Comparison of the 2022 World Health Organization Classification and International Consensus Classification in Myelodysplastic Syndromes/Neoplasms

doi:10.21203/rs.3.rs-3795533/v1

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Comparison of the 2022 World Health Organization Classification and International Consensus Classification in Myelodysplastic Syndromes/Neoplasms

https://doi.org/10.21203/rs.3.rs-3795533/v1

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published 09 Apr, 2024

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In 2022, two novel classification systems for myelodysplastic syndromes/neoplasms (MDS) have been proposed: the International Consensus Classification (ICC) and the 2022 World Health Organization (WHO-2022) classification. These two contemporary systems exhibit numerous shared features but also diverge significantly in terminology and the definition of new entities. Thus, we retrospectively validated the ICC and WHO-2022 classification and found that both systems promoted efficient segregation of this heterogeneous disease. After examining the distinction between the two systems, we showed that a peripheral blood blast percentage ≥ 5% indicates adverse survival. Identifying MDS/acute myeloid leukemia with MDS-related gene mutations or cytogenetic abnormalities helps differentiate survival outcomes. In MDS, not otherwise specified patients, those diagnosed with hypoplastic MDS displayed a trend of superior survival compared to other low-risk MDS patients. Furthermore, the impact of bone marrow fibrosis on survival was less pronounced within the ICC framework. Allogeneic transplantation appears to improve outcomes for patients diagnosed with MDS with excess blasts in the ICC and those with MDS with increased blasts in WHO-2022 classification. Therefore, we proposed an integrated system that may lead to the accurate diagnosis and advancement of future research for MDS. Prospective studies are warranted to validate this refined classification.

Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome

Biological sciences/Genetics/Clinical genetics/Genetic testing

myelodysplastic syndromes/neoplasms

WHO-2022 classification

International Consensus Classification

prognosis

Myelodysplastic neoplasms (MDS) are a diverse set of clonal myeloid neoplasms with dysregulated hematopoiesis, causing cytopenia and dysplastic hematopoietic cells. MDS is marked by recurrent chromosomal abnormalities, clinical and genetic diversity, and varying prognoses (1, 2). The classification criteria for hematopoietic neoplasms, including MDS, were collated, beginning with the third edition of the World Health Organization (WHO) classification of hematologic malignancies in 2001 (3–5). In 2016, the WHO, in collaboration with the Society for Hematopathology and the European Association for Hematopathology, published the revised fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO-2016) (6).

Recently, major advances in molecular technology and the development of next-generation sequencing (NGS) have deepened our understanding of MDS pathobiology (7, 8). Revisions to the current classification system are needed for precise diagnosis, classification, and prognostication. Hence, the International Consensus Classification (ICC), developed with input from a global Clinical Advisory Committee of pathologists, hematologists, oncologists, and geneticists, was published in 2022 (9). The ICC's innovative changes in MDS include reclassifying MDS with 10–19% blasts as MDS/acute myeloid leukemia (AML), MDS with mutated SF3B1 without excess blasts as MDS-SF3B1 regardless of ring sideroblast count, and introducing novel molecular categories like myeloid neoplasms with mutated TP53, and MDS/AML with MDS-related gene mutations. Concurrently, the 5th edition of the WHO (WHO-2022) classification was released (10). Emphasizing molecular features, tissue architecture, and histological appearance, WHO-2022 classification introduced new categories, including MDS with biallelic TP53 inactivation (MDS-biTP53), hypoplastic MDS (MDS-h), and MDS with fibrosis (MDS-f) (10). These two systems exhibit several shared features but also differ significantly. The term MDS with increased blasts-2 remains in WHO-2022 classification but changes to MDS/AML in the ICC. Moreover, the ICC requires a 10% blast threshold to define AML with recurrent genetic abnormalities (excluding BCR::ABL and TP53), unlike WHO-2022, where most AML with defining genetic abnormalities can be diagnosed regardless of blast count. Additionally, a novel risk-scoring system, the Molecular IPSS (IPSS-M), combining clinical parameters, cytogenetic abnormalities, and somatic mutations of 31 genes, was established, stratifying MDS patients into six risk categories (11).

Few studies have concurrently explored the ICC and WHO-2022 classification within the IPSS-M context, evaluating their differences. This study retrospectively reviewed a cohort of 635 patients diagnosed with primary MDS using WHO-2016, WHO-2022, and ICC criteria. We elucidated differences in clinical characteristics, IPSS-M category distribution, genetic features, and outcomes among MDS subtypes per ICC and WHO-2022 classification and further compared these systems' applicability in the IPSS-M framework.

A total of 635 patients with primary MDS whose bone marrow (BM) samples were adequately cryopreserved for deep-targeted sequencing were included, and available data for the revised IPSS (IPSS-R) (12) and IPSS-M (11) risk assessments were obtained. Patients with prior chemotherapy/radiotherapy or hematologic malignancies were excluded, considering the distinct mutational profiles of primary and secondary MDS (13, 14). BM cellularity and the grade of fibrosis were evaluated by reticulin staining and confirmed by pathologists. The Research Ethics Committee of the National Taiwan University Hospital approved this study (approval numbers: 201709072RINC, 202109078RINB, and 20220705RINB), and all participants provided written informed consent in accordance with the Declaration of Helsinki.

Cytogenetic analyses were performed and interpreted according to the International System for Human Cytogenetic Nomenclature (15, 16). The TruSight myeloid sequencing panel (Illumina, San Diego, CS, USA) and HiSeq platform (Illumina, San Diego, CA, USA) were used to analyze alterations in 54 myeloid-neoplasm-related genes (18) (Supplemental Table 1). Five of the residual genes (ETNK1, GNB1, NF1, PPM1D, and PRPF8) defined by the IPSS-M model were not included in the current study. Library preparation and sequencing were performed according to the manufacturer’s instructions. The median reading depth was 10550x. Somatic mutations were cataloged using cancer database v86, SNP database v151, ClinVar, PolyPhen-2, and SIFT algorithms for variant consequence evaluation. The variant analysis algorithm for diagnostics is previously described (19). NGS limitations necessitated FLT3-ITD analysis via polymerase chain reaction (PCR) and fluorescence capillary electrophoresis and KMT2A-PTD analysis via PCR and Sanger sequencing(16, 20).

