A phase 2 study of ibrutinib maintenance following first-line high-dose methotrexate-based chemotherapy for elderly patients with primary central nervous system lymphoma.
elderly
ibrutinib
maintenance treatment
primary central nervous system lymphoma
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
12 Aug 2023
12 Aug 2023
Historique:
revised:
06
05
2023
received:
27
09
2022
accepted:
28
06
2023
medline:
13
8
2023
pubmed:
13
8
2023
entrez:
12
8
2023
Statut:
aheadofprint
Résumé
Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression-free survival (PFS) of 6-16 months. Ibrutinib penetrates the blood-brain barrier and has shown activity in PCNSL. This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2-year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60-85 years old who responded to first-line high-dose methotrexate (HDMTX)-based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity. Twenty patients were enrolled, with a median age of 72 years (range, 61-80). Median time on ibrutinib maintenance was 12.5 (range, 2-46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1- and 2-year PFS are 90% and 72.6%, respectively, and the 2-year OS is 89%. The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly.
Sections du résumé
BACKGROUND
BACKGROUND
Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression-free survival (PFS) of 6-16 months. Ibrutinib penetrates the blood-brain barrier and has shown activity in PCNSL.
METHODS
METHODS
This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2-year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60-85 years old who responded to first-line high-dose methotrexate (HDMTX)-based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity.
RESULTS
RESULTS
Twenty patients were enrolled, with a median age of 72 years (range, 61-80). Median time on ibrutinib maintenance was 12.5 (range, 2-46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1- and 2-year PFS are 90% and 72.6%, respectively, and the 2-year OS is 89%.
CONCLUSIONS
CONCLUSIONS
The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Janssen Pharmaceuticals
ID : 54179060LYM2017
Informations de copyright
© 2023 American Cancer Society.
Références
Garcilazo-Reyes Y, Alentorn A, Duran-Pena A, Hoang-Xuan K, Houillier C. Treatment of primary central nervous system lymphoma in immunocompetent patients. Curr Treat Options Neurol. 2019;21(8):39. doi:10.1007/s11940-019-0578-x
Houillier C, Soussain C, Ghesquieres H, et al. Management and outcome of primary CNS lymphoma in the modern era: An LOC network study. Neurology. 2020;94(10):e1027-e1039. doi:10.1212/wnl.0000000000008900
Ferreri AJM, Cwynarski K, Pulczynski E, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017;4(11):e510-e523. doi:10.1016/s2352-3026(17)30174-6
Yuan Y, Ding T, Wang S, Chen H, Mao Y, Chen T. Current and emerging therapies for primary central nervous system lymphoma. Biomark Res. 2021;9(1):32. doi:10.1186/s40364-021-00282-z
Holdhoff M, Mrugala MM, Grommes C, et al. Challenges in the treatment of newly diagnosed and recurrent primary central nervous system lymphoma. J Natl Compr Cancer Netw. 2020;18(11):1571-1578. doi:10.6004/jnccn.2020.7667
Correa DD, Shi W, Abrey LE, et al. Cognitive functions in primary CNS lymphoma after single or combined modality regimens. Neuro Oncol. 2012;14(1):101-108. doi:10.1093/neuonc/nor186
Bairey O, Shargian-Alon L, Siegal T. Consolidation treatment for primary central nervous system lymphoma: which modality for whom? Acta Haematol. 2021;144(4):389-402. doi:10.1159/000511208
Steffanoni S, Calimeri T, Anzalone N, Mastaglio S, Bernardi M, Ferreri AJ. A narrative review of consolidation strategies for young and fit patients with newly-diagnosed primary central nervous system lymphoma. Expert Rev Hematol. 2022;15(1):33-43. doi:10.1080/17474086.2022.2018297
Martinez-Calle N, Isbell LK, Cwynarski K, Schorb E. Advances in treatment of elderly primary central nervous system lymphoma. Br J Haematol. 2022;196(3):473-487. doi:10.1111/bjh.17799
Houillier C, Ghesquieres H, Chabrot C, et al. Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study. J Neuro Oncol. 2017;133(2):315-320. doi:10.1007/s11060-017-2435-7
Siegal T, Bairey O. Primary CNS lymphoma in the elderly: the challenge. Acta Haematol. 2019;141(3):138-145. doi:10.1159/000495284
Roth P, Hoang-Xuan K. Challenges in the treatment of elderly patients with primary central nervous system lymphoma. Curr Opin Neurol. 2014;27(6):697-701. doi:10.1097/wco.0000000000000145
Roth P, Martus P, Kiewe P, et al. Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial. Neurology. 2012;79(9):890-896. doi:10.1212/wnl.0b013e318266fcb2
Kaji FA, Martinez-Calle N, Bishton MJ, et al. Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom. Br J Haematol. 2021;195(4):561-570. doi:10.1111/bjh.17747
Martinez-Calle N, Poynton E, Alchawaf A, et al. Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival. Br J Haematol. 2020;190(3):394-404. doi:10.1111/bjh.16592
Welch MR, Omuro A, Deangelis LM. Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro Oncol. 2012;14(10):1304-1311. doi:10.1093/neuonc/nos207
