Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia

Seber, Adriana; Castro Junior, Claudio Galvãode de; Kerbauy, Lucila N; Hirayama, Alexandre V; Bonfim, Carmem; Fernandes, Juliana Folloni; Souza, Mair; Schafell, Rony; Nabhan, Samir; Loggetto, Sandra Regina; Simões, Belinda Pinto; Rocha, Vanderson; Lima, Marcos de; Guerino-Cunha, Renato L; Bittencourt, Henrique

doi:10.1016/j.htct.2021.09.002

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Special article • Hematol., Transfus. Cell Ther. 43 (suppl 2) • 2021 • https://doi.org/10.1016/j.htct.2021.09.002 copy

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapeutic modality for acute lymphoblastic leukemia (ALL) with robust outcomes in patients with refractory or relapsed disease. At the same time, CAR-T cell therapy is associated with unique and potentially fatal toxicities, such as cytokine release syndrome (CRS) and neurological toxicities (ICANS). This manuscript aims to provide a consensus of specialists in the fields of Hema- tology Oncology and Cellular Therapy to make recommendations on the current scenario of the use of CAR-T cells in patients with ALL.

Keywords:
Cellular therapy; Car-T cells; Immunotherapy; Adoptive cellular therapy; Advanced cellular therapy; Acute lymphoblastic leukemia; Acute lymphoid leukemia

Pre-apheresis evaluation/selection of patients	Post-apheresis evaluation/selection of patients and prior to lymphodepletion	Evaluation/selection of patients prior to the CAR-T cell infusion and post-lymphodepletion
- Confirmation of the presence of the CD19 antigen on the lymphoblasts - attention to the prior use of blinatumomab. - Minimum necessary serology: hepatitis B and C and HIV. - Patients with active infection are not eligible to receive CD19 CAR-T therapy. - Absence of active bacterial, fungal or viral infection. - Minimal lymphocyte count: - total lymphocytes > 500/mm3 and CD3 > 150/mm3. - A low number of blood CD3 usually make various apheresis procedures necessary. - In patients who underwent allogeneic transplant, a minimum 12-week interval should be respected between the transplant and the apheresis. It is important not to have active acute or chronic host versus graft disease at the moment of apheresis and already suspended immunosuppressants, two weeks of calcineurin inhibitors cyclosporine/tacrolimus and one week of corticoid. - The minimum washout period is variable and is recommended prior to the apheresis for the following therapies: - 1-day intrathecal cytarabine - 3-day short action anti proliferative (ex. hydroxyurea) - 5-day short action growth factors (ex. G-CSF) and nilotinib - 7-day intrathecal methotrexate and cytarabine in doses < 100 mg/m² - 14-day systemic chemotherapy and, in general, long-action growth factors, imatinib, dasatinib, ponatinib and blinatumomab. - 12-week fludarabine and bendamustine - 4-week PEG-asparaginase and DLI - 8-week clofarabine and cranial radiotherapy - mínimum of 8 weeks of lytic agents, such as ATG and campath. Some manufacturers suggest a longer washout (6 months) to be discussed case by case by the manufacturer's medical team, if a smaller interval is possible - 12-week fludarabine and bendamustine - 6-month ATG or alemtuzumab. It is suggested to make contact with the CAR-T manufacturer to define if a shorter interval than this is possible. - A minimally adequate function of the kidneys, liver, heart and lungs are indicated for the performance of apheresis. The patient must be previously evaluated by the apheresis team. An evaluation of the venous access is fundamental. In case of peripheral access in adults and most pediatric patients, the use of a central catheter of the dialysis type is recommended. - It is important to verify that the patient is not pregnant and that that patient agrees to follow the effective contraception following the CAR-T cell infusion. Conception is not recommended following the CAR-T cell infusion, as the risk for the child is unknown.	Evaluation of the ALL status (bone marrow tap and lumbar tap). The high tumor load increases the chance of CRS and ICANS - Evaluation of the presence of active bacterial, fungal or viral infection. In case of active infection, it is important to weigh the risk and the benefit of initiating chemotherapy before complete control. - Evaluation of the presence of new toxicities of target organs which might impact the capacity of the patient to receive chemotherapy (or subsequent CAR-T infusion). - Evaluation of the presence of acute or chronic GVHD which might have been reactivated following the apheresis. - Central venous access with at least a two-way port. - Vaccines with live vírus should be avoided in the 6 weeks preceding the lymphodepletion. - It is recommended to request from the patient or legal guardian prior to initiating lymphodepletion a consent term informing the risks of serious complications associated with the treatment. -	Evaluation of the presence of rapidly progressive disease on the days preceding the infusion, as this increases the risk for CRS and the failure of the treatment. - Absence of active bacterial, fungal or viral infection If there is active infection, the infusion should be postponed and the patient should receive complete treatment for the infection. The presence of active infection at the moment of the CAR-T infusion increases significantly the risk for CRS. - Absence of active GVHD - acute, grades II - IV, and extensively chronic. - Exclusion of the presence of gestation - Evaluation of the presence of new toxicities in target organs which may impact the patient capacity to receive the CAR-T infusion. Special attention to the necessity for oxygen supplementation prior to the infusion and the presence of uncontrolled arrhythmias. - A minimum and variable washout period is recommended prior to the CAR-T infusion for the following therapies: - 3-day short-action proliferative agents (ex. hydroxyurea), tyrosine-kinase inhibitors and corticosteroids at a therapeutic dose. The use of hydrocortisone replacement or an equivalent at a dose less than 12mg/m²/day is permitted. The prescription of steroids for the management of adverse reactions during and following the CAR-T infusion. - 5-day short-action growth factors (ex. G-CSF) and nilotinib - 7-day vincristine, 6-MP, 6-TG, methotrexate (< 25mg/m²), cytarabine (< 100mg/m²), non-pegylated asparaginase, intrathecal chemotherapy (methotrexate, cytarabine) - 14-day Other systemic chemotherapies, such as clofarabine, methotrexate (> 25mg/m²), cytarabine (> 100mg/m2) and Other agents (except those used in the lymphodepletion) and radiotherapy for sites beyond the central nervous system. - 4-week PEG-asparaginase or immunosuppressants used in the treatment of GVHD. This last restriction is mainly to ensure that there be no relapse of GVHD prior to the CAR-T infusion. - 6-week infusion of lymphocytes from the donor (DLI) - 8-week cranial radiotherapy and lytic agents for T-cells, such as ATG and alemtuzumab - Contact with the intensive therapy team. - Verify with the pharmacy the availability of at least two doses of tocilizumab reserved for the patient for treatment of CRS

