes † 1	2/170 (1.18%)	0/168 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	3/170 (1.76%)	8/168 (4.76%)
Faecaluria † 1	1/170 (0.59%)	0/168 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	0/170 (0.00%)	2/168 (1.19%)
Acute respiratory failure † 1	1/170 (0.59%)	0/168 (0.00%)
Chronic obstructive pulmonary disease † 1	1/170 (0.59%)	1/168 (0.60%)
Dyspnoea † 1	3/170 (1.76%)	1/168 (0.60%)
Epistaxis † 1	0/170 (0.00%)	1/168 (0.60%)
Hypoxia † 1	3/170 (1.76%)	2/168 (1.19%)
Lung opacity † 1	1/170 (0.59%)	0/168 (0.00%)
Pleural effusion † 1	1/170 (0.59%)	0/168 (0.00%)
Respiratory failure † 1	1/170 (0.59%)	1/168 (0.60%)
Tachypnoea † 1	2/170 (1.18%)	0/168 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis † 1	1/170 (0.59%)	0/168 (0.00%)
Rash maculo-papular † 1	0/170 (0.00%)	1/168 (0.60%)
Surgical and medical procedures
Haematopoietic stem cell mobilisation † 1	1/170 (0.59%)	0/168 (0.00%)
Vascular disorders
Embolism † 1	2/170 (1.18%)	0/168 (0.00%)
Hypotension † 1	15/170 (8.82%)	3/168 (1.79%)
Orthostatic hypotension † 1	1/170 (0.59%)	0/168 (0.00%)
1 Term from vocabulary, MedDRA 25.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Axicabtagene Ciloleucel	Standard of Care Therapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	170/170 (100.00%)	166/168 (98.81%)
Blood and lymphatic system disorders
Anaemia † 1	71/170 (41.76%)	90/168 (53.57%)
Febrile neutropenia † 1	0/170 (0.00%)	24/168 (14.29%)
Leukopenia † 1	9/170 (5.29%)	6/168 (3.57%)
Neutropenia † 1	75/170 (44.12%)	28/168 (16.67%)
Thrombocytopenia † 1	22/170 (12.94%)	40/168 (23.81%)
Cardiac disorders
Sinus tachycardia † 1	58/170 (34.12%)	16/168 (9.52%)
Tachycardia † 1	13/170 (7.65%)	10/168 (5.95%)
Ear and labyrinth disorders
Tinnitus † 1	0/170 (0.00%)	11/168 (6.55%)
Gastrointestinal disorders
Abdominal distension † 1	4/170 (2.35%)	11/168 (6.55%)
Abdominal pain † 1	23/170 (13.53%)	23/168 (13.69%)
Constipation † 1	34/170 (20.00%)	58/168 (34.52%)
Diarrhoea † 1	71/170 (41.76%)	66/168 (39.29%)
Dry mouth † 1	16/170 (9.41%)	8/168 (4.76%)
Dyspepsia † 1	5/170 (2.94%)	14/168 (8.33%)
Nausea † 1	68/170 (40.00%)	116/168 (69.05%)
Stomatitis † 1	4/170 (2.35%)	29/168 (17.26%)
Vomiting † 1	33/170 (19.41%)	55/168 (32.74%)
General disorders
Asthenia † 1	14/170 (8.24%)	16/168 (9.52%)
Chills † 1	46/170 (27.06%)	14/168 (8.33%)
Fatigue † 1	69/170 (40.59%)	87/168 (51.79%)
Malaise † 1	15/170 (8.82%)	9/168 (5.36%)
Mucosal inflammation † 1	1/170 (0.59%)	15/168 (8.93%)
Oedema peripheral † 1	20/170 (11.76%)	28/168 (16.67%)
Pyrexia † 1	149/170 (87.65%)	40/168 (23.81%)
Hepatobiliary disorders
Hypertransaminasaemia † 1	11/170 (6.47%)	1/168 (0.60%)
Immune system disorders
Hypogammaglobulinaemia † 1	19/170 (11.18%)	1/168 (0.60%)
Infections and infestations
Oral candidiasis † 1	14/170 (8.24%)	5/168 (2.98%)
Upper respiratory tract infection † 1	9/170 (5.29%)	5/168 (2.98%)
Injury, poisoning and procedural complications
Infusion related reaction † 1	1/170 (0.59%)	12/168 (7.14%)
