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Myelodysplastic Syndrome

  • Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
 
Updated: Apr 21, 2016
 

Background

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.

Blood film (1000× magnification) demonstrating a v Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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.)

For discussion of MDS in children, see Pediatric Myelodysplastic Syndrome. For a summary of MDS management guidelines, see Myelodysplastic Syndromes Guidelines.

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Pathophysiology

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:

  • Cytotoxic chemotherapy
  • Radiation
  • Viral infection
  • 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.

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Etiology

Cytogenetically, patients with MDS or AML fall into three groups:

  • Normal karyotype
  • 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.[3] 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.[4]

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Epidemiology

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.[5] 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.[9]

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).[10]

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.[8]

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.[11]

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Prognosis

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[12] :

  • 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.[11]

Bone marrow film (1000× magnification) demonstrati Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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.

Blood film (1000× magnification) demonstrating a v Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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.[13] 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.

WHO Classification

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[14] :

  • Refractory cytopenia with unilineage dysplasia – this includes refractory anemia, refractory neutropenia, or refractory thrombocytopenia
  • RARS
  • RAEB
  • Refractory cytopenia with multilineage dysplasia
  • MDS with isolated deletion of 5q
  • MDS, unclassifiable
  • Childhood MDS

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:

  • Hemoglobin level
  • Absolute neutrophil count
  • Platelet count
  • Percentage of bone marrow blasts
  • Cytogenetic category

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:

Table 1. Revised International Prognostic Scoring System risk groups and prognosis[16] (Open Table in a new window)

Risk Group Time to Development of AML (y) Median Survival (y)
Very low NR 8.8
Low 10.8 5.3
Intermediate 3.2 3.0
High 1.4 1.6
Very High 0.7 0.8
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
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Contributor Information and Disclosures
Author

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Chief Editor

Koyamangalath Krishnan, MD, FRCP, FACP Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
This bone marrow film (400× magnification) demonstrates an almost complete replacement of normal hematopoiesis by blasts in a refractory anemia with an excess of blasts in transformation. Note the signs of abnormal maturation such as vacuolation, double nucleus, and macrocytosis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Bone marrow film (1000× magnification) demonstrating granular and clotlike positive reaction in periodic acid-Schiff staining in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Table 1. Revised International Prognostic Scoring System risk groups and prognosis [16]
Risk Group Time to Development of AML (y) Median Survival (y)
Very low NR 8.8
Low 10.8 5.3
Intermediate 3.2 3.0
High 1.4 1.6
Very High 0.7 0.8
AML – Acute myelogenous leukemia
Table 2 Cytogenetic abnormalities assigned an IPSS-R value for scoring
Cytogenetic prognostic subgroups Cytogenetic abnormalities 
Very good -Y, del(11q)
Good Normal, del(5q), del(12p), del(20q), double



including del(5q)



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
Table 3.Calculation of IPSS-R score
  Points Assigned
0 0.5 1 1.5 2 3 4
 



 



 



Variable



Cytogenetic subgroup Very Good   Good   Intermediate Poor Very Poor
Bone marrow blasts (%) ≤2   >2-



<5



  5-10 >10  
Hemoglobin (g/dL) ≥10   8-9.9 <8      
Platelet count (x 109/L) ≥100 50-99.9 <50        
Absolute neutrophil count (x 109/L) ≥0.8 <0.8          
Table 4. IPSS-R prognostic risk scores and categories
Risk Score Risk Category
≤1.5 Very Low
>1.5-3 Low
>3-4.5 Intermediate
>4.5-6  High
>6 Very High
Table 5. Clinical outcome by IPSS-R 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
Table 6. Categories of FAB classification versus WHO classification for myelodysplastic syndrome (MDS)
FAB



Classification



WHO–2004



Classification



WHO–2008



Classification



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
RAEB-T AML AML
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