Diagnosis, Prognosis, and Treatment
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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 high-risk 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, risk-adapted 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.
The 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).
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) 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 long-term (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, 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 (<5%, 5% to 9%, or ≥ 10% to 19%), and
- evidence of a deletion on the long arm of chromosome 5 (del(5q)).
The aim of the classification is to define MDS types with different prognoses. A distinction is made between refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ring sideroblasts (RARS) as entities in which the signs of dysplasia are limited to erythropoiesis, and refractory cytopenia with multilineage dysplasias (RCMD), in which two or, usually, three cell lineages are dysplastic. With a median survival time of about 3 years, patients with RCMD have a poorer prognosis and a higher risk of leukemia than those with RCUD and RARS (median survival about 6 years). If the cytogenetic analysis shows an isolated del(5q) without excess of blasts, a diagnosis of MDS with del(5q) is made. This entity has a good prognosis so long as it does not transform into leukemia (13). In patients with refractory anemia with excess of blasts (RAEB I or II), the presence of a malignant cell population in the bone marrow has been shown, with blasts making up 5% to 9% of cells in RAEB I and 10% to 19% of cells in RAEB II. These patients have a much higher risk of developing AML, and mean survival is about 1 to 2 years (e2). Chronic myelomonocytic leukemia (CMML I and II) and refractory anemia with ring sideroblasts with thrombocytosis (RARS-T) both belong to the group of myelodysplastic–myeloproliferative neoplasias (12–14) and display characteristics of myeloproliferative syndromes, expressed in CMML as a proliferation of monocytes and splenomegaly (e1) and in RARS-T as thrombocytosis and, frequently, evidence of sf3b1 and jak2 mutations (e4, e5). Cases where more than 20% of the cells in bone marrow or blood are blasts are classed as acute leukemia.
Histomorphological analysis of a bone marrow biopsy is a necessary part of the diagnostic work-up in order to determine the presence of bone marrow fibrosis, which is associated with a poorer prognosis (15).
Chromosome analysis of 20 to 25 metaphases (e6) of the bone marrow cells is essential, in particular with a view to estimating the prognosis (16–18). Around 50% to 60% of patients show cytogenetic abnormalities (16). The German–Austrian MDS Working Group together with other international groups has identified the paramount prognostic significance of chromosomal findings and has undertaken a new grouping of different karyotypes (Table 2) (17). In the few cases of dry tap (punctio sicca), in which no bone marrow can be aspirated, the cytogenetic analysis can be carried out on blood cells. Fluorescence in situ hybridization (FISH) can also be carried out on blood cells, and is particularly successful on CD34+ selected cells. This method can also be employed during the course of the disease for treatment monitoring (e7). In addition, there is the possibility of submitting bone marrow specimens from biopsy in isotonic saline solution and blood for cytogenetic analysis.
Assessment of prognosis
The course of the disease, and hence the prognosis, are essentially determined by disease-specific characteristics such as bone marrow blast cells, chromosomal abnormalities, and the extent of hematopoietic insufficiency, but also by patient-specific factors such as age, sex, comorbidities, and transfusion requirement (19, e8–e12). Prognostic scores combine prognostic factors with the aim of identifying low-risk patients, for whom a wait-and-see approach seems justified, and high-risk patients, who so far as possible should be offered more intensive treatment, including allogeneic blood stem cell transplantation.
The International Prognostic Scoring System (IPSS) is used in both routine clinical practice and in clinical studies (20). Recently, a multinational working group refined the IPSS on the basis of retrospective data from over 7000 patients (IPSS-R) (21). The main innovations are:
- new grouping of chromosomal abnormalities into five rather than three risk categories (17),
- new definition of risk groups depending on the proportion of medullary blast cells (>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-foundation.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 about 71% of patients with MDS and 93% of patients with CMML, and can be used for diagnostic and prognostic purposes in cases where cytogenetic abnormalities are absent and sufficient cytological criteria are lacking (24–26, e17–e25). For five abnormalities (tp53, especially in MDS del(5q), etv6, runx1, asxl1, ezh2), an independent unfavorable prognostic effect was shown. Evidence of an sf3b1 mutation is associated with anemia with ring sideroblasts and evidence of an srsf2 mutation with CMML. Recent investigation techniques such as proteomics or gene array analysis are of great scientific interest but are not yet included among routine clinical diagnostic procedures (e17–e25).
