급성골수성백혈병의 개정된 세계보건기구 기준에 의한 대규모 환자군의 분류: 재분류된 사례의 빈도 및 특성
Revised World Health Organization Criteria-Defined Acute Myeloid Leukemia in a Large Cohort: Highlighting the Frequency and Characterization of Recategorized Cases
울산대학교 의과대학 서울아산병원 진단검사의학과1, 경희대학교 의과대학 강동경희대학교병원 진단검사의학과2
Department of Laboratory Medicine1, University of Ulsan, College of Medicine and Asan Medical Center, Seoul; Department of Laboratory Medicine2, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul, KoreaCorrespondence to:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lab Med Online 2021; 11(2): 115-123
Published April 1, 2021
Copyright © The Korean Society for Laboratory Medicine.
방법: 기존 및 개정된 WHO 기준에 따라 환자군을 다음 7가지 범주로 나누었다: 반복유전자이상 AML (AML with recurrent genetic abnormalities, RGA), 골수형성이상관련 AML (AML with myelodysplasia-related changes, MRC), 치료관련 AML, 상세불명 AML (AML not otherwise speci ed, NOS), 다운증후군관련 AML, 아형미결정 AML, 그리고 MDS.
결과: 총 1,185예의 AML 증례를 검토하였다. 두 기준 사이의 일치율은 93.4%이었다. 78예의 불일치 사례 중 가장 흔한 패턴 3개는 RGA에서 NOS, MRC에서 MDS, 그리고 MRC에서 RGA이었으며, 각각 CEBPA 단일 돌연변이, 적백혈병(erythroleukemia), 그리고 골수형성이상을 보이는 반복유전자이상으로 인한 불일치였다. MDS 위주 치료보다 항암화학요법으로 임상적 이득을 취할 수 있는 NPM1 돌연변이 동반 적백혈병이 3예에서 확인되었다. 그리고 결실된 유전자의 홑배수부전(haploinsuf ciency) 혹은 유전자 사이의 상호작용을 통해 백혈병을 유발할 수 있는 9번 염색체 장완의 결실이 환자의 3%에서 확인되었다.
결론: 본 연구를 통해 AML 환자의 약 7%에서 새로운 질환명의 도입, 변경된 정의, 그리고 정밀한 하위범주화로 인해 다른 범주로 재분류됨을 확인하였다. 이에 따라 다음 개정 시에는 추가적인 세밀한 개선이 고려되어야 할 것이다.
Methods: We divided the patients into the following seven categories based on the previous and the revised WHO criteria: AML with recurrent genetic abnormalities (RGA), AML with myelodysplasia-related changes (MRC), therapy-related AML, AML not otherwise specified (NOS), AML associated with Down syndrome, AML with subcategory not determined, and myelodysplastic syndrome (MDS).
Results: In total, 1,185 AML cases were reviewed. The concordance rate in categorization between the two criteria was 93.4%. Among 78 discrepant cases, the three most common discrepancy patterns were for the RGA to NOS, MRC to MDS, and MRC to RGA, representing cases with a single mutation in CEBPA, erythroleukemia, and recurrent genetic abnormalities showing myelodysplasia, respectively. We identified three cases of erythroleukemia harboring an NPM1 mutation, who might clinically benefit from chemotherapy rather than MDS-oriented treatment; we also found AML with del(9q) in 3% of patients, which might contribute to leukemogenesis either via haploinsufficiency of deleted genes or gene-to-gene interaction.
Conclusions: This study revealed that approximately 7% of patients with AML were reclassified into a different category due to the introduction of new entities, changed definitions, and refined subcategorization. Therefore, further refinement should be considered during the next revision.
The key updates in the revised 2016 WHO criteria for the recategorization of acute myeloid leukemia (AML) are as follows [1-3]. 1) Two new provisional entities, AML with
Since the publication of the revised 2016 WHO criteria, several studies have been undertaken on AML reclassification [4-9]. Half of these studies have investigated erythroleukemia or erythroid-dominant AML, the subtype that underwent critical changes in the revised criteria [4, 6, 7]. The remaining studies have focused on cases harboring a
MATERIALS AND METHODS
The BM archive of our laboratory was searched for newly diagnosed patients with AML from January 2009 to December 2018. We reviewed patient data including karyotype, presence of multilineage dysplasia (MLD), mutational status (
2. Mutational analyses and cytogenetics
3. Statistical analyses
Descriptive statistics including frequency and distribution were calculated. A Sankey diagram was drawn using R and an R package, ‘ggplot2,’ was used to visualize the pattern of recategorization. Overall survival (OS) was calculated from the date of diagnosis to the date of death (uncensored) or the last follow-up (censored). OS was compared using a log-rank test and plotted using Kaplan-Meier curves. Results with
1. Frequency of categorization in patients with AML
Based on the 2008 WHO criteria, the number of patients in each category was as follows: RGA 551 (46.5%), MRC 327 (27.6%), NOS 211 (17.8%), TR 47 (4.0%), DS 4 (0.3%), and ND 45 (3.8%). Based on the revised criteria, the number of patients in each category was as follows: RGA 542 (45.7%), MRC 286 (24.1%), NOS 237 (20.0%), TR 46 (3.9%), DS 4 (0.3%), MDS 25 (2.1%), and ND 45 (3.8%). The ND category was obtained using the incomplete mutation (
Figure 1. Comparison of categorization based on the previous and revised WHO criteria. Categories based on the previous 2008 WHO criteria are shown on the left, and categories based on the revised 2016 WHO criteria are shown on the right. The gradient colors represent the diagnostic categories and the widths of the bands are proportional to the counts of cases in each category based on the previous and revised criteria.
