- Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP more...
Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders commonly found in the aging population. All are characterized by one or more peripheral blood cytopenias. Bone marrow is usually hypercellular, but rarely, a hypocellular marrow mimicking aplastic anemia may be seen. Bone marrow cells display aberrant morphology and maturation (dysmyelopoiesis), resulting in ineffective blood cell production.
MDS affects hematopoiesis at the stem cell level, as indicated by cytogenetic abnormalities, molecular mutations, and morphologic and physiologic abnormalities in maturation and differentiation of one or more of the hematopoietic cell lines.[1, 2] See the image below.
See Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options, a Critical Images slideshow, to help identify, classify, work up, and treat these disorders.
MDS may involve one, two, or all three myeloid hematopoiesis cell lineages—erythrocytic, granulocytic, megakaryocytic—depending on the subtype and stage of the disease. The heterogeneity of MDS reflects the fact that its course involves a series of cytogenetic events. In a subgroup of patients, the acquisition of additional genetic abnormalities results in the transformation of MDS into acute myelogenous leukemia (AML). Thus, although clonal, MDS is considered a premalignant condition.
Patients with MDS may present with clinical manifestations of anemia, thrombocytopenia, and/or neutropenia (see Presentation). The workup in patients with possible MDS includes a complete blood count with differential, peripheral blood smear, and bone marrow studies (see Workup).
Standard care for MDS is constantly changing, but it typically includes supportive therapy, including transfusions, and may include bone marrow stimulation and cytotoxic chemotherapy. Bone marrow transplantation has a limited role. (See Treatment.)
MDS develops when a clonal mutation predominates in the bone marrow, suppressing healthy stem cells. The clonal mutation may result from genetic predisposition or from hematopoietic stem cell injury caused by exposure to any of the following:
Genotoxic chemicals (eg, benzene)
MDS can be classified as primary (de novo) or secondary to aggressive treatment of other cancers, with exposure to radiation, alkylating agents, or topoisomerase II inhibitors; it also occurs in heavily pretreated patients with autologous bone marrow transplants.
In the early stages of MDS, the main cause of cytopenias is increased apoptosis (programmed cell death). As the disease progresses and converts into leukemia, further gene mutation occurs, and a proliferation of leukemic cells overwhelms the healthy marrow.
Cytogenetically, patients with MDS or AML fall into three groups:
Balanced chromosomal abnormality causing the generation of fusion oncogenes
Complex karyotypes (usually >3 abnormalities)
Patients with complex karyotypes constitute 30% of primary MDS cases (only 20% of de novo AML) and up to 50% of therapy-related MDS and AML cases. These patients have a worse prognosis and response to treatment.
Balanced translocation abnormalities lead to the generation of fusion oncogenes such as Bcr-Abl in chronic myelogenous leukemia (CML) and PML-Rar alpha in acute promyelocytic leukemia (APL). Unbalanced recurrent aberrations, most commonly -5, 5q-,-7, 7q-, +8, 11q-, 13q-, and 20q-, suggest that genes within these regions have a role in the pathogenesis of MDS or myeloproliferative disorder (MPD), which is based on loss of tumor suppressor genes or haploinsufficiency of genes necessary for normal myelopoiesis.
Approximately 80% of patients with MDS do not have an obvious exposure or cause for MDS. In these cases, the disorder is classified as primary or idiopathic MDS.
The World Health Organiztion (WHO) classifies secondary MDS as MDS or acute leukemia that develops years after known exposure to sources of chromosomal damage. Patients who survive cancer treatment with alkylating agents, with or without radiotherapy, have a high risk of developing MDS or secondary acute leukemia 5-7 years after the exposure. These drugs are associated with a high prevalence of chromosomal abnormalities in bone marrow—in particular, the -5, del(5q), -7, del(q) and complex karyotype.
Secondary MDS after treatment with a topoisomerase II inhibitors such as an anthracycline or etoposide occurs 1-3 years after exposure to these agents. The chromosomal abnormalities commonly involve the MLL gene (11q23).
MDS may also develop after exposure to certain chemicals (eg, benzene). Insecticides, weed killers, and fungicides are also possible causes of MDS and secondary leukemia. Viral infections have also been implicated. Less evidence supports genetic predisposition, but familial incidences have been described. Some of the congenital platelet disorders with RUNX1 and GATA2 mutations can predispose to MDS.
Although familial cases of myelodysplastic syndromes are rare, they are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial MDS is familial platelet disorder with propensity to myeloid malignancy, which is caused by heterozygous germline RUNX1 mutations. The incidence of MDS/AML in affected pedigrees is over 40%, with a median age of onset of 33 years. Familial monosomy 7; unusually short telomeres in dyskeratosis congenita; and, recently, four pedigrees with inherited MDS caused by heterozygous mutations in GATA2 have been reported. These familial forms may occasionally be found in the course of screening family members of a patient with MDS as bone marrow transplant donors.
