Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. III: anti-CD19 CAR-T cell therapy for patients with nonHodgkin lymphoma

Alencar, Alvaro J; Hirayama, Alexandre V; Clé, Diego V; Salvino, Marco Auré; Perini, Guilherme; Arrais, Celso; Baiocchi, Otávio; Palma, Leonardo Carvalho; Colturato, Iago; Vaz, Jorge; Chiattone, Ricardo; Lima, Marcos de; Schmidt Filho, Jayr; Nabhan, Samir; Rocha, Vanderson; Guerino-Cunha, Renato L; Chiattone, Carlos S

doi:10.1016/j.htct.2021.09.003

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Hematology, Transfusion and Cell Therapy

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Special article • Hematol., Transfus. Cell Ther. 43 (suppl 2) • 2021 • https://doi.org/10.1016/j.htct.2021.09.003 copy

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. III: anti-CD19 CAR-T cell therapy for patients with nonHodgkin lymphoma

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

The treatment and evolution of B-cell non-Hodgkin lymphoma (B-NHL) has undergone important changes in the last years with the emergence of targeted therapies, such as monoclonal antibodies, small molecules, antibody-drug conjugates, and bispecific antibodies. Nevertheless, a significant portion of patients remains refractory or relapsed (R/R) to the new therapeutic modalities, representing thus an unmet medical need. The use of CAR-T cells for the treatment of B-NHL patients has shown to be a promising therapy with impressive results in patients with R/R disease. The expectations are as high as the imminent approval of CAR-T cell therapy in Brazil, which it is expected to impact the prognosis of R/R B-NHL. The aim of this manuscript is to offer a consensus of specialists in the field of onco-hematology and cellular therapy, working in Brazil and United States, in order to discuss and offer recommendations in the present setting of the use of CAR-T cells for patients with B-NHL.

Keywords:
Cellular therapy; CAR-T cells; Immunotherapy; Adoptive cellular therapy; Advanced cellular therapy; Non-Hodgkin lymphoma

Study	ZUMA-1 (13)	JULIET(10)	TRANSCEND (12)	ZUMA-2(16)	ZUMA-5(17)
Indication	DLBCL	DLBCL	DLBCL	MCL	FL (grade 1-3A)
	PMBCL	TFL	PMBCL		MZ
	TFL	HGBCL	TFL
	HGBCL		HGBCL
	At least 2 prior treatment lines	At least 2 prior treatment lines	At least 2 prior treatment lines	Up to 5 prior treatment lines	At least 2 prior treatment lines
Main inclusion criteria	ECOG 0-1	ECOG 0-1	ECOG 0-2	ECOG 0-1	ECOG 0-1
	ANC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 1000/uL	ANC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 1000/uL	No minimal counts	ANC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 1000/uL	ANC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 1000/uL
	ALC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 100/uL	ALC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 300/uL		ALC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 100/uL	ALC³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 100/uL
	Platelet count 75,000/uL	Platelet count³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 50,000/uL		Platelet count³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 75,000/uL	Platelet count³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 75,000/uL
	CrCl³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 60 mL/min	CrCl³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 60 mL/min		CrCl³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 60 mL/min	CrCl³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 60 mL/min
			CrCl> 30 mL/min
	EF³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 50% with no pericardial effusion	EF³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 45%		EF³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 50% with no pericardial effusion	EF³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 50% with no pericardial effusion
			EF³3 Perry AM, Diebold J, Nathwani BN, MacLennan KA, M€uller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non- Hodgkin Lymphoma Classification Project. Haematologica. 2016;101(10):1244-50. [Internet][cited 2021 Jul 19]. Available from: https://pubmed.ncbi.nlm.nih.gov/27354024/ https://pubmed.ncbi.nlm.nih.gov/27354024... 40%
	No clinically significant pleural effusion			No clinically significant pleural effusion	No clinically significant pleural effusion
	O2 sat >92% at room air			O2 sat >92% at room air	O2 sat >92% at room air
		O2 sat >91% at room air
			O2 sat >92% at room air
Main exclusion Criteria	No prior allo transplant	No prior allo transplant	Exclusive CNS involvement	No prior allo transplant	No prior allo transplant
	No active or history of CNS involvement	No active CNS involvement		No active or history of CNS involvement	No auto transplant within 6 months
		No PMBCL			No active or history of CNS involvement
Bridging allowed	NO	YES	YES	YES	NO
Manufacturing failure, n (%)	1 (1)	12 (7)	2 (1)
Complete response rate (%)	58^¶/54^#	40	53	67 12-mo: 61 (for pts in CR)	76 12-mo: 74 (for pts in CR)
PFS estimate (%)	24-mo: 72	12-mo: 83 (for pts in CR/PR at 3 mo)	12-mo: 65
PFS estimate (%)	(for pts in CR at 3 mo)	12-mo: 83 (for pts in CR/PR at 3 mo)	(for pts in CR)
OS estimate (%)	24-mo: 50.5	12-mo: 49	12-mo: 57.9	12-mo: 83	12-mo: 93
CRS any grade/ grade ≥ 3, n (%)	94 (93)/ 13 (13)	64 (58)/ 24 (22)	113 (42)/ 6 (2)	62 (91) / 10 (15)	- / - (7)
Neurologic events any grade/ grade ≥ 3, n (%)	65 (64)/ 28 (28)	23 (21)/ 13 (12)	80 (30)/ 27 (10)	43 (63) / 21 (31) 42 (70)	- / - (19)
Tocilizumab use (%)	45 (29)	14 (10)	18 (10)

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH) R. Dr. Diogo de Faria, 775 cj 133, 04037-002, São Paulo / SP - Brasil - São Paulo - SP - Brazil
E-mail: htct@abhh.org.br

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[1] * Corresponding author at: Departamento de Clínica Médica da Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil. E-mail address: carlos.chiattone@terra.com.br (C.S. Chiattone).