Table 2. Subsequent malignancies of... | American Society of Hematology

Table 2.

Subsequent malignancies of T-cell origin reported after axi-cel

Patient	Patient information			T-cell malignancy
Patient	Age, y	Reported indication for CAR T-cell therapy	Prior lines of therapy, n	Preferred term	Time to onset from axi-cel infusion, mo	Event outcome as reported (survival status)∗
1	68	DLBCL	Not reported	T-cell lymphoma	1.9	Fatal
2	29	Large cell lymphoma	2	Lymphoproliferative disorder	6.7	Not resolved (alive at last follow-up 3.7 y after event onset date)
2	29	Large cell lymphoma	2	Lymphocytic leukemia	6.7	Not reported
3†	62	DLBCL	2	Large granular lymphocytosis	18.9	Not resolved (alive at last follow-up 3.0 y after event onset date)
4	63	DLBCL	5	Large granular lymphocytosis	15.4	Not reported (alive at last follow-up 3.6 y after event onset date)
5	59	DLBCL	2	T-cell lymphoma	19.6	Not resolved (survival status unknown)
6	59	DLBCL	2	Lymphoproliferative disorder	8.9	Resolving (survival status unknown)
7	80	TFL	4	T-cell lymphoma	30	Not reported (survival status unknown)
8‡	63	DLBCL	1	Large granular lymphocytosis	58.5	Not resolved (alive at last follow-up 9.5 mo after event onset date)
9	30	Unknown indication§	1	T-cell lymphoma	<7\|\|	Not resolved (survival status unknown)
10	68	DLBCL	3	Angioimmunoblastic T-cell lymphoma	37.6	Fatal
11	64	B-cell lymphoma	2	T-cell lymphoma	3	Not reported (death due to non–small cell lung cancer)
12	59	Large B-cell lymphoma	2	T-cell lymphoma	1.8	Fatal
13†	62	DLBCL	2	Large granular lymphocytosis	18.9	Not resolved (alive at last follow-up 3.0 y after event onset date)

Patient	Patient information			T-cell malignancy
Patient	Age, y	Reported indication for CAR T-cell therapy	Prior lines of therapy, n	Preferred term	Time to onset from axi-cel infusion, mo	Event outcome as reported (survival status)∗
1	68	DLBCL	Not reported	T-cell lymphoma	1.9	Fatal
2	29	Large cell lymphoma	2	Lymphoproliferative disorder	6.7	Not resolved (alive at last follow-up 3.7 y after event onset date)
2	29	Large cell lymphoma	2	Lymphocytic leukemia	6.7	Not reported
3†	62	DLBCL	2	Large granular lymphocytosis	18.9	Not resolved (alive at last follow-up 3.0 y after event onset date)
4	63	DLBCL	5	Large granular lymphocytosis	15.4	Not reported (alive at last follow-up 3.6 y after event onset date)
5	59	DLBCL	2	T-cell lymphoma	19.6	Not resolved (survival status unknown)
6	59	DLBCL	2	Lymphoproliferative disorder	8.9	Resolving (survival status unknown)
7	80	TFL	4	T-cell lymphoma	30	Not reported (survival status unknown)
8‡	63	DLBCL	1	Large granular lymphocytosis	58.5	Not resolved (alive at last follow-up 9.5 mo after event onset date)
9	30	Unknown indication§	1	T-cell lymphoma	<7\|\|	Not resolved (survival status unknown)
10	68	DLBCL	3	Angioimmunoblastic T-cell lymphoma	37.6	Fatal
11	64	B-cell lymphoma	2	T-cell lymphoma	3	Not reported (death due to non–small cell lung cancer)
12	59	Large B-cell lymphoma	2	T-cell lymphoma	1.8	Fatal
13†	62	DLBCL	2	Large granular lymphocytosis	18.9	Not resolved (alive at last follow-up 3.0 y after event onset date)