Statistical analysis

The Mann–Whitney U test was used for continuous variables, and Fisher’s exact test or the χ² test was used for discrete variables. The Kruskal-Wallis test was used to identify any significant disparities in medians among three or more groups. Leukemia-free survival (LFS) was defined as the interval between the date of diagnosis and the last follow-up, documented leukemic transformation, or death from any cause, whichever occurred first. Overall survival (OS) was defined as the interval between the date of diagnosis and the last follow-up or death from any cause, whichever occurred first. Survival curves were plotted using Kaplan-Meier analysis, and statistical significance was calculated using the log-rank test. The Cox proportional hazards model was used for univariable and multivariable analyses. Allogeneic hematopoietic stem cell transplantation (HSCT) was used as a time-dependent covariate (21). All P-values were two-sided and considered statistically significant at P < 0.05. All analyses were performed using IBM SPSS Statistics v23 for Windows.

Case allocation according to the ICC and 2022-WHO classification

The classification of the 635 patients diagnosed as having primary MDS based on the WHO-2016 classification and case allocation using the ICC and WHO-2022 criteria are presented in Table 1 and Fig. 1. In the ICC, 74.5% of patients remained in the MDS group, while 25.5% of patients were reclassified to the MDS/AML group. In the WHO-2016 classification, the MDS-5q subgroup was renamed to MDS with del(5q) in the ICC and MDS with low blasts and isolated 5q deletion in WHO-2022 classification. Nine (20.0%) patients in both the MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD) and MDS-RS and multilineage dysplasia (MDS-RS-MLD) subgroups, all with wild-type SF3B1, were distinguished from those with mutated SF3B1 (Table 1). One patient in the MDS-RS-MLD group harboring biallelic TP53 mutations experienced rapid progression to AML within three months.

Table 1

Case allocation from 2016 World Health Organization classification to 2022 International Consensus Classification and 2022 World Health Organization classification of 635 patients with myelodysplastic syndromes/neoplasms
WHO-2016	n (%)	ICC	n = 635	WHO-2022	n (%)
MDS-5q	4 (100)	MDS with del(5q)	4	MDS-5q	4 (100%)
MDS-SLD	4 (6.8)	MDS with mutated SF3B1	59	MDS-SF3B1	59 (100%)
MDS-MLD	3 (5.1)
MDS-RS-SLD	36 (61.0)
MDS-RS-MLD	16 (27.1)
MDS-SLD	90 (84.9)	MDS, NOS, with SLD	106	MDS-LB and RS	9 (8.5)
MDS-RS-SLD	9 (8.5)			MDS-LB	58 (54.7)
MDS-U	7 (6.6)			MDS-h	39 (36.8)
MDS-MLD	138 (93.9)	MDS, NOS, with MLD	147	MDS-SF3B1	3 (2.0)
MDS-RS-MLD	9 (6.1)			MDS-LB and RS	7 (4.8)
				MDS-LB	82 (55.8)
				MDS-h	55 (37.4)
MDS-EB1	108 (82.4)	MDS with EB	131	MDS-IB1	99 (75.6)
MDS-EB2	23 (17.6)			MDS-IB2	19 (14.5)
				MDS-f	13 (9.9)
MDS-RS-MLD	1 (4.3)	MDS with mutated TP53	23	MDS-biTP53	17 (73.9)
MDS-EB1	18 (78.3)			MDS-IB1	1 (4.3)
MDS-EB2	4 (17.4)			MDS-IB2	1 (4.3)
				MDS-f	4 (17.4)
MDS-EB2	37 (100)	MDS/AML with mutated TP53	37	MDS-biTP53	29 (78.4)
MDS-EB2	37 (100)	MDS/AML with mutated TP53	37	MDS-IB2	8 (21.6)
MDS-EB2	93 (100)	MDS/AML with MDS-related gene*	93	MDS-IB2	87 (93.5)
MDS-EB2	93 (100)	MDS/AML with MDS-related gene*	93	MDS-f	6 (6.5)
MDS-EB2	12 (100)	MDS/AML with MDS-related cytogenetics^†	12	MDS-IB2	12 (100)
MDS-EB2	20 (100)	MDS/AML, NOS	20	MDS-IB2	19 (95.0)
MDS-EB2	20 (100)	MDS/AML, NOS	20	MDS-f	1 (5.9)
MDS-EB2	3 (10)	AML with CEBPA	3	MDS-IB2	3 (100)
Abbreviations: AML, acute myeloid leukemia; EB, excess of blasts; ICC, International Consensus Classification; MDS, myelodysplastic syndromes/neoplasms; MDS-RS, MDS with ring sideroblasts; MDS-EB, MDS with excess blasts; MDS-SLD, MDS with single lineage dysplasia; MDS-MLD, MDS with multilineage dysplasia; MDS-RS-SLD, MDS with ring sideroblasts and single lineage dysplasia; MDS-RS-MLD, MDS with ring sideroblasts and multilineage dysplasia; MDS-U, MDS, unclassifiable; MDS-5q, MDS with low blasts and isolated 5q deletion; MDS-SF3B1, MDS with low blasts and SF3B1 mutation; MDS-LB and RS, MDS with low blasts and ring sideroblasts; MDS-LB, MDS with low blasts; MDS-h, hypoplastic MDS; MDS-IB1, MDS with increased blasts-1; MDS-IB2, MDS with increased blasts-2; MDS-f, MDS with fibrosis; MDS-biTP53, MDS with biallelic TP53 inactivation; NOS, not otherwise specified; WHO, World Health Organization
MDS-related gene mutations: ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2*
^†MDS-related cytogenetic abnormalities: complex (≥ 3 clones) karyotype (in the absence of a TP53 mutation), del(5q)/t(5q)/add(5q), -7/del(7q), + 8, del(12p)/t(12p)/add(12p), i(17q), -17/add(17p) or del(17p), del(20q), and/or idic(X)(q13) clonal abnormalities

