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17.09.2024 | Research

Only FLT3-ITD co-mutation did not have a deleterious effect on acute myeloid leukemia patients with NPM1 mutation, but concomitant with DNMT3A co-mutation or a < 3log reduction of MRD2 predicted poor survival

verfasst von: Wenbing Duan, Jinsong Jia, Jing Wang, Xiaohong Liu, Wenjing Yu, Xiaolu Zhu, Ting Zhao, Qian Jiang, Guorui Ruan, Xiaosu Zhao, Hongxia Shi, Yingjun Chang, Yu Wang, Lanping Xu, Xiaohui Zhang, Xiaojun Huang, Hao Jiang

Erschienen in: Annals of Hematology | Ausgabe 11/2024

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Abstract

Co-occurring mutations are frequently observed in acute myeloid leukemia (AML) with NPM1 mutation, and NPM1 measurable residual disease (MRD) is an effective prognostic biomarker. This retrospective study investigated the impact of gene co-mutations and NPM1 MRD on outcomes in these patients. Among 234 patients, 11.5% carried the rare type NPM1 mutation (NPM1RT). The median age was 49 years (IQR 36–58), with a median follow-up of 30.4 months (IQR 12.1–55.7). Nine genes were mutated in > 10%, with DNMT3A (53.8%) and FLT3-ITD (44.4%) being most prevalent. Univariable analysis in 137 patients showed FLT3-ITD, DNMT3A co-mutations, and MRD2 < 3 log reduction predicted poorer survival. FLT3-ITD and DNMT3A co-mutations correlated with the lowest event-free (EFS) and overall survival (OS) (3-year EFS 30.0%; 3-year OS 34.4%; both p < 0.001). FLT3-ITD alone did not worsen survival compared to patients without FLT3-ITD. Multivariable analysis identified DNMT3A co-mutation [EFS, HR = 1.9, p = 0.021; OS, HR = 2.2, p = 0.023] and MRD2 ≥ 3 log reduction (EFS, HR = 0.2; OS, HR = 0.1, both p < 0.001) as independent survival predictors. Patients with FLT3-ITD and DNMT3A co-mutations or a MRD2 < 3 log reduction were identified as high risk, but allogeneic hematopoietic stem cell transplantation (allo-HSCT) improved survival significantly compared to chemotherapy only (3-year EFS, 57.9% vs. 30.0%, p = 0.012; 3-year OS, 72.9% vs. 34.4%, p = 0.001). In AML patients with NPM1 mutation, the detrimental impact of FLT3-ITD mutation was exacerbated by DNMT3A co-mutation. Poor-risk younger patients identified by FLT3-ITD and DNMT3A co-mutations or MRD2 < 3 log reduction benefit from allo-HSCT.
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Literatur
1.
Zurück zum Zitat Thiede C et al (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107(10):4011–4020CrossRefPubMed Thiede C et al (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107(10):4011–4020CrossRefPubMed
2.
Zurück zum Zitat Falini B et al (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352(3):254–266CrossRefPubMed Falini B et al (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352(3):254–266CrossRefPubMed
4.
Zurück zum Zitat Polyatskin IL, Artemyeva AS, Krivolapov YA (2019) Revised WHO classification of tumors of hematopoietic and lymphoid tissues, 2017 (4th edition):lymphoid tumors. Arkh Patol 81(3):59–65CrossRefPubMed Polyatskin IL, Artemyeva AS, Krivolapov YA (2019) Revised WHO classification of tumors of hematopoietic and lymphoid tissues, 2017 (4th edition):lymphoid tumors. Arkh Patol 81(3):59–65CrossRefPubMed
5.
Zurück zum Zitat Döhner K et al (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106(12):3740–3746CrossRefPubMed Döhner K et al (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106(12):3740–3746CrossRefPubMed
6.
Zurück zum Zitat Schnittger S et al (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106(12):3733–3739CrossRefPubMed Schnittger S et al (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106(12):3733–3739CrossRefPubMed
7.
Zurück zum Zitat Schlenk RF et al (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1909–1918CrossRefPubMed Schlenk RF et al (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1909–1918CrossRefPubMed
8.
Zurück zum Zitat Döhner H et al (2022) Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel on behalf of the ELN. Blood 140:1345–1377CrossRefPubMed Döhner H et al (2022) Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel on behalf of the ELN. Blood 140:1345–1377CrossRefPubMed