Molecular analysis results
Patient	T-cell malignancy	Tumor sample received by Kite	Method for transgene testing	Sample test result details	Assessment
1	T-cell lymphoma	Not received	N/A	N/A	N/A
2	Lymphoproliferative disorder/lymphocytic leukemia	Not received	N/A	N/A	N/A
3†	Large granular lymphocytosis	Not received	N/A	N/A	N/A
4	Large granular lymphocytosis	Not received	N/A	N/A	N/A
5	T-cell lymphoma	PB and BM aspirate	ddPCR for CAR transgene in blood; flow cytometric analysis of CAR T cells from BM aspirate	CD19 CAR transgene was detectable at low levels in the diagnostic BM aspirate by flow cytometry, at the lower limit of detection, and at low levels in peripheral blood samples by ddPCR; neither frequency of CAR-positive cells nor levels of CAR transgene indicated a pronounced CAR T-cell presence above the limit of detection. Disease involvement was restricted to BM. Combined with the lack of T lymphoblasts detected in the BM diagnostic sample, these data did not indicate presence of CAR-positive cells outside the normal immune cell repertoire.	Molecular analysis results do not support causality
6	Lymphoproliferative disorder	Not received	N/A	N/A	N/A
7	T-cell lymphoma	Not received	N/A	N/A	N/A
8‡	Large granular lymphocytosis	PB and BM biopsy (FFPE)	ddPCR for CAR transgene in blood and BM; qPCR for RCR in blood	CD19 CAR transgene was detected near the lower limit of quantification by ddPCR in the blood, and the CAR transgene was not detected by ddPCR in a diagnostic BM biopsy. RCR was undetected in blood	Molecular analysis results do not support causality
9	T-cell lymphoma	Not received	N/A	N/A	N/A
10	Angioimmunoblastic T-cell lymphoma	Not received	N/A	N/A	N/A
11	T-cell lymphoma	Not received; analysis performed by primary medical team	qPCR for CAR transgene	Molecular testing performed was previously reported.⁵ The lymph node tumor was reported to have 8 CAR transgene copies per microgram of DNA by qPCR, corresponding to 0.005% of cells analyzed. The reporter concluded that the very low level of CAR signal was more likely to be due to infiltrating CAR T cells than the TCL harboring the CAR transgene. The T-cell population from which the neoplastic T-cell clone arose was preexisting and present at the time of axi-cel infusion and, likely, at the time of apheresis (day −28).	Molecular analysis results do not support causality
12	T-cell lymphoma	Not received; analysis performed by primary medical team	Peripheral blood:flow cytometry and qPCR for CAR transgene, BCR clonoSEQ (ctDNA), CAPP-seq (ctDNA), TCR-seq (ctDNA), and EBV titer. BM-derived TCL: qPCR for CAR transgene, CAR vector capture sequencing, CAPP-seq, scRNA-seq, scDNA-seq DLBCL: CAPP-seq	Deep molecular characterization of the EBV⁺ TCL at the bulk and single-cell level with longitudinal analysis in blood and original DLBCL. Bulk flow cytometric analysis of the TCL demonstrated absence of CAR-positive T cells. qPCR of the TCL showed CAR transgene is below the limit of detection; vector capture sequencing also showed absence of CAR transgene. Results at the single-cell level demonstrated no CAR transgene RNA expression or DNA integration in the TCL cells. Dominant TCRβ clone in TCL was detectable in LN DLBCL and blood before axi-cel infusion. EBV expression and clonal hematopoiesis DNMT3A and TET2 mutations detected at high frequency (91.4%) in the TCL also preexisted in the DLBCL tumor before CAR infusion.⁶	Molecular analysis results do not support causality
13†	Large granular lymphocytosis	Not received; analysis performed by primary medical team	Flow cytometric analysis of CAR frequency in BM	A preliminary report of the case was described.⁷ CAR positivity in the peripheral blood of a patient harboring a population of TCRγ rearranged, potentially oligoclonal T granular lymphocytes. Approximately, 1%-2% CD8⁺CD57⁺CAR T cells were detected among total viable blood cells by flow cytometry. Clear identification of T-LGL cells was not established because limited markers (CD3, CD8, CD57 and CD5) were available to demarcate the T-LGL cells and distinguish from normal persisting CAR T-cell presence in the BM.	Insufficient molecular analysis to determine relation to CAR

