Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
02
07
2021
accepted:
10
11
2021
pubmed:
19
12
2021
medline:
27
4
2022
entrez:
18
12
2021
Statut:
ppublish
Résumé
Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.
Identifiants
pubmed: 34921238
doi: 10.1038/s41591-021-01622-0
pii: 10.1038/s41591-021-01622-0
doi:
Substances chimiques
Antigens, CD19
0
Receptors, Antigen, T-Cell
0
tisagenlecleucel
Q6C9WHR03O
Banques de données
ClinicalTrials.gov
['NCT03568461']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
325-332Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Swerdlow, S. H. et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127, 2375–2390 (2016).
pubmed: 26980727
pmcid: 4874220
Marcus, R. et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N. Engl. J. Med. 377, 1331–1344 (2017).
doi: 10.1056/NEJMoa1614598
pubmed: 28976863
Lansigan, F. et al. The prognostic significance of PFS24 in follicular lymphoma following firstline immunotherapy: a combined analysis of 3 CALGB trials. Cancer Med. 8, 165–173 (2019).
doi: 10.1002/cam4.1918
pubmed: 30575311
Salles, G. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377, 42–51 (2011).
doi: 10.1016/S0140-6736(10)62175-7
pubmed: 21176949
Rivas‐Delgado, A. et al. Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era. Br. J. Haematol. 184, 753–759 (2019).
doi: 10.1111/bjh.15708
pubmed: 30515755
Link, B. K. et al. Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. Br. J. Haematol. 184, 660–663 (2019).
doi: 10.1111/bjh.15149
pubmed: 29611177
Casulo, C. et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J. Clin. Oncol. 33, 2516–2522 (2015).
doi: 10.1200/JCO.2014.59.7534
pmcid: 4879714
Sarkozy, C. et al. Cause of death in follicular lymphoma in the first decade of the rituximab era: a pooled analysis of French and US cohorts. J. Clin. Oncol. 37, 144–152 (2019).
doi: 10.1200/JCO.18.00400
pubmed: 30481079
Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).
doi: 10.1056/NEJMoa1314583
pubmed: 24450858
pmcid: 4039496
Salles, G. et al. Efficacy and safety of idelalisib in patients with relapsed, rituximab-and alkylating agent-refractory follicular lymphoma: a subgroup analysis of a phase 2 study. Haematologica 102, e156–e159 (2017).
doi: 10.3324/haematol.2016.151738
pubmed: 27979923
pmcid: 5395130
Dreyling, M. et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J. Clin. Oncol. 35, 3898–3905 (2017).
doi: 10.1200/JCO.2017.75.4648
pubmed: 28976790
Zinzani, P. L. et al. DYNAMO: A phase 2 study demonstrating the clinical activity of duvelisib in patients with double-refractory follicular lymphoma. https://library.ehaweb.org/eha/2017/22nd/182064/pier.luigi.zinzani.dynamo.a.phase.2.study.demonstrating.the.clinical.activity.html (2017).
Ukoniq; https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213176Orig1s000,%20213176Orig2s000ltr.pdf (2021).
US Food and Drug Administration. FDA approves lenalidomide for follicular and marginal zone lymphoma. May 2019; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenalidomide-follicular-and-marginal-zone-lymphoma#:~:text=On%20May%2028%2C%202019%2C%20the,marginal%20zone%20lymphoma%20(MZL) (2021).
Leonard, J. P. et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J. Clin. Oncol. 37, 1188–1199 (2019).
pubmed: 30897038
pmcid: 7035866
Rummel, M. J. et al. MAGNIFY: phase IIIb interim analysis of induction lenalidomide + rituximab (R2) followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. In 25th Congress of the European Hematology Association (EHA) Poster EP1161 (2020).
Bodor, C. et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 122, 3165–3168 (2013).
doi: 10.1182/blood-2013-04-496893
pubmed: 24052547
pmcid: 3814734
Morschhauser, F. et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 21, 1433–1442 (2020).
doi: 10.1016/S1470-2045(20)30441-1
pubmed: 33035457
pmcid: 8427481
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
doi: 10.1056/NEJMoa1709866
pubmed: 29385370
pmcid: 5996391
Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).
doi: 10.1056/NEJMoa1804980
pubmed: 30501490
US Food and Drug Administration. FDA grants accelerated approval to axicabtagene ciloleucel for relapsed or refractory follicular lymphoma; https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-axicabtagene-ciloleucel-relapsed-or-refractory-follicular-lymphoma (2021).
Chong, E. A. et al. CD19-directed CAR T cell therapy (CTL019) for relapsed/refractory diffuse large B-cell and follicular lymphomas: four year outcomes. In 15th International Conference on Malignant Lymphoma Abstract 090 (2019).
Chong, E. A., Ruella, M. & Schuster, S. J., Lymphoma Program Investigators at the University of Pennsylvania. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N. Engl. J. Med. 384, 673–674 (2021).
doi: 10.1056/NEJMc2030164
pubmed: 33596362
Cheson, B. D. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol. 32, 3059–3068 (2014).
doi: 10.1200/JCO.2013.54.8800
pubmed: 25113753
pmcid: 4979083
Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).
doi: 10.1182/blood-2014-05-552729
pubmed: 24876563
pmcid: 4093680
Bruna, R. et al. Prolonged survival in the absence of disease-recurrence in advanced-stage follicular lymphoma following chemo-immunotherapy: 13-year update of the prospective, multicenter randomized GITMO-IIL trial. Haematologica 104, 2241–2248 (2019).
doi: 10.3324/haematol.2018.209932
pubmed: 31666344
pmcid: 6821615
Awasthi, R. et al. Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL. Blood Adv. 4, 560–572 (2020).
doi: 10.1182/bloodadvances.2019000525
pubmed: 32045475
pmcid: 7013261
Mueller, K. T. et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood 130, 2317–2325 (2017).
doi: 10.1182/blood-2017-06-786129
pubmed: 28935694
pmcid: 5731220
Jacobson, C. et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory indolent non-Hodgkin lymphoma. In 62nd ASH Annual Meeting and Exposition Abstract 700 (2020).
Assouline, S. E. et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial. In 62nd ASH Annual Meeting and Exposition Abstract Abstract 702 (2020).
Hutchings, M. et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J. Clin. Oncol. 39, 1959–1970 (2021).
Schuster, S. J. et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. Blood 134, 6 (2019).
doi: 10.1182/blood-2019-123742
Chavey, W. E. 2nd et al. Guideline for the management of heart failure caused by systolic dysfunction: part I. Guideline development, etiology and diagnosis. Am. Fam. Physician 64, 769–774 (2001).
pubmed: 11563568