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Blood Res (2024) 59:41

Published online December 18, 2024

https://doi.org/10.1007/s44313-024-00044-4

© The Korean Society of Hematology

Acute myeloid leukemia and myelodysplastic neoplasms: clinical implications of myelodysplasia-related genes mutations and TP53 aberrations

Hyunwoo Kim1, Ja Young Lee1,2* , Sinae Yu3, Eunkyoung Yoo1, Hye Ran Kim1, Sang Min Lee4 and Won Sik Lee4

1 Department of Laboratory Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea. 2 Paik Institute for Clinical Research, Inje University Busan Paik Hospital, Busan, Korea. 3 Department of Laboratory Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea. 4 Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.

Correspondence to : Ja Young Lee
liring@hanmail.net

Received: August 26, 2024; Accepted: November 5, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Purpose The fifth World Health Organization (WHO) classification (2022 WHO) and International Consensus Classification (ICC) of myeloid neoplasms have recently been published. In this study, patients were reclassified according to the revised classification and their prognoses were analyzed to confirm the clinical utility of the new classifications.
Methods We included 101 adult patients, 77 with acute myeloid leukemia (AML) and 24 with myelodysplastic neoplasms (MDS), who underwent bone marrow aspiration and next-generation sequencing (NGS) between August 2019 and July 2023. We reclassified the patients according to the revised criteria, examined the differences, and analyzed the prognosis using survival analysis.
Results According to the 2022 WHO and ICC, 23 (29.9%) patients and 32 (41.6%) patients were reclassified into different groups, respectively, due to the addition of myelodysplasia-related (MR) gene mutations to the diagnostic criteria or the addition of new entities associated with TP53 mutations. The median overall survival (OS) of patients with AML and MR gene mutations was shorter than that of patients in other AML groups; however, the difference was not significant. Patients with AML and TP53 mutation had a significantly shorter OS than the other AML group (p = 0.0014, median OS 2.3 vs 10.3 months). They also had significantly shorter OS than the AML and MR mutation group (p = 0.002, median OS 2.3 vs 9.6 months).
Conclusion The revised classifications allow for a more detailed categorization based on genetic abnormalities, which may be helpful in predicting prognosis. AML with TP53 mutations is a new ICC category that has shown a high prognostic significance in a small number of cases.

Keywords Acute myeloid leukemia, Gene mutations, International Consensus Classification, World Health Organization

Article

RESEARCH

Blood Res 2024; 59():

Published online December 18, 2024 https://doi.org/10.1007/s44313-024-00044-4

Copyright © The Korean Society of Hematology.

Acute myeloid leukemia and myelodysplastic neoplasms: clinical implications of myelodysplasia-related genes mutations and TP53 aberrations

Hyunwoo Kim1, Ja Young Lee1,2* , Sinae Yu3, Eunkyoung Yoo1, Hye Ran Kim1, Sang Min Lee4 and Won Sik Lee4

1 Department of Laboratory Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea. 2 Paik Institute for Clinical Research, Inje University Busan Paik Hospital, Busan, Korea. 3 Department of Laboratory Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea. 4 Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.

Correspondence to:Ja Young Lee
liring@hanmail.net

Received: August 26, 2024; Accepted: November 5, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Purpose The fifth World Health Organization (WHO) classification (2022 WHO) and International Consensus Classification (ICC) of myeloid neoplasms have recently been published. In this study, patients were reclassified according to the revised classification and their prognoses were analyzed to confirm the clinical utility of the new classifications.
Methods We included 101 adult patients, 77 with acute myeloid leukemia (AML) and 24 with myelodysplastic neoplasms (MDS), who underwent bone marrow aspiration and next-generation sequencing (NGS) between August 2019 and July 2023. We reclassified the patients according to the revised criteria, examined the differences, and analyzed the prognosis using survival analysis.
Results According to the 2022 WHO and ICC, 23 (29.9%) patients and 32 (41.6%) patients were reclassified into different groups, respectively, due to the addition of myelodysplasia-related (MR) gene mutations to the diagnostic criteria or the addition of new entities associated with TP53 mutations. The median overall survival (OS) of patients with AML and MR gene mutations was shorter than that of patients in other AML groups; however, the difference was not significant. Patients with AML and TP53 mutation had a significantly shorter OS than the other AML group (p = 0.0014, median OS 2.3 vs 10.3 months). They also had significantly shorter OS than the AML and MR mutation group (p = 0.002, median OS 2.3 vs 9.6 months).
Conclusion The revised classifications allow for a more detailed categorization based on genetic abnormalities, which may be helpful in predicting prognosis. AML with TP53 mutations is a new ICC category that has shown a high prognostic significance in a small number of cases.

