MEDICINE

REVIEW ARTICLE

Myelodysplastic Syndromes: Diagnosis, Prognosis, and Treatment Ulrich Germing, Guido Kobbe, Rainer Haas, Norbert Gattermann

SUMMARY Background: Myelodysplastic syndromes (MDS) are malignant stem-cell diseases that are usually diagnosed in elderly patients who present with anemia or, less commonly, bi- or pancytopenia. Their incidence in persons over age 80 is above 50 new cases per 100 000 persons per year. Their clinical course is highly variable. About one-quarter of all patients with MDS develop acute leukemia. The median survival time from the moment of diagnosis is about 30 months. Methods: We selectively searched the PubMed database for pertinent articles and guidelines from the years 2000–2013. We used the search term “myelodysplastic syndromes.” Results: MDS are diagnosed by cytology, with consideration of the degree of dysplasia and the percentage of blast cells in the blood and bone marrow, and on a cytogenetic basis, as recommended in the WHO classification. In particular, chromosomal analysis is necessary for prognostication. The Revised International Prognosis Scoring System (IPSS-R) enables more accurate prediction of the course of disease by dividing patients into a number of low- and highrisk groups. The median survival time ranges from a few months to many years. The approved treatments, aside from transfusion therapy, include iron depletion therapy for low-risk patients, lenalidomide for low-risk patients with a deletion on the long arm of chromosome 5, and 5-azacytidine for high-risk patients. High-risk patients up to age 70 who have no major accompanying illnesses should be offered allogenic stem-cell transplantation with curative intent. The cure rates range from 30% to 50%. Mucositis, hemorrhages, infections, and graft-versus-host diseases are the most common complications of this form of treatment. Conclusion: Myelodysplastic syndromes are treated on an individualized, riskadapted basis after precise diagnostic evaluation and after assessment of the prognosis. More studies are needed so that stage-adapted treatment can be improved still further. ►Cite this as: Germing U, Kobbe G, Haas R, Gattermann N: Myelodysplastic syndromes: diagnosis, prognosis and treatment. Dtsch Arztebl Int 2013; 110(46): 783–90. DOI: 10.3238/arztebl.2013.0783

Department of Haematology, Oncology and Clinical Immunology, Düsseldorf University Hospital: Prof. Dr. med. Germing, Prof. Dr. med. Kobbe, Prof. Dr. med. Haas, Prof. Dr. med. Gattermann

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(46): 783–90

he myelodysplastic syndromes (MDS) are among the commonest hematological malignant diseases, with an incidence of around 4 per 100 000 head of population per year and a prevalence of about 7 in 100 000 (1). The incidence of MDS rises sharply with advancing age, reaching over 50 per 100 000/year in the age group over 80 years (e1). Median age at disease onset is around 70 years; only about 10% of patients are below the age of 50 (2). The main symptoms are signs of hematopoietic insufficiency, particularly symptoms of anemia; less often, susceptibility to infection and signs of bleeding occur. The MDS are diseases of the hematopoietic stem cells. They are characterized by disturbances of differentiation and maturation, and by changes in the bone marrow stroma (3, 4). These are accompanied not only by reduced blood cell counts, but also by an increased risk (about 20% to 25%) of developing acute myeloid leukemia (AML) (4, e2). The disease course varies greatly from patient to patient, with median survival times ranging from a few months to many years (e2). For this reason, particularly with a view to choosing treatment, it is very important to estimate the prognosis as accurately as possible. In recent years a new classification and new prognostic scoring systems have been developed. In addition, new drugs have been shown to be effective and have been introduced into the treatment of MDS patients. The present review is based on a selective literature search and takes account of the National Comprehensive Cancer Network guidelines (5), the European Leukemia Net guidelines (6), and the guidelines of the German Society of Hematology and Oncology (Deutsche Gesellschaft für Hämatologie und Onkologie) (7).

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Diagnosis In most cases, those involved in diagnosing MDS (Box) are family doctors and hematologists. This is because it is often the family doctor who identifies anemia during a routine examination, or else MDS is identified on the basis of blood tests carried out to investigate the cause of symptoms of anemia. Once the more frequent causes of anemia have been ruled out, such as iron deficiency, vitamin B12 and folic acid deficiency, and hemolysis, referral to a hematologist for further investigation is advisable. In particular, the presence of bi- or pancytopenia (about 30%) can be a warning signal (red flag)

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MEDICINE

TABLE 1 Differential diagnoses in myelodysplastic syndrome and appropriate diagnostic tests for identifying myelodysplastic syndromes Differential diagnosis

Diagnostic tests

Aplastic anemia, pure red cell aplasia (PRCA)

Histology, cytology, parvovirus B19

Toxic bone marrow injury (alcohol, lead, NSAR, etc.)

