Editorial theme │ Understanding MDS classification and stratification systems: WHO and ICC

The first article in our editorial theme series focuses on understanding the updated classification and stratification systems in myelodysplastic syndromes (MDS). We focus on the 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors and the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemia, both previously covered by the MDS Hub.

Here, we summarize updates to these systems and provide an overview of presentations from the European Hematology Association (EHA) 2023 Congress. Ulrich Germing and Rafael Bejar discussed the pros and cons of these classification systems,^1,2 Rami Komrokji presented results from an expanded analysis validating the 5th edition WHO classification and the ICC,³ and Claudia Haferlach covered results of a cohort study classifying patients based on genetics.⁴

Differences in diagnosis, classification, and prognosis between the 5th edition WHO and ICC^1,2

The 5th edition WHO classification separates morphologically and genetically defined MDS subtypes and omits MDS-unclassified subtypes. Figure 1 shows the 5th edition WHO classification hierarchy of diagnostic findings. The ICC includes new semantics and subtype refinement.

BM, bone marrow; PB, peripheral blood; RS, ring sideroblast.
*Adapted from Germing.¹

Comparison of 4th and 5th edition WHO classification and the ICC²

The 4th edition WHO classification primarily focused on pathology and was limited to disease defining genetics; it relied on bone marrow (BM) blast percentage for MDS subtype classification, while the 5th edition added subtype updates to BM blast percentage criteria (Figure 2).

AML, acute myeloid leukemia; EB, excess blast; IB, increased blast; ICC, International Consensus Classification; MDS, myelodysplastic syndrome; MDS-f, MDS with fibrosis; MDS-h, MDS, hypoplastic MDS-SLD, MDS-single lineage dysplasia; MDS-MLD, MDS-multi-lineage dysplasia; MDS-RS, MDS-ring sideroblast; WHO, World Health Organization.
*Adapted from Germing¹ and Bejar.²

Use of morphology in the ICC

The ICC retained single-lineage dysplasia (SLD) and multi-lineage dysplasia (MLD), with a threshold of ≥10 lineages for MDS definition. Key prognostic differences between SLD and MLD are highlighted in the ICC, and ring sideroblast (RS) assessment using iron stain is retained. MDS with excess/increased blasts remain defined by 5% BM blasts and 2% peripheral blood (PB) blasts.

Updates to 5th WHO and ICC systems

MDS, hypoplastic¹

The 5th edition WHO category of MDS, hypoplastic is defined as a myeloid malignancy with morphological dysplasia, BM blasts <5% and/or PB blasts <2%, and decreased BM cellularity (<25%). Previous cytological results indicated inaccurate cellularity information; the new MDS, hypoplastic category requires histology and trephine biopsy to determine cellularity.

MDS with low blasts¹

In the 5th edition WHO classification, this category includes myeloid neoplasm associated with ≥1 cytopenia and BM blasts <5% and/or PB blasts <2%. MDS with low blasts retains the distinction between MDS-SLD and MDS-MLD subtypes.

MDS with mutated SF3B1 replaces MDS-RS in the ICC²

This category replaces MDS with RS and includes MDS with mutated SF3B1. It is a more biologically homogenous category without adverse genetically defined groups (e.g., del(5q), −7/del(7q), complex karyotype, or abnormal 3q26.2), and requires ≥10% variant allele frequency (VAF) SF3B1 mutation without RUNX1 or multi-hit TP53. The MDS with mutated SF3B1 category excludes cases with RS and wild-type SF3B1, which are classified as MDS not otherwise specified.

The 5th edition WHO classification for MDS with SF3B1 mutation is generally consistent with the ICC; however, it retains MDS-RS for low blast cases with ≥15% RS and without SF3B1 mutations, which may have implications for patients with previously different subtype classifications.

MDS isolated del(5q)¹

The 5th edition WHO classification update to the MDS isolated del(5q) category includes two new subtypes; MDS-del(5q) with mono-allelic TP53 mutation, and MDS-del(5q) with SF3B1 mutation. Consequentially, TP53 assessment is now required in addition to RS/SF3B1 mutation status. The classification does not consider SLD and MLD in the MDS low blasts with SF3B1 mutation subtype, which may impact patients who are at risk of developing acute myeloid leukemia (AML).

TP53 mutated MDS in the WHO 5^th edition and the ICC^1,2

The 5th edition WHO classification and the ICC include a new provisional entity, MDS with biallelic TP53 inactivation, which is independent of other co-mutations. TP53 biallelic mutations always have complex karyotypes and are associated with adverse outcomes, including high early relapse rates.

Both the 5th edition WHO classification and the ICC consider cytopenic patients with TP53-mutated MDS:

• The WHO classification regards TP53 mutations independent of blast count.
• The ICC treats TP53-mutated AML and MDS/AML as a combined category, considering TP53 mutations with VAF ≥10% and single mutation.

MDS with increased blasts¹

This category in the 5th edition WHO classification includes three subtypes:

• MDS with increased blasts 1: 5–9% BM blasts and/or 2–4% blasts in PB without Grade 2/3 reticulin fibrosis.

• MDS with increased blasts 2: 10–19% BM blasts and/or 5–19% blasts in PB without Grade 2/3 reticulin fibrosis.
• MDS with fibrosis: 5–19% BM blasts and/or 2–19% blasts in PB with Grade 2/3 reticulin fibrosis; a new pathological category with a distinct clinical course.

AML-defining genetic features²

The ICC includes some AML-defining genetic entities with a threshold of 10% blasts, which are not considered by the 5th edition WHO classification. For example, a patient with <5% blasts with NPM1 mutations will be considered as having NPM1-mutated MDS by the ICC, but NPM1-mutated AML by the 5th edition WHO classification.

MDS-AML²

The ICC category of MDS-AML is a terminology change, with characteristics of included entities remaining consistent (10–19% blasts). The ICC introduced this category to acknowledge the continuum between MDS and AML, taking into account uncertainty around 20% threshold and blast counting ambiguity. It offers treatment expansion opportunities by enabling patients with MDS/AML to be eligible for both MDS and AML trials. However, MDS and AML treatment approaches are becoming increasingly unclear, warranting further studies on factors that influence treatment choices.

Validation of ICC/WHO classification in MDS^2,3

Two cohorts comprising 7,017 patients with MDS from the Moffitt Cancer Center, USA, and GenoMed4all, Europe, were analyzed in a study validating the 5th WHO classification and the ICC. The study reclassified patients by the 5th edition WHO classification and ICC and compared overall survival (OS) and leukemia-free survival (LFS) in both cohorts (Figures 3 and 4).

GM, GenoMed4all; ICC, International Consensus Classification; MDS, myelodysplastic syndrome; MCC, Moffitt Cancer Center; OS, overall survival; WHO, World Health Organization.
*Adapted from Komrokji.³

 

GM, GenoMed4all; ICC, International Consensus Classification; MDS, myelodysplastic syndrome; MCC, Moffitt Cancer Center; LFS, leukemia-free survival; WHO, World Health Organization.
*Adapted from Komrokji.³

• Comparison of MDS-RS SF3B1 wild-type and MDS with low blasts showed similar outcomes in the Moffitt Cancer Center (OS, p = 0.99; LFS, p = 0.72) and GenoMed4all cohorts (OS, p = 0.82; LFS, p = 0.79).
• MDS with increased blasts 2 vs MDS-with increased blasts 1 demonstrated an association between excess blasts and worse outcomes (OS, p = 0.79; LFS, p < 0.01).
  • However, the blast cutoff threshold (5–9% vs 10–19%) was unclear.
• Comparison between MDS-MLD and MDS-SLD showed that the former had significantly better OS (p < 0.01) and LFS (p < 0.01).
• The 5th edition WHO MDS-hypoplastic and MDS low blast categories showed similar OS (p = 0.46) and LFS (p = 0.58).
• MDS with fibrosis was associated with worse OS (p < 0.01) and LFS (p = 0.03) vs MDS-IB.
• BM fibrosis ≥2 was associated with significantly improved OS (p = 0.009) and LFS (p = 0.002).

Pre-MDS states²

Both the 5th edition WHO and ICC recognize the pre-MDS state. Dysplasia differentiates MDS from pre-MDS clonal cytopenia of undetermined significance and absence of cytopenia differentiates MDS from clonal hematopoiesis of indeterminate potential (Figure 5). However, cases such as TP53 (VAF ≥10%), SF3B1 (VAF ≥10%), and complex karyotype will be classed as MDS even in the absence of dysplasia; this suggests that dysplasia is an inaccurate diagnostic feature and is not MDS-specific.

AML, acute myeloid leukemia; CCUS, clonal cytopenia of undetermined significance; CHIP, clonal hematopoiesis of indeterminate potential; DNA, deoxyribonucleic acid; MDS, myelodysplastic syndrome; VAF, variant allele frequency.
*Adapted from Bejar.^2
†In the ICC, CMUS is CHIP + unexplained monocytosis with or without cytopenias

Classifying MDS and AML based on genetic markers⁴

The cohort study presented by Haferlach included 958 patients with MDS, AML myelodysplasia-related, and AML according to the 5th WHO classification (Figure 6).

AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MR, myelodysplasia related.
*Adapted from Haferlach.⁴

Further progression marker (PM) categories based on combined genomic and survival data were identified, including acute myeloid neoplasm (MN) (n = 166), high-risk MN (n = 286), and low-risk MN (n = 506).

• Median OS differed significantly between categories (0.6 vs 1.9 vs 6.8 years; p < 0.001).
• Presence of PMs was associated with worse outcomes in all genetic subtypes.
• TP53 biallelic (35%) and complex karyotypes (12%) exhibited the most frequent PM patterns.
• Differences were observed in PM frequency across genetic subtypes; del(5q) (47%), SF3B1 (77%), spliceosome (27%), IDH/DTA (44%), and no abnormality (74%).

Conclusion

The ICC MDS-AML category expands treatment opportunities by allowing MDS/AML patients to be eligible for both MDS and AML trials.² However, there are implications for pathologists, such as the need to report using both the 5th edition WHO classification and the ICC for compatibility with future studies,² and both classification systems requiring further validation and refinement. ^1,2,3 Komrokji highlighted that remapping the 4th edition WHO MDS categories against the 5th edition WHO and ICC revealed that most categories were similar, suggesting that the classifications are a reform rather than a replacement.³ Both the 5th edition WHO classification and the ICC confirmed that TP53 mutations were associated with the poorest outcomes.¹ Haferlach⁴ showed that AML and MDS can be classified into distinct biological subtypes and PM categories based solely on genetics, suggesting a potential resolution for blast threshold discrepancy between the 5th edition WHO classification and the ICC.