Myelodysplastic Syndromes
Synonyms
Definition
Myelodysplastic syndromes (MDS) are a group of stem cell disorders, mainly of the elderly, characterized by defects in maturation of bone marrow cells, resulting in cytopenia in peripheral blood, possibly associated with increased medullary and peripheral blasts and an increased risk of evolution to acute myeloid leukemia. Cytopenia refers to a deficiency of cellular element of the blood; pancytopenia – an abnormal deficiency in all blood cells (red blood cells and white blood cells and platelets), usually associated with bone marrow tumor or with aplastic anemia; hematocytopenia, an abnormally low number of red blood cells.; and thrombocytopenia, a decrease in the number of platelets.
Characteristics
Epidemiology
MDS are disease mainly of the elderly. The median age at diagnosis is about 72 years. Less than 10% of the patients are younger than 50 years. MDS patients in Asia are 10 years younger in median. The male-female ratio shows a slight preponderance of males. The incidence of MDS is about 4–5/100,000/year and more than 30/100,000/years in patients older than 70 years ( Cancer Epidemiology). This means that MDS are one of the most frequent malignant bone marrow disorders. There is no evidence of age-adjusted increasing incidence, whereas the number of newly diagnosed MDS patients rises with the graying of the population.
Causative Factors
The vast majority patients develop MDS without known reasons. About 10% of the patients develop a treatment-related MDS after being treated with chemotherapy, radiation therapy, or radioiodine therapy. In particular alkylating agents, but also topoisomerase II inhibitors, as well as azathioprine can cause MDS. A very small proportion of the patients have inherited disorders that may promote MDS, such as Fanconi anemia and paroxysmal nocturnal hemoglobinuria (PNH), as well as family history of hematopoietic cancers. Environmental and occupational noxes may also play a role in the development of MDS. Smoking and exposure to agriculture chemicals, benzene, and other solvents ( Benzene and Leukemia) increase the risk of MDS significantly. Polymorphisms and mutations of detoxifying enzymes such as glutathione-S transferases possibly play also a role in the risk of MDS development.
Clinical Presentation
Almost all MDS patients present with a hemoglobin level of less than 10 g/dl. Less frequent is a bicytopenia and about 30% are pancytopenic. The resulting clinical features are signs of anemia, infections, and less frequently, bleeding ( neutropenia).
Diagnosis and Classification
MDS is always a diagnosis of exclusion; there is no pathognomonic finding. Morphologic assessment of blood and bone marrow cytology is the backbone of diagnostic measures. The presence of dysplastic signs in the peripheral blood in case of unexplained cytopenias leads to bone marrow examination by cytologic as well as histologic means. Major morphologic signs in the blood and marrow are dysplastic features in at least one, mostly two to three, cell lineage as well as the presence of blasts up to 19% of the nucleated cells. Typical signs of dysplasia of the erythropoiesis are megaloblastoid changes, nuclear abnormalities such as bridging, karyorrhexis, basophilic stippling, ring sideroblasts, and impaired maturation. Dysplastic features of the granulopoiesis are the presence of pseudo-Pelger cells, hypogranulation of promyelocytes and myelocytes, elevated blast count, and peroxidase insufficiency. Micromegakaryocytes, mononuclear megakaryocytes, and megakaryocytes with multiple nuclear fragments are typical features of dysmegakaryopoiesis. None of these criteria alone is diagnostic, but the combination of different dysplastic features allows making the diagnosis of MDS. Almost all MDS patients show dyserythropoiesis in more than 10% of all erythroid cells. The terms “dysmegakaryopoiesis” and “dysgranulopoiesis” are used if more than 10% of the respective cell lines are dysplastic. It is necessary to assess the amount of dysplasia within a marrow, because the number of affected cell lines plays a major role in the classification of MDS and provides valuable prognostic information. The percentage of medullary blasts should be assessed as exact as possible for classification and prognostic purposes.
