MDS

WHO 2022: The classification introduces the term myelodysplastic neoplasms (abbreviated MDS) to replace myelodysplastic syndromes, underscoring their neoplastic nature and harmonizing terminology with

MPN.

MDS classification:

MDS with defining genetic abnormalities (del 5q, SF3B1, biTP53)
MDS, morphologically defined (low blasts, hypoplastic, increased blasts, fibrotic)

WHO 2022: Cytopenia definitions are harmonized for CCUS, MDS, and MDS/MPN; they include

Hb <13 g/dL(<7.8 mmol/L) in males and <12 g/dL (<7.2 mmol/l) in females for anaemia;
absolute neutrophil count <1.8 10E9/L for leukopenia;
platelets <150 10E9/L for thrombocytopenia.

MDS (WHO 2022)

MDS with defining genetic abnormalities

MDS with defining genetic abnormalities are grouped together and include:

MDS with low blasts and isolated 5q deletion (MDS-5q)
MDS with low blasts and SF3B1 mutation (MDS-SF3B1)
- Recent studies have identified MDS-SF3B1 as a distinct disease type that includes over 90% of MDS with ≥5% ring sideroblasts
MDS with biallelic TP53 inactivation (MDS-biTP53). The latter supersedes MDS-5q and MDS-SF3B1.

Pathogenic TP53 alterations of any type (sequence variations, segmental deletions and copy neutral loss of heterozygosity) are detected in 7-11% of MDS. Among these, about 66% of patients have multiple TP53 hits (multi-hit), consistent with biallelic TP53 alterations. Biallelic TP53 (biTP53) alterations may consist of multiple mutations or mutation with concurrent deletion of the other allele. This “multi-hit” mutational status results in a neoplastic clone that lacks any residual wild-type p53 protein.

Clinical detection of biallelic TP53 alterations is based on sequencing analysis (covering at least exons 4 to 11), often coupled with a technique to detect copy number status, usually FISH with a probe set specific for the TP53 locus on 17p13.1 and/or array techniques (e.g., comparative genomic hybridization or single nucleotide polymorphism arrays). Loss of genetic material at the TP53 locus may also be inferred by next-generation sequencing. A TP53 VAF ≥ 50% may be regarded as presumptive (not definitive) evidence of copy loss on the trans allele or copy neutral loss of heterozygosity when a constitutional TP53 variant can be ruled out. When two or more TP53 mutations are detected, they usually affect both alleles and can be considered a multi-hit status.

Over 90% of patients with MDS-biTP53 have complex, mostly very complex (>3), karyotype and thus are regarded as very high risk in IPSS-R. Additional studies are needed to determine whether biTP53 status is per se AML-defining, a point for consideration in future editions. Notwithstanding, published data suggests that MDS-biTP53 may be regarded as AML-equivalent for therapeutic considerations.

TP53 heeft een belangrijke rol in de tumor suppressie respons van cellen. In reactie op stress stimuli, zoals DNA schade, brengt TP53 de cel in apoptose of cell-cycle arrest totdat het DNA is hersteld. Daarmee voorkomt TP53 celdeling van cellen met genetische afwijkingen.

Een mutatie in TP53 is sterk geassocieerd met tumoren; voor het eerst beschreven in het Li-Fraumeni syndroom waarbij er een kiembaan TP53 mutatie is met dus hoge incidentie van kinderkanker.

In hematologische maligniteiten is een TP53 mutatie ook sterk geassocieerd met een slechte prognose en matige respons op immunochemotherapie.

Ten aanzien van de bepaling is het goed te realiseren dat verlies van TP53 functie kan komen door zowel een deletie 17 p en/of TP53 mutaties.

60% van de TP53 mutaties komt door een del 17p en kan dus dmv cytogenetica/FISH worden bepaald, maar dan mis je 40% van de muaties in de TP53. Daarom doe je ook moleculaire diagnostiek naar TP53.

MDS, morphologically defined

MDS-LB: low blast MDS
MDS-h; hypoplastische MDS
MDS-IB: increased blast MDS
- MDS-f: fibrotic MDS

Hypoplastic MDS (MDS-h) is listed as a distinct MDS type in WHO 2022. Long recognized as having distinctive features, MDS-h is associated with a T-cell mediated immune attack on haematopoietic stem and progenitor cells, along with oligoclonal expansion of CD8 + cytotoxic T-cells overproducing IFNγ and/or TNFα. Several features overlap across the triad of MDS-h, paroxysmal nocturnal haemoglobinuria (PNH) and aplastic anaemia (AA), including an association with CH.

Many patients with MDS-h have sustainable responses to agents used in patients with AA (i.e., anti-thymocyte globulin, ATG). As such, an emphasis is placed on careful morphologic evaluation, typically requiring trephine biopsy evaluation in addition to evaluation of bone marrow smears and touch preparations, and detection of mutations and/or clonal cytogenetic abnormalities. Individuals

with germline pathogenic variants in GATA2, DDX41, Fanconi anaemia (FA) or telomerase complex genes can have hypoplastic bone marrow and evolve to MDS and/or AML and do not respond to immunosuppressive treatment.

As the number of dysplastic lineages is usually dynamic and often represents clinical and phenotypic manifestation of clonal evolution – rather than per se defining a specific MDS type, the distinction between single lineage and multilineage dysplasia is now considered optional. The updated MDS classification scheme

and the incorporation of CCUS in the classification obviates the need for “NOS” or “unclassifiable” attributes. Specifically, MDS, unclassifiable, which was present in the prior edition, is removed.

MDS versus AML

The boundary between MDS and AML is softened, but the 20% blast cutoff to define AML is retained. Reassessment of the bone marrow blast percentage defining the boundary of MDS-IB2 and AML has been advocated for several cogent reasons and in view of novel therapeutic approaches that show efficacy in patients currently classified as MDS or AML with 10-30% myeloid blasts. Salient practical challenges

underpinning arguments for such a reassessment include:

any blast-based cutoff is arbitrary and cannot reflect the biologic continuity naturally inherent in myeloid pathogenic mechanisms;
blast enumeration is subject to sampling variations/error and subjective evaluation;
no gold standard for blast enumeration exists, and orthogonal testing platforms can and often do produce discordant results.

The pros and cons of merging MDS-IB2 with AML and adopting a 10% cutoff for what would be called MDS/AML were explored in multidisciplinary expert discussions and at editorial board meetings in the course of producing this classification. Lowering the blast cutoff to define AML was felt to suffer from the same challenges listed above and would merely replace one cutoff with another. Further, an arbitrary cutoff of 10% blasts to define AML (even if qualified as MDS/AML or AML/MDS) carries a risk of overtreatment. Accordingly, a balanced approach was adopted by eliminating blast cutoffs for most AML types with defining genetic alterations but retaining a 20% blast cutoff to delineate MDS from AML. Notwithstanding, there was broad agreement that MDS-IB2 may be regarded as AML-equivalent for therapeutic considerations and from a clinical trial design perspective when appropriate.

MDS SF3B1: Luspatercept, ijzerchelatie (meer kans op stapeling), EPO+GCSF of lena.