Prognosis and Risk Factors for ASXL1 Mutations in Patients with Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Syndrome

Overview

Journal Cancer Med

Specialty Oncology

Date 2023 Dec 26

PMID 38146893

Authors

Liqing Yang

Xiaoyu Wei

Yuping Gong

Affiliations

Soon will be listed here.

Abstract

Objective: The objective of the study was to determine the prognosis and risk factors for additional sex combs like 1 (ASXL1) mutations in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Population And Methods: This retrospective study enrolled 219 adult patients with newly diagnosed AML and MDS, who were treated in West China Hospital from October 2018 to January 2022. The primary clinical outcome was evaluated by overall survival (OS) followed up to January 2023. Kaplan-Meier analysis and Cox multivariate regression analysis were performed to identify potential prognostic parameters in patients with ASXL1 mutations (mt).

Results: A total of 34 (15.53%) ASXL1 were detected, which occurred more frequently in the elderly and MDS cohorts (p < 0.001). Significantly lower blasts% (p < 0.001) and higher frequencies of mutant RUNX1, SRSF2, STAG2, EZH2, and SETBP1 (p < 0.02) were observed in the ASXL1 cohort. Patients with ASXL1 manifested with a worse complete remission rate (p = 0.011), and an inferior OS was shown in subgroups with MDS, co-mutations of RUNX1, SRSF2, or NRAS, as well as mutations in G646W (p < 0.05). Multivariate analysis considering age, diagnosis, co-mutations, and mutation site confirmed an independently adverse prognosis of mutations in G646W (HR = 4.302, 95% CI: 1.150-16.097) or RUNX1 co-mutations (HR = 4.620, 95% CI: 1.385-15.414) in the ASXL1 cohort.

Conclusion: Our study indicated that mutations in G646W or RUNX1 co-mutations are closely associated with a dismal clinical outcome in patients with AML and MDS harboring ASXL1. Considering the poor prognosis and risk factors in patients with ASXL1, more available treatments should be pursued.

Citing Articles

Impact of ASXL1 Gene Alterations on Myelodysplastic Syndrome With Isolated 20q Deletion.

Chang Y, Liu L, Cui C, He J, Li C, Jia Y Cancer Med. 2025; 14(5):e70747.

PMID: 40047093 PMC: 11883421. DOI: 10.1002/cam4.70747.

Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.

Yang L, Wei X, Gong Y Cancer Med. 2023; 13(1):e6871.

PMID: 38146893 PMC: 10807681. DOI: 10.1002/cam4.6871.

References

Hoischen A, van Bon B, Rodriguez-Santiago B, Gilissen C, Vissers L, De Vries P . De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet. 2011; 43(8):729-31. DOI: 10.1038/ng.868. View

Kuusanmaki H, Leppa A, Polonen P, Kontro M, Dufva O, Deb D . Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. Haematologica. 2019; 105(3):708-720. PMC: 7049363. DOI: 10.3324/haematol.2018.214882. View

Zhang A, Wang S, Ren Q, Wang Y, Jiang Z . Prognostic value of ASXL1 mutations in patients with myelodysplastic syndromes and acute myeloid leukemia: A meta-analysis. Asia Pac J Clin Oncol. 2022; 19(5):e183-e194. DOI: 10.1111/ajco.13897. View

Micol J, Pastore A, Inoue D, Duployez N, Kim E, Chun-Wei Lee S . ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia. Nat Commun. 2017; 8:15429. PMC: 5454368. DOI: 10.1038/ncomms15429. View

Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci M, Birnbaum D . Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012; 5:12. PMC: 3355025. DOI: 10.1186/1756-8722-5-12. View

Bai J, Chen Z, Chen C, Zhang M, Zhang Y, Song J . Reducing hyperactivated BAP1 attenuates mutant ASXL1-driven myeloid malignancies in human haematopoietic cells. Cancer Lett. 2021; 519:78-90. DOI: 10.1016/j.canlet.2021.06.019. View

Dohner H, Wei A, Appelbaum F, Craddock C, DiNardo C, Dombret H . Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022; 140(12):1345-1377. DOI: 10.1182/blood.2022016867. View

Chou W, Huang H, Hou H, Chen C, Tang J, Yao M . Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood. 2010; 116(20):4086-94. DOI: 10.1182/blood-2010-05-283291. View

Sallman D, Komrokji R, Cluzeau T, Vaupel C, Al Ali N, Lancet J . ASXL1 frameshift mutations drive inferior outcomes in CMML without negative impact in MDS. Blood Cancer J. 2017; 7(12):633. PMC: 5802523. DOI: 10.1038/s41408-017-0004-0. View

10.

Khoury J, Solary E, Abla O, Akkari Y, Alaggio R, Apperley J . The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022; 36(7):1703-1719. PMC: 9252913. DOI: 10.1038/s41375-022-01613-1. View

11.

Yonal-Hindilerden I, Daglar-Aday A, Akadam-Teker B, Yilmaz C, Nalcaci M, Yavuz A . Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms. J Blood Med. 2015; 6:157-75. PMC: 4459634. DOI: 10.2147/JBM.S78826. View

12.

Wu P, Weng J, Li M, Lu Z, Deng C, Sun Q . Co-occurrence of RUNX1 and ASXL1 mutations underlie poor response and outcome for MDS patients treated with HMAs. Am J Transl Res. 2019; 11(6):3651-3658. PMC: 6614648. View

13.

Sasaki K, Kanagal-Shamanna R, Montalban-Bravo G, Assi R, Jabbour E, Ravandi F . Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. Cancer. 2019; 126(4):765-774. DOI: 10.1002/cncr.32566. View

14.

Hamadou W, Abed R, Besbes S, Bourdon V, Fabre A, Youssef Y . Familial hematological malignancies: ASXL1 gene investigation. Clin Transl Oncol. 2015; 18(4):385-90. DOI: 10.1007/s12094-015-1379-7. View

15.

Yang L, Wei X, Gong Y . Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Cancer Med. 2023; 13(1):e6871. PMC: 10807681. DOI: 10.1002/cam4.6871. View

16.

Ni J, Hong J, Long Z, Li Q, Xia R, Zeng Q . Mutation profile and prognostic relevance in elderly patients with de novo acute myeloid leukemia treated with decitabine-based chemotherapy. Int J Lab Hematol. 2020; 42(6):849-857. DOI: 10.1111/ijlh.13299. View

17.

Bhansali R, Pratz K, Lai C . Recent advances in targeted therapies in acute myeloid leukemia. J Hematol Oncol. 2023; 16(1):29. PMC: 10039574. DOI: 10.1186/s13045-023-01424-6. View

18.

Bejar R . What biologic factors predict for transformation to AML?. Best Pract Res Clin Haematol. 2018; 31(4):341-345. DOI: 10.1016/j.beha.2018.10.002. View

19.

Seiter K, Htun K, Baskind P, Liu Z . Acute myeloid leukemia in a father and son with a germline mutation of . Biomark Res. 2018; 6:7. PMC: 5809979. DOI: 10.1186/s40364-018-0121-3. View

20.

Duployez N, Micol J, Boissel N, Petit A, Geffroy S, Bucci M . Unlike ASXL1 and ASXL2 mutations, ASXL3 mutations are rare events in acute myeloid leukemia with t(8;21). Leuk Lymphoma. 2015; 57(1):199-200. DOI: 10.3109/10428194.2015.1037754. View