Abbreviations: RGA, AML with recurrent genetic abnormalities; MRC, AML with myelodysplasia-related changes; NOS, AML not otherwise specified; TR, therapy-related AML; ND, AML with subcategory not determined; DS, AML associated with Down syndrome.
2. Features and categorization patterns of discrepant cases
Table 1 summarizes the recategorization patterns of discrepant cases and their details. Among the discrepancies, RGA to NOS (N=28, 35.9%) was the most common recategorization and included cases with a single mutation of
3. Characterization of specific subtypes
We further analyzed the categorization patterns in patients with specific subtypes that underwent critical changes in the revised 2016 criteria. Patients with
Figure 2. Pattern and frequency of categorization in AML patients with (A)
NPM1mutation, (B) CEBPAbi mutation, (C) del(9q), and (D) erythroleukemia. The black-brimmed pieces indicate a discrepancy and non-brimmed pieces indicate an agreement. There may be overlapping cases in each patient group.
Abbreviations: RGA, AML with recurrent genetic abnormalities; MRC, AML with myelodysplasia-related changes; NOS, AML not otherwise specified; TR, therapy-related AML; ND, AML with subcategory not determined;
CEBPAbi, biallelic CEBPA.
Figure 3. Influence of MDS history on the outcomes of patients with AML harboring gene mutations identified in the MRC to RGA recategorization. Kaplan-Meier plots for overall survival according to the defining criteria for the MRC category using the 2008 WHO criteria, including multilineage dysplasia or del(9q) (N=9) and a prior history of MDS or MDS/MPN (N=6).
Abbreviations: MRC, AML with myelodysplasia-related changes; RGA, AML with recurrent genetic abnormalities; MDS/MPN, myelodysplastic/myeloproliferative neoplasm.
Patients harboring del(9q) (N=36, 3.0% of all patients) revealed 27 (75.0%) agreements and 9 (25.0%) discrepancies. In total, 22 patients (61.1%) were categorized as MRC using the previous criteria and were split into MRC (N=13, 36.1%), RGA (N=5, 13.9%), NOS (N=2, 5.6%), ND (N=1, 2.8%), and MDS (N=1, 2.8%) using the revised criteria. Among these, five cases in the MRC to RGA recategorization included those with
According to the revised 2016 criteria, the 2008 criteria-defined patients with AML were most commonly categorized as RGA (45.7%), followed by MRC (24.1%), NOS (20.0%), TR (3.9%), ND (3.8%), MDS (2.1%), and DS (0.3%). The discrepancy rate between the two criteria was 6.6%. The RGA to NOS (35.9% of discrepancy) recategorization was the most common and represented cases with
The frequency of discrepancy (approximately 7%) was not high between the two classification systems because the revision largely inherited the concept of the previous criteria and incorporated clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics to define the disease entities of clinical significance. This frequency is largely in line with the discrepancy frequency (8.9%) of a recent study that performed categorization using two classification systems in 610 patients . The RGA to NOS and MRC to MDS recategorizations were anticipated consequences. However, further discussion is required regarding the MRC to RGA recategorization. This is partly due to the result of classifying the newly-introduced subtype, AML with
Del(9q) is a recurrent cytogenetic abnormality in AML and accounts for approximately 2% of unselected cases . It is enriched in core binding factor AML, particularly in t(8;21), or patients with
A vast majority of erythroleukemia cases were recategorized as MDS in the present study. This finding is consistent with a recent study in which 30 (88.2%) of 34
In conclusion, the present study highlights that applying the revised 2016 WHO criteria identified discrepancies in categorization using the previous criteria in approximately 7% of patients with AML. The study demonstrated that these discrepancies were due to the introduction of new entities, changed definitions, and refined subcategorization. Further refinement could be considered for the next version of the WHO criteria, including the precedence of a history of MDS over
Abbreviations: MRC, AML with myelodysplasia-related changes; NOS, AML not otherwise specified; RGA, AML with recurrent genetic abnormalities.
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