Synonyms: MDS, myelodysplasia, dysmyelopoiesis syndrome, pre-leukaemia

Myelodysplastic syndromes (MDS) are a heterogeneous group of acquired clonal disorders affecting the haematopoietic system. The bone marrow becomes hypercellular or hypocellular with disordered growth and maturation of a clonal proliferation of abnormal cells. This causes peripheral blood cytopenias due to insufficient haematopoiesis among healthy marrow cells, affecting the myeloid (white cells), erythroid (red cells) and megakaryocyte (platelets) lines. The degree to which each cell line is affected is very variable. The disease course is highly variable, from indolent to aggressive with swift progression to acute myeloid leukaemia (AML) in 30% of cases.¹

About 10% of MDS are secondary, most often due to radiotherapy or chemotherapy for cancer. The time from treatment of a primary malignancy (particularly prostate, breast, bladder, lung or non-Hodgkin's lymphoma) to the development of MDS is about five years. A small number of cases are due to occupational exposure to radiation, benzene or other organic solvents. Secondary MDS have a worse prognosis than primary MDS.²

Epidemiology

• Approximately 60-70% of patients are classified as primary myelodysplastic syndrome (MDS).¹
• The overall prevalence of the syndromes appears to be increasing due to an ageing population and better diagnosis.³
• Population prevalence in the USA is estimated at 30,000-40,000 cases with the majority having indolent (early) MDS.
• The estimated incidence of MDS increases significantly with age, ranging from 0.7/100,000 during the fourth decade to 20.8-36.3/100,000 in those aged over 70 years.⁴
• MDS is more common in men and in smokers.²

Risk factors

• It is mainly a disease of older people with ~80% of cases in those aged >60 years.
• Previous cancer therapy including radiotherapy, alkylating agents (peak 4-10 years after therapy), epipodophyllotoxins (peak within five years of therapy), topoisomerase II inhibitors or colony-stimulating factors used to stimulate marrow function during chemotherapy.⁵
• Prolonged use of alkylator therapy for other illnesses, e.g. rheumatological disease.
• Environmental toxins, especially benzene and other organic solvents, smoking, petroleum products, fertilisers, semi-metal, stone dusts and cereal dusts.
• More unusually, it may be associated with other genetically associated diseases, e.g. Schwachman-Diamond syndrome, Fanconi's anaemia and neurofibromatosis type 1, which are all associated with an increased risk.

Presentation

Anaemia

• Variable in severity and is usually two or more distinct populations of red cells with normal or a hypochromic microcytic red cells and macrocytes.
• An unexplained macrocytic anaemia with no evidence of megaloblastosis and/or a mild thrombocytopenia or neutropenia may be the initial indicator of a problem and precede symptomatic illness or a definitive haematological diagnosis of myelodysplastic syndrome (MDS) by several years.
• Typically in an older patient presenting with symptoms of chronic anaemia, e.g. fatigue and exertional dyspnoea.
• There may be worsening of pre-existing pathology, due to presence of anaemia, particularly cardiac problems, e.g. angina, congestive cardiac failure.

Neutropenia

• Neutropenia often occurs and is variable in severity.
• If granulocyte depletion occurs, patients may present with recurrent or unusual infections or overwhelming sepsis.

Thrombocytopenia

• The platelet count is often decreased with abnormal platelets.
• If thrombocytopenia is present, patients may notice petechiae, bruising or complain of nosebleeds or bleeding from gums after brushing teeth.
• May present as a bleeding diathesis with haemoptysis, haematuria or rectal bleeding.

There may be constitutional symptoms such as anorexia, weight loss, sweats and fevers, which occur in more advanced disease.

Signs

• Examination should seek evidence of petechiae and ecchymoses (check under waistbands of clothing or other pressure points).
• Inspect conjunctivae to look for evidence of anaemia.
• Look for other clinical evidence of anaemia, such as cardiac failure or tachycardia.
• Examine the mouth for evidence of anaemia and infections such as candidiasis.
• Splenomegaly and lymphadenopathy are uncommon.²

Differential diagnosis

• Other causes of anaemia, e.g. B12 deficiency or folate deficiency, chronic kidney disease, blood loss or haemolysis.
• Other causes neutropenia, e.g. viral infection or drugs.
• Other causes of thrombocytopenia, e.g. idiopathic thrombocytopenic purpura or drugs.
• Chronic myeloid leukaemia.
• Bone marrow failure.
• Causes of reactive bone marrow dysplasia, e.g. HIV infection, alcoholism, recent cytotoxic therapy and severe intercurrent illness.
• Agranulocytosis.
• Aplastic anaemia.
• Myeloproliferative disorders.
• Hairy cell leukaemia.