Kasenda B, Ferreri AJ, Marturano E, et al. First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis. Ann Oncol. 2015;26(7):1305-1313. doi:10.1093/annonc/mdv076
Mendez JS, Ostrom QT, Gittleman H, et al. The elderly left behind-changes in survival trends of primary central nervous system lymphoma over the past 4 decades. Neuro Oncol. 2018;20(5):687-694. doi:10.1093/neuonc/nox187
Bairey O, Siegal T. The possible role of maintenance treatment for primary central nervous system lymphoma. Blood Rev. 2018;32(5):378-386. doi:10.1016/j.blre.2018.03.003
Palma M, Mulder TA, Osterborg A. BTK inhibitors in chronic lymphocytic leukemia: biological activity and immune effects. Front Immunol. 2021;12:686768. doi:10.3389/fimmu.2021.686768
Shirley M. Bruton tyrosine kinase inhibitors in B-cell malignancies: their use and differential features. Targeted Oncol. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8
Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922-926. doi:10.1038/nm.3884
Soussain C, Choquet S, Blonski M, et al. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. Eur J Cancer. 2019;117:121-130. doi:10.1016/j.ejca.2019.05.024
Grommes C, Tang SS, Wolfe J, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019;133(5):436-445. doi:10.1182/blood-2018-09-875732
Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833-843.e835. doi:10.1016/j.ccell.2017.04.012
Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 2017;7(9):1018-1029. doi:10.1158/2159-8290.cd-17-0613
Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034-5043. doi:10.1200/jco.2005.13.524
Simsek C, Esin E, Yalcin S. Metronomic chemotherapy: a systematic review of the literature and clinical experience. J Oncol. 2019;2019:5483791. doi:10.1155/2019/5483791
Andre N, Carre M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol. 2014;11(7):413-431. doi:10.1038/nrclinonc.2014.89
Schaff LR, Ambady P, Doolittle ND, Grommes C. Primary central nervous system lymphoma: a narrative review of ongoing clinical trials and goals for future studies. Ann Lymphoma. 2021;5:8. doi:10.21037/aol-20-47
Langner-Lemercier S, Houillier C, Soussain C, et al. Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network. Neuro Oncol. 2016;18(9):1297-1303. doi:10.1093/neuonc/now033
van der Meulen M, Bromberg JEC, Nijland M, Visser O, Doorduijn JK, Dinmohamed AG. Primary therapy and survival in patients aged over 70-years-old with primary central nervous system lymphoma: a contemporary, nationwide, population-based study in the Netherlands. Haematologica. 2021;106:597-600.
Bodor C, Alpar D, Marosvari D, et al. Molecular subtypes and genomic profile of primary central nervous system lymphoma. J Neuropathol Exp Neurol. 2020;79(2):176-183. doi:10.1093/jnen/nlz125
Grommes C, DeAngelis LM. Primary CNS lymphoma. J Clin Oncol. 2017;35(21):2410-2418. doi:10.1200/jco.2017.72.7602
Nakamura T, Tateishi K, Niwa T, et al. Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol. 2016;42(3):279-290. doi:10.1111/nan.12259
Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57. doi:10.1186/s12943-018-0779-z
da Cunha-Bang C, Niemann CU. Targeting Bruton's tyrosine kinase across B-cell malignancies. Drugs. 2018;78(16):1653-1663. doi:10.1007/s40265-018-1003-6
Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879. doi:10.3324/haematol.2017.182907
Zhou Y, Lu H, Yang M, Xu C. Adverse drug events associated with ibrutinib for the treatment of elderly patients with chronic lymphocytic leukemia: a systematic review and meta-analysis of randomized trials. MedicineMedicine (Baltim). 2019;98(33):e16915. doi:10.1097/md.0000000000016915
Goldwirt L, Beccaria K, Ple A, Sauvageon H, Mourah S. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol. 2018;81(4):783-789. doi:10.1007/s00280-018-3546-3
Chamoun K, Choquet S, Boyle E, et al. Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: a retrospective case series. Neurology. 2017;88(1):101-102. doi:10.1212/wnl.0000000000003420
Chen F, Pang D, Guo H, et al. Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib-based combination therapy: a real-world experience of off-label ibrutinib use. Cancer Med. 2020;9(22):8676-8684. doi:10.1002/cam4.3499
Lewis KL, Chin CK, Manos K, et al. Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience. Br J Haematol. 2021;192(6):1049-1053. doi:10.1111/bjh.16946
Lauer EM, Waterhouse M, Braig M, et al. Ibrutinib in patients with relapsed/refractory central nervous system lymphoma: a retrospective single-centre analysis. Br J Haematol. 2020;190(2):e110-e114. doi:10.1111/bjh.16759
Renaud L, Bossard JB, Carpentier B, et al. Treatment with temozolomide and ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL). Eur J Haematol. 2021;107(3):370-373. doi:10.1111/ejh.13667
Rogers KA, Mousa L, Zhao Q, et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019;33(10):2527-2530. doi:10.1038/s41375-019-0481-1
Tsang M, Rubenstein JL, Pulczynski EJ. Primary central nervous system lymphoma in older adults and the rationale for maintenance strategies: a narrative review. Ann Lymphoma. 2021;5:25. doi:10.21037/aol-20-43
Fritsch K, Kasenda B, Schorb E, et al. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017;31(4):846-852. doi:10.1038/leu.2016.334