Keywords: Acute myeloid leukemia, Gene mutations, International Consensus Classification, World Health Organization

Fig 1.

Figure 1.Sankey diagram showing the reclassification of patients with (A) acute myeloid leukemia and (B) myelodysplastic neoplasm, from the 2016 World Health Organization (WHO) to the 2022 WHO and International Consensus Classification

Fig 2.

Figure 2.Molecular landscape of patients with acute myeloid leukemia

Fig 3.

Figure 3.Survival analysis of patients with acute myeloid leukemia (AML) and myelodysplasia-related (MR) gene mutations based on the 2022 WHO classification. (A) Survival outcomes between patients with AML and MR mutations and those with other types of AML. (B) Survival outcomes between groups of patients with AML with myelodysplastic changes (MRC), classified according to the 2016 WHO and MR gene mutation criteria in the 2022 WHO, and those with AML, not otherwise specified, according to the 2016 WHO and AML with MR gene mutation in the 2022 WHO. (C) Survival outcomes between groups of patients with AML with MRC based on the 2016 WHO and AML with MR gene mutations in the 2022 WHO, and those with AML with MRC in the 2016 WHO but without MR gene mutation in the 2022 WHO. (D) Survival outcomes between groups of patients of AML with MR gene mutations and cytogenetic abnormalities

Fig 4.

Figure 4.Survival analysis of patients with AML and TP53 mutations based on the international consensus classification. A Survival outcomes between patients in AML with TP53 mutations and other AML group. B Survival outcomes between patients in AML with TP53 mutation and AML with myelodysplasia-related gene mutations

Table 1 . Reclassification of acute myeloid leukemia and myelodysplastic neoplasm based on the 2022 WHO and ICC.

2016 WHON%2022 WHON%ICCN%
AMLRUNX1-RUNX1T133.9%RUNX1::RUNX1T133.9%RUNX1::RUNX1T133.9%
CBFB-MYH1122.6%CBFB::MYH1122.6%CBFB::MYH1122.6%
PML-RARA33.9%PML::RARA45.2%PML::RARA45.2%
DEK-NUP21422.6%DEK::NUP21422.6%DEK::NUP21422.6%
MLLT3-KMT2A45.2%KMT2A rearrangement67.8%MLLT3::KMT2A45.2%
Other KMT2A22.6%
NPM11316.9%NPM1 mutation1316.9%mutated NPM11316.9%
biCEBPA67.8%CEBPA mutation67.8%bZIP CEBPA67.8%
Myelodysplasia-related changes1722.1%Myelodysplasia-related3039.0%MR gene2431.2%
MR cytogenetic abnormalities11.3%
Panmyelosis with myelofibrosis45.2%Blast-phase MPN33.9%NA
NANAmutated TP531013.0%
Not otherwise specified1823.4%Defined by differentiation810.4%Not otherwise specified67.8%
Therapy-related56.5%NANA
MDSSingle lineage dysplasia14.2%Low blasts1041.7%NOS with single lineage dysplasia14.2%
Multilineage dysplasia937.5%NOS with multilineage dysplasia937.5%
Excess blasts-128.3%Increased blasts-128.3%Excess blasts28.3%
Excess blasts-2520.8%Increased blasts-2625.0%MDS/AML28.3%
MDS/AML with MR gene mutations416.7%
MDS/AML with TP53312.5%
Ring sideroblasts14.2%Low blasts and SF3B114.2%SF3B114.2%
NAbiTP53520.8%mutated with TP5328.3%
Unclassifiable14.2%NANA
Therapy-related520.8%NANA

Abbreviations: WHO World Health Organization, ICC International Consensus Classification, AML acute myeloid leukemia, bZIP basic leucine zipper, MR myelodysplasiarelated, NA not applicable, MDS myelodysplastic neoplasm.


Table 2 . Patient characteristics and gene mutations in myelodysplastic neoplasm.