Investigations

• FBC and blood film:
  • Anaemia, either normocytic or macrocytic.
  • There may be cytopenias affecting the other cell lines: there may be neutropenia, thrombocytopenia, neutrophilia, monocytosis, thrombocytosis.
  • Blood film characteristically shows dimorphic red cells, Pappenheimer bodies, basophilic stippling, dysplasia evidenced as erythrocytes with anisocytosis (varying sizes) and poikilocytosis (abnormal shape). Platelets may be large or hypogranular.
• Serum ferritin, vitamin B12 and red blood cell folate levels are usually normal. Check renal function tests, LFTs; CXR and ECG to assess comorbidity.
• Bone marrow aspirate/biopsy plus cytogenetics - typically showing hypercellular marrow due to ineffective haematopoiesis and commonly showing megaloblastoid erythropoiesis.
• Cytogenetic marrow studies show chromosomal abnormalities in 48-64% of cases, depending on series.¹
• More advanced cytogenetic analyses, such as fluorescent in-situ hybridisation, can reveal abnormalities in up to 79% of cases.¹
• There are a variety of clonal chromosomal abnormalities including loss of part of a chromosome, monosomy or trisomy, usually affecting chromosomes 5, 7 and 8.

Associated diseases

• Chronic myelomonocytic leukaemia (monocytosis with >1,000 cells/μl and trilineage dysplasia) appears to be an overlap condition between myelodysplastic syndrome (MDS) and myeloproliferative disorders.
• MDS also appears to show overlap features with severe aplastic anaemia and paroxysmal nocturnal haemoglobinuria.¹

Classifying myelodysplastic syndrome

Staging

• The classification of myelodysplastic syndrome (MDS) is continuously evolving.⁶ Every new validated classification reflects better understanding of the disease, its pathogenesis and prognosis.⁷
• The traditional classification is the French-American-British (FAB) classification. However, it is thought that this system is inadequate in terms of clinical homogeneity and outlook within the groups.⁸
• An International Prognostic Scoring System (IPSS) and a World Health Organization (WHO) classification have now been devised, which assess the type and extent of cytogenetic marrow abnormality and the cell lines affected, to improve classification of patients in terms of prognosis and enrolment into trials of potentially beneficial treatment.²
• Although the newer classifications have not yet been universally accepted, they do provide a helpful diagnostic and predictive framework.

The IPSS is based on the percentage of bone marrow blast cells and the number of cytopenias to calculate the risk score. Patients can be categorised into one of four groups: low-risk, intermediate-1 and intermediate-2 risks and high-risk.

Clinical variants of MDS

There are clinical variants identified that do not neatly fall into the classification system. These include:

• Chronic myelomonocytic leukaemia (CMML), which is the fifth element in the FAB classification but is an MDS/myeloproliferative disease (MPD) condition according to the WHO classification (see next section).
• 5-q syndrome - a clinically distinct form of MDS that follows a more indolent course and predominantly occurs in female patients.
• Pure sideroblastic anaemia - in these patients, dysplasia is confined to erythropoietic cells and is associated with improved survival rates (77% at 3 years).
• Secondary MDS - the incidence of this is increasing due to successful chemotherapy in a greater proportion of the population. The prognosis is worse than with de novo disease.
• Hypoplastic MDS - this occurs in less than 15% of cases and may be difficult to distinguish from aplastic anaemia. Diagnosis is based on investigations as above and its significance is that it may respond to immune therapy.
• Fibrotic MDS - although almost half the patients have an element of bone marrow fibrosis, this is marked in about 15% of patients (more commonly in secondary MDS); it is associated with rapid deterioration.

Myelodysplastic/myeloproliferative diseases (MDS/MPD)

This is a category of disease created within the WHO classification of myeloid neoplasms for a group of disorders that have both dysplastic and proliferative features at diagnosis and which are therefore difficult to designate as either myelodysplastic or myeloproliferative. They include:

• CMML.
• Atypical chronic myeloid leukaemia.
• Juvenile myelomonocytic leukaemia.
• Unclassifiable MDS/MPD.

Management¹

The management of myelodysplastic syndrome (MDS) is constantly evolving with new agents being trialled and licensed on a regular basis. There is little consensus on the optimal therapy and patient selection for these conditions; patients should be considered for entry into a clinical trial, preferably at a regional or tertiary referral centre. Ultimately, bone marrow haematopoietic stem cell transplantation is the only curative treatment for MDS.⁶

Patients with low-risk, indolent MDS require no active management but are usually followed up in a haematology clinic. In the early phases, when increased bone marrow apoptosis results in ineffective hematopoiesis, retinoids and hematopoietic growth factors are indicated. In late stages, cytotoxic chemotherapy and bone marrow transplantation may be necessary. All of these modes of therapy are undergoing clinical trials to determine the overall benefit to quality of life and survival.

Supportive care

• Anaemia and thrombocytopenia:
  • In symptomatic anaemia, in those with anaemia-related cardiovascular disease, bleeding episodes and/or high risk of significant bleeds, treatment is supportive blood and platelet transfusions.
  • Many patients can live for prolonged periods with regular blood/platelet transfusions; patients who receive long-term recurrent transfusion require monitoring of their iron status (ferritin levels) and iron-chelation therapy (e.g. with desferrioxamine) if necