Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
07
07
2020
accepted:
21
01
2021
revised:
11
12
2020
pubmed:
20
2
2021
medline:
6
10
2021
entrez:
19
2
2021
Statut:
ppublish
Résumé
Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
Identifiants
pubmed: 33603142
doi: 10.1038/s41375-021-01148-x
pii: 10.1038/s41375-021-01148-x
pmc: PMC8410595
doi:
Substances chimiques
Antineoplastic Agents
0
Sorafenib
9ZOQ3TZI87
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2517-2525Informations de copyright
© 2021. The Author(s).
Références
Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5:835–44.
doi: 10.1038/nrd2130
Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation. 2008;118:2081–90.
doi: 10.1161/CIRCULATIONAHA.108.779751
Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, et al. BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006;98:326–34.
doi: 10.1093/jnci/djj069
Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst. 2008;100:184–98.
doi: 10.1093/jnci/djm328
Zhang W, Konopleva M, Ruvolo VR, McQueen T, Evans RL, Bornmann WG, et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia. 2008;22:808–18.
doi: 10.1038/sj.leu.2405098
Röllig C, Serve H, Huttmann A, Noppeney R, Muller-Tidow C, Krug U, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:1691–9.
doi: 10.1016/S1470-2045(15)00362-9
Padro T, Ruiz S, Bieker R, Burger H, Steins M, Kienast J, et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood. 2000;95:2637–44.
doi: 10.1182/blood.V95.8.2637
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl J Med. 2017;377:454–64.
doi: 10.1056/NEJMoa1614359
Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113:983–8.
doi: 10.1046/j.1365-2141.2001.02850.x
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–9.
doi: 10.1182/blood.V97.8.2434
Mathew NR, Baumgartner F, Braun L, O’Sullivan D, Thomas S, Waterhouse M, et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat Med. 2018;24:282–91.
doi: 10.1038/nm.4484
Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J Clin Oncol. 2020;38:2993–3002.
doi: 10.1200/JCO.19.03345
Sasaki K, Kantarjian HM, Kadia T, Patel K, Loghavi S, Garcia-Manero G, et al. Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. Cancer. 2019;125:3755–66.
doi: 10.1002/cncr.32387
Ohanian M, Garcia-Manero G, Levis M, Jabbour E, Daver N, Borthakur G, et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am J Hematol. 2018;93:1136–41.
doi: 10.1002/ajh.25198
Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Eur J Haematol. 2017;121:4655–62.
Rautenberg C, Nachtkamp K, Dienst A, Schmidt PV, Heyn C, Kondakci M, et al. Sorafenib and azacitidine as salvage therapy for relapse of FLT3-ITD mutated AML after allo-SCT. Eur J Haematol. 2017;98:348–54.
doi: 10.1111/ejh.12832
Metzelder SK, Schroeder T, Finck A, Scholl S, Fey M, Götze K, et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia. 2012;26:2353–9.
doi: 10.1038/leu.2012.105