Analysis of ICC vs. WHO-2022 classification differences showed that 39 (36.8%) and 55 (37.4%) individuals with MDS, not otherwise specified (NOS) with SLD or MLD, respectively, qualified for hypoplastic MDS (MDS-h) diagnosis. Meanwhile, nine (8.5%) in the MDS, NOS with SLD group, and seven (4.8%) in the MDS, NOS with MLD group (wild type SF3B1) were diagnosed as MDS with low blasts (LB) and RS in WHO-2022 classification (Table 1). Notably, three (2.0%) in the MDS, NOS with MLD group were diagnosed with MDS-SF3B1 in WHO-2022 classification. Among these, two patients had RUNX1 mutation and one had mutated SF3B1 with variant allele frequency (VAF) < 10%, excluding them from MDS-SF3B1 in ICC. Thirteen (9.9%) diagnosed with MDS with excess blasts (EB) in ICC, having significant BM fibrosis, were classified as MDS-f in WHO-2022 classification. In WHO-2022 classification, peripheral blood (PB) blast percentage criteria remain (5–19% as increased blasts-2 [IB2]), but < 10% is considered MDS with EB, not MDS/AML in ICC. Thus, nineteen (14.5%) with PB blast percentages of 5–9% were diagnosed as MDS-IB2 in WHO-2022 classification (Table 1).

Over 90% of patients with multi-hit TP53 mutations exhibit complex karyotypes (22, 23). However, the WHO-2022 criteria consider MDS-biTP53 only in cases with two or more TP53 mutations or one mutation plus TP53 copy number loss. Conversely, the ICC considers TP53 mutation with complex karyotype as multi-hit TP53 if TP53 locus heterozygosity information is unavailable. Thus, 14 patients (23.3%) in the MDS or MDS/AML group with mutated TP53 in the ICC were classified as MDS-IB or MDS-f in WHO-2022 classfication (Table 1, Fig. 1). Due to differing blast percentage criteria, three patients identified as AML with CEBPA mutation in the basic leucine zipper domain per ICC were placed in MDS-IB2 (14.5%, 15.2%, 19% blasts in BM) as per WHO-2022 criteria (Table 1, Fig. 1).

Comparison of the demographic features of patients with different MDS subtypes

Clinical characteristics and genetic profiles of patients with various MDS subtypes per ICC/WHO-2022 classification are in Table 2 and Supplemental Table 2. In ICC, MDS-SF3B1 patients showed the highest neutrophil counts, while del(5q) patients had the lowest hemoglobin levels (Supplemental Table 2a). Among MDS/AML subtypes, MDS/AML-NOS patients were the youngest (Supplemental Table 2b).

Table 2

Clinical characteristics of patients with myelodysplastic neoplasms, categorized by the 2022 World Health Organization classification
Clinical characters	5q (n = 4)	SF3B1 (n = 62)	LB + RS (n = 16)	LB (n = 140)	MDS-h (n = 94)	biTP53 (n = 46)	IB1 (n = 100)	IB2 (n = 149)	MDS-f (n = 24)	P value
Sex										0.440
Female	3 (75)	17 (27)	6 (38)	60 (43)	33 (35)	17 (37)	38 (38)	50 (34)	9 (37)
Male	1 (25)	45 (73)	10 (62)	80 (57)	61 (65)	29 (63)	62 (62)	99 (66)	15 (63)
Age*	71	71	68	63	63	67	67	67	64	0.116
Laboratory data*
WBC, ×10⁹ /L	3.5	4.0	3.9	3.2	3.1	4.1	2.6	3.0	4.4	0.005
ANC, ×10⁹ /L	1.7	2.1	2.5	1.7	1.5	1.5	1.1	1.1	2.1	< 0.001
Hb, g/dL	5.7	8.2	7.5	8.3	8.0	7.6	8.3	8.2	7.5	0.105
Platelet, ×10⁹ /L	214	190	89	61	58	60	75	77	82	< 0.001
BM blast (%)	2	1.6	1.9	2	2	12	7	13	7	< 0.001
PB blast (%)	0	0	0	0	0	2	0	1	1	< 0.001
IPSS-R										< 0.001
Very low	0 (0)	7 (11)	2 (12)	9 (7)	4 (4)	0 (0)	0 (0)	0 (0)	0 (0)	< 0.001
Low	1 (25)	41 (66)	6 (37)	65 (46)	44 (47)	0 (0)	8 (8)	1 (1)	3 (13)	< 0.001
Intermediate	3 (75)	12 (20)	4 (25)	53 (38)	36 (38)	0 (0)	36 (36)	19 (13)	5 (21)	< 0.001
High	0 (0)	2 (3)	2 (13)	9 (6)	9 (10)	2 (4)	39 (39)	66 (44)	7 (29)	< 0.001
Very high	0 (0)	0 (0)	2 (13)	4 (3)	1 (1)	44 (96)	17 (17)	63 (42)	9 (37)	< 0.001
IPSS-M										< 0.001
Very low	0 (0)	2 (3)	1 (6)	9 (6)	4 (4)	0 (0)	2 (2)	0 (0)	0 (0)	0.030
Low	0 (0)	39 (63)	4 (25)	44 (32)	37 (40)	0 (0)	5 (5)	1 (1)	2 (8)	< 0.001
Moderate low	0 (0)	14 (23)	1 (6)	36 (26)	22 (23)	0 (0)	15 (15)	3 (2)	2 (8)	< 0.001
Moderate high	2 (50)	4 (6)	4 (25)	27 (19)	19 (20)	0 (0)	19 (19)	12 (8)	4 (17)	< 0.001
High	1 (25)	2 (3)	5 (32)	17 (12)	10 (11)	0 (0)	38 (38)	37 (25)	5 (21)	< 0.001
Very high	1 (25)	1 (2)	1 (6)	7 (5)	2 (2)	46 (100)	21 (21)	96 (64)	11 (46)	< 0.001
Treatment
HMA	1 (25)	4 (7)	2 (13)	8 (6)	1 (1)	17 (37)	43 (43)	65 (44)	11 (46)	< 0.001
Intensive chemotherapy	0 (0)	1 (2)	1 (6)	1 (1)	0 (0)	1 (2)	3 (3)	10 (7)	2 (8)	0.047
Clinical trial	0 (0)	0 (0)	1 (6)	6 (4)	4 (4)	3 (7)	7 (7)	6 (4)	0 (0)	0.588
HSCT	0 (0)	6 (10)	0 (0)	12 (9)	7 (7)	5 (11)	29 (29)	33 (22)	9 (38)	< 0.001
Supportive care	3 (75)	38 (64)	8 (50)	91 (66)	49 (53)	19 (42)	30 (30)	43 (29)	3 (13)	< 0.001
Other treatment^†	0 (0)	16 (27)	5 (31)	31 (23)	38 (41)	7 (16)	16 (16)	20 (13)	5 (21)	< 0.001
AML transformation	2 (50)	3 (5)	2 (13)	12 (9)	7 (7)	18 (39)	30 (30)	65 (44)	8 (33)	< 0.001
Death	2 (50)	17 (27)	9 (56)	50 (36)	29 (31)	35 (76)	61 (61)	91 (61)	17 (71)	< 0.001
Early mortality^§	2 (50)	7 (11)	2 (13)	10 (7)	10 (11)	17 (37)	11 (11)	21 (14)	0 (0)	< 0.001
Data are presented as n (%). P values of < 0.05 are statistically significant
*Median.
^†Other treatment: include low-dose cytarabine, rabbit-derived anti-thymocyte globulin (rATG), cyclosporine, danazol, eltrombopag, erythropoietin-stimulating agents (ESA), thalidomide, steroid, venetoclax-based therapy and oral chemotherapy.
^§Death within 3 months of diagnosis.