CAR-T: chimeric antigen receptor T cells, ALL: acute lymphoblastic leukemia, CRS: cytokine release syndrome, ICANS: immune effector cell-associated neurotoxicity syndrome, GVHD: graft versus host disease, DLI: donor lymphocyte infusion, G-CSF: granulocyte colony-stimulating factor, 6-MP: 6-mercaptopurine, 6-TG: 6-thioguanine, ATG: anti-thymocyte globulin

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Table based on references:¹⁰10 Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bitten- court H, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378 (5):439-48.¹⁸18 Pillai V, Muralidharan K, Meng W, Bagashev A, Oldridge DA, Rosenthal J, et al. CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumo- mab therapy. Blood Adv. 2019;3(22):3539-49.¹⁹19 Dourthe ME, Rabian F, Yakouben K, Chevillon F, Cabannes- Hamy A, Méchinaud F, et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia. 2021 May 17. https://doi.org/10.1038/s41375-021-01281-7. [Epub ahead of print].
https://doi.org/10.1038/s41375-021-01281... ²²22 McGuirk J, Waller EK, Qayed M, Abhyankar S, Ericson S, Hol- man P, et al. Building blocks for institutional preparation of CTL019 delivery. Cytotherapy. 2017 Sep;19(9):1015-24.

23 Korell F, Laier S, Sauer S, Veelken K, Hennemann H, Schubert ML, et al. Current challenges in providing good leukapheresis products for manufacturing of CAR-T cells for patients with relapsed/refractory NHL or ALL. Cells. 2020 May 15;9(5):1225.