WHO-Classifikation of myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasias
| MDS-subtype | Blood | Bone marrow |
|---|---|---|
| Refractory cytopenia with unilineage Dysplasia (RCUD) RA: Refractory anemia RN: Refractory neutropenia RT: Refractory thrombopenia | <1% Blasts Uni- or bicytopenia | <5% Blasts Dysplasia in ≥10% of cells of one lineage |
| Refractory anemia with ring sideroblasts (RARS) | Anemia, no blasts | <5% Blasts, ≥15% ring sideroblasts within erythropoiesis, only dyserythropoesis |
| Refractory cytopenia with multilineage dysplasia (RCMD) with or without ring sideroblasts | <1% Blasts Cytopenia(s) <1000/μl Monocytes | <5% blasts, dysplasie of ≥10% of cells of 2-3 lineages |
| MDS with isolated del(5q) | <1% Blasts Anemia, often plateltes increased | Often typical mononuclear megakaryocytes, <5% blasts, isolated del(5q) anomaly |
| Refractory anemia with excess blasts I (RAEB I) | Cytopenia(s), <5% Blasts, <1000/μl Monocytes | Uni- or multilineage dysplasia, blasts 5-9%, no Auer rods |
| Refractory anemia with excess blasts II (RAEB II) | Cytopenia(s), <20% blasts, <1000/μl Monocytes Auer rods possible | Uni- or multilineage dysplasia, blasts 10-19%, Auer rods possible |
| Unclassifiable MDS (MDS-U) a) RCUD with pancytopenia b) RCMD/RCUD with 1% blasts in blood c) MDS-typical chromosomal aberrations without clear dysplasia | <1% Blasts, <1000/μl Monocytes | <5% Blasts |
| Myelodysplastisch/myeloproliferative neoplasia | ||
| Chronic myelomonocytic leukemia I (CMML I) | <5% Blasts Uni- or Bicytopenia >1000/μl Monocytes/μl no Auer rods | <10% Blasts, dysplasia in >10% of cells of 1-3 lineages, no Auer rods |
| Chronic myelomonocytic leukemia II (CMML II) | <20% Blasts Uni- or bicytopenia >1000/μl Monocytes/μl Auer rods possible | <20% Blasts, dysplasia in >10% of cells of 1-3 lineages Auer rods possible |
| Refractory anemia with ring sideroblasts und Thrombocytosis (RARS-T) | Cytopenia(a), thrombocytes >450.000/μl <1% Blasts | <5% Blasts, >15% ring sideroblasts within erythropoiesis, dyplasia in >10% of cells of 1-3 lineages, no Auer rods, often SF3B1 and JAK-2 mutations |
Cytogenetic Findings
About 50–60% of all MDS patients show chromosomal aberrations in hematopoietic cells at the time of diagnosis. There is a great variability of numerical and structural cytogenetic findings in MDS. Although there are some typical findings, there is no aberration that is restricted to MDS. The most frequent aberrations are del(5q) (~30% of abnormal cases), complex abnormalities (~25%), −7/7q- (~15%), trisomy 8 (~15%), 20q- (~5%), and –Y (~5%).
Some of the aberrations are associated with a distinct type of MDS and have prognostic implications. In general patients with del(11q) and –Y are considered to have a very good prognosis; patients with a normal karyotype, del(5q)(isolated or with another aberration), del(20q), and del(12p) have a good prognosis. Patients with del(7q), +8, i(17q), +19, independent clones, or any other aberration have an intermediate prognosis; patients with inv(3)/t(3q)/del(3q), −7, −7/7q, and double aberrations including −7/7q- or complex karyotypes with three abnormalities have poor prognosis and patients with complex karyotypes with >3 abnormalities have a very poor prognosis.
In cases of unclear diagnosis, i.e., mild cytopenia, mild dysplasia, and no blasts in the marrow and blood, the karyotype has a diagnostic impact when a chromosomal aberration can be found. Chromosomal aberrations also play a role with regard to treatment, as some compounds produce higher response rates in the presence of distinct cytogenetic findings ( Chromosomal Translocations).
Cytology of the blood and marrow, histology of the marrow, and chromosomal analysis are mandatory in the diagnostic work up in MDS.
Prognosis
IPSS-R (revised version of International Prognostic Scoring System)
| Prognostic variable | 0 | 0.5 | 1 | 1.5 | 2 | 3 | 4 |
|---|---|---|---|---|---|---|---|
| Cytogenetics | Very good | Good | Intermediate | Poor | Very poor | ||
| BM blast% | ≤2 | >2–<5% | 5–10% | >10% | |||
| Hemoglobin | ≥10 | 8–<10 | <8 | ||||
| Platelets | ≥100 | 50–< 100 | <50 | ||||
| ANC | ≥0.8 | <0.8 |
| Cytogenetic categories | |
|---|---|
| Very good | del(11q), -Y |
| Good | normal, del(5q), double aberrations including del(5q), |
| del(12p), del(20q) | |
| Intermediate | del(7q), +8, i(17q), +19, any other independent clones |
| Poor | inv(3)/t(3q)/del(3q), −7, −7/7q, |
| Double aberrations including −7/7q- | |
| Complex karyotypes with 3 abnormalities | |
| Very poor | Complex karyotypes with >3 abnormalities |
| Category | Points |
|---|---|
| Very low | ≤1.5 |
| Low | >1.5–3 |
| Intermediate | >3–4.5 |
| High | >4.5–6 |
| Very high | >6 |
Treatment Options
Therapeutic interventions should be discussed with the patient very carefully.
Supportive Care
The standard of care included supportive care measures, including red cell transfusions in case of low hemoglobin levels and transfusions of platelets in case of bleeding or severe thrombocytopenia. Due to frequent red cell transfusions, the patients develop iron overload, potentially resulting in end-organ damage, primarily of the heart. Patients who show ferritin levels of >1,000 ng/ml should be considered to receive iron chelation, preferably with the oral iron chelator deferasirox. Low-risk MDS patients, who received 50–100 red cell transfusions are at risk to become iron overloaded, as well as high-risk patients facing an allogeneic stem cell transplantation are candidates for iron chelation.