Abbreviations: AML, acute myeloid leukemia; ANC, absolute neutrophil; MDS, myelodysplastic neoplasms; 5q, MDS with low blasts and isolated 5q deletion, count; biTP53, MDS with biallelic TP53 inactivation; f, MDS with fibrosis; h, MDS, hypoplastic; Hb, hemoglobin; HMA, hypomethylating agent; HSCT, hematopoietic stem cell transplantation; IB1, MDS with increased blasts-1; IB2, MDS with increased blasts-2; IPSS-R, Revised International Prognosis Scoring System; IPSS-M, Molecular International Prognosis Scoring System; LB, MDS with low blasts; RS, ring sideroblasts; SF3B1, MDS with low blasts and SF3B1 mutation

In the WHO-2022 classification, with the exception of MDS-5q, other MDS subtypes were associated with male predominance. Patients diagnosed with MDS-5q or MDS-SF3B1 exhibited normal median platelet counts at diagnosis. Additionally, the median BM blasts in patients with MDS-biTP53 (12%) and MDS-IB2 (13%) were significantly higher than those with MDS-IB1 (7%) and MDS-f (7%) (all P < 0.001).

The IPSS-R and IPSS-M risk distributions for each MDS subtype are presented in Table 2, Supplemental Table 2, and Supplemental Fig. 1. In the ICC, all patients with mutated TP53 had high- or very high-risk IPSS-R/IPSS-M, whereas only one patient with MDS-SF3B1 had high-risk IPSS-M because of the presence of co-mutations including CBL, GATA2, and CEBPA. Moreover, MDS-EB subgroup patients were at higher risk according to IPSS-R or IPSS-M than MDS, NOS with SLD or MLD patients. All MDS/AML patients had intermediate to very high-risk IPSS-R. In the MDS/AML subgroup, 3.2% with MDS-related gene mutations and 5.0% with MDS/AML-NOS were moderate low-risk IPSS-M. MDS/AML patients with mutated TP53 showed the highest incidence of very high-risk IPSS-R or IPSS-M. In the WHO-2022 classification, patients classified as having MDS-LB and RS had similar IPSS-R and IPSS-M risk stratification distributions to those with MDS-LB, which were distinct from those with MDS-SF3B1. Patients with MDS-SF3B1 more frequently had low-risk IPSS-R (66%) and IPSS-M (63%) than did patients with the other two subtypes (MDS-LB and RS: 37% for IPSS-R, and 25% for IPSS-M; MDS-LB: 46% for IPSS-R, and 32% for IPSS-M, all P < 0.05; Table 2, Supplemental Fig. 1c and 1d). The distributions of the IPSS-R and IPSS-M scores among patients with MDS-f were comparable to those among individuals with MDS-IB1 (Table 2, Supplemental Fig. 1c and 1d). Additionally, all patients with MDS-biTP53 had very high-risk IPSS-M (Table 2 and Supplemental Fig. 1d).

Fewer patients with MDS with mutated TP53 (8.7%, ICC), MDS/AML with mutated TP53 (8.1%, ICC), or MDS-biTP53 (10.9%, WHO-2022 criteria) underwent HSCT compared to other those with high risk MDS, despite being at a higher risk (Supplemental Table 2 and Table 2). This was attributed to a 22–43% early mortality rate at 3 months (Supplemental Table 2 and Table 2), no complete remission in patients before HSCT, and leukemic transformation within a median of 7.5 months post-MDS diagnosis, limiting transplantation feasibility in MDS-biTP53 patients.

Comparison of the genetic profiles among patients with different MDS subtypes

In the ICC, patients with MDS, NOS with SLD, and those with MDS, NOS with MLD exhibited similar mutation profiles (Supplemental Table 3a). Patients with MDS-SFB31 harbored distinct mutation patterns with higher frequencies of DNMT3A mutations (17% vs. 5%, P = 0.008 compared with the SLD group, P = 0.004 in the MLD group) and TET2 mutations (34% vs. 10% compared with the SLD group, P < 0.001; 34% vs. 12% compared with the MLD group, P < 0.001) compared to those with MDS, NOS with SLD or MLD (Supplemental Table 3a). Moreover, patients with mutated TP53 harbored a significantly higher frequency of TET2 mutations (26% vs. 9%, P = 0.019) but a lower frequency of ASXL1 (4% vs. 35%, P = 0.003) and RUNX1 (0% vs. 22%, P = 0.008) mutations compared to the EB subgroup (Supplemental Table 3a).