History, lab tests

Reactive bone marrow changes (sepsis, HIV, chronic infections, Tbc, autoimmune diseases etc.), copper deficiency

Cytology, history, lab tests

Monocytosis of other etiology

History, lab tests, molecular genetic testing

Paroxysmal nocturnal hemoglobinuria (PNH)

Immunophenotyping

Immune thrombocytopenia

History, course

Megaloblastic anemia

Vitamin B12/folic acid concentration

Hypersplenic syndromes

History/clinical features (splenomegaly)

Acute leukemia (especially erythroleukemia, FAB-M6)

Cytology, genetic and molecular genetic testing

Myeloproliferative diseases (especially aCML, PMF)

Histology, cytogenetic and molecular genetic testing

Hairy cell leukemia, LGL

Cytology, immunophenotyping, molecular genetic testing (braf, stat3), T-cell receptor

Congenital dyserythropoietic anemia (rare)

Moleculargenetic (sec23b und cdan-1)

NSAR, nonsteroidal antirheumatics; Tbc, tuberculosis; aCML, atypical chronic myeloid leukemia; PMF, primary myelofibrosis; LGL, large granular lymphoma

and may indicate bone marrow disease. If blood cell counts and the differential cell count are normal, MDS is extremely unlikely. Patients who have undergone chemotherapy for any other disease, benign or malignant, especially with alkylating drugs (cyclophosphamide, ifosfamide, carmustine, dacarbazine, and others) and/or radiation therapy or radioiodine therapy in the past are at greater risk of developing MDS: around 10% of MDS patients developed the disease after treatment with cytotoxic agents or radiation (8, 9). Occupational history and any notifications to the employers’ liability insurance association (10) appear to be important if there is a possibility that there may have been longterm (many years) exposure to benzole, since this increases the risk of MDS. Once hematological and nonhematological differential diagnoses have been ruled out (Table 1), careful cytomorphological analysis of blood and bone marrow are necessary, ideally performed by an experienced hematologist or pathologist. It is not unusual, however, for even experienced diagnosticians to fail to make a definite diagnosis, and for this reason repeat bone marrow investigations can sometimes be necessary if the cytopenia persists. In many patients, the differential blood tests show signs of dysplasia in the granulocytes. Bone marrow cytology usually shows several signs of dysplasia,

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affecting more than 10% of the nucleated cells of one or more cell lineages (e3). None of the signs of dysplasia is pathognomonic of MDS, as the myeloproliferative syndromes, AML, and other hematological and nonhematological diseases can all show dysplasias. eTable 1 shows the current WHO classification of MDS and the myelodysplastic–myeloproliferative dysplasias (11, 12). Important decision criteria are: ● the extent of the signs of dysplasia (only one cell lineage affected, or several?), ● the degree of blast proliferation (2%, 3% to 4%, 5% to 9%, 10% to 19%) (e13), ● account taken of the grade of cytopenia. This prognostic score defines five risk groups (Table 2) that differ significantly in terms of median survival and risk of developing AML. Patients in the very high risk group have a median survival time of only 0.8 years, whereas median survival for patients in the very low risk group is 8.8 years, hardly different from the life expectancy of the age-matched healthy population (21). The score can also be calculated by computer after input of the required parameters (www.mds-foun dation.org). The score has not yet been prospectively validated. Other prognostic factors already established earlier, such as bone marrow fibrosis (15), lactate dehydrogenase (LDH) (e14–e15), β2-microglobulin (e16), and transfusion requirement (19) have been confirmed. For patients with CMML, too, a new score has been developed and validated that uses a medullary blast cell proportion of >10%, leukocyte count of >13 000/μL, transfusion requirement, and a poor karyotype as risk factors to define four risk groups (22) (eTable 2). The MDS Comorbidity Score—a validated score for patients with MDS—uses only patient-associated risk factors, namely cardiac, hepatic, renal, and pulmonary comorbidities together with evidence of a solid tumor (23) (eTable 3). Molecular abnormalities are found in Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(46): 783–90

BOX

How to diagnose myelodysplastic syndromes* ● Peripheral blood – Blood count, mandatory – Leukocyte count often

Myelodysplastic syndromes: diagnosis, prognosis, and treatment.

Myelodysplastic syndromes (MDS) are malignant stem-cell diseases that are usually diagnosed in elderly patients who present with anemia or, less commo...
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