Blood Res (2024) 59:41
Published online December 18, 2024
https://doi.org/10.1007/s44313-024-00044-4
© The Korean Society of Hematology
Correspondence to : Ja Young Lee
liring@hanmail.net
© 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/.
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
Blood Res 2024; 59():
Published online December 18, 2024 https://doi.org/10.1007/s44313-024-00044-4
Copyright © The Korean Society of Hematology.
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
© 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/.
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
Table 1 . Reclassification of acute myeloid leukemia and myelodysplastic neoplasm based on the 2022 WHO and ICC.
2016 WHO | N | % | 2022 WHO | N | % | ICC | N | % | |
---|---|---|---|---|---|---|---|---|---|
AML | RUNX1-RUNX1T1 | 3 | 3.9% | RUNX1::RUNX1T1 | 3 | 3.9% | RUNX1::RUNX1T1 | 3 | 3.9% |
CBFB-MYH11 | 2 | 2.6% | CBFB::MYH11 | 2 | 2.6% | CBFB::MYH11 | 2 | 2.6% | |
PML-RARA | 3 | 3.9% | PML::RARA | 4 | 5.2% | PML::RARA | 4 | 5.2% | |
DEK-NUP214 | 2 | 2.6% | DEK::NUP214 | 2 | 2.6% | DEK::NUP214 | 2 | 2.6% | |
MLLT3-KMT2A | 4 | 5.2% | KMT2A rearrangement | 6 | 7.8% | MLLT3::KMT2A | 4 | 5.2% | |
Other KMT2A | 2 | 2.6% | |||||||
NPM1 | 13 | 16.9% | NPM1 mutation | 13 | 16.9% | mutated NPM1 | 13 | 16.9% | |
biCEBPA | 6 | 7.8% | CEBPA mutation | 6 | 7.8% | bZIP CEBPA | 6 | 7.8% | |
Myelodysplasia-related changes | 17 | 22.1% | Myelodysplasia-related | 30 | 39.0% | MR gene | 24 | 31.2% | |
MR cytogenetic abnormalities | 1 | 1.3% | |||||||
Panmyelosis with myelofibrosis | 4 | 5.2% | Blast-phase MPN | 3 | 3.9% | NA | |||
NA | NA | mutated TP53 | 10 | 13.0% | |||||
Not otherwise specified | 18 | 23.4% | Defined by differentiation | 8 | 10.4% | Not otherwise specified | 6 | 7.8% | |
Therapy-related | 5 | 6.5% | NA | NA | |||||
MDS | Single lineage dysplasia | 1 | 4.2% | Low blasts | 10 | 41.7% | NOS with single lineage dysplasia | 1 | 4.2% |
Multilineage dysplasia | 9 | 37.5% | NOS with multilineage dysplasia | 9 | 37.5% | ||||
Excess blasts-1 | 2 | 8.3% | Increased blasts-1 | 2 | 8.3% | Excess blasts | 2 | 8.3% | |
Excess blasts-2 | 5 | 20.8% | Increased blasts-2 | 6 | 25.0% | MDS/AML | 2 | 8.3% | |
MDS/AML with MR gene mutations | 4 | 16.7% | |||||||
MDS/AML with TP53 | 3 | 12.5% | |||||||
Ring sideroblasts | 1 | 4.2% | Low blasts and SF3B1 | 1 | 4.2% | SF3B1 | 1 | 4.2% | |
NA | biTP53 | 5 | 20.8% | mutated with TP53 | 2 | 8.3% | |||
Unclassifiable | 1 | 4.2% | NA | NA | |||||
