【Leukemia】 852 patients from Tianjin Blood Research Institute compared the MDS WHO 2016 and 2022 classification

The fifth edition of the 2022 WHO classification of lymphohematopoietic system tumors was released this year, which replaced "myelodysplastic syndromes" with a new concept, "myelodysplastic neoplasms"
.
However, the abbreviation "myelodysplastic neoplasms" should be "MDN", but the update still uses "MDS" as the abbreviation
.
Probably because MDS is used far more often than "myelodysplastic neoplasms"
.

The WHO 2022 classification reorganizes the classification
of MDS by emphasizing histological and genetic variables.
The diagnostic criteria for MDS with low blasts and isolated del (5q) (MDS-5q) remain unchanged, but MDS with biallelic TP53 inactivation (MDS-biTP53) was introduced as a new subtype, defined as the presence of multi-strike TP53 mutations and replacing other MDS subtypes
。 SF3B1 mutation and the presence of low blasts are consistent with the diagnosis of MDS (MDS low blasts with SF3B1 mutation, MDS-SF3B1) and replacement of prior MDS with ring sideroblasts (MDS-RS
).
。 Among histologically defined subtypes, the WHO 2022 classification retained the cut-off value
between MDS with low blasts (MDS-LB) and MDS with increased blasts (MDS-IB).
。 Nonblastocytosis is classified as hypoplastic MDS (MDS-h) and MDS-LB, while patients with blastocytosis are classified as MDSIB1, MDS-IB2, and MDS with fibrosis (MDS-f).

MDS-h and MDS-f are different subtypes that emphasize the importance of
trephine bone marrow biopsy.

Professor Xiao Zhijian of the Hematology Hospital of the Chinese Academy of Medical Sciences and others analyzed the dataset of 852 consecutive patients initially diagnosed with MDS using WHO 2016 criteria, aiming to compare the classification of these patients by WHO 2022, and the analysis results supported the improvement
of WHO 2022.
The article was recently published in Leukemia, the corresponding author is Professor Xiao Zhijian, and the first authors are Professor Zhang Yudi and Professor
Wu Junying.

Study design

The authors analyzed the continuous enrollment of 852 patients aged ≥18 years with newly diagnosed MDS who met the 2016 (4th edition) WHO criteria between 30.
08.
2016 and 22.
09.
2021, and reclassified
the patients according to the WHO 2022 classification.
Prognostic impact
was assessed using the International Prognostic Scoring System Revised (IPSSR) and the International Prognostic Scoring System-Molecular (IPSS-M).

The baseline features at diagnosis are shown in Table 1
.
Follow-up data were available
for 789 patients (93%).
The last follow-up date was 04.
06.
2022, and the median follow-up of survivors was 2 years
.
Patients undergo bone marrow evaluation, multiparametric flow cytometry, cytogenetic analysis, and target gene sequencing
.

Research results

Reclassification from WHO 2016 to 2022

The diagnostic criteria for WHO 2022 remain largely unchanged with the following exceptions: (1) patients with KMT2A, MECOM, NUP98 rearrangement, and NPM1 mutations are classified as acute myeloid leukemia (AML), regardless of blast percentage; (2) The diagnosis of unclassified MDS (MDS-U) was excluded, partially replaced with clonal cytopenia of undefined significance (CCUS).

。 The WHO 2016 criteria were reclassified as AML in 30 subjects with NPM1 mutations, previously classified as MDS with hyperblastic blast type 2 (MDS-EB2; n= 13), MDS with multilineage pathological hematopoiesis (MDS-MLD; n= 9), MDS with blast hyperblast type 1 (MDS-EB1; n = 6) and MDS-U (n = 2); Nine patients previously classified as MDS-U were reclassified to CCUS
.

The other 813 patients were reclassified according to WHO 2016 to WHO 2022 as shown in Table 2 and Figure 1
.
The classification of 11 patients with MDS-5q remained unchanged
.
In addition to previous MDS-RS subjects (N = 45), 25 patients without blasts were reclassified as MDS-SF3B1 because the new criteria do not limit
the number of ring sideroblasts.
Fifty-three patients were reclassified to MDS-biTP53, most commonly in patients with blastic hypercytosis (34/53; 64%)
.
Among patients without these genetic abnormalities, 80 subjects previously classified as MDS-SLD/MLD or MDS-U were reclassified as MDS-h, and the remaining 293 were reclassified as MDS-LB.

After excluding patients with MDS-f (N= 42), patients previously classified as MDS-EB1 or EB2 were reclassified as MDS IB1 (N= 161) or IB2 (N= 103).

IPSS-R and IPSS-M based gene profiling and risk classification

Of the 813 patients diagnosed with MDS according to WHO 2022 criteria, 617 (76%) had ≥ 1 mutation, of which 241 (30%) had 1 mutation, 167 (20%) had 2 mutations, and 209 (26%) had ≥3 mutations
。 The 9 genes that > 5% of patients had mutations included U2AF1 (23%), ASXL1 (19%), RUNX1 (12%), SF3B1 (11%), TP53 (10%), TET2 (8%), DMNT3A (7%), SRSF2 (6%), and BCOR (5%)
.
The distribution of mutation > 1% is shown in
Figure 2.