Immunomodulatory agents: Lenalidomide, a devoid of thalidomide is an immunomodulatory compound that shows erythroid responses in patients with del(5q) anomalies. Within large studies, the efficacy and an acceptable side effect profile could be shown. About two-thirds of anemic patients with low-risk MDS and isolated del(5q) achieve long-lasting normalization of the cell counts, and in addition the majority of the patients achieve cytogenetic responses as well. The median increase of hemoglobin level is about 4–5 g/dl and the time to response is about 1–3 months. The main side effect is transitional drop of neutrophils and platelets.
Patients who present with low EPO levels (<500) should receive erythropoietin subcutaneously in order to avoid red cell transfusions. The lower the erythropoietin level in the blood, the better is the response with regard to the hemoglobin level. In case of nonresponse, GCSF can be added.
Epigenetic Agents ( Epigenetic Therapy)
Besides genetic aberration, epigenetic changes may play a role in the pathophysiology of MDS. Gene silencing by variable states of DNA methylation and histone modification (Histone Deacetylation) can lead to chromatin remodeling. Genes involved into cell cycle, differentiation, and cell death may be inactivated via methylation status. DNA methyltransferase inhibitors like 5-azacytidine (Vidaza, s.c.) and 5-aza-2deoxyctidine (Dacog, i.v.) have been shown to prolong survival in high-risk MDS patients. In up to 50% of the patients, a remission or at least improvement of cell counts can be achieved. Vidaza is approved for patients with high-risk MDS. A combination of these drugs with histone deacetylase inhibitors may be even more powerful.
Immunosuppressive Agents ( Immunotherapy)
As inhibitory cytokines in the marrow may play also a role in the development of cytopenia, immunoinhibitory therapy can be used to restore the hematopoiesis. Antithymocyte globulin (ATG) and cyclosporine A (CSA), as well as anti-Cd 52 antibody Campath, can result in long-lasting remissions with normalizing the peripheral cell counts. This treatment can be appropriate for patients with RCUD and RCMD.
Intensive Chemotherapy and Allogeneic Hematopoietic Stem Cell Transplantation ( Chemotherapy)
AML like induction chemotherapy followed by a consolidation based on cytarabine and an anthracycline can be administered to high-risk MDS patients. About 60% achieve complete remission, but the vast majority relapses within a year. Long-term remissions can be seen in less than 10% of the patients. Only those high-risk MDS patients that present with a normal karyotype potentially benefit from induction chemotherapy. Patients with a high-risk karyotype, especially those with a complex karyotype, should not be treated with induction as long as they are not going to receive allogeneic stem cell transplantation.
Allogeneic hematopoietic stem cell transplantation is potentially a curative treatment approach for patients with MDS aged less than 60–65 years without relevant comorbidities. The long-term success of this therapy is primarily influenced by disease- and patient-related factors, such as medullary blast count at the time of transplantation, karyotype, age, and comorbidities. Allogeneic hematopoietic stem cell transplantation should be taken into consideration in high-risk patients whenever possible. Intermediate risk patients maybe candidates for allogeneic hematopoietic stem cell transplantation in case of progressive disease or very severe cytopenia. A non-myeloablative conditioning regimen can be useful for elderly patients with MDS.
Cross-References
References
- Brunning RD, Orazi A, Germing U, Le Beau MM, Porwit A, Baumann I, Vardiman JW, Hellstrom-Lindberg E (2008) Myelodysplastic syndromes/neoplasms, overview. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman J (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC press, LyonGoogle Scholar
- Germing U, Kobbe G, Haas R, Gattermann N (2013) Myelodysplastic syndromes: diagnosis, prognosis and treatment. Dtsch Arztebl Int 110(46):783–790PubMedPubMedCentralGoogle Scholar
- Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D (2012) Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120(12):2454–2465PubMedPubMedCentralCrossRefGoogle Scholar
- Hofmann WK, Platzbecker U, Stauder R, Passweg J, Germing U (2013) Leitlinie Myelodys-plastische Syndrome, Onkopedia. Deutsche Gesellschaft für Hämatologie und Onkologie. http://www.dgho-onkopedia.de/de/onkopedia/leitlinien/mds
- Malcovati L, Hellström-Lindberg E, Bowen D, Adès L, Cermak J, Del Cañizo C, Della Porta MG, Fenaux P, Gattermann N, Germing U, Jansen JH, Mittelman M, Mufti G, Platzbecker U, Sanz GF, Selleslag D, Skov-Holm M, Stauder R, Symeonidis A, van de Loosdrecht AA, de Witte T, Cazzola M, Net EL (2013) Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 122(17):2943–2964PubMedPubMedCentralCrossRefGoogle Scholar