Investigations
Alanine aminotransferase increased † 1	31/170 (18.24%)	16/168 (9.52%)
Aspartate aminotransferase increased † 1	24/170 (14.12%)	15/168 (8.93%)
Blood alkaline phosphatase increased † 1	10/170 (5.88%)	14/168 (8.33%)
Blood creatinine increased † 1	10/170 (5.88%)	15/168 (8.93%)
C-reactive protein increased † 1	15/170 (8.82%)	4/168 (2.38%)
Lymphocyte count decreased † 1	31/170 (18.24%)	21/168 (12.50%)
Neutrophil count decreased † 1	51/170 (30.00%)	45/168 (26.79%)
Platelet count decreased † 1	30/170 (17.65%)	64/168 (38.10%)
Serum ferritin increased † 1	15/170 (8.82%)	0/168 (0.00%)
Weight decreased † 1	11/170 (6.47%)	6/168 (3.57%)
Weight increased † 1	1/170 (0.59%)	12/168 (7.14%)
White blood cell count decreased † 1	46/170 (27.06%)	37/168 (22.02%)
Metabolism and nutrition disorders
Decreased appetite † 1	42/170 (24.71%)	41/168 (24.40%)
Hyperglycaemia † 1	27/170 (15.88%)	17/168 (10.12%)
Hypoalbuminaemia † 1	22/170 (12.94%)	12/168 (7.14%)
Hypocalcaemia † 1	27/170 (15.88%)	17/168 (10.12%)
Hypokalaemia † 1	44/170 (25.88%)	47/168 (27.98%)
Hypomagnesaemia † 1	20/170 (11.76%)	34/168 (20.24%)
Hyponatraemia † 1	19/170 (11.18%)	7/168 (4.17%)
Hypophosphataemia † 1	45/170 (26.47%)	29/168 (17.26%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	19/170 (11.18%)	14/168 (8.33%)
Back pain † 1	15/170 (8.82%)	23/168 (13.69%)
Bone pain † 1	7/170 (4.12%)	14/168 (8.33%)
Muscular weakness † 1	17/170 (10.00%)	10/168 (5.95%)
Myalgia † 1	14/170 (8.24%)	7/168 (4.17%)
Pain in extremity † 1	14/170 (8.24%)	9/168 (5.36%)
Nervous system disorders
Aphasia † 1	31/170 (18.24%)	0/168 (0.00%)
Dizziness † 1	36/170 (21.18%)	21/168 (12.50%)
Dysgeusia † 1	4/170 (2.35%)	14/168 (8.33%)
Encephalopathy † 1	18/170 (10.59%)	1/168 (0.60%)
Headache † 1	69/170 (40.59%)	43/168 (25.60%)
Paraesthesia † 1	7/170 (4.12%)	14/168 (8.33%)
Peripheral sensory neuropathy † 1	0/170 (0.00%)	10/168 (5.95%)
Somnolence † 1	14/170 (8.24%)	2/168 (1.19%)
Tremor † 1	41/170 (24.12%)	1/168 (0.60%)
Psychiatric disorders
Anxiety † 1	11/170 (6.47%)	14/168 (8.33%)
Confusional state † 1	34/170 (20.00%)	4/168 (2.38%)
Insomnia † 1	21/170 (12.35%)	26/168 (15.48%)
Renal and urinary disorders
Acute kidney injury † 1	12/170 (7.06%)	16/168 (9.52%)
Urinary incontinence † 1	12/170 (7.06%)	5/168 (2.98%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	42/170 (24.71%)	18/168 (10.71%)
Dyspnoea † 1	12/170 (7.06%)	20/168 (11.90%)
Hiccups † 1	5/170 (2.94%)	21/168 (12.50%)
Hypoxia † 1	34/170 (20.00%)	13/168 (7.74%)
Oropharyngeal pain † 1	11/170 (6.47%)	14/168 (8.33%)
Pleural effusion † 1	10/170 (5.88%)	3/168 (1.79%)
Skin and subcutaneous tissue disorders
Alopecia † 1	3/170 (1.76%)	10/168 (5.95%)
Erythema † 1	10/170 (5.88%)	3/168 (1.79%)
Pruritus † 1	7/170 (4.12%)	9/168 (5.36%)
Vascular disorders
Hypertension † 1	15/170 (8.82%)	15/168 (8.93%)
Hypotension † 1	66/170 (38.82%)	23/168 (13.69%)
1 Term from vocabulary, MedDRA 25.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