A study by Kristinsson et al found that chronic immune stimulation is a trigger for acute leukemia and MDS development. The underlying mechanisms may also be caused by a genetic predisposition or treatment for infections or autoimmune conditions.
The actual incidence of MDS in the United States is unknown. MDS was first considered a separate disease in 1976, and its occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder. MDS was not classified as neoplastic and included in cancer registries until 2001. Current estimates of the incidence of MDS in the United States vary widely, from 13,000 to 30,000-55,000 new cases each year.[5, 6, 7, 8] The higher figures have been questioned as possible overestimates resulting from inclusion of other hematopoietic conditions.
The incidence of MDS has appeared to be increasing. The apparent rise is believed to reflect the increase in the elderly population, but may also reflect improvements in recognition and criteria for the diagnosis.
Although MDS may occur in persons of any age, including children, MDS primarily affects elderly people, with the median onset in the seventh decade of life. Data from 2001 through 2003 of the first National Cancer Institute's Surveillance, Epidemiology & End Reports (SEER) indicate 86% of MDS cases were diagnosed in individuals who were 60 years of age or older (median age: 76y).
Other data from SEER also show that the estimated incidence of MDS increases significantly with age, ranging from 0.7 per 100,000 population during the fourth decade of life to 20.8-36.3/100,000 after age 70 years. There is a fivefold difference in risk between age 60 and ≥80 years.
At all ages, MDS is more common in males than in females. In SEER data from 2001-2003, the incidence rate was significantly higher in men than in women (4.5 vs 2.7 per 100,000 population).
MDS is found worldwide and is similar in characteristics throughout the world. Data based mainly on European numbers from Germany and Sweden were very similar to the US numbers.
A review of United Kingdom population-based data from September 2004 to August 2013 found marked variations in MDS incidence, depending on the standard population used to calculate rates. For example, using the 1996 world standard, the population with the greatest weighting towards younger groups, the incidence rate was 1.67 per 100,000 population; using the 2013 European Standard Population, which has the greatest weighting towards older ages, the rate was 4.4 per 100,000 population.
In some patients, MDS is an indolent disease. Other patients develop significant cytopenias; the resulting complications (eg, bleeding and infections) account for almost all the mortality related to MDS. In the remainder of cases the disease follows an aggressive course and converts into an acute form of leukemia.
Risk classification systems to estimate prognosis in patients with MDS have been developed by the French-American-British (FAB) Cooperative Group, the World Health Organization (WHO), and the MDS Risk Analysis Workshop.
The FAB system classifies MDS into the following five subgroups, differentiating them from acute myeloid leukemia :
Refractory anemia (RA)
RA with ringed sideroblasts (RARS)
RA with excess blasts (RAEB; 6-20% myeloblasts)
RAEB in transition to AML (RAEB-T; 21-30% myeloblasts)
Chronic myelomonocytic leukemia (CMML)
An underlying trilineage dysplastic change in the bone marrow cells is found in all subtypes.
RA and RARS are characterized by 5% or less myeloblasts in bone marrow. RARS is defined morphologically as having 15% erythroid cells with abnormal ringed sideroblasts (see the image below), reflecting an abnormal accumulation of iron in the mitochondria. Both RA and RARS have a prolonged clinical course and a low prevalence of progression to acute leukemia. In a review of United Kingdom population-based data, with followup of 2 to 11 years, progression to acute leukemia occurred in 5% of RARS cases, compared with 25% of RAEB cases.
RAEB and RAEB-T (see the image below) are characterized by greater than 5% myeloblasts. The higher the percentage of myeloblasts present, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia.
Transition from early to more advanced stages may occur, which indicates that these subtypes are merely stages of disease rather than distinct entities. Elderly patients with MDS who progress to acute leukemia are often considered to have a poor prognosis because their disease response to chemotherapy is worse than that of de novo acute myeloid leukemia patients.
The 1999 WHO classification proposed including all cases of RAEB-T in the category of acute leukemia because these patients have similar prognostic outcomes. However, the response to therapy is worse than in patients with de novo or more typical AML or acute nonlymphocytic leukemia.
The fifth type of MDS, CMML, is the most difficult to classify. This subtype can have any percentage of myeloblasts but manifests as a monocytosis of 1000/μL or more, a total white blood cell (WBC) count of less than 13,000/μL, and trilineage dysplasia.