All MDS2022 WHO
Low blastsIncreased blastsbiTP53p
Patients241185
Sex, male: female15:96:56:23:20.656
Age, years (range)73(54–86)73 (56–83)70 (54–85)70 (58–80)0.930
Laboratory findings, median value
White blood cell, × 109/L, median (range)2.48 (0.31–34.12)2.44 (0.31–3.78)2.27 (1.05–34.12)3.46 (1.70–7.87)0.406
Hemoglobin, g/dL, median (range)8.3 (4.1–12.7)9.1 (5.5–11.0)6.9 (5.9–12.7)7.5 (4.1–9.7)0.537
Platelet, × 109/L, median (range)67.5 (6.0–264.0)77.0 (6.0–259.0)57.5 (10.0–264.0)62.0 (21.0–102.0)0.931
Blasts in peripheral blood, %, median (range)0 (0–9)0 (0–1)1 (0–9)3 (0–7)0.004
Blasts in bone marrow, %, median (range)4.8 (0–19.2)2.2 (0–4.5)14.5 (5.1–19.2)13.0 (2.6–13.4)< 0.001
Cytogenetics
Abnormal karyotype, N (%)11 (45.8%)4 (36.4%)3 (37.5%)4 (80.0%)0.226
Complex karyotype, N (%)6 (25.0%)2 (18.2%)0 (0%)4 (80.0%)0.003
Gene mutations
N, median (range)2 (0–7)0 (0–3)4 (0–7)0 (0–2)0.040
Tumor suppressor
TP535 (20.8%)005 (100%)< 0.001
Transcription factors (except MR gene)
RUNX14 (16.7%)04 (42.9%)00.008
CEBPA2 (8.3)02 (28.6%)00.113
Myelodysplasia related genes
ASXL15 (20.8%)05 (62.5%)00.002
BCOR3 (12.5%)1 (9.1%)2 (25.0%)00.373
SF3B12 (8.3%)1 (9.1%)000.725
SRSF22 (8.3%)02 (25.0%)00.113
STAG24 (16.7%)04 (50.0%)00.008
U2AF11 (4.2%)01 (12.5%)00.352
ZRSR21 (4.2%)1 (9.1%)000.540
DNA methylation
DNMT3A3 (12.5%)2 (18.2%)1 (12.5%)00.595
IDH21 (4.2%)01 (12.5%)00.352
TET21 (4.2%)01 (12.5%)00.352
RNA helicase
DDX412 (8.3%)2 (18.2%)000.276

Abbreviations: MDS myelodysplastic neoplasm, WHO World Health Organization, MR myelodysplasia.


Table 3 . Patient characteristics and gene mutations in acute myeloid leukemia.