On the other hand, based on the WHO-2022 criteria, patients with MDS-LB and MDS-LB and RS exhibited comparable mutation profiles (Fig. 2), whereas patients with MDS-SF3B1 had significantly different mutation patterns when compared to those of the former two subtypes. Patients with MDS-SF3B1 had significantly more DNMT3A (16% vs. 6%, P = 0.029) and TET2 mutations (32% vs. 14%, P = 0.004) but fewer STAG2 mutation (2% vs. 9%, P = 0.068) than did those with MDS-LB, while fewer of them harbored SRSF2 mutations when compared to those with MDS-LB and RS (3% vs. 25%, P = 0.014) (Supplemental Table 3b).

We evaluated the genetic profiles of the patients diagnosed with MDS-LB or MDS-h. With the exception of the U2AF1 mutation (MDS-LB vs. MDS-h, 9% vs. 1%, P = 0.017), patients in these two groups exhibited similar molecular landscapes. Among the patients with MDS-IB1, MDS-IB2, or MDS-f, patients with MDS-IB2 exhibited higher frequencies of NRAS (9% vs. 2%, P = 0.019), TET2 (19% vs. 10%, P = 0.059), and monoallelic TP53 (7% vs. 1%, P = 0.031) mutations than did those with MDS-IB1. At the same time, patients with MDS-f exhibited lower incidences of TET2 (0% vs. 19%, P = 0.020) and STAG2 mutations (8% vs. 27%, P = 0.050) compared to those diagnosed with MDS-IB. Mutational profile analysis indicated that patients with biallelic TP53 inactivation had specific genetic alterations, with different co-occurring patterns from those observed in patients with MDS-IB or MDS-f (Fig. 2 and Supplemental Table 3b). Excluding SF3B1 and TP53, the binary features and VAF of gene mutations were similar across WHO-2022 categories (data not shown).

Survival analysis and impact of HSCT

We performed pairwise comparisons of survivals among patients with each subtype of MDS, defined by the ICC and WHO-2022 classification, with the exclusion of the MDS-del(5q) subgroup, which comprised a very limited number of patients (n = 4). In the ICC, patients diagnosed with MDS, NOS with SLD or MLD had comparable prognoses (162.1 vs. 185.5 months, P = 0.274 for LFS; P = 0.269 for OS). Among the subtypes of MDS/AML, patients with MDS/AML-NOS had the best outcomes (14.5 months for LFS, 28.1 months for OS) (Supplemental Fig. 2). Furthermore, individuals carrying TP53 mutations experienced the worst outcomes, regardless of their blast percentage (MDS with mutated TP53 vs. MDS/AML with mutated TP53, 4.1 vs. 4.0 months for LFS, P = 0.396; 5.2 vs. 5.1 months for OS, P = 0.590) (Supplemental Fig. 2).

In the WHO-2022 classification, patients with MDS-h had a significantly longer median LFS and OS (185.5 months for both median LFS and OS) compared to those with MDS-LB and RS (38.3 months for median LFS [P = 0.013] and OS [P = 0.010]) but had a similar outcome to those with MDS-LB (170.2 months for median LFS [P = 0.152] and OS [P = 0.146]), and MDS-SF3B1 (114.6 months for median LFS [P = 0.549] and OS [P = 0.528]) (Fig. 3). Notably, patients with biTP53 mutations had worse outcomes (median LFS: 3.9 months and median OS: 4.5 months, all P < 0.001) than did those with MDS-f (median LFS:16.6 months, and median OS:17.7 months), MDS-IB2 (median LFS:10.0 months, median OS:17.7 months), and MDS-IB1 (median LFS:25.6 months and median OS:31.4 months). Patients with MDS-f had similar survival to those with MDS-IB2, and patients with MDS-IB2 had a shorter LFS (P = 0.003) and OS (P = 0.027) than those with MDS-IB1 (Fig. 3).

Subgroup analysis of the impact of transplantation using time-dependent Cox regression analysis revealed that in the ICC, HSCT could improve both LFS and OS (HR for LFS:0.262, P < 0.001; OS:0.354, P = 0.001) in patients diagnosed with MDS with EB (Supplemental Table 4). For patients with MDS/AML with MDS-related cytogenetic abnormalities, HSCT showed potential benefits in LFS (HR:0.490; P = 0.069). Additionally, in the WHO-2022 classification, patients with MDS-IB1 benefited from HSCT for both LFS and OS (HR for LFS:0.239; OS:0.350; P < 0.001), and HSCT improved LFS (HR:0.537, P = 0.049) in patients with MDS-IB2 (Supplemental Table 5). For patients with MDS-f, HSCT showed a trend to prolong their LFS (HR:0.305; P = 0.078); however, transplantation failed to improve the poor outcomes in patients with MDS-biTP53.

Subtypes analysis based on the interaction between the ICC and WHO-2022 classification

Based on the ICC, we further classified patients by the diagnostic criteria of the WHO-2022 classification and explored the survival and genetic differences between each subtype. In the group of patients with MDS, NOS with SLD (n = 106) or MLD (n = 147), patients could be classified into the subtypes of MDS-SF3B1 (n = 3), MDS-LB and RS (n = 16), MDS-LB (n = 140), and MDS-h (n = 94), according to the WHO-2022 classification (Table 1). MDS-LB and RS were consolidated into the MDS-LB subgroup due to their comparable mutation profiles. Individuals diagnosed with MDS-h had a trend of better outcomes compared to those with MDS-LB (185.5 vs. 162.1 months, P = 0.075 for LFS; 185.5 vs. 101.1 months, P = 0.070 for OS) (Supplemental Fig. 3).