• The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
• The study has been completed at all study sites for at least 2 years

Results Point of Contact

• Name/Title: Medical Information
• Organization: Kite, A Gilead Company
• Phone: 844-454-5483 (1-844-454-KITE)
• EMail: medinfo@kitepharma.com

Publications:

Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-90. doi: 10.1182/blood-2016-01-643569. Epub 2016 Mar 15.

Elsawy M, Chavez JC, Avivi I, Larouche JF, Wannesson L, Cwynarski K, Osman K, Davison K, Rudzki JD, Dahiya S, Dorritie K, Jaglowski S, Radford J, Morschhauser F, Cunningham D, Martin Garcia-Sancho A, Tzachanis D, Ulrickson ML, Karmali R, Kekre N, Thieblemont C, Enblad G, Dreger P, Malladi R, Joshi N, Wang WJ, Solem CT, Snider JT, Cheng P, To C, Kersten MJ. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022 Nov 24;140(21):2248-2260. doi: 10.1182/blood.2022015478.

Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. doi: 10.1016/j.jtct.2023.01.008. Epub 2023 Jan 14.

Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Munoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. doi: 10.1056/NEJMoa2116133. Epub 2021 Dec 11.

Westin JR, Locke FL, Dickinson M, Ghobadi A, Elsawy M, van Meerten T, Miklos DB, Ulrickson ML, Perales MA, Farooq U, Wannesson L, Leslie L, Kersten MJ, Jacobson CA, Pagel JM, Wulf G, Johnston P, Rapoport AP, Du L, Vardhanabhuti S, Filosto S, Shah J, Snider JT, Cheng P, To C, Oluwole OO, Sureda A. Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma. Clin Cancer Res. 2023 May 15;29(10):1894-1905. doi: 10.1158/1078-0432.CCR-22-3136.

Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators; Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. doi: 10.1056/NEJMoa2301665. Epub 2023 Jun 5.

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

The Lancet Haematology. The role of conferences in tackling inequalities. Lancet Haematol. 2022 Feb;9(2):e81. doi: 10.1016/S2352-3026(22)00008-4. No abstract available.

Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available.

Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Kambhampati S, Hunter B, Varnavski A, Fakhri B, Kaplan L, Ai WZ, Pampaloni M, Huang CY, Martin T 3rd, Damon L, Andreadis CB. Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):246-256.e2. doi: 10.1016/j.clml.2020.11.005. Epub 2020 Nov 11.

• Responsible Party: Gilead Sciences ( Kite, A Gilead Company )
• ClinicalTrials.gov Identifier: NCT03391466
• Other Study ID Numbers: KTE-C19-107; 2017-002261-22 ( EudraCT Number )
• First Submitted: December 21, 2017
• First Posted: January 5, 2018
• Results First Submitted: December 20, 2023
• Results First Posted: March 7, 2024
• Last Update Posted: March 7, 2024