CMML may be associated with splenomegaly. This subtype overlaps with myeloproliferative disease (MPD) and may have an intermediate clinical course. CMML must be differentiated from classic chronic myelocytic leukemia, which is characterized by a negative Ph chromosome.
The 2008 WHO classification proposed that juvenile myelomonocytic leukemia and CMML be listed as separate entities within a group of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. WHO criteria for these forms of CMML include splenomegaly and a WBC count greater than 13,000/μL.
The WHO classification scheme for MDS was published in 1999. Updates to the scheme were published in 2008. Under the revised scheme, single-lineage dysplasia is considered a valid criterion for diagnosis of MDS. As well, refractory cytopenia with unilineage dysplasia (RCUD) became an official entity under the new WHO classification.
The 2008 WHO classification of MDS is as follows :
Refractory cytopenia with unilineage dysplasia – this includes refractory anemia, refractory neutropenia, or refractory thrombocytopenia
Refractory cytopenia with multilineage dysplasia
MDS with isolated deletion of 5q
The WHO classification also includes a provisional entity: refractory cytopenia of childhood.
International Prognostic Scoring System
To improve prognostic classification, the MDS Risk Analysis Workshop developed the Myelodysplastic Syndrome International Prognostic Scoring System (IPSS). The IPSS was published in 1997 and updated in 2012.[15, 16] The revised IPPS (IPSS-R) score is calculated on the basis of five variables:
Absolute neutrophil count
Percentage of bone marrow blasts
With the IPSS, patients were stratified tinofour risk groups: low, intermediate 1 and 2, and high. The IPSS-R score is used to stratify patients into five risk groups, as shown in Table 1, below:
|Risk Group||Time to Development of AML (y)||Median Survival (y)|
|AML – Acute myelogenous leukemia|
Mean survival is 18-24 months or longer in patients with the following features:
Single or mild cytopenias
Normal chromosomes or a single chromosomal abnormality (except those involving chromosome 7)
Fewer than 10% myeloblasts in the bone marrow
Mean survival is 6-12 months in patients with the following features:
Pancytopenia requiring red blood cell or platelet transfusions
Chromosome 7 abnormalities or multiple chromosomal abnormalities
Greater than 10% myeloblasts
Besa EC. Myelodysplastic syndromes (refractory anemia). A perspective of the biologic, clinical, and therapeutic issues. Med Clin North Am. 1992 May. 76(3):599-617. [Medline].
Germing U, Kobbe G, Haas R, Gattermann N. Myelodysplastic syndromes: diagnosis, prognosis, and treatment. Dtsch Arztebl Int. 2013 Nov 15. 110(46):783-90. [Medline].
Goldberg H, Lusk E, Moore J, Nowell PC, Besa EC. Survey of exposure to genotoxic agents in primary myelodysplastic syndrome: correlation with chromosome patterns and data on patients without hematological disease. Cancer Res. 1990 Nov 1. 50(21):6876-81. [Medline]. [Full Text].
Kristinsson SY, Bjorkholm M, Hultcrantz M, et al. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J Clin Oncol. 2011 Jul 20. 29(21):2897-903. [Medline]. [Full Text].
What are the key statistics about myelodysplastic syndromes?. American Cancer Society. Available at http://www.cancer.org/cancer/myelodysplasticsyndrome/detailedguide/myelodysplastic-syndromes-key-statistics. Accessed: November 8, 2015.
Rollison DE, Hayat M, Smith M, et al. First report of national estimates of the incidence of myelodysplastic syndromes and chronic myeloproliferative disorders from the U.S. SEER program [abstract 247]. Blood. 2006. 108:77a. [Full Text].
Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008 Jul 1. 112(1):45-52. [Medline]. [Full Text].
Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012 Jul. 125 (7 Suppl):S2-5. [Medline].
Roman E, Smith A, Appleton S, Crouch S, Kelly R, Kinsey S, et al. Myeloid malignancies in the real-world: Occurrence, progression and survival in the UK's population-based Haematological Malignancy Research Network 2004-15. Cancer Epidemiol. 2016 Apr 15. [Medline]. [Full Text].
Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med. 1985 Oct. 103(4):620-5. [Medline].
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999 Dec. 17(12):3835-49. [Medline]. [Full Text].
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30. 114(5):937-51. [Medline]. [Full Text].
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep 20. 120 (12):2454-65. [Medline]. [Full Text].
Adema V, Bejar R. What lies beyond del(5q) in myelodysplastic syndrome?. Haematologica. 2013 Dec. 98(12):1819-21. [Medline].
Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002 Aug 6. 137(3):156-63. [Medline]. [Full Text].
Musto P, Lanza F, Balleari E, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2005 Jan. 128(2):204-9. [Medline].
[Guideline] Myelodysplastic Syndromes Version 1.2016. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed: November 7, 2015.
Jadersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellstrom-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005 Aug 1. 106(3):803-11. [Medline]. [Full Text].
Clark RE, Jacobs A, Lush CJ, Smith SA. Effect of 13-cis-retinoic acid on survival of patients with myelodysplastic syndrome. Lancet. 1987 Apr 4. 1 (8536):763-5. [Medline].
Crisà E, Foli C, Passera R, Darbesio A, Garvey KB, Boccadoro M, et al. Long-term follow-up of myelodysplastic syndrome patients with moderate/severe anaemia receiving human recombinant erythropoietin + 13-cis-retinoic acid and dihydroxylated vitamin D3: independent positive impact of erythroid response on survival. Br J Haematol. 2012 Jul. 158 (1):99-107. [Medline].
List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5. 355 (14):1456-65. [Medline]. [Full Text].
Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15. 20(10):2429-40. [Medline]. [Full Text].
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar. 10(3):223-32. [Medline].
Bejar R, Lord A, Stevenson K, Bar-Natan M, Pérez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014 Oct 23. 124 (17):2705-12. [Medline]. [Full Text].
Parikh AR, Olnes MJ, Barrett AJ. Immunomodulatory treatment of myelodysplastic syndromes: antithymocyte globulin, cyclosporine, and alemtuzumab. Semin Hematol. 2012 Oct. 49 (4):304-11. [Medline]. [Full Text].
Platzbecker U. Who benefits from allogeneic transplantation for myelodysplastic syndromes?: new insights. Hematology Am Soc Hematol Educ Program. 2013. 2013:522-8. [Medline].
Sandhu KS, Brunstein C, DeFor T, Bejanyan N, Arora M, Warlick E, et al. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged ≥70 Years. Biol Blood Marrow Transplant. 2015 Sep 28. [Medline].
Shaffer BC, Ahn KW, Hu ZH, Nishihori T, Malone AK, et al. Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome. J Clin Oncol. 2016 Apr 4. [Medline].
General Information About Myelodysplastic Syndromes. National Cancer Institute. Available at http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/HealthProfessional/page1#Reference1.9.
Saunthararajah Y. Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes. Hematology Am Soc Hematol Educ Program. 2013. 2013:511-21. [Medline].
Visor MT, et.al. Revised International Prognostic Scoring System (IPSS) Predicts survival and Leukemia Evaluation of Myelodysplastic Syndromes Significantly Better than IPSS and WHO Prognostic System: Validation by the Gruppo Romano Mielodisplasie Italian Regional Database. Journal of Clinical Oncology. 2013. 31:2671-2677.
Liew E, and Owen C. Familial myelodysplastic syndromes: a review of literature. Haematologica. 2011. 10:1536-1542.
- Table 1. Revised International Prognostic Scoring System risk groups and prognosis
- Table 2 Cytogenetic abnormalities assigned an IPSS-R value for scoring
- Table 3.Calculation of IPSS-R score
- Table 4. IPSS-R prognostic risk scores and categories
- Table 5. Clinical outcome by IPSS-R risk category
- Table 6. Categories of FAB classification versus WHO classification for myelodysplastic syndrome (MDS)
|Risk Group||Time to Development of AML (y)||Median Survival (y)|
|AML – Acute myelogenous leukemia|
|Cytogenetic prognostic subgroups||Cytogenetic abnormalities|
|Very good||-Y, del(11q)|
|Good||Normal, del(5q), del(12p), del(20q), double
|Intermediate||Del(7q), +8, +19, t(17q), any other single or
double independent clones
|Poor||-7, inv(3)/t(3q)/del(3q), double including
-7,/del(7q), complex: 3 abnormalities
|Very poor||Complex: >3 abnormalities|
|Cytogenetic subgroup||Very Good||Good||Intermediate||Poor||Very Poor|
|Bone marrow blasts (%)||≤2||>2-
|Platelet count (x 109/L)||≥100||50-99.9||<50|
|Absolute neutrophil count (x 109/L)||≥0.8||<0.8|
|Risk Score||Risk Category|
|IPSS-R Risk Category|
|Very Low||Low||Intermediate||High||Very High|
|Clinical Outcome||Median survival (years)||8.8||5.3||3.0||1.6||0.8|
|Median time to 25% acute myelogenous leukemia evolution (years)||NR||10.8||3.2||1.4||0.7|
|RA||RA RCMD 5q-||RCUD RCMD 5q-|
|RARS||RARS RCMD-RS||RARS RCMD-RS RARS-T|
|RAEB||RAEB-1 RAEB-2||RAEB-1 RAEB-2|
|CMML||CMML-1 CMML-2||CMML-1 CMML-2|