Patients diagnosed with MDS with EB (blast < 10% in PB and BM) could be classified into the subtypes of MDS-IB1 (n = 99), MDS-IB2 (n = 19), and MDS-f (n = 13). Importantly, a blast percentage of 5–10% in PB implied shorter LFS (MDS-IB2 vs. MDS-IB1, 7.0 vs. 26.2 months, P = 0.004; MDS-IB2 vs. MDS-f, 7.0 vs. 21.9 months, P = 0.042) (Supplemental Fig. 4). Moreover, patients with 5–10% blast in PB showed similarly poor outcomes as those classified as MDS/AML (blast percentage ≥ 10% in PB or BM; LFS 10.0 vs. 8.7 months, P = 0.586; OS 16.8 vs. 16.0 months, P = 0.824) (Fig. 4). BM fibrosis did not confer adverse effects in patients diagnosed with MDS with EB, MDS with mutated TP53, and MDS/AML with MDS-related gene mutations (Supplemental Figs. 4–6).

Alternatively, under the WHO-2022 classification, patients with MDS-LB could be reclassified into subtypes based on the ICC, including MDS, NOS with SLD (n = 58) or MDS, NOS with MLD (n = 82) (Supplemental Table 6). Patients with MLD, despite similar mutation profiles, had significantly lower white blood cell (2.9 vs. 3.7 ×10⁹ /L, P = 0.001), absolute neutrophil (1.5 vs. 2.2 ×10⁹ /L), and platelet counts (54 vs. 101 ×10⁹ /L, P = 0.006), with a trend towards shorter survivals than did SLD counterparts (77.3 vs. 170.2 months, P = 0.153 for LFS, P = 0.140 for OS; Supplemental Fig. 7).

For patients with biallelic TP53 inactivation in the WHO-2022 criteria, MDS (n = 17) or MDS/AML (n = 29) with mutated TP53 in the ICC (Supplemental Table 6) exhibited a similar prognosis (3.9 vs. 4.0 months for LFS, P = 0.211; 4.4 vs. 7.0 months for OS, P = 0.293) (Supplemental Fig. 8). Additionally, patients with MDS-IB2 could be classified as having MDS with EB (n = 19, peripheral blast 5–9%), MDS with mutated TP53 (n = 1, single TP53 mutation with VAF 41.2% and complex karyotype), MDS/AML with mutated TP53 (n = 8), MDS/AML with MDS-related gene mutations (n = 87), MDS/AML with MDS-related cytogenetic abnormalities (n = 12), MDS/AML-NOS (n = 19), and AML with CEBPA (n = 3) (Supplemental Table 6). Patients with MDS/AML and MDS-related gene mutations had a higher risk under IPSS-R or IPSS-M than did those with MDS with EB (92.0% vs. 63.2% for high or very-high risk IPSS-R, P < 0.001; 95.4% vs. 73.6% for high or very-high risk IPSS-M, P = 0.002) and MDS/AML-NOS (95.4% vs. 73.7% for high or very-high risk IPSS-M, P = 0002).

Survival analysis among these patients showed that those with MDS/AML with mutated TP53 (4.0 months for LFS, 4.1 months for OS) and with MDS-related cytogenetic abnormalities (10.6 months for LFS and OS) had the worst outcomes, followed by those with MDS-related gene mutations (10.7 months for LFS, 20.7 months for OS). Moreover, those with MDS/AML-NOS had the longest survivals (8.1 months for LFS, 28.1 months for OS) (Supplemental Fig. 9). In patients with MDS-f, survival differences were also noted among those with MDS with EB (n = 13, LFS 21.9 months, OS 22.2 months), MDS with mutated TP53 (n = 4, LFS 5.2 months, OS 5.9 months), and MDS/AML with MDS-related gene mutations (n = 6, LFS 12.7 months, OS 13.9 months) when classified by the ICC (Supplemental Fig. 10).

Proposed integrated system based on the ICC and WHO-2022 classification

From our analysis, we propose: (1) MDS-h patients differ from MDS, NOS with SLD or MLD; (2) Patients with ≥ 5% blasts in PB show outcomes akin to MDS/AML, worse than do those with lower blasts.

(3) When patients have a PB blast percentage ≥ 10%, not only multi-hit but also single-hit TP53 mutations confer detrimental effects. Therefore, it is crucial to differentiate these patients from those with MDS with mutated TP53; (4) In MDS-IB2 patients, further distinction is needed for those with MDS-related gene mutations and cytogenetic abnormalities due to differing prognoses; (5) Within the ICC framework, BM fibrosis' survival impact was less pronounced, prompting the refinement of the two-class system. MDS-h patients were segregated from MDS, NOS, and individuals with 5–10% PB blasts were shifted from MDS with EB to MDS/AML. Univariable analysis linked bedside IPSS-M, IPSS-R, older age, and male sex with poorer outcomes (Supplemental Table 7). Patients were categorized into five subgroups using the refined system. Multivariable analysis showed IPSS-M (P < 0.001), older age (P < 0.001), and the refined system (P < 0.001) as independent predictors of LFS and OS, with HSCT improving LFS (HR, 0.521, P = 0.003) (Table 3).

