Un traitement intensif par rapport à un traitement non intensif chez les patients atteints d’une leucémie myéloïde aiguë (LMA)
Résumé
Les traitements récemment approuvés ont élargi les options disponibles pour les patients atteints de leucémie myéloïde aiguë (LMA), mais ont également soulevé des questions concernant le choix du traitement le plus approprié pour chaque individu (tableaux 1 et 2). Les essais qui ont mené à l’approbation de ces traitements étaient basés sur des données génétiques limitées (p. ex., la cytogénétique, la présence de mutation du gène FLT3 (FMS-like tyrosine kinase 3) et de paramètres cliniques (l’âge, les comorbidités, le traitement ou une LMA secondaire). Les données concernant l’efficacité ou l’inefficacité d’un médicament ou d’un schéma thérapeutique dans des sous-groupes spécifiques de LMA sont souvent déterminées après l’autorisation du médicament. Par exemple, le traitement non intensif (TNI) associant le vénétoclax (VEN) et l’azacitidine (AZA), qui est approuvé pour le traitement des patients atteints d’une LMA nouvellement diagnostiquée non candidats à un traitement intensif (TI) ou de > 75 ans, s’est avéré avoir une efficacité limitée chez les patients présentant une mutation du gène TP53. Malgré les indications approuvées par les autorités réglementaires pour un TNI à base de VEN, certains patients âgés ou certains jeunes peuvent être sélectionnés pour un TNI ou pour un TI. De plus, avec la possibilité d’un traitement d’entretien après un TI, plusieurs questions importantes ont été soulevées concernant le rôle du TI chez les patients âgés.
Aucune étude prospective publiée n’a comparé le TI à un TNI chez des patients atteints d’une LMA nouvellement diagnostiquée ayant pour un bon état de santé général « fit », afin d’éclairer le choix du traitement. Deux analyses rétrospectives de données réelles appariées selon le score de propension ont été réalisées sur les résultats obtenus chez des patients atteints d’une LMA nouvellement diagnostiquée (quel que soit leur profil génétique) ayant reçu une induction par VEN + AZA ou un TI. Elles n’ont révélé aucune différence en termes de survie globale (SG). Une étude a cependant montré une amélioration des taux de réponse complète (RC) et/ou de greffe allogénique de cellules souches hématopoïétiques (alloGCSH) en faveur du traitement intensif (60,9 % contre 44,2 %, p = 0,006 et 18,1 % contre 8,0 %, p = 0,012, respectivement). D’autres études rétrospectives monocentriques comparant VEN + AZA à un traitement intensif ont donné des résultats contradictoires. Aucune de ces études n’a fourni d’informations concernant l’utilisation d’un traitement d’entretien par l’AZA orale. Les études ont suggéré que les résultats contradictoires pourraient dépendre d’anomalies génétiques spécifiques et/ou de facteurs cliniques. Actuellement, plusieurs essais de phase 2 comparent le VEN + AZA à un traitement intensif chez des patients adultes atteints d’une LMA nouvellement diagnostiquée (NCT04801797, NCT05904106, NCT05554406, NCT05554393).
Deux cas patients seront examinés ici afin de mettre en évidence les questions relatives au choix du traitement. Le cas 1 : patient ayant bon état de santé général (fit) âgé de > 75 ans atteint d’une LMA nouvellement diagnostiquée de risque favorable, tel que défini par l’European LeukemiaNet (ELN). Le cas 2 : patient de > 18 ans atteint d’une LMA nouvellement diagnostiquée de risque défavorable - tel que défini par l’ELN - candidat à un traitement intensif et qui nécessite une greffe allogénique à visée curative à la première réponse complète (RC1).
Références
Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018;36(26):2684-92.
Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021;8(7):e481-e91.
Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-16.
Lambert J, Pautas C, Terre C, Raffoux E, Turlure P, Caillot D, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019;104(1):113-9.
Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-96.
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(5):454-64.
Stone RM, Yin J, Mandrekar SJ, Benner A, Saadati M, Galinsky IA, et al. 10 Year Follow-up of CALGB 10603/Ratify: Midostaurin Versus Placebo Plus Intensive Chemotherapy in Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia Patients Aged 18-60 Years. Blood. 2024;144(Supplement 1):218.
Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Zak P, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10388):1571-83.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617-29.
Pratz KW, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Dohner H, et al. Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024;99(4):615-24.
Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-45.
Wei AH, Panayiotidis P, Montesinos P, Laribi K, Ivanov V, Kim I, et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). Blood Cancer J. 2021;11(10):163.
Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022;386(16):1519-31.
Rucker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, 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(9):2114-21.
Fleming S, Tsai XC, Morris R, Hou HA, Wei AH. TP53 status and impact on AML prognosis within the ELN 2022 risk classification. Blood. 2023;142(23):2029-33.
Wei AH, Dohner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020;383(26):2526-37.
Zeidan AM, Pollyea DA, Borate U, Vasconcelos A, Potluri R, Rotter D, et al. Venetoclax plus azacitidine compared with intensive chemotherapy as induction for patients with acute myeloid leukemia: retrospective analysis of an electronic medical record database in the United States. Ann Hematol. 2023;102(4):749-54.
Matthews AH, Perl AE, Luger SM, Loren AW, Gill SI, Porter DL, et al. Real-world effectiveness of CPX-351 vs venetoclax and azacitidine in acute myeloid leukemia. Blood Adv. 2022;6(13):3997-4005.
Cherry EM, Abbott D, Amaya M, McMahon C, Schwartz M, Rosser J, et al. Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Adv. 2021;5(24):5565-73.
Diebold K, Mudd T, Jarodiya J, Parks K, Hardee M, Bachiashvili K, et al. Superior survival with intensive chemotherapy, compared to hypomethylating agent + venetoclax, in patients with intermediate/adverse risk acute myeloid leukemia unable to proceed to transplant. Blood. 2024;144(Supplement 1):2900-1.
Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-19.
Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-28.
Falini B, Brunetti L, Sportoletti P, Martelli MP. NPM1-mutated acute myeloid leukemia: from bench to bedside. Blood. 2020;136(15):1707-21.
Dohner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-77.
Dohner H, DiNardo CD, Appelbaum FR, Craddock C, Dombret H, Ebert BL, et al. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations. Blood. 2024;144(21):2169-73.
Othman J, Potter N, Ivey A, Tazi Y, Papaemmanuil E, Jovanovic J, et al. Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML. Blood. 2024;144(7):714-28.
Zale A, Ambinder AJ, Kaduluri VPS. A retrospective analysis of intensive chemotherapy vs. venetoclax/hypomethylating agents for patients aged 60-75 with favorable-risk, NPM1-mutated AML. Blood. 2024;144(Supplement 1):450-1.
Bewersdorf JP, Shimony S, Shallis RM, Liu Y, Berton G, Schaefer EJ, et al. Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML. Blood Adv. 2024;8(18):4845-55.
Juliusson G. Older patients with acute myeloid leukemia benefit from intensive chemotherapy: an update from the Swedish Acute Leukemia Registry. Clin Lymphoma Myeloma Leuk. 2011;11 Suppl 1:S54-9.
Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361(13):1235-48.
Recher C, Rollig C, Berard E, Bertoli S, Dumas PY, Tavitian S, et al. Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries. Leukemia. 2022;36(4):913-22.
Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840-51.
Dohner H, Weber D, Krzykalla J, Fiedler W, Kuhn MWM, Schroeder T, et al. Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2023;10(7):e495-e509.
Borate U, Welkie RL, Huang Y, Swords RT, Traer E, Stein EM, et al. Demographics, characteristics, survival and outcomes in older, untreated, acute myeloid leukemia patients with NPM1 mutations or KMT2A rearrangements from the Beat AML Master Clinical Trial. Blood. 2024;144(Supplement 1):1564.
Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015;125(25):3878-85.
Wei AH, Dohner H, Sayar H, Ravandi F, Montesinos P, Dombret H, et al. Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: Updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial. Am J Hematol. 2023;98(4):E84-E7.