All AML2022 WHOICC
AML-MRAML-otherspAML-TP53AML-MRAML-othersp
Patients773047102542
Sex, male: female43:3420:1023:240.1968:214:1121:210.229
Age, years (range)67 (19–88)71 (32–87)62 (19–88)0.00269.5 (57–87)71 (32–83)62 (19–88)0.034
Laboratory findings, median value
WBC, × 109/L, median (range)5.94 (0.81–231.1)3.25 (1.03–224.18)13.71(0.81–231.05)0.0053.29 (1.57–26.92)3.33 (1.02–224.18)15.27 (0.81–231.05)0.009
Hemoglobin, g/dL, median (range)8.0 (2.6–15.0)7.9 (2.7–11.0)8.3 (2.6–15.0)0.1548.3 (5.3–9.8)7.8 (2.7–11.0)8.3 (2.6–15.0)0.647
Platelet, × 109/L, median (range)40.0 (3.0–344.0)39.5 (3–143)42.0 (6–344)0.71136.0 (3.0–48.0)51.0 (4.0–143.0)35.0 (6.0–344.0)0.458
Blasts in PB, %, median (range)27 (0–96)18.5 (0–90)30 (0–96)0.3394.5 (0–90)27.0 (0–88)30.0 (0–96)0.218
Blasts in BM, %, median (range)57.4 (13.7–92.7)52.0 (21.2–92.7)60.2 (13.7–91.8)0.13743.7 (23.2–90.3)52.0 (21.2–92.7)60.2 (13.7–91.8)0.511
Cytogenetics
Abnormal karyotype, N (%)45 (58.4%)20 (66.7%)25 (53.2%)0.4588 (80.0%)13 (52.0%)24 (57.1%)0.060
Complex karyotype, N (%)14 (18.2%)13 (43.3%)1 (2.1%)< 0.0018 (80.0%)5 (20.0%)1 (2.4%)< 0.001
Gene mutations
N, median (range)2 (0–9)2.5 (0–6)2 (0–9)0.5571 (1–6)3 (0–6)2 (0–9)0.082
RAS pathway-related
NRAS14 (18.2%)4 (13.3)10 (21.3)0.56304 (16.0%)10 (23.8%)0.202
KRAS5 (6.5%)2 (6.7)3 (6.4)0.67102 (8.0%)3 (7.1%)0.667
KIT2 (2.6%)02 (4.3)0.682002 (4.8%)0.425
FLT3-ITD13 (16.9%)4 (13.3)9 (19.1)0.72504 (16.0%)9 (21.4%)0.264
FLT3-TKD7 (9.1%)1 (3.3)6 (12.8)0.31902 (8.0%)5 (11.9%)0.487
PTPN115 (6.5%)05 (10.6)0.1701 (10.0)04 (9.5%)0.276
Tumor suppressor
TP5311 (14.3%)8 (26.7)3 (6.4)0.03210 (100.0)01 (2.3)< 0.001
PHF61 (1.3%)1 (3.3)00.82001 (4.0%)00.349
WT16 (7.8%)1 (3.3)5 (10.6)0.46501 (4.0%)5 (11.9%)0.311
Transcription factors (except MR gene)
RUNX18 (10.4%)6 (20.0)2 (4.3)0.06808 (32.0%)0< 0.001
CEBPA6 (7.8%)06 (12.8)0.109006 (14.3%)0.067
SETBP11 (1.3%)1 (3.3)00.82001 (4.0%)00.349
GATA24 (5.2%)1 (3.3)3 (6.4)0.95101 (4.0%)3 (7.1%)0.624
Myelodysplasia related
ASXL114 (18.2)9 (30.0)5 (10.6)0.065010 (43.5)4 (9.5%)0.002
BCOR3 (3.9)3 (10.0)00.10803 (12.0%)00.039
SF3B12 (2.6)2 (6.7)00.29002 (8.0%)00.118
SRSF27 (9.1)6 (20.0)1 (2.1)0.0241 (10.0)5 (20.0%)1 (2.4%)0.051
STAG22 (2.6)1 (3.3)1 (2.1)0.68201 (4.0%)1 (2.4%)0.791
U2AF13 (3.9)2 (6.7)1 (2.1)0.6891 (10.0)2 (8.0%)00.148
ZRSR23 (3.9)3 (10.0)00.10803 (12.0%)00.039
DNA methylation
DNMT3A13 (16.9)5 (16.7)8 (17.0)0.7861 (10.0)4 (16.0%)8 (19.0%)0.782
IDH14 (5.2)2 (6.7)2 (4.3)0.95103 (12.0%)1 (2.4%)0.168
IDH214 (18.2)6 (20.0)8 (17.0)0.9781 (10.0)8 (32.0%)5 (11.9%)0.092
TET29 (11.7)4 (13.3)5 (10.6)0.9961 (10.0)4 (16.0%)4 (9.5%)0.716
Risk group by ELN 2022 guideline
Favorable, N (%)20 (26.0)020 (42.6%)< 0.0010020 (47.6%)< 0.001
Intermediate, N (%)18 (23.4)018 (38.3%)0018 (42.9%)
Adverse, N (%)39 (50.6)30 (100%)9 (19.1%)10 (100%)25 (100%)4 (9.5%)

Abbreviations: AML acute myeloid leukemia, WHO World Health Organization, ICC International Consensus Classification, MR myelodysplasia-related, PB peripheral blood, BM bone marrow, ELN European Leukemia Net.


Table 4 . Comparison of survival outcomes in patients with acute myeloid leukemia based on the presence of myelodysplasia-related gene mutations.

GeneNMedian OS (months)Range
ASXL1147.80.5–28.3
BCOR3NA8.2–26.6
SF3B1210.42.6–18.2
SRSF273.850.4–8.2
STAG226.73.3–10.1
U2AF13NA0.6–6.7
ZRSR237.87.2–14.1

Abbreviations: OS overall survival, NA not applicable.


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