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Personalized management of MDS
Genomics in the International Prognostic Scoring System risk assessment
Recent molecular studies have demonstrated the major impact on survival and disease progression of specific somatic mutations, including those that are additive to the IPSS-R clinical characterization.23-25,89-91 At least five genes - TP53, ASXL1, EZH2, ETV6, and RUNX1 - have an adverse prognostic impact whereas SF3B1 has a positive impact. Additionally, a group of approximately 60 genes have been recurrently demonstrated to be involved in the vari- ous subtypes of MDS, with varying incidence levels (Table 4). Bone marrow samples from a representative cohort of over 3,000 MDS patients were sequenced using a next- generation sequencing panel optimized for myeloid dis- ease. Analysis of TP53 mutations in 380 patients enabled segregation of patients according to two TP53 states: a mono-allelic state in which one wildtype allele remained and a multi-hit/bi-allelic state in which TP53 was altered multiple times by either mutations, deletions or copy neu- tral loss of heterozygosity (67% of TP53-mutated patients).92 TP53 state rather than mutation alone was found to be an independent diagnostic and prognostic bio- marker in MDS. Mono-allelic TP53 patients had more favorable disease than multi-hit TP53 patients and were enriched in low-risk WHO subtypes. Critically, multi-hit TP53 was associated with a worse overall survival as com- pared to mono-allelic TP53, and with more pronounced AML transformation.92
Patients’ management
MDS is a complex disease displaying marked inter-indi- vidual differences with regard to disease mechanisms and potential therapeutic options. Compared to many other blood cancers, the diagnostic process is more challenging and effective targeted treatments less abundant. In
Europe, the MDS-Europe platform offers comprehensive consensus-based MDS guidelines for diagnosis, prognosis and treatment derived from two consecutive European Union research projects (www.mds-europe.eu).83 Moreover, many Western countries have local web-based guidelines with links from mds-europe.org. In the USA the NCCN guidelines (www.nccn.org/professionals/physician_gls/PDF/ mds.pdf)9 offer the same service.
Diagnostic work-up
The diagnostic work-up follows the recommendations in the WHO 2016 classification.1 Cornerstones are bone marrow morphology and histopathology, and cytogenetic analysis. Flow cytometry immune-phenotyping is recom- mended but not mandatory.93 It is a necessary tool to exclude certain differential diagnoses, such as paroxysmal nocturnal hemoglobinuria and large granular lymphocytic leukemia. Molecular genetics, mainly targeted DNA sequencing, is strongly recommended, in particular in patients who are candidates for active treatment.25,60 Differential diagnoses of MDS encompass a long list of both benign and malignant diagnoses, as summarized in Table 5. Since management depends on a correct diagno- sis, many national cancer programs mandate that diagno- sis and prognosis are established in multi-professional conferences.
Clonal cytopenia of unknown significance
Clonal hematopoiesis becomes more prevalent with increasing age and may be present in the absence of cytopenias [CHIP/aging-related clonal hematopoiesis (ARCH)]. Interestingly, a recent study based on the Danish twin registry failed to show a clear relation between CHIP
Table 5. Causes of cytopenia and/or dysplasia other than myelodysplastic syndromes.
Differential diagnosis
Aplastic anemia, pure red cell aplasia
Metastatic carcinoma
Toxic bone marrow injury (alcohol, lead, zinc, copper deficiency, nonsteroidal anti-rheumatic drugs, etc.)
Reactive bone marrow changes (infections e.g. sepsis, HIV, hepatitis, tuberculosis and other chronic infections, autoimmune diseases, thyroid disease, etc.), copper deficiency
Paroxysmal nocturnal hemoglobinuria Immune thrombocytopenia Megaloblastic anemia
Hypersplenic syndromes
Acute leukemia (especially erythroleukemia, FAB-M6)
Myeloproliferative diseases (especially CMML, aCML, PMF) Hairy cell leukemia, large granular lymphocytic leukemia
Congenital dyserythropoietic anemia (rare)
Idiopathic cytopenia of undetermined significance
Clonal cytopenia of undetermined significance
Diagnostic tests
Histology, cytology, parvovirus B19
Histology, immunohistochemistry History, laboratory tests
Cytology, history, laboratory tests
Immunophenotyping
History, course
Vitamin B12/folic acid concentration
History/clinical features (splenomegaly)
Cytology, histology, immunophenotyping, genetic and molecular genetic testing
Histology, cytogenetic and molecular genetic testing
Cytology, immunophenotyping, molecular genetic testing (BRAF, STAT3), T-cell receptor
Molecular genetic testing
ICUS minimal diagnostic criteria
CCUS diagnostic criteria
HIV: human immunodeficiency virus; FAB: French-American-British; CMML: chronic myelomonocytic leukemia; aCML: atypical chronic myeloid leukemia; PMF: primary myelofi- brosis; ICUS: idiopathic cytopenia of undetermined significance; CCUS: clonal cytopenia of undetermined significance.
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