Myelodysplastic syndromes D46.9

Myelodysplastic syndrome (MDS) is a group of clonal disorders of hematopoietic stem cells characterized by dysplasia of blood and bone marrow cells with hematopoietic insufficiency and increased risk of developing acute myeloid leukemia. The leading finding is usually anemia, often also bi- or pancytopenia. The bone marrow is often normo- or hypercellular, in about 10% of cases hypocellular. Dysplasia of one or more cell series is diagnostic. At least 10 % of the cells in a row must show clear signs of dysplasia for the diagnosis of MDS to be made.

In about 90% of cases, the cause cannot be determined with certainty (primary MDS). In 10% of cases (secondary MDS or also therapy-associated MDS > 80% chromosomal aberrations), previous chemotherapy and/or radiotherapy are known and probably causative.

The types traditionally assigned to MDS are divided into 2 major groups in the current WHO classification: In addition to pure MDS, a group of mixed myelodysplastic-myeloproliferative neoplasms is delineated. The blast percentage discriminating from acute leukemia is 20% in blood and bone marrow. However, the current prognosis score for MDS (IPSS-R) still includes patients with up to 30% blasts.

MDS is divided into several subgroups according to the WHO 2016 classification, based on morphology, blast content, and genetic alterations.

• RCUD: Refractory anemia with unilateral dysplasia (<1% blasts).
• RARS: Refractory anemia with ring sideroblasts (<1% blasts)
• RCMD: Refractory cytopenia with multilinear dysplasia (≤1% blasts; <1000/μl monocytes)
• MDS del (5q): isolated del (5q) (few blasts, anemia with/without further cytopenia).
• RAEB I: refractory anemia with blast proliferation (cytopenias, <5% blasts, <1,000 μl monocytes)
• RAEB II: Refractory anemia with blast proliferation (cytopenias, <19% blasts, <1,000 μl monocytes).
• MDSU (MDS unclassified): ≤1% blasts , cytopenias.

Patients with MDS have a highly variable course in terms of progression to AML and also overall survival. The risk can be estimated using prognostic scores such as the IPSS-R. Variables included in this score are the number of blasts, genetics, and the number and severity of cytopenias. Accordingly, patients can be divided into those at low and high risk for transition to AML and risk of death.

Incidence in Germany approx. 4/100,000 inhabitants. In the age over 70 years, the incidence increases to 20-50/100,000.

Pathogenetically, MDS is a complex process in which a gradual accumulation of genomic damage (chromosomal aberrations, DNA mutations and epigenetic changes) in hematopoietic stem cells is assumed to be the cause. This process leads in the further course to a selection of malignant stem cells. These increasingly colonize the bone marrow clonally with their progenitor cells. This displaces physiological hematopoiesis. This explains the increasing risk of developing MDS in the course of life.

In the meantime, molecular high-throughput methods have been used to identify numerous molecular aberrations that occur more frequently in MDS. Point mutations in genes of the splicing apparatus (e.g. SF3B1, SRSF2, ZRSR2, U2AF1), in regulators of epigenetic modifications (e.g. DNMT3A, TET2, ASXL1, IDH1/IDH2, EZH2) and of transcription factors (e.g. RUNX1, TP53, ETV6, NPM1, CEBPalpha, GATA2) have been detected (Haferlach T et al. (2014). In about 90% of all MDS patients at least one of the recurrent mutations known so far can be detected. The bone marrow microenvironment also seems to play a role in the pathogenesis of MDS. It has been shown that genetic damage in the bone marrow stroma can produce an MDS phenotype (Medyouf H et al. 2014).

Therapy-associated MDS(tMDS): Risk factors for the development of MDS are all influences that promote the development of genetic alterations in blood stem cells.

tMDS after chemotherapies: In particular, treatment with alkylants in combination with radiation therapy (e.g. for lymphoma, breast carcinoma) is associated with the risk of the occurrence of MDS as a secondary neoplasia. The latency period for the occurrence of tMDS is on average 2-6 years.

MDS as an occupational disease: A special form of MDS occurs after long-term exposure to benzene-containing substances or other organic solvents. This applies to occupational groups such as former petrol station attendants, painters and varnishers, and others. The prerequisite for recognition as an occupational disease in these cases is long-term exposure (usually 10-20 years) to the chemicals mentioned.