Therapy-related | 5 | 20.8% | NA | NA |
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 MDS | 2022 WHO | ||||
---|---|---|---|---|---|
Low blasts | Increased blasts | biTP53 | p | ||
Patients | 24 | 11 | 8 | 5 | |
Sex, male: female | 15:9 | 6:5 | 6:2 | 3:2 | 0.656 |
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 | |||||
TP53 | 5 (20.8%) | 0 | 0 | 5 (100%) | < 0.001 |
Transcription factors (except MR gene) | |||||
RUNX1 | 4 (16.7%) | 0 | 4 (42.9%) | 0 | 0.008 |
CEBPA | 2 (8.3) | 0 | 2 (28.6%) | 0 | 0.113 |
Myelodysplasia related genes | |||||
ASXL1 | 5 (20.8%) | 0 | 5 (62.5%) | 0 | 0.002 |
BCOR | 3 (12.5%) | 1 (9.1%) | 2 (25.0%) | 0 | 0.373 |
SF3B1 | 2 (8.3%) | 1 (9.1%) | 0 | 0 | 0.725 |
SRSF2 | 2 (8.3%) | 0 | 2 (25.0%) | 0 | 0.113 |
STAG2 | 4 (16.7%) | 0 | 4 (50.0%) | 0 | 0.008 |
U2AF1 | 1 (4.2%) | 0 | 1 (12.5%) | 0 | 0.352 |
ZRSR2 | 1 (4.2%) | 1 (9.1%) | 0 | 0 | 0.540 |
DNA methylation | |||||
DNMT3A | 3 (12.5%) | 2 (18.2%) | 1 (12.5%) | 0 | 0.595 |
IDH2 | 1 (4.2%) | 0 | 1 (12.5%) | 0 | 0.352 |
TET2 | 1 (4.2%) | 0 | 1 (12.5%) | 0 | 0.352 |
RNA helicase | |||||
DDX41 | 2 (8.3%) | 2 (18.2%) | 0 | 0 | 0.276 |
Abbreviations: MDS myelodysplastic neoplasm, WHO World Health Organization, MR myelodysplasia.
Table 3 . Patient characteristics and gene mutations in acute myeloid leukemia.
All AML | 2022 WHO | ICC | ||||||
---|---|---|---|---|---|---|---|---|
AML-MR | AML-others | p | AML-TP53 | AML-MR | AML-others | p | ||
Patients | 77 | 30 | 47 | 10 | 25 | 42 | ||
Sex, male: female | 43:34 | 20:10 | 23:24 | 0.196 | 8:2 | 14:11 | 21:21 | 0.229 |
Age, years (range) | 67 (19–88) | 71 (32–87) | 62 (19–88) | 0.002 | 69.5 (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) | 0.005 | 3.29 (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) | 0.154 | 8.3 (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) | 0.711 | 36.0 (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) | 0.339 | 4.5 (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) | 0.137 | 43.7 (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%) | 0.458 | 8 (80.0%) | 13 (52.0%) | 24 (57.1%) | 0.060 |
Complex karyotype, N (%) | 14 (18.2%) | 13 (43.3%) | 1 (2.1%) | < 0.001 | 8 (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) | 0.557 | 1 (1–6) | 3 (0–6) | 2 (0–9) | 0.082 |
RAS pathway-related | ||||||||
NRAS | 14 (18.2%) | 4 (13.3) | 10 (21.3) | 0.563 | 0 | 4 (16.0%) | 10 (23.8%) | 0.202 |
KRAS | 5 (6.5%) | 2 (6.7) | 3 (6.4) | 0.671 | 0 | 2 (8.0%) | 3 (7.1%) | 0.667 |