24 Mahadeo KM, Khazal SJ, Abdel-Azim H, Fitzgerald JC, Tarase- viciute A, Bollard CM, et al. Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Management guide- lines for paediatric patients receiving chimeric antigen recep- tor T cell therapy. Nat Rev Clin Oncol. 2019;16(1):45-63. https://doi.org/10.1038/s41571-018-0075-2
https://doi.org/10.1038/s41571-018-0075-...

25 Kansagra AJ, Frey NV, Bar M, Laetsch TW, Carpenter PA, Savani BN, et al. Clinical utilization of chimeric antigen receptor T cells in B cell acute lymphoblastic leukemia: an expert opinion from the european society for blood and marrow transplanta- tion and the American Society for Blood and Marrow Trans- plantation. Bone Marrow Transplant. 2019;54(11):1868-80.²⁶26 Los-Arcos I, Iacoboni G, Aguilar-Guisado M, Alsina-Manrique L, Díaz de Heredia C, Fortuny-Guasch C, et al. Recommenda- tions for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T- cell therapy: a position paper. Infection. 2021 Apr;49(2):215-31..

Author, year, clinical trial	Population	Construct	N	Lympho-depletion	CR and CR with negative MRD	Outcome	Relapse	CD19 negative relapse	Allogeneic HSCT following the CAR-T	Observation
Maude SL⁵⁰50 Maude SL. Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children with relapsed ALL. Maude SL, Barret DM, Rheingold SR, Aplenc R, Teachy DT eat al. ASCO 2016 abstract 3007. ASCO 2016 Philadelphia UPenn	Pediatric	FMC63-4-1BB-z	59	Cy 43% Flu Cy	55/59 (93%) 88%	12 months SLD - 55% SG - 79%	36% (20/55)	24% (13/55)
Maude SL¹⁰10 Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bitten- court H, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378 (5):439-48. NEJM 2018 ELIANA trial Fase II	Pediatric AYA	FMC63-4-1BB-z	92 (75)	Flu Cy	61/75 (81%) 81%	12 months SLD - 50% SG - 76%	33% (20/61)	25% (15/61)	8/75	61% previous HSCT
Lee DW⁵¹51 Lee DW, Kochendorfer JN, Settler-Stevenson M, Cui YK, Del- brook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in chil- dren and young adults: a phase 1 dose-escalation trial. Lancet. 2015 Feb 7;385(9967):517-28. Lancet 2015/ Blood 2016⁵²52 Lee DW. Long-term outcomes following CD19 CAR T cell ther- apy for B-ALL are superior in patients receiving a fludarabine/ cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood. 2016;128 (22):218. Abstract ASH 2016. NCI Phase II	Pediatric AYA	FMC63-CD28-z	51	Flu Cy	31/51 (60,8%) 28/31 (90%)	18 months SLD - 49,5%	29% (8/28)	18% (5/25)	21/28	Significant improvement in survival with HSCT (= 0.0006)
Gardner RA²⁹29 Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322-31., Blood 2017 Seattle Fase I	Pediatric AYA	FMC63-4-1BB-z	45	Flu Cy	40/45 89%	12 months SLE - 50.8% SG - 69.5%	45% (18/40)	18% (7/40)	11/40	62% previous HSCT
Pasquini MC¹⁴14 Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4(21):5414-24., Blood Adv 2020	Pediatric AYA	FMC63-4-1BB-z	255	Flu Cy	85,5% 115/116	12 months SLE - 52.4% SG - 77.2%	-	NA	34/218	27.8% previous HSCT
Hay KA⁴⁶46 Hay KA, Gauthier J, Hirayama AV, Voutsinas JM, Wu Q, Li D, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019 Apr 11;133(15):1652-63. https://doi.org/10.1182/blood-2018-11-883710 https://doi.org/10.1182/blood-2018-11-88... , Blood 2019 Fred Hutchinson Fase I	Adult	FMC63-4-1bb-z	53	79% Flu Cy	45/53 (85%) 100%	SG - 20 months SLE -7.6 months	31% (9/29)*	7% (2/29)*	18/45	43 % previous HSCT