Radioactive exposure: In connection with the increased incidence of leukaemia following exposure to radiation (atomic bombing of Japan in 1945, reactor accident at Chernobyl in 1986), an increased incidence of myelodysplastic diseases was observed, which relatively quickly developed into acute leukaemia. It can be assumed that high radiation exposure causes changes in haematopoiesis which may lead to the development of MDS. The therapy-associated forms of MDS often have high-risk genetic markers (see below) and, accordingly, respond poorly to therapy.

Primary MDS: Diseases that occur without evidence of the factors outlined are referred to as primary MDS. In recent years, germline mutations have been identified that are associated with a familial risk of MDS or AML. Since the age of onset can be around 60-70 years for some germline mutations (e.g. DDX41 mutation), the family history is also decisive here.

At the time of diagnosis of MDS, patients are on average about 75 years old. Women are affected somewhat less frequently than men

Signs of anemia: The most common initial manifestation of MDS is anemia (in about 70-80%). This is often noticed during a routine examination (blood count check). Not infrequently, nonspecific complaints such as fatigue, loss of appetite, gastrointestinal complaints and fatigue are described. Furthermore, symptoms of anemia such as exertional dyspnea, tachycardia, and headache are observed, and symptoms of cardiac or cerebrovascular insufficiency or coronary artery disease may be exacerbated. If the anemia develops rapidly, visual disturbances or confusion may occur. Other clinical findings include pallor of the mucous membranes (hemoglobin (Hb) usually below 10 g/dL) and nail bed (Hb usually below 8 g/dL).

Infection tendencies: Many patients report recurrent infections (bronchitides, pyoderma) at initial diagnosis of MDS, due to neutropenia or neutrophil granulocyte dysfunction.

Signs of thrombocytopenia: Initial bleeding complications are rare. More common are petechiae, gingival bleeding, or hematomas after minor trauma. In 10% of MDS patients, the disease manifests with severe bleeding, for example of the gastrointestinal tract, urinary tract, retina or central nervous system.

Autoimmunologic disorders(ADs) occur in 10% to 20% of patients with MDS. Available data suggest that ADs more often affect younger patients at higher risk of IPSS. Reportedly, defined clinical entities such as vasculitides, connective tissue diseases, inflammatory arthritides have been reported (Grignano E et al. 2018). In general, ADs do not seem to worsen survival.

Dermatologic symptoms: Skin symptoms in MDS occur sporadically. Sweet syndrome has been described several times in connection with MDS, furthermore pyoderma faciale, pyoderma gangraenosum as well as pustulosis of the skin as so-called "neutophilic dermatoses " (Vignon-Pennamen MD et al. 2017; Fox MC et al. 2008). Isolated reports exist of cases of neutrophilic panniculitis as well as IgA vasculitides (e.g., Schönlein-Henoch purpura) (Chen HC et al. 2004).

Rarely, specific skin infiltrations by myelomonocytic cells occur. They are then usually to be interpreted as signs of progression of MDS. Clinico-morphologically, they appear as uncharacteristic reddish nodules or plaques (clinical and histological incidental findings) (Avivi I et al. 1999).

Auto-immunological manifestations: arthritides, osteochondritis or vasculitides suggest possible autoimmune phenomena.

Examinations in detail:

The focus of diagnostics is the cytomorphology of the blood and bone marrow including iron staining to identify signs of dysplasia and to determine the proportion of monocytic cells and the proportion of ring sideroblasts. Taking into account the guidelines of the IPSS-R (Greenberg PL et al. 2012), an exact specification of the medullary blast percentage is necessary from a prognostic point of view (0-2 % vs. 3-4 % vs. 5-9 % vs. 10-19 % - see classification below). It is also obligatory to determine whether the dysplasia affects only one or 2-3 cell series. Based on these parameters, the classification is made according to one of the WHO types (Arber DA et al. 2016; Bejar R et al. 2011). In addition to cytology, histology (bone marrow) is also important. It allows determining the degree of organization of hematopoiesis (assessing bone marrow architecture and the fibrosis).