Molecular analysis results
Patient	T-cell malignancy	Tumor sample received by Kite	Method for transgene testing	Sample test result details	Assessment
1	T-cell lymphoma	Not received	N/A	N/A	N/A
2	Lymphoproliferative disorder/lymphocytic leukemia	Not received	N/A	N/A	N/A
3†	Large granular lymphocytosis	Not received	N/A	N/A	N/A
4	Large granular lymphocytosis	Not received	N/A	N/A	N/A
5	T-cell lymphoma	PB and BM aspirate	ddPCR for CAR transgene in blood; flow cytometric analysis of CAR T cells from BM aspirate	CD19 CAR transgene was detectable at low levels in the diagnostic BM aspirate by flow cytometry, at the lower limit of detection, and at low levels in peripheral blood samples by ddPCR; neither frequency of CAR-positive cells nor levels of CAR transgene indicated a pronounced CAR T-cell presence above the limit of detection. Disease involvement was restricted to BM. Combined with the lack of T lymphoblasts detected in the BM diagnostic sample, these data did not indicate presence of CAR-positive cells outside the normal immune cell repertoire.	Molecular analysis results do not support causality
6	Lymphoproliferative disorder	Not received	N/A	N/A	N/A
7	T-cell lymphoma	Not received	N/A	N/A	N/A
8‡	Large granular lymphocytosis	PB and BM biopsy (FFPE)	ddPCR for CAR transgene in blood and BM; qPCR for RCR in blood	CD19 CAR transgene was detected near the lower limit of quantification by ddPCR in the blood, and the CAR transgene was not detected by ddPCR in a diagnostic BM biopsy. RCR was undetected in blood	Molecular analysis results do not support causality
9	T-cell lymphoma	Not received	N/A	N/A	N/A
10	Angioimmunoblastic T-cell lymphoma	Not received	N/A	N/A	N/A
11	T-cell lymphoma	Not received; analysis performed by primary medical team	qPCR for CAR transgene	Molecular testing performed was previously reported.⁵ The lymph node tumor was reported to have 8 CAR transgene copies per microgram of DNA by qPCR, corresponding to 0.005% of cells analyzed. The reporter concluded that the very low level of CAR signal was more likely to be due to infiltrating CAR T cells than the TCL harboring the CAR transgene. The T-cell population from which the neoplastic T-cell clone arose was preexisting and present at the time of axi-cel infusion and, likely, at the time of apheresis (day −28).	Molecular analysis results do not support causality
12	T-cell lymphoma	Not received; analysis performed by primary medical team	Peripheral blood:flow cytometry and qPCR for CAR transgene, BCR clonoSEQ (ctDNA), CAPP-seq (ctDNA), TCR-seq (ctDNA), and EBV titer. BM-derived TCL: qPCR for CAR transgene, CAR vector capture sequencing, CAPP-seq, scRNA-seq, scDNA-seq DLBCL: CAPP-seq	Deep molecular characterization of the EBV⁺ TCL at the bulk and single-cell level with longitudinal analysis in blood and original DLBCL. Bulk flow cytometric analysis of the TCL demonstrated absence of CAR-positive T cells. qPCR of the TCL showed CAR transgene is below the limit of detection; vector capture sequencing also showed absence of CAR transgene. Results at the single-cell level demonstrated no CAR transgene RNA expression or DNA integration in the TCL cells. Dominant TCRβ clone in TCL was detectable in LN DLBCL and blood before axi-cel infusion. EBV expression and clonal hematopoiesis DNMT3A and TET2 mutations detected at high frequency (91.4%) in the TCL also preexisted in the DLBCL tumor before CAR infusion.⁶	Molecular analysis results do not support causality
13†	Large granular lymphocytosis	Not received; analysis performed by primary medical team	Flow cytometric analysis of CAR frequency in BM	A preliminary report of the case was described.⁷ CAR positivity in the peripheral blood of a patient harboring a population of TCRγ rearranged, potentially oligoclonal T granular lymphocytes. Approximately, 1%-2% CD8⁺CD57⁺CAR T cells were detected among total viable blood cells by flow cytometry. Clear identification of T-LGL cells was not established because limited markers (CD3, CD8, CD57 and CD5) were available to demarcate the T-LGL cells and distinguish from normal persisting CAR T-cell presence in the BM.	Insufficient molecular analysis to determine relation to CAR

BCR, B-cell receptor; BM, bone marrow; CAPP-seq, cancer personalized profiling by deep sequencing; ctDNA, circulating tumor DNA; ddPCR, droplet digital polymerase chain reaction; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FFPE, formalin-fixed paraffin-embedded; LN, lymph node; N/A, not applicable; PB, peripheral blood; qPCR, quantitative polymerase chain reaction; RCR, replication-competent retrovirus; scDNA-seq, single-cell DNA sequencing; scRNA-seq, single-cell RNA sequencing; TCL, T-cell lymphoma; TCR, T-cell receptor; TCR-seq, T-cell receptor sequencing; TFL, transformed follicular lymphoma; T-LGL, T-cell large granular lymphocytosis.

∗

Event outcome and survival status was reported with Global Safety Database case information as of 23 April 2024, after the cumulative review on 5 March 2024.

†

After the review of the Global Safety Database cases, case 3 was determined to be a duplicate of case 13 and the cases were merged.

‡

Patient was enrolled in the ZUMA-7 clinical trial (ClinicalTrials.gov identifier: NCT03391466) and the T-cell malignancy event occurred after the data cutoff date of the primary overall survival analysis.²

A follow-up to the case reported: “The initial diagnosis of DLBCL might not be accurate. The indication and current condition of B-cell lymphoma was removed (pending clarification).” As of 23 April 2024, Kite has not received clarification regarding the indication.

Specifically reported as shortly after axi-cel infusion. The time from infusion to the case reported to the Gilead Global Safety Database was within 7 months.

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