Outcomes in patients with newly diagnosed TP53-mutated acute myeloid leukemia with or without venetoclax-based therapy.
TP53
acute myeloid leukemia (AML)
hypomethylating agent
venetoclax (VEN)
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
01 10 2021
01 10 2021
Historique:
revised:
13
04
2021
received:
08
03
2021
accepted:
04
05
2021
pubmed:
29
6
2021
medline:
11
3
2022
entrez:
28
6
2021
Statut:
ppublish
Résumé
Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53 In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53 Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment. The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53
Sections du résumé
BACKGROUND
Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53
METHODS
In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53
RESULTS
Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment.
CONCLUSIONS
The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53
Substances chimiques
Bridged Bicyclo Compounds, Heterocyclic
0
Sulfonamides
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3541-3551Subventions
Organisme : NCI NIH HHS
ID : CA016672
Pays : United States
Informations de copyright
© 2021 American Cancer Society.
Références
Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018;392:593-606.
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424-447.
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008.
Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia. 2008;22:1539-1541.
Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114-2121.
Bowen D, Groves MJ, Burnett AK, et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia. 2009;23:203-206.
Hou HA, Chou WC, Kuo YY, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5:e331.
Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552-555.
Stirewalt DL, Kopecky KJ, Meshinchi S, et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001;97:3589-3595.
Kadia TM, Jain P, Ravandi F, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016;122:3484-3491.
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617-629.
Short NJ, Montalban-Bravo G, Hwang H, et al. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. Blood Adv. 2020;4:5681-5689.
Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106-1117.
DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7-17.
Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37:1277-1284.
Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135:2137-2145.
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642-4649.
Short NJ, Rafei H, Daver N, et al. Prognostic impact of complete remission with MRD negativity in patients with relapsed or refractory AML. Blood Adv. 2020;4:6117-6126.
Khoury JD, Sen F, Abruzzo LV, Hayes K, Glassman A, Medeiros LJ. Cytogenetic findings in blastoid mantle cell lymphoma. Hum Pathol. 2003;34:1022-1029.
Montalban-Bravo G, Kanagal-Shamanna R, Benton CB, et al. Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes. Blood Adv. 2020;4:482-495.
Aldoss I, Zhang J, Pillai R, et al. Venetoclax and hypomethylating agents in TP53-mutated acute myeloid leukaemia. Br J Haematol. 2019;187:e45-e48.
Middeke JM, Fang M, Cornelissen JJ, et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood. 2014;123:2960-2967.
Melo MB, Ahmad NN, Lima CS, et al. Mutations in the p53 gene in acute myeloid leukemia patients correlate with poor prognosis. Hematology. 2002;7:13-19.
Seifert H, Mohr B, Thiede C, et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia. 2009;23:656-663.
Ciurea SO, Chilkulwar A, Saliba RM, et al. Prognostic factors influencing survival after allogeneic transplantation for AML/MDS patients with TP53 mutations. Blood. 2018;131:2989-2992.
Nabih M, Norman S, Louis D, et al. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020;105:1539-1551.
Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021;39:1584-1594.
Aprea Therapeutics. Aprea Therapeutics Announces Results of Primary Endpoint from Phase 3 Trial of Eprenetapopt in TP53 Mutant Myelodysplastic Syndromes (MDS) [press release]. Aprea Therapeutics; 2020. Accessed January 22, 2021. https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-announces-results-primary-endpoint-phase-3
Sallman DA, Asch AS, Al Malki MM, et al. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results [abstract]. Blood. 2019;134(suppl 1):569.
Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286-299.
Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10:e0137345.
Sallman DA, Malki MA, Asch AS, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: phase Ib results [abstract]. J Clin Oncol. 2020;38(15 suppl):7507.
Haubner S, Perna F, Kohnke T, et al. Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia. 2019;33:64-74.
Moore PA, Zhang W, Rainey GJ, et al. Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood. 2011;117:4542-4551.
Vadakekolathu J, Lai C, Reeder S, et al. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Adv. 2020;4:5011-5024.
Chen X, Glytsou C, Zhou H, et al. Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment. Cancer Discov. 2019;9:890-909.
Nechiporuk T, Kurtz SE, Nikolova O, et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 2019;9:910-925.
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15:49-63.
Teh TC, Nguyen NY, Moujalled DM, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018;32:303-312.
Lina H, Qi Z, Monique D, et al. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models. Haematologica. 2020;105:697-707.
Dutta S, Pregartner G, Rucker FG, et al. Functional classification of TP53 mutations in acute myeloid leukemia. Cancers (Basel). 2020;12:637.