9.
Zurück zum Zitat Döhner H et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447CrossRefPubMedPubMedCentral Döhner H et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Balsat M et al (2017) Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol 35(2):185–193CrossRefPubMed Balsat M et al (2017) Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol 35(2):185–193CrossRefPubMed
11.
Zurück zum Zitat Heiblig M et al (2021) The impact of DNMT3A Status on NPM1 MRD predictive value and survival in elderly AML patients treated intensively. Cancers (Basel) 13(9):2156CrossRefPubMed Heiblig M et al (2021) The impact of DNMT3A Status on NPM1 MRD predictive value and survival in elderly AML patients treated intensively. Cancers (Basel) 13(9):2156CrossRefPubMed
12.
Zurück zum Zitat 中华医学会血液学分会, 成人急性髓系白血病(非急性早幼粒细胞白血病)中国诊疗指南(2011年版). Chinese J Hematol 2011. 32: 804–807 中华医学会血液学分会, 成人急性髓系白血病(非急性早幼粒细胞白血病)中国诊疗指南(2011年版). Chinese J Hematol 2011. 32: 804–807
13.
Zurück zum Zitat Döhner H et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115(3):453–474CrossRefPubMed Döhner H et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115(3):453–474CrossRefPubMed
14.
Zurück zum Zitat Xu L et al (2018) The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol 11(1):33CrossRefPubMedPubMedCentral Xu L et al (2018) The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol 11(1):33CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Lu DP et al (2006) Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood 107(8):3065–3073CrossRefPubMed Lu DP et al (2006) Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood 107(8):3065–3073CrossRefPubMed
16.
Zurück zum Zitat Ruan GR et al (2009) Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia. Ann Hematol 88(2):159–166CrossRefPubMed Ruan GR et al (2009) Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia. Ann Hematol 88(2):159–166CrossRefPubMed
17.
Zurück zum Zitat Schuurhuis GJ et al (2018) Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 131(12):1275–1291CrossRefPubMedPubMedCentral Schuurhuis GJ et al (2018) Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 131(12):1275–1291CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Angenendt L et al (2019) Chromosomal abnormalities and prognosis in NPM1-Mutated Acute Myeloid Leukemia: a pooled analysis of individual patient data from nine international cohorts. J Clin Oncol 37(29):2632–2642CrossRefPubMedPubMedCentral Angenendt L et al (2019) Chromosomal abnormalities and prognosis in NPM1-Mutated Acute Myeloid Leukemia: a pooled analysis of individual patient data from nine international cohorts. J Clin Oncol 37(29):2632–2642CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Hubmann M et al (2014) Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica 99(8):1317–1325CrossRefPubMedPubMedCentral Hubmann M et al (2014) Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica 99(8):1317–1325CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Lambert J et al (2014) MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget 5(15):6280–6288CrossRefPubMedPubMedCentral Lambert J et al (2014) MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget 5(15):6280–6288CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Zhao T et al (2017) Prognostic significance of early assessment of minimal residual disease in acute myeloid leukemia with mutated NPM1 patients. Zhonghua Xue Ye Xue Za Zhi 38(1):10–16PubMed Zhao T et al (2017) Prognostic significance of early assessment of minimal residual disease in acute myeloid leukemia with mutated NPM1 patients. Zhonghua Xue Ye Xue Za Zhi 38(1):10–16PubMed
22.
Zurück zum Zitat Ivey A et al (2016) Assessment of minimal residual disease in standard-risk AML. N Engl J Med 374(5):422–433CrossRefPubMed Ivey A et al (2016) Assessment of minimal residual disease in standard-risk AML. N Engl J Med 374(5):422–433CrossRefPubMed
23.
Zurück zum Zitat Guolo F et al (2019) Longitudinal minimal residual disease (MRD) evaluation in acute myeloid leukaemia with NPM1 mutation: from definition of molecular relapse to MRD-driven salvage approach. Br J Haematol 186(6):e223–e225CrossRefPubMed Guolo F et al (2019) Longitudinal minimal residual disease (MRD) evaluation in acute myeloid leukaemia with NPM1 mutation: from definition of molecular relapse to MRD-driven salvage approach. Br J Haematol 186(6):e223–e225CrossRefPubMed
25.
Zurück zum Zitat Bezerra MF et al (2020) Co-occurrence of DNMT3A, NPM1, FLT3 mutations identifies a subset of acute myeloid leukemia with adverse prognosis. Blood 135(11):870–875CrossRefPubMed Bezerra MF et al (2020) Co-occurrence of DNMT3A, NPM1, FLT3 mutations identifies a subset of acute myeloid leukemia with adverse prognosis. Blood 135(11):870–875CrossRefPubMed
26.
Zurück zum Zitat Guryanova OA et al (2016) DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 22(12):1488–1495CrossRefPubMedPubMedCentral Guryanova OA et al (2016) DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 22(12):1488–1495CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Othman J et al (2024) Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML. Blood 144:714–728CrossRefPubMed Othman J et al (2024) Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML. Blood 144:714–728CrossRefPubMed
28.
Zurück zum Zitat Yao Y et al (2024) Co-mutation landscape and its prognostic impact on newly diagnosed adult patients with NPM1-mutated de novo acute myeloid leukemia. Blood Cancer J 14(1):118CrossRefPubMedPubMedCentral Yao Y et al (2024) Co-mutation landscape and its prognostic impact on newly diagnosed adult patients with NPM1-mutated de novo acute myeloid leukemia. Blood Cancer J 14(1):118CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Perry M et al (2018) FLT3-TKD Mutations Associated With NPM1 Mutations Define a Favorable-risk Group in Patients With Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 18(12):e545–e550CrossRefPubMed Perry M et al (2018) FLT3-TKD Mutations Associated With NPM1 Mutations Define a Favorable-risk Group in Patients With Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 18(12):e545–e550CrossRefPubMed
30.
31.
Zurück zum Zitat DiNardo CD et al (2020) Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 383(7):617–629CrossRefPubMed DiNardo CD et al (2020) Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 383(7):617–629CrossRefPubMed
32.
Zurück zum Zitat Yu WJ et al (2022) Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience. Zhonghua Xue Ye Xue Za Zhi 43(2):134–140PubMed Yu WJ et al (2022) Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience. Zhonghua Xue Ye Xue Za Zhi 43(2):134–140PubMed
33.
Zurück zum Zitat Jimenez-Chillon C et al (2024) Venetoclax-based low intensity therapy in molecular failure of NPM1-mutated AML. Blood Adv 8(2):343–352CrossRefPubMed Jimenez-Chillon C et al (2024) Venetoclax-based low intensity therapy in molecular failure of NPM1-mutated AML. Blood Adv 8(2):343–352CrossRefPubMed
34.
Zurück zum Zitat Stahl M et al (2021) Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Blood Adv 5(5):1552–1564CrossRefPubMedPubMedCentral Stahl M et al (2021) Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Blood Adv 5(5):1552–1564CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Yu S et al (2024) Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study. J Intern Med 295(2):216–228CrossRefPubMed Yu S et al (2024) Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study. J Intern Med 295(2):216–228CrossRefPubMed
Metadaten
Titel
Only FLT3-ITD co-mutation did not have a deleterious effect on acute myeloid leukemia patients with NPM1 mutation, but concomitant with DNMT3A co-mutation or a < 3log reduction of MRD2 predicted poor survival
verfasst von
Wenbing Duan
Jinsong Jia
Jing Wang
Xiaohong Liu
Wenjing Yu
Xiaolu Zhu
Ting Zhao
Qian Jiang
Guorui Ruan
Xiaosu Zhao
Hongxia Shi
Yingjun Chang
Yu Wang
Lanping Xu
Xiaohui Zhang
Xiaojun Huang
Hao Jiang
Publikationsdatum
17.09.2024
Verlag
Springer Berlin Heidelberg
Erschienen in
Annals of Hematology / Ausgabe 11/2024
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-024-06001-6

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