Roboz GJ, Ravandi F, Wei AH, Dombret H, Thol F, Voso MT, et al. Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status. Blood. 2022;139(14):2145-55.
Dohner H, Wei AH, Roboz GJ, Montesinos P, Thol FR, Ravandi F, et al. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine. Blood. 2022;140(15):1674-85.
Schlenk RF, Paschka P, Krzykalla J, Weber D, Kapp-Schwoerer S, Gaidzik VI, et al. Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study. J Clin Oncol. 2020;38(6):623-32.
Kapp-Schwoerer S, Weber D, Corbacioglu A, Gaidzik VI, Paschka P, Kronke J, et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial. Blood. 2020;136(26):3041-50.
Dohner H, Pratz KW, DiNardo CD, Wei AH, Jonas BA, Pullarkat VA, et al. Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine. Blood. 2024;144(21):2211-22.
Pratz KW, Jonas BA, Pullarkat V, Recher C, Schuh AC, Thirman MJ, et al. Measurable Residual Disease Response and Prognosis in Treatment-Naive Acute Myeloid Leukemia With Venetoclax and Azacitidine. J Clin Oncol. 2022;40(8):855-65.
Heiblig M, Requena GA, Tauveron-Jalenques U, Tavernier E, Cornillon J, Carre M, et al. Measurable residual disease (MRD) determinants, kinetics and its impact on survival in patients treated with azacitidine and venetoclax for acute myeloid leukemia in frontline setting : a multicentric study from French Auraml Group. Blood. 2024;144(Supplement 1):846-7.
Terwijn M, van Putten WL, Kelder A, van der Velden VH, Brooimans RA, Pabst T, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31(31):3889-97.
Freeman SD, Virgo P, Couzens S, Grimwade D, Russell N, Hills RK, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31(32):4123-31.
Pratz KW, DiNardo CD, Selleslag D, Li J, Yamamoto K, Konopleva M, et al. Postremission cytopenia management in patients with acute myeloid leukemia treated with venetoclax and azacitidine in VIALE-A. Am J Hematol. 2022;97(11):E416-E9.
Chua CC, Hammond D, Kent A, Tiong IS, Konopleva MY, Pollyea DA, et al. Treatment-free remission after ceasing venetoclax-based therapy in patients with acute myeloid leukemia. Blood Adv. 2022;6(13):3879-83.
Garciaz S, Dumas PY, Bertoli S, Sallman DA, Decroocq J, Belhabri A, et al. Outcomes of acute myeloid leukemia patients who responded to venetoclax and azacitidine and stopped treatment. Am J Hematol. 2024;99(10):1870-6.
Alibhai SM, Breunis H, Timilshina N, Brignardello-Petersen R, Tomlinson G, Mohamedali H, et al. Quality of life and physical function in adults treated with intensive chemotherapy for acute myeloid leukemia improve over time independent of age. J Geriatr Oncol. 2015;6(4):262-71.
Timilshina N, Breunis H, Tomlinson GA, Brandwein JM, Buckstein R, Durbano S, et al. Long-term recovery of quality of life and physical function over three years in adult survivors of acute myeloid leukemia after intensive chemotherapy. Leukemia. 2019;33(1):15-25.
Roboz GJ, Dohner H, Pocock C, Dombret H, Ravandi F, Jang JH, et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021;106(12):3240-4.
Dillman RO, Davis RB, Green MR, Weiss RB, Gottlieb AJ, Caplan S, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991;78(10):2520-6.
Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of Minimal Residual Disease in Standard-Risk AML. N Engl J Med. 2016;374(5):422-33.
Heuser M, Freeman SD, Ossenkoppele GJ, Buccisano F, Hourigan CS, Ngai LL, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138(26):2753-67.
Bataller A, Onate G, Diaz-Beya M, Guijarro F, Garrido A, Vives S, et al. Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease. Br J Haematol. 2020;191(1):52-61.
Fenaux P, Jonveaux P, Quiquandon I, Lai JL, Pignon JM, Loucheux-Lefebvre MH, et al. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood. 1991;78(7):1652-7.
