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Circumstances of discovery and clinical presentation
The circumstances of discovering a myelodysplastic syndrome vary: discovery of cytopaenia(s) on a haemogram, consultation for asthenia, infectious problems, haemorrhagic problems, consultation for tumour syndromes, exploration of dysimmune disease (atrophic polychondritis, seronegative polyarthritis, neutrophilic dermatoses (Sweet’s syndrome)).
In a third of cases, the disease is asymptomatic and discovered fortuitously on a complete blood count (CBC) that finds one or more cytopaenias. Anaemia is the most common; it is normo- or macrocytic and aregenerative.
When symptomatic, the clinical outlook is poor, with asthenia and secondary signs of cytopaenias. Autoimmune manifestations are observed in 20% of cases. There is no organomegaly.
5q- syndrome mainly affects women (3/1) aged over 60 years; it accounts for about 3% of all MDS cases. Characterised by macrocytic anemia, moderate neutropaenia and normal platelet count or mild thrombocytosis, its diagnosis is cytological (typically the presence of megakaryocytes with a hypolobulated or unlobulated nucleus and < 5% blasts in the marrow) and cytogenetic. It has a good prognosis with a median survival of 116 months.
Diagnostic and prognostic work-up
In an evocative context and in the case of discovering cytopaenia(s), besides medical history (exposure to toxic substance? radiation?) and a clinical examination, it is necessary to first exclude the other causes of cytopaenia; to do this, carry out a martial work-up, an inflammatory work-up, a haemolysis work-up, vitamins B9 and B12 assays (before transfusion!) and a liver function test, etc.
The mandatory tests for suspected MDS are a CBC, a myelogram and a bone marrow karyotype (+/- a FISH).
Blood and medullary cytology
- Cytopenias are evaluated on a CBC: anaemia: Hb < 10,0 g/dL, neutropaeia: ANC 1.8 G/L, thrombopaenia: Platelets < 100 G/L.
- The myelogram is essential to make the diagnosis of MDS and perform complementary tests: phenotyping, karyotype, molecular study.
The marrow is of normal or increased cellularity, with morphological abnormalities affecting one or more lines and a variable percentage of blasts.
The term dysplasia is used if:
- more than 10% of the cells in the line are dystrophic;
- Presence of at least 15% ring sideroblasts (Perls staining) or at least 5% if there is an SF3B1 mutation (MDS classification 2017 revision).
Caution, dysplasia may be observed in circumstances other than MDS: HIV infection, treatment with mycophenolate mofetil or Cellcept® (de-granulated ANC), treatment with azathioprine or Imurel® (megakaryocytic dysplasia), vitamin B12 deficiencies.
- Dyserythropoiesis: in the blood, there is anisocytosis, poykilocytosis, anisochromia, sometimes with a double population of normochromic and hypochromic red blood cells, and circulating erythroblasts. These quite frequent anomalies are not specific to MDS. DIA 4
- Dysgranulopoiesis: more specific, it has a strong diagnostic value.
Hyposegmented polynuclears (PN) are seen in the blood (sometimes up to PN pseudo-Pelger: monosegmented), de-granulated, sometimes containing vacuoles or Döhle bodies. DIA 6
In the bone marrow, nuclear PN abnormalities should be investigated.
Hyposegmentation is very characteristic (pseudo-Pelger type monolobulated PN) and is often associated with abnormal chromatin condensation or other abnormalities. Sometimes, binucleated cells or cells with an abnormal nucleus are observed. At cytoplasm level, vacuoles and especially hypogranulation or even complete loss of granulations in neutrophil PNs often exist. The presence of Auer bodies in blasts and very rarely in granulates must be reported because their presence switches MDS to MDS-EB 2. DIA 7
- Dysmegakaryopoiesis: large or giant platelets and empty platelets or platelets with abnormal granulations associated with functional abnormalities may be observed in the blood. DIA2 and 3
In the marrow, there are mainly nuclear abnormalities with hypo/hyperlobulated or non-lobulated megakaryocytes, multinucleated megakaryocytes, and small megakaryocytes (micromegakaryocytes).
An excess of blasts is found in about a quarter of patients. They are undifferentiated blasts, myeloblasts and monoblastes. They remain less than 20% of the cells in the blood and in the marrow (beyond that, it is AML).
Blastosis may increase as MDS develops.