Table 3

Multivariable Cox regression analysis of the impact of different variables on the leukemia-free survival and overall survival of patients with myelodysplastic syndromes/neoplasms
Variables	Number	LFS		OS
Variables	Number	HR (95% CI)	P value	HR (95% CI)	P value
Age^*	-	1.022 (1.013–1.031)	< 0.001	1.030 (1.021–1.039)	< 0.001
Female	231	0.702 (0.552–0.893)	0.004	0.720 (0.564–0.919)	0.008
Refined system			< 0.001		< 0.001
MDS-h	94	Reference	-	Reference	-
Low-risk MDS^†	222	1.425 (0.924–2.198)	0.109	1.372 (0.890–2.116)	0.153
MDS with EB^‡	111	2.149 (1.311–3.523)	0.002	1.726 (1.053–2.830)	0.030
MDS/AML^§	145	2.606 (1.577–4.305)	< 0.001	1.953 (1.178–3.238)	0.009
Mutated TP53^¶	60	6.376 (3.500-11.617)	< 0.001	7.239 (3.942–13.294)	< 0.001
IPSS-M			< 0.001		< 0.001
Very low/low	150	1.081 (0.420–2.781)	0.872	1.025 (0.398–2.636)	0.959
Moderate low	93	2.112 (0.820–5.444)	0.122	2.144 (0.832–5.527)	0.114
Moderate high	90	3.060 (1.198–7.820)	0.019	2.782 (1.084–7.139)	0.033
High	114	3.965 (1.558–10.093)	0.004	3.904 (1.533–9.937)	0.004
Very high	185	7.447 (2.843–19.504)	< 0.001	6.667 (2.540–17.500)	< 0.001
HSCT	98	0.521 (0.339-0.800)	0.003	0.952 (0.646–1.402)	0.802
Note: Only 17 patients (2.7%) were categorized as IPSS-M very low risk and there was no inter-group difference between IPSS-M very low and low risk subgroups in both OS and LFS; accordingly, we put IPSS-M very low and low groups together.
P values of < 0.05 are statistically significant.
*As continuous variables analysis.
^†Low-risk MDS included MDS with del(5q), MDS with mutated SF3B1, MDS, NOS with SLD or MLD
^‡MDS patients with EB and blast percentage < 5% in peripheral blood.
^§MDS/AML with MDS-related gene mutations, MDS-related cytogenetic abnormalities, or not otherwise specified. Patients with MDS with EB and blast percentage ≥ 5% in peripheral blood were included in this group.
^¶MDS or MDS/AML with mutated TP53
Abbreviations: CI, confidence interval; HR, hazard ratio; HSCT, allogeneic hematopoietic stem cell transplantation; h, hypoplastic; IPSS-M, Molecular International Prognostic Scoring System; LFS, leukemia-free survival; MDS, myelodysplastic neoplasm; OS, overall survival.

In a cohort of 635 MDS patients, we retrospectively assessed the clinicopathological significance and prognostic implications of the ICC and WHO-2022 classification in the context of IPSS-M. Differences in clinical characteristics, genetic features, and outcomes among MDS subtypes based on these two novel systems were observed. Apart from the substitution of MDS-SF3B1 for MDS-RS, additional innovative changes in the WHO-2022 criteria have included the introduction of MDS-biTP53, MDS-f, and MDS-h. Moreover, the ICC highlights molecular features in diagnosis and classification, introducing categories like MDS with mutated SF3B1 without excess blasts as MDS-SF3B1 regardless of RS percentage and MDS or MDS/AML with mutated TP53. It also introduces the concept of MDS/AML with MDS-related gene mutations. These systems share many features yet differ in terminology and defining new entities (9, 10, 25). The threshold for myelodysplastic features is set at 10% across all hematopoietic cell lineages in both systems. While SLD and MLD distinction remains in MDS, NOS subclassification in the ICC is optional in WHO-2022 criteria. Our study revealed that MDS, NOS patients with MLD had marginally shorter survivals compared to those with SLD, despite similar mutation profiles. Additionally, blast percentage criteria variances led to diagnostic discrepancies between MDS and AML, such as AML with CEBPA mutations (≥ 10% blasts in ICC; ≥ 20% in WHO-2022 criteria) or AML with mutated NPM1 (≥ 10% blasts in ICC; any percentage in WHO-2022 criteria). The term MDS with IB2 is retained in the WHO-2022 criteria, whereas it is modified to MDS/AML in the ICC to emphasize the continuum spectrum between MDS and AML. In the group of MDS/AML, patients could be further classified according to genetic profiles (TP53 mutation or MDS-related gene mutations) and cytogenetic abnormalities. Exploring these subtypes, we found PB blast percentage ≥ 5% linked to adverse outcomes, classifying it under the MDS/AML subtype. Identifying MDS/AML with MDS-related gene mutations or cytogenetic abnormalities aids in distinguishing patients' survival rates.

Because the SF3B1 mutation significantly correlates with the presence of RS in MDS patients and mutated SF3B1 has been recognized as a distinct subtype of MDS in recent studies (26, 27), MDS-RS-SLD/MLD based on the WHO-2016 classification was renamed as MDS with low blasts and SF3B1 mutations if SF3B1 mutation is present in WHO-2022 criteria. In cases with wild-type SF3B1 and ≥ 15% RS, MDS with LB and RS is an acceptable alternative. However, in the ICC, MDS with RS but lacking an SF3B1 mutation is classified as MDS, NOS, regardless of RS count, and cases with concurrent RUNX1 and SF3B1 mutations are excluded from MDS-SF3B1. Our study revealed distinct features in patients with MDS-SF3B1 compared to those with MDS-LB and RS, and MDS-LB, the latter two subtypes showing similar mutational landscapes.

MDS-h, a new entity in the WHO-2022 classification but not in ICC, comprises 10–15% of all MDS cases (28). It is frequently observed in Asian MDS cohort or children cases (29, 30). MDS-h patients show activated immune system features, especially effector T cells targeting hematopoietic stem and progenitor cells (28, 31). They typically have severe cytopenia, fewer somatic mutations (32), higher immunosuppressive therapy response (33), and better outcomes with regards to the low-risk IPSS-R (34). In our study, MDS, NOS patients with MDS-h showed a trend of improved survival compared to other low-risk MDS cases. Recognizing these patients aids in enhancing patient care through tailored treatment strategies.

BM fibrosis is correlated with higher white blood cell counts, BM blast percentages, and more pronounced dysmegakaryocytopoiesis in MDS. It is also associated with mutations in the TP53, SETBP1, and JAK2 genes (35, 36). Additionally, several studies have recognized fibrosis as an independent factor for poor prognosis (35, 37–40). We found that in the patients with increased blasts, BM fibrosis adversely affected outcomes in the WHO-2022 classification, and patients with MDS-f had fewer STAG2 and TET2 mutations. However, the negative impact of BM fibrosis appeared to be less prominent within the framework of the ICC.