Shahzad M, Amin MK, Daver NG, Shah MV, Hiwase D, Arber DA, et al. What have we learned about TP53-mutated acute myeloid leukemia? Blood Cancer J. 2024;14(1):202.
Lachowiez CA, Long N, Saultz J, Gandhi A, Newell LF, Hayes-Lattin B, et al. Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia. Blood Adv. 2023;7(9):1899-909.
Sargas C, Ayala R, Larrayoz MJ, Chillon MC, Rodriguez-Arboli E, Bilbao C, et al. Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group. Blood Cancer J. 2023;13(1):77.
Daver NG, Iqbal S, Huang J, Renard C, Lin J, Pan Y, et al. Clinical characteristics and overall survival among acute myeloid leukemia patients with TP53 gene mutation or chromosome 17p deletion. Am J Hematol. 2023;98(8):1176-84.
Short NJ, Montalban-Bravo G, Hwang H, Ning J, Franquiz MJ, Kanagal-Shamanna R, et al. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. Blood Adv. 2020;4(22):5681-9.
Badar T, Atallah E, Shallis RM, Goldberg AD, Patel A, Abaza Y, et al. Outcomes of TP53-mutated AML with evolving frontline therapies: Impact of allogeneic stem cell transplantation on survival. Am J Hematol. 2022;97(7):E232-E5.
Badar T, Shahzad M, Atallah E, Litzow MR, Kharfan-Dabaja MA. Transplant or no transplant for TP53 mutated AML. Oncotarget. 2024;15:674-6.
Badar T, Atallah E, Shallis R, Saliba AN, Patel A, Bewersdorf JP, et al. Survival of TP53-mutated acute myeloid leukemia patients receiving allogeneic stem cell transplantation after first induction or salvage therapy: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Leukemia. 2023;37(4):799-806.
Eissa Y, Remberger, Jamani K, Chen M, Vasudevan Nampoothiri R, Che A, et al. Outocmes of allogeneic stem cell transplantation in TP53-mutated myeloid malignancies: a mulitcenter Canadian study. EBMT annual meeting 2025 2025:A025.
Nawas MT, Kosuri S. Utility or futility? A contemporary approach to allogeneic hematopoietic cell transplantation for TP53-mutated MDS/AML. Blood Adv. 2024;8(3):553-61.
Grob T, Al Hinai ASA, Sanders MA, Kavelaars FG, Rijken M, Gradowska PL, et al. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2022;139(15):2347-54.
Loke J, Labopin M, Craddock C, Cornelissen JJ, Labussiere-Wallet H, Wagner-Drouet EM, et al. Additional cytogenetic features determine outcome in patients allografted for TP53 mutant acute myeloid leukemia. Cancer. 2022;128(15):2922-31.
Chan O, Hunter A, Talati C, Sallman DA, Asghari H, Song J, et al. Impact of TP53 gene mutation clearance and conditioning intensity on outcome in MDS or AML patients prior to allogeneic stem cell transplantation. Blood. 2019;134(Supplement 1):149.
Lindsley RC, Gibson CJ, Murdock HM, Stone RM, Cortes JE, Uy GL, et al. Genetic characteristics and outcomes by mutation status in a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML). Blood. 2019;134:15.
Shimony SO, Murdock H, Keating J, Reilly CR, Tsai HK, Gibson CJ, et al. AML-MR mutations drive the benefit of CPX-351 over 7+3 in the pivotal phase 3 AML trial. Blood. 2024;144(Supplement 1):60-1.
Jen WY, Sasaki K, Ravandi F, Kadia TM, Wang SA, Wang W, et al. Impact of measurable residual disease clearance kinetics in patients with AML undergoing intensive chemotherapy. Blood Adv. 2025;9(4):783-92.
Pollyea DA, Pratz KW, Wei AH, Pullarkat V, Jonas BA, Recher C, et al. Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine. Clin Cancer Res. 2022;28(24):5272-9.
Publié
Comment citer
Numéro
Rubrique
Licence
© Actualité hématologique au Canada 2025
Cette œuvre est sous licence Creative Commons Attribution - Pas d'Utilisation Commerciale - Pas de Modification 4.0 International.