Other parameters:

• Differential blood count, cytology with iron and esterase staining, reticulocytes, cytogenetics; histology, LDH, ferritin, endogenous erythropoietin; folic acid, vitamin B12, HLA typing if necessary. Immunophenotyping of cells in blood smear and bone marrow ; chromosome analysis: in about 60% aberrations of chromosomes especially 5, 7, 8, 20; in 10% complex aberrations of ≥ 3 chromosomes; in 15% 1-2chromosomes are affected).
• Molecular cytogenetics: detection of mutations(ASXL1, in RARS often mutations of SF3B1; furthermore: TP53-, EZH2-mutations)
• Immunophenotyping: Immunophenotyping is becoming increasingly important as a tool to estimate the blast percentage and to show signs of dysplasia. A variety of molecular markers now allow to support the diagnosis of MDS (versus PMF, e.g. JAK2, CALR, MPL) or to determine prognosis (in addition to established clinical and cytogenetic parameters). Especially in patients with normal karyotype, additional molecular analyses (unfavorable are mutations in ASXL1, RUNX1, TP53, EZH2) can be important for clinical evaluation and also therapy composition(Arber DA et al. (2016).

Clinic

Usually the disease is discovered by chance (signs of cytopenia). Differential blood count and bone marrow examination (pathological cytology and histology) readily lead to the diagnosis.

• Aplastic anemia;
• Pure Red Cell Aplasia (PRCA);
• Toxic KM damage (alcohol, lead, NSAIDs, etc);
• Reactive KM changes (sepsis, HIV, chronic infections, TB, autoimmune diseases, etc.).
• Monocytosis of other genesis
• Paroxysmal nocturnal haemoglobinuria (PNH)
• Immune thrombocytopenia
• Megaloblastic anemia
• Hypersplenia syndrome
• Acute leukemias (especially erythroleukemia, FAB-M6)
• Myeloproliferative disorders (especially aCML, OMF)
• Hairy cell leukemia, LGL
• Congenital dyserythropoietic anemia (rare)

The therapy options should always be individually tailored to the patient with the aim of gaining quality of life and lifetime. The only curative procedure is allogeneic stem cell transplantation. However, this procedure is only considered for a minority of patients > 70 years of age.

The basis of therapy is supportive therapy, above all with the administration of erythropoiesis-stimulating factors (ESF), erythrocyte concentrates (EC) and, if necessary, iron chelation.

For patients with advanced MDS, without indication for allogeneic stem cell transplantation, azacitidine is an effective and tolerable therapy that can be performed on an outpatient basis. Other drugs, are available in clinical trials.

Supportive therapy: The main component of supportive therapy is the transfusion of red cell concentrates depending on the clinical condition (not depending on the Hb value; exception: patients with severe coronary heart disease and/or other severe concomitant diseases should be kept with the Hb value above 10 g/dl).

Bleeding tendencies: Clinically significant bleeding is to be expected above a threshold value of < 10 /nl platelets. The substitution of platelet concentrates has to be adjusted individually and should only be done in case of clinical bleeding signs (risk of allo-immunization). Tranexamic acid may alleviate bleeding symptoms in case of severe thrombocytopenia.

Antibiotics: The use of antibiotics in case of infections (even minor infections) should be generous, especially in neutropenic patients.

Vaccinations: it is recommended to vaccinate patients against pneumococci (STIKO recommendation from the age of 65) as well as against influenza viruses and SARS-Cov2.

Iron chelators: Polytransfused patients are at longer term risk of concomitant secondary haemochromatosis (cardiomyopathy). In patients with a life expectancy > 2 years with at least 20 red cell concentrates, or a serum ferritin level of >1000 ng/ml, therapy with iron chelators (deferasirox, desferoxamine) should be considered (Nolte Fet al 2013; Gattermann N et al 2010;List AF et al 2012). Iron chelation is of particular importance prior to allogeneic stem cell transplantation. It is recommended until the onset of conditioning, as iron overload is associated with increased mortality (Wermke M et al. 2018).

The discussion about the time course of the occurrence of disease-determining molecular alterations (e.g. mutations in genes that are significantly correlated with the occurrence of MDS) is still ongoing. However, the annual MDS/AML rate in individuals with CHIP is only 0.5-1%. However, this rate is significantly increased compared to the normal population without CHIP.

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