727 (89%) cytogenetically assessable patients with IPSS-R and IPSS-M stratification findings, both IPSS-R and IPSS-M were prognostically accurate (Figure 3A).

In addition, the distribution of IPSS-R and IPSS-M risk groups varied between WHO subtypes, with the largest number of high- and very high-risk patients in the MDS-biTP53, MDS-f, and MDS-IB subpopulations (Figure 3B).

Clinical features and survival analysis of WHO 2022 MDS types

The median survival of patients classified as MDS according to WHO 2016 criteria was 4 years, which decreased to 45 months according to WHO 2022 criteria, with patients with MDS-biTP53 and MDS-f having significantly shorter survival compared with other subtypes (10 months versus 15 months); Figure 4A).

WHO 2022 removes MDS-f and part of MDS-biTP5
from the WHO 2016 MDS-EB subtype.
MDS-IB1 (24 months) and MDS-IB2 (26 months) had significantly longer median survival than MDS-EB1 (23 months) and MDS-EB2 (17 months; Figure 4A, B).

Patients classified by WHO 2022 as MDS-IB1 and MDS-IB2 had similar clinical and haematologic factors and survival, and patients with MDS-f had lower haemoglobin concentrations (75 vs 80 g/L; P = 0.
02), low platelet concentration (41 vs 61 × 10⁹/L; P< 0.
001).

Patients with MDS-biTP53 had lower haemoglobin concentrations (80 vs 72 g/L; P< 0.
001), cytogenetics was more complex (14% versus 82%; P< 0.
001), IPSS-R and IPSS-M also had higher rates of very high risk (P< 0.
001).

Compared with patients with MDS-IB1, BCOR (6 versus 15%; P = 0.
02) and WT1 (1% vs 7%; P = 0.
03) mutation rate is higher
.
Patients with MDS-f had a higher rate of U2AF1 mutations compared with patients with MDS-IB (21% vs 40%; P = 0.
01) but RUNX1 mutation rate was lower (24% vs 7%; P = 0.
01)
。 Compared with MDS-IB patients, ASXL1 in MDS-biTP53 patients (24% vs 4%; P < 0.
001)、RUNX1 (24% vs 2%； P< 0.
001)、SRSF2 (13% vs 2%，P= 0.
02)、BCOR(9 vs 0%； P = 0.
02) and STAG2 (8 vs 0%; P = 0.
03) mutation rate was significantly reduced
.

Compared with MDS-LB subjects, MDS-h subjects had WBC (2.
68 vs 2.
40 × 10⁹/L; P = 0.
004), neutrophils (1.
26 vs 1.
04 × 10⁹/L; P = 0.
004) and platelets (62 vs 40 × 10⁹/L; P = 0.
03) concentrations; The frequency of MDS-associated mutations was significantly lower in subjects with MDS-h, including ASXL1 (8 versus 22 percent; P = 0.
003) and U2AF1 (15% vs 30%, P = 0.
007).

In addition, median survival was not achieved in either cohort, but patients with MDS-h had longer survival (P = 0.
09).

Unlike WHO 2016, WHO 2022 does not distinguish the number of
dysplasia lineages.
Some studies suggest that patients with monophyletic dysplasia have a lower
risk compared with participants with multilineage dysplasia.
Therefore, the authors examined the prognostic value
of the number of dysplasia lineages in patients with MDS-LB.
34 patients had MDS-LB with monolineage dysplasia (MDS-LB-SLD), 259 patients had MDS-LB with multilineage dysplasia (MDS-LB-MLD); Results Hemoglobin of MDS-LB-SLD subjects (93 vs 81 g/L; P= 0.
001)、WBC(3.
80 vs 2.
57 × 10⁹/L； P = 0.
002) and neutrophils (2.
14 vs 1.
21 × 10⁹/L; P = 0.
001) concentrations were higher, and IPSS-R (P = 0.
003) and IPSS-M (P = 0.
004) were also at
low risk.
In addition, the mutation pattern was similar between patients with MDS-LB-SLD and MDS-LB-MLD, with median survival not achieved by both but longer survival for MDS-LB-SLD (P=0.
02).

conclusion

In this study, the authors evaluated the 2022 (5th edition) WHO MDS classification using data from 852 subjects with continuous myelodysplastic neoplasia (MDS) diagnosed by WHO criteria in 2016 (4th edition), which generally supports the improvement
of WHO 2022.

References

Yudi Zhang,Junying Wu,Tiejun Qin ,et al.
Comparison of the revised 4th (2016) and 5th (2022) editions of the World Health Organization classification of myelodysplastic neoplasms.
Leukemia .
2022 Oct 12.
doi: 10.
1038/s41375-022-01718-7.

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