Once a precise diagnosis and estimated prognosis have been made, and unless only mild cytopenia is present that does not require treatment, the patient should be offered appropriate therapy taking into account his or her age, general condition of health, comorbidities (if any), and wishes. Repeat bone marrow diagnostic tests should be carried out if cell counts deteriorate.
Recommendations for treatment are based primarily on guidelines by international working groups and only to a small extent on phase III studies. The evidence level is therefore often not very high. A basic principle is that, for low-risk patients, the priority is maintenance or restoration of quality of life, whereas for high-risk patients, prolonging life expectancy is also an important therapeutic goal (7). Treatment should not be delayed until leukemia has developed, but should start as soon as the patient has complaints that impair his or her quality of life or has a high-risk profile. The mainstay of all treatments is transfusion of red blood cell concentrates and, for patients with bleeding and/or platelet counts in single figures, platelet concentrates. The use of red blood cell concentrates should not be guided primarily by hemoglobin values, but should be directed according to individual need (7). Typically, transfusions are given to patients with hemoglobin values below 8 to 9 g/dL. Supportive therapies include vaccinations in accordance with the recommendations of the German Standing Committee on Vaccination (STIKO, Ständige Impfkommission), early use of antibiotics in cases of fever, and tranexamic acid in patients with marked thrombocytopenia and bleeding diathesis (5–7).
Patients with a chronic transfusion requirement develop iron overload, which can lead to organ damage. For this reason, for low-risk patients who have received at least 25 red blood cell concentrates and whose serum ferritin concentration is over 1000 ng/mL, treatment with a chelating agent should be considered. A survival advantage from iron chelation has been shown in retrospective analysis but not yet proven in a prospective randomized trial. Iron chelation therapy leads to improved cell counts in about 15% to 20% of patients (27). Since iron overload is associated with higher complication rates after allogenic stem cell transplantation, patients should also be treated with an approved chelating agent—deferoxamine or, if deferoxamine is contraindicated, desferasirox—before transplantation (28, e26, e27) (evidence level IIa).
Two-thirds of low-risk patients with an endogenous erythropoietin concentration of <500 U/L and only mild transfusion requirement become transfusion-free with high dose therapy with erythropoietin (29, 30). However, the erythropoietins have not yet been approved for treatment of patients with MDS (evidence level Ib).
Around two-thirds of patients with deletion (5q) without excess of blasts over 9% become transfusion-free after treatment with lenalidomide (31). Lenalidomide is approved for the treatment of transfusion-dependent patients with isolated del(5q) in the IPSS low- and intermediate-risk groups (evidence level IIa). tp53 mutations in patients with MDS and del(5q) are associated with a poorer prognosis (e28).
Basically, allogenic blood stem cell transplantation is the only therapeutic measure that offers a potential cure to appropriate patients (e29). This treatment is appropriate for patients aged up to 70 years without relevant comorbidities. In exceptional cases, patients aged over 70 have successfully undergone transplantation (32). The time point for transplantation is largely determined by the disease pathology. In patients with low and intermediate disease risk, transplantation should not be carried out until progression occurs (33). High-risk patients benefit from early transplantation (34). In individual cases, marked cytopenia can be an indication for transplantation (34). Transplants from HLA-matched unrelated donors are today equivalent to those from HLA-identical sibling donors. Current data even show that, for older patients, younger unrelated donors given better outcomes than “old” sibling donors (35). If transplantation is indicated and a donor has been identified, high-risk patients should undergo transplantation without delay (36).
