A Proposal for a Classification of Ccus, MDS and AML Primarily Based on Genetic Abnormalities Considering the Biological Continuum of These Entities

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.6492-6492
• Main Authors: Haferlach, Claudia, Huber, Sandra, Baer, Constance Regina, Hutter, Stephan, Meggendorfer, Manja, Kern, Wolfgang, Hoermann, Gregor, Haferlach, Torsten
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-179188

Background: According to the 5 th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) the main parameters used for the definition of CCUS, MDS and AML are cytopenias, dysplasia, blast count and distinct genetic abnormalities. These entities represent a disease continuum as CCUS can progress to MDS and MDS to AML. Thus, we asked the question whether this continuum can be reflected in a proposed comprehensive classification system. Methods: We evaluated 222 CCUS, 718 de novo MDS and 751 de novo AML. The diagnosis was established following WHO 2022. Bone marrow samples were analyzed by cytomorphology, chromosome banding analysis, targeted NGS panel sequencing (median coverage 1500x) and WGS (median coverage 100x). Overall survival (OS) was available for 1552/1691 patients. Median follow-up with respect to OS was CCUS: 1.7 years, MDS: 9.3 years, AML: 6.7 years. Results: In the WHO 2022 classification a subset of AML entities (AML with defining genetic abnormalities (DGA)) is defined by fusions ( PML:: RARA, RUNX1:: RUNX1T1, CBFB:: MYH11, DEK:: NUP214, RBM15:: MRTFA other defined genetic alterations/ ODGA), rearrangements ( KMT2A, NUP98, MECOM) and distinct mutations ( NPM1, CEBPA). These well-established distinct entities were kept in the classification proposal. 511 AML cases (67%) were classified as AML DGA (Figure 1). The remaining 240 AML cases classified as AML myelodysplasia-related and AML defined by differentiation according to WHO 2022 were combined with MDS and CCUS cases and categorized hierarchically into 5 distinct groups based on the presence of the following genetic abnormalities (GA group): 1. 5q deletion, 2. SF3B1 mutation, 3. other spliceosome mutations (SP: SRSF2, U2AF1, ZRSR2), 4. IDH1/2 or DNMT3A or TET2 mutations (I/D/T), 5. None of these (NO) (Figure 1). Next, within these GA groups the presence of progression markers (PM) was evaluated: PM subset A: presence of a) biallelic TP53 alterations ( TP53bi), or b) mutations in RUNX1 or ASXL1 and mutations in RAS pathway genes or KMT2A-PTD (R/A+RAS/PTD); PM subset B: presence of a) complex karyotype without TP53bi (complex), or b) RUNX1,or ASXL1 mutations (R/A), or RAS pathway mutations or KMT2A-PTD (RAS/PTD); PM subset C: absence of these PM. The assignment into GA groups and PM subsets differed substantially between CCUS, MDS and AML. With respect to GA group CCUS, MDS and AML cases were assigned into GA groups del(5q): CCUS (0%), MDS (76%), AML (