Up to 10% of patients with primary MDS have mutations in TP53, which results in a heightened risk of AML transformation and dismal outcomes (41), particularly in the setting of multiple hits (23). Only patients with multiple hits displayed specific associations with complex karyotypes, a few co-occurring mutations, high-risk presentations, and short survival (23). Furthermore, monoallelic patients did not differ from TP53 wild-type patients in terms of outcome or response to therapy (23). Both the ICC and WHO-2022 classification introduce MDS with mutated TP53 (ICC) and MDS with biallelic TP53 inactivation (WHO-2022). Minor differences exist in defining multi-hit TP53 mutations and classification. In the ICC, patients with a TP53 mutation and complex karyotype are recognized as having multi-hit TP53 mutations if TP53 locus heterozygosity information is unavailable, which is not permitted under the WHO-2022 criteria. Additionally, for patients with a blast percentage ≥ 10%, the presence of any TP53 mutation classifies them as MDS/AML with mutated TP53, regardless of allelic status. In this study, MDS-biTP53 patients had the shortest survival, with a distinct mutational landscape compared to MDS-IB or MDS-f patients (Fig. 2 and Supplemental Table 3). MDS or MDS/AML patients with TP53 mutations defined by the ICC had unfavorable prognoses. Patients with a single TP53 mutation and complex karyotype showed outcomes similar to those with multiple TP53 mutations, justifying classifying these cases into this entity. Cox regression analysis revealed HSCT did not improve outcomes in these patients, as per either ICC or 2022-WHO classification (Supplemental Table 4, 5), consistent with prior reports (42–44).

Through an expanded analysis of 7,017 patients on behalf of the International Consortium for MDS (45), Komrokji et al. documented that genetically defined entities (SF3B1, del5q, and biTP53) were unique, and the survival of patients with LB and RS (wild-type SF3B1) was similar to that of patients with MDS-LB. Our results are consistent with these findings. Although MDS-IB1 patients had longer OS, their LFS was comparable to MDS-IB2 in the Moffitt Cancer Center cohort. Survival analysis of our and the GenoMed4all cohort showed significant LFS and OS differences between subtypes (45). Thus, the optimal cutoff value for the blast percentage requires further investigation. A unified classification system that included MDS-5q, MDS-SF3B1, MDS-h, MDS-SLD, MDS-MLD, MDS-LB, MDS-biTP53, MDS-f, and MDS-EB was proposed by the Moffitt Cancer Center (46). According to our analysis, we tried to refine and tie two classification systems together. We posited that MDS-h subtype, distinguishable from MDS, NOS with SLD or MLD, should be separately recognized. Patients with PB blast ≥ 5% should be identified due to poorer outcomes.

The study's limitations include its retrospective nature, limited case number, and heterogeneity in treatment regimens, though most high-risk MDS patients received hypomethylating agents or transplantation. Prospective studies are needed to validate the refined MDS classification and assess HSCT's impact on high-risk MDS patient outcomes.

In conclusion, the ICC and WHO-2022 classification effectively segregate this heterogeneous disease. However, coexisting diagnostic standards challenge clinicians in treatment and diagnosis and hinder clinical trials and research progress. Therefore, we propose an integrated classification system for accurate MDS diagnosis and effective risk-adapted treatment.

AML

acute myeloid leukemia

ANC

absolute neutrophil

MDS

myelodysplastic neoplasms

MDS with low blasts and isolated 5q deletion,count

biTP53

MDS with biallelic TP53 inactivation

MDS with fibrosis

MDS,hypoplastic

hemoglobin

HMA

hypomethylating agent

HSCT

hematopoietic stem cell transplantation

IB1

MDS with increased blasts-1

IB2

MDS with increased blasts-2

IPSS-R

Revised International Prognosis Scoring System

IPSS-M

Molecular International Prognosis Scoring System

MDS with low blasts

ring sideroblasts

SF3B1

MDS with low blasts and SF3B1 mutation

Acknowledgments

We would like to acknowledge the service provided by the Departments of Laboratory Medicine and Medical Research, National Taiwan University Hospital, and Tai-Chen Cell Therapy Center. Moreover, we would like to acknowledge the service provided by the DNA Sequencing Core of the First Core Laboratory, National Taiwan University College of Medicine. This work was partially supported with grants from the Hematology Society of Taiwan, Ministry of Science and Technology (Taiwan) (MOST 104–2314-B-002–128-MY4, 106-2314-B-002-226-MY3 and 108-2628-B-002-015, 109-2314-B-002-213 and 111-2314-B-002-279) and the Ministry of Health and Welfare (Taiwan) (MOHW 107-TDU-B-211-114009 and 111-TDU-B-221-114001).

Author contributions

WHL was responsible for data collection and management, statistical analysis and interpretation, literature research, and manuscript writing. CHT, YYK, HIS, MHT, and YKC were responsible for next-generation sequencing data collection and interpretation. MCL was responsible for cytogenetic analyses. CCL, FMT, MYL, WCC, MKC, BSK, YTY, JLT, and HFT were responsible for data collection and management. SCY and CTY were responsible for grading of bone marrow fibrosis. HAH designed, conceived, and coordinated the study, analyzed and interpret data, wrote, and revised the manuscript. All authors reviewed and approved the manuscript

Competing interests

The authors declare no competing financial interests.

Data availability statement

The datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

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There is NO conflict of interest to disclose.

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published 09 Apr, 2024

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Editorial decision: revise
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Comparison of the 2022 World Health Organization Classification and International Consensus Classification in Myelodysplastic Syndromes/Neoplasms

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Journal Publication

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Abstract

Figures

Introduction

Materials and methods

Statistical analysis

Results

Case allocation according to the ICC and 2022-WHO classification

Comparison of the demographic features of patients with different MDS subtypes

Comparison of the genetic profiles among patients with different MDS subtypes

Survival analysis and impact of HSCT

Subtypes analysis based on the interaction between the ICC and WHO-2022 classification

Proposed integrated system based on the ICC and WHO-2022 classification

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1