The intensity of chemotherapy immediately preceding the transplantation (“conditioning”) should be individually adjusted to the patient’s age and comorbidities. Doses are reduced for older patients, while young patients receive high-dose therapy, because both cytotoxic and immunological mechanisms are essential for successful transplantation (37). Post-transplantation aftercare is particularly important, so that complications and any incipient relapse may be recognized at an early stage. The main complications are direct consequences of the conditioning, such as mucositis, bleeding, and infection during the time of cytopenia, and acute and chronic graft-versus-host disease, which can damage organs directly or indirectly, since the immune suppression required to treat it promotes severe bacterial and viral infections. At present, the therapy-related mortality rate is between 15% and 30%. Around 30% to 50% of patients can be cured by allogenic transplantation, and in 30% to 50% the MDS recurs (38).
Since the hematopoietic cells in MDS patients also show epigenetic changes in the form of pathological DNA hypermethylation, treatment with the demethylating drug 5-azacitidine may be considered. Once this drug was shown in an international phase III study to be superior to other forms of treatment (supportive treatment alone, low-dose AraC, intensive chemotherapy) and to prolong median survival by 10 months (39), it was approved for the treatment of patients with a poor risk profile (evidence level Ib). The overall response rate is around 50%, but the treatment is not curative (39). The main unwanted effect is deterioration of blood cell counts at the start of treatment, which does not mean that treatment should be stopped (40). Treatment outcome should not be assessed until after six cycles of therapy (40). Induction chemotherapy can be used in high-risk patients with a good karyotype (5–7, e30).
Patients with CMML who develop leukocytosis (>20 000/μL) can also be treated with oral hydroxyurea or low-dose cytoarabinoside (evidence level IIa). Figures 1 and 2 show the current treatment algorithm for the various risk groups.
In the long-term, patient management requires intelligent multidisciplinary collaboration between the family doctor, the hematologist, and the MDS center involved (if any). Regular (e.g. monthly) cell counts in peripheral blood and assessment of the patient’s general state of health can be done by the family doctor. Any transfusions or medical treatment required are carried out by the specialist hematologist, while, especially where approved drugs are unavailable or the patient ceases to respond to treatment, MDS centers can contribute expertise and the opportunity of involvement in clinical studies.
It is in this context that the German MDS Study Group has long been working hard to carry out studies, usually multicenter, in order to offer treatment to as many patients as possible. These are “investigator-initiated trials” and trials run by the pharmaceutical industry. The MDS Registry in Düsseldorf collects diagnostic, clinical, prognostic, and therapeutic data recorded in many participating centers, in order to enable joint scientific projects. A German Cancer Aid–supported project (Krebshilfeverbundprojekt) (chair: W.K. Hofmann, Mannheim) involves central biobanking in Düsseldorf and research subprojects in Mannheim, Göttingen, Hannover, Regensburg, and Freiburg (www.mds-verbund.de). An up-to-date overview of clinical studies and contacts in the various centers, together with publications of the German–Austrian–Swiss MDS Group may be seen at www.mds-register.de.
Conflict of interest statement
Professor Germing received financial support for writing a paper and reimbursement of travel costs from Celgene. He has received lecture fees from Novartis, Celgene, and Janssen-Cilag. He has received research funding (third party) from Celgene, Novartis, Amgen, and Janssen-Cilag.
Professor Kobbe has received reimbursement of conference fees and travel costs from Medac, Celgene, and Novartis. He has received lecture fees from Celgene and Novartis. He has received research funding (third party) from Celgene and Novartis.
Professor Gattermann has received consultancy fees (advisory board work) from Novartis and Celgene. He has received financial support for the publication of the results of clinical MDS studies sponsored by Novartis and Celgene. He has also received reimbursement of conference fees by Novartis. He has had travel costs reimbursed and lecture fees paid by Novartis and Celgene. He has also received research funding (third party) from Novartis and Celgene.
Professor Haas declares that no conflict of interest exists.
Manuscript received on 15 January 2013, revised version accepted on 23 July 2013.
Translated from the original German by Kersti Wagstaff, MA.
Prof. Ulrich Germing
Klinik für Hämatologie, Onkologie und Klinische Immunologie
Moorenstr. 5, 40225 Düsseldorf, Germany
@For eReferences please refer to::
onkopedia.de/de/onkopedia/leitlinien/mds. Last accessed on 14 October 2013.
Prof. Dr. med. Germing, Prof. Dr. med. Kobbe, Prof. Dr. med. Haas, Prof. Dr. med. Gattermann
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