KIT | 2 (2.6%) | 0 | 2 (4.3) | 0.682 | 0 | 0 | 2 (4.8%) | 0.425 |
FLT3-ITD | 13 (16.9%) | 4 (13.3) | 9 (19.1) | 0.725 | 0 | 4 (16.0%) | 9 (21.4%) | 0.264 |
FLT3-TKD | 7 (9.1%) | 1 (3.3) | 6 (12.8) | 0.319 | 0 | 2 (8.0%) | 5 (11.9%) | 0.487 |
PTPN11 | 5 (6.5%) | 0 | 5 (10.6) | 0.170 | 1 (10.0) | 0 | 4 (9.5%) | 0.276 |
Tumor suppressor | ||||||||
TP53 | 11 (14.3%) | 8 (26.7) | 3 (6.4) | 0.032 | 10 (100.0) | 0 | 1 (2.3) | < 0.001 |
PHF6 | 1 (1.3%) | 1 (3.3) | 0 | 0.820 | 0 | 1 (4.0%) | 0 | 0.349 |
WT1 | 6 (7.8%) | 1 (3.3) | 5 (10.6) | 0.465 | 0 | 1 (4.0%) | 5 (11.9%) | 0.311 |
Transcription factors (except MR gene) | ||||||||
RUNX1 | 8 (10.4%) | 6 (20.0) | 2 (4.3) | 0.068 | 0 | 8 (32.0%) | 0 | < 0.001 |
CEBPA | 6 (7.8%) | 0 | 6 (12.8) | 0.109 | 0 | 0 | 6 (14.3%) | 0.067 |
SETBP1 | 1 (1.3%) | 1 (3.3) | 0 | 0.820 | 0 | 1 (4.0%) | 0 | 0.349 |
GATA2 | 4 (5.2%) | 1 (3.3) | 3 (6.4) | 0.951 | 0 | 1 (4.0%) | 3 (7.1%) | 0.624 |
Myelodysplasia related | ||||||||
ASXL1 | 14 (18.2) | 9 (30.0) | 5 (10.6) | 0.065 | 0 | 10 (43.5) | 4 (9.5%) | 0.002 |
BCOR | 3 (3.9) | 3 (10.0) | 0 | 0.108 | 0 | 3 (12.0%) | 0 | 0.039 |
SF3B1 | 2 (2.6) | 2 (6.7) | 0 | 0.290 | 0 | 2 (8.0%) | 0 | 0.118 |
SRSF2 | 7 (9.1) | 6 (20.0) | 1 (2.1) | 0.024 | 1 (10.0) | 5 (20.0%) | 1 (2.4%) | 0.051 |
STAG2 | 2 (2.6) | 1 (3.3) | 1 (2.1) | 0.682 | 0 | 1 (4.0%) | 1 (2.4%) | 0.791 |
U2AF1 | 3 (3.9) | 2 (6.7) | 1 (2.1) | 0.689 | 1 (10.0) | 2 (8.0%) | 0 | 0.148 |
ZRSR2 | 3 (3.9) | 3 (10.0) | 0 | 0.108 | 0 | 3 (12.0%) | 0 | 0.039 |
DNA methylation | ||||||||
DNMT3A | 13 (16.9) | 5 (16.7) | 8 (17.0) | 0.786 | 1 (10.0) | 4 (16.0%) | 8 (19.0%) | 0.782 |
IDH1 | 4 (5.2) | 2 (6.7) | 2 (4.3) | 0.951 | 0 | 3 (12.0%) | 1 (2.4%) | 0.168 |
IDH2 | 14 (18.2) | 6 (20.0) | 8 (17.0) | 0.978 | 1 (10.0) | 8 (32.0%) | 5 (11.9%) | 0.092 |
TET2 | 9 (11.7) | 4 (13.3) | 5 (10.6) | 0.996 | 1 (10.0) | 4 (16.0%) | 4 (9.5%) | 0.716 |
Risk group by ELN 2022 guideline | ||||||||
Favorable, N (%) | 20 (26.0) | 0 | 20 (42.6%) | < 0.001 | 0 | 0 | 20 (47.6%) | < 0.001 |
Intermediate, N (%) | 18 (23.4) | 0 | 18 (38.3%) | 0 | 0 | 18 (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.
Gene | N | Median OS (months) | Range |
---|---|---|---|
ASXL1 | 14 | 7.8 | 0.5–28.3 |
BCOR | 3 | NA | 8.2–26.6 |
SF3B1 | 2 | 10.4 | 2.6–18.2 |
SRSF2 | 7 | 3.85 | 0.4–8.2 |
STAG2 | 2 | 6.7 | 3.3–10.1 |
U2AF1 | 3 | NA | 0.6–6.7 |
ZRSR2 | 3 | 7.8 | 7.2–14.1 |
Abbreviations: OS overall survival, NA not applicable.
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