WHO 2016 cytogenetics
Cytogenetic analysis should be performed on bone marrow. There are abnormalities in 40 to 60% of cases, of a wide variety, listed in the IPSS-R score
We distinguish the MDS entity with del(5q) isolated or associated with an additional abnormality, excluding the abnormality of 7 (2016).
The IPSS-R (Revised International Prognostic Scoring System) score takes into account the percentage of bone marrow blasts, cytogenetic abnormalities and the level of cytopaenia(s) (2, 3).
Calculators have been developed to establish this score, allowing the patient’s risk to be categorised as “very low, low, intermediate, high, very high”. This categorisation helps guide the clinician in choosing the best therapeutic option.
Molecular biology: contribution of NGS in the diagnosis and prognosis of MDS
In the WHO 2017 classification, only the presence of a mutation on the SF3B1 gene is involved in diagnosing MDS. But many publications since 2017 provide new molecular data, especially for prognosis.
The analysis in NGS can be performed on blood or bone marrow. Its contribution to MDS is threefold:
- diagnosis: in a cytopaenia work-up, the myelogram is sometimes not very contributory (or shows only some signs of dyserythropoiesis or dysgranulopoiesis) and cytogenetics can recover a normal karyotype (in 40 to 50% of cases). An NGS panel can make it possible to make the diagnosis by demonstrating a mutation on SF3B1 or a molecular clonality which is frequent given the large number of mutated genes in MDS. However, the interpretation must take into account CHIPs (clonal haematopoiesis of undetermined significance) that affect the elderly.
- prognosis: MDS with an isolated SF3B1 mutation has a favourable prognosis. Conversely, some mutations are associated with an unfavourable prognosis (risk of transformation to AML): TP53, EZH2, ETV6, RUNX1, ASXL1, CBL, DNMT3A, IDH1/2.
In 2022-23, there is a shift towards the use of a new molecular MDS score that could further improve the prognostic stratification of patients.
This molecular score (IPSS-M) was presented to the ASH in 2021 (4): it associates with haemoglobin, platelets, percentage of blasts and cytogenetic IPSS-R, the study of 16 main genes and 15 “secondary” genes. The 16 main genes are TP53, MLL, FLT3, SF3B1, NPM1, NRAS, ETVS, IDH2, CBL, EZH2, U2AF1, SRSF2, DNMT3A, ASXL1 and KRAS. The 15 secondary genes are BCOR, BCORL1, CEBPA, ETNK1, GATA2, GNB1, IDH1, NF1, PHF6, PPMD1, PRPF8, PTPN11, SETBP1, STAG2 and WT1.
The study presented to the ASH conducted on 2,957 patients showed that with this new prognostic score incorporating molecular data, 46% of patients changed their prognostic group: 74% switched to higher risk, 26% switched to lower risk and 6% of low risk patients switched to high risk, resulting in a very significant impact on patient management.
The accuracy of the prognosis by the search for these mutations thus allows the optimisation of patient management.
- On a theranostic level and response to treatment:
Patients with 5q- syndrome usually respond very well to lenalidomide treatment, but some of them are resistant to it. We now know that this resistance is associated with a mutation on TP53.
Furthermore, mutations on IDH1/2 or FLT3, which are rare, are potential therapeutic targets and should be reported.
Finally, the efficacy of hypomethylating agents (Vidaza®) is associated with certain mutational profiles: patients with a mutation on TET2 respond better; those with a mutation on ASXL1 respond a bit less well.
Bone marrow immunophenotyping can also be performed to help count blasts when cytology is very difficult, or looking for an HPN clone involving 1 to 2% of patients (hypoplastic marrow MDS).
Flow cytometry (FCM) immunophenotyping also allows the evaluation of dysplasia and the calculation of scores, the most used of which are Ogata score and Red-score (for erythroid maturation).
Immunophenotyping is a useful aid in the diagnosis of MDS.
Synthesis of the biological work-up
Required for diagnosis:
- Myelogram (BMB depending on the country)
- Medullary karyotype
- Ferritin: evaluation and monitoring of transfusion haemosiderosis
Differential diagnosis of anaemia:
- Iron, transferrin saturation
- B9 and B12 assays
- Liver function test
- Search for an inflammatory syndrome
- Haptoglobin and bilirubin
- HIV serologies, hepatitis B and C
HLA typing if a graft is considered, extended erythrocyte phenotype for transfusions
EPO assay: predictive of response to EPO treatment.