Park JH²⁷27 Park JH, Riviere I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lym- phoblastic leukemia. N Engl J Med. 2018;378(5):449-59., NEJM 2018 Memorial Sloan-Kettering Fase I	Adult	SJ25C1-CD28-z	53	Flu Cy	44/53 (83%) 32/48 (67%)	SG-12.9 months SLE-6.1 months	57% (25/44)	9% (4/44)	17/44	36% previous HSCT
Pan J et al⁵³53 Pan J, Yang JF, Deng BP, Zhao XJ, Zhang X, Lin YH, et al. High efficacy and safety of low-dose CD19-directed CAR-T cell ther- apy in 51 refractory or relapsed B acute lymphoblastic leuke- mia patients. Leukemia. 2017 Dec;31(12):2587-93., Leukemia 2017	Adult and pediatric	4-1BB-z	42 9	Flucy	36/40 (90%) 34/40 (85%)		11/45 2 after HSCT	NA	27/45
Frey NV⁵⁴54 Frey NV, Shaw PA, Hexner EO, Pequignot E, Gill S, Luger SM, et al. Optimizing chimeric antigen receptor T-Cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol. 2020 Feb 10;38(5):415-22., JCO 2020 UPenn	Adult	FMC63-4-1BB-z	35	25 somente Cy	24/35 (69%) 19 DRM -	SG - 19,5 months SLE - 5.6 months		NA	9/24	37% previous HSCT
Gu R et al⁵⁵55 Gu R, Liu F, Zou D. Efficacy and safety of CD19 CAR T con- structed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia. J Hematol Oncol. 2020;122. https://doi.org/10.1186/s13045-020-00953-8 https://doi.org/10.1186/s13045-020-00953... , BMC 2020	Pediatric and adult	HI19α-4-1BB-ζ	22	Flu Cy	82% 18/18 100%	SLD - 6.9 months SG - 12.9 months	8/18	3/8
Zhang X et al.⁵⁶56 Zhang X, Lu X-a, Yang J, Zhang G, Li J, Song L, et al. Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B- cell acute lymphoblastic leukemia with high-risk features. Blood Advances. 2020 May 26;4(10):2325-38. https://doi.org/10.1182/bloodadvances.2020001466.2020 . https://doi.org/10.1182/bloodadvances.20... , Blood Adv 2020	Pediatric and adult	89 - 4-1BB-z 21 - CD28-z	110	Flu Cy	92.7% 87.3%	SG: (HSCT vs. not) 79.1% vs. 32.0% SLD: (HSCT vs. not) 76.9% vs. 11.6%;	23/110	7/23	75/102	16/110 previous HSCT Significant improvement in survival with allogeneic HSCT
Shah BD¹⁷17 Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassa- day RD, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single- arm, open-label, multicentre ZUMA-3 study.Lancet. 2021;398 (10299):491-502., Lancet 2021 ZUMA-3	Adult		55	Flu Cy	39 (71%) 38/39 (99%)	12 months SG - 71% 6 months SLD - 58%	12/39		12/39	42% previous HSCT
Shah N⁵⁷57 Shah NN, Lee DW, Yates B, Yuan CM, Shalabi H, Martin S, et al. Long-term follow-Up of CD19-CAR T-cell therapy in children and young adults with B-ALL. J Clin Oncol. 2021 May 20;39 (15):1650-9. https://doi.org/10.1200/JCO.20.02262 Epub 2021 Mar 25. PMID: 33764809; PMCID: PMC8274806. https://doi.org/10.1200/JCO.20.02262... , JCO 2021 Fase I	Pediatric and Adult	28ζ	50	Flu-Cy and others	62% 90.3%	4.8 years SG - 10.5 months	9.5% after HSCT		75%	SLE 5 years after HSCT - 62%

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[1] * Corresponding author at: Departamento de Imagens Médicas, Hematologia e Oncologia Clínica da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Rua Tenente Catão Roxo, 2501, Vila Monte Alegre, Ribeirão Preto, SP, Brazil. E-mail address: rlgc@usp.br (R.L. Guerino-Cunha).