Next-generation Sequencing Reveals Relapse and Leukemia-free Survival Risks in Newly Diagnosed Acute Myeloid Leukemia Treated with CAG Regimen Combined with Decitabine

Overview

Journal Cancer Pathog Ther

Specialty Oncology

Date 2024 Apr 11

PMID 38601484

Authors

Sai Huang

Peng Chen

Lu Wang

Lingmin Xu

Nan Wang

Fei Li

Liping Dou

Daihong Liu

Affiliations

Soon will be listed here.

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities, as well as those with specific gene mutations. However, the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined. Therefore, this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML.

Methods: This study analyzed the clinical data and genetic mutations based on next-generation sequencing (NGS) in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army (PLA) General Hospital from January 2008 to August 2020. Factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in patients newly diagnosed with AML were analyzed.

Results: The most adverse prognosis of DCAG-treated patients was observed in those with or mutations during univariable analysis, whereas mutation was solely significant in multivariable analysis, with an increased likelihood of CIR ( = 0.001) and reduced LFS duration ( = 0.077). Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk ( = 0.044) and decreased LFS duration ( = 0.042) in multivariable analysis. In this study, we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range.

Conclusion: NGS demonstrated a dismal overall outcome in patients with the rare mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.

Citing Articles

Clinical and Molecular Predictors of Response and Survival Following Venetoclax Plus Hypomethylating Agents in Relapsed/Refractory Acute Myeloid Leukemia: A Single-Center Study in Chinese Patients.

Wang L, Gao H, Fu Q, Jiang Q, Jiang H, Wang Y Cancers (Basel). 2025; 17(4).

PMID: 40002181 PMC: 11852425. DOI: 10.3390/cancers17040586.

References

Huang J, Hong M, Zhu Y, Zhao H, Zhang X, Wu Y . Decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin is as effective as standard dose chemotherapy in the induction treatment for patients aged from 55 to 69 years old with newly diagnosed acute myeloid leukemia. Leuk Lymphoma. 2018; 59(11):2570-2579. DOI: 10.1080/10428194.2018.1443328. View

Sakaguchi M, Yamaguchi H, Najima Y, Usuki K, Ueki T, Oh I . Prognostic impact of low allelic ratio ITD and mutation in acute myeloid leukemia. Blood Adv. 2018; 2(20):2744-2754. PMC: 6199656. DOI: 10.1182/bloodadvances.2018020305. View

Alfayez M, Issa G, Patel K, Wang F, Wang X, Short N . The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia. Leukemia. 2020; 35(3):691-700. DOI: 10.1038/s41375-020-0920-z. View

Wang L, Luo J, Chen G, Fang M, Wei X, Li Y . Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study. Clin Epigenetics. 2020; 12(1):132. PMC: 7466805. DOI: 10.1186/s13148-020-00923-4. View

Swoboda D, Al Ali N, Chan O, Padron E, Kuykendall A, Song J . PTPN11 mutations are associated with poor outcomes across myeloid malignancies. Leukemia. 2020; 35(1):286-288. DOI: 10.1038/s41375-020-01083-3. View

Angenendt L, Rollig C, Montesinos P, Martinez-Cuadron D, Barragan E, Garcia R . Chromosomal Abnormalities and Prognosis in -Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts. J Clin Oncol. 2019; 37(29):2632-2642. PMC: 8462529. DOI: 10.1200/JCO.19.00416. View

Pogosova-Agadjanyan E, Moseley A, Othus M, Appelbaum F, Chauncey T, Chen I . AML risk stratification models utilizing ELN-2017 guidelines and additional prognostic factors: a SWOG report. Biomark Res. 2020; 8:29. PMC: 7425159. DOI: 10.1186/s40364-020-00208-1. View

Newell L, Cook R . Advances in acute myeloid leukemia. BMJ. 2021; 375:n2026. DOI: 10.1136/bmj.n2026. View

George B, Kantarjian H, Baran N, Krocker J, Rios A . in Acute Myeloid Leukemia: Molecular Aspects and Patterns of Mutation. Int J Mol Sci. 2021; 22(19). PMC: 8509740. DOI: 10.3390/ijms221910782. View

10.

Wang J, Lu R, Wu Y, Jia J, Gong L, Liu X . Detection of measurable residual disease may better predict outcomes than mutations based on next-generation sequencing in acute myeloid leukaemia with biallelic mutations of CEBPA. Br J Haematol. 2020; 190(4):533-544. DOI: 10.1111/bjh.16535. View

11.

Pandey R, Saxena M, Kapur R . Role of SHP2 in hematopoiesis and leukemogenesis. Curr Opin Hematol. 2017; 24(4):307-313. PMC: 5709049. DOI: 10.1097/MOH.0000000000000345. View

12.

DiNardo C, Wei A . How I treat acute myeloid leukemia in the era of new drugs. Blood. 2019; 135(2):85-96. DOI: 10.1182/blood.2019001239. View

13.

Pasupuleti S, Chao K, Ramdas B, Kanumuri R, Palam L, Liu S . Potential clinical use of azacitidine and MEK inhibitor combination therapy in PTPN11-mutated juvenile myelomonocytic leukemia. Mol Ther. 2023; 31(4):986-1001. PMC: 10124140. DOI: 10.1016/j.ymthe.2023.01.030. View

14.

Folta A, Culen M, Jeziskova I, Herudkova Z, Tom N, Hlubinkova T . Prognostic significance of mutation profile at diagnosis and mutation persistence during disease remission in adult acute myeloid leukaemia patients. Br J Haematol. 2019; 186(2):300-310. DOI: 10.1111/bjh.15916. View

15.

Bullinger L, Dohner K, Dohner H . Genomics of Acute Myeloid Leukemia Diagnosis and Pathways. J Clin Oncol. 2017; 35(9):934-946. DOI: 10.1200/JCO.2016.71.2208. View

16.

Sun Y, Zhang F, Huo L, Cai W, Wang Q, Wen L . Clinical characteristics and prognostic analysis of acute myeloid leukemia patients with PTPN11 mutations. Hematology. 2022; 27(1):1184-1190. DOI: 10.1080/16078454.2022.2140274. View

17.

Huang S, Chen P, Wang L, Xu L, Jia M, Chen J . Next-generation sequencing revealed factors associated with cumulative incidence of relapse and leukemia-free survival in patients with newly diagnosed acute myeloid leukemia. Cancer Pathog Ther. 2024; 1(1):25-32. PMC: 10846322. DOI: 10.1016/j.cpt.2022.09.003. View

18.

Stasik S, Eckardt J, Kramer M, Rollig C, Kramer A, Scholl S . Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia. Blood Adv. 2021; 5(17):3279-3289. PMC: 8525221. DOI: 10.1182/bloodadvances.2021004631. View

19.

Dou L, Xu Q, Wang M, Xiao Y, Cheng L, Li H . Clinical efficacy of decitabine in combination with standard-dose cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor in the treatment of young patients with newly diagnosed acute myeloid leukemia. Onco Targets Ther. 2019; 12:5013-5023. PMC: 6605041. DOI: 10.2147/OTT.S200005. View

20.

Linch D, Hills R, Burnett A, Russell N, Gale R . Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia. Br J Haematol. 2019; 188(6):852-859. DOI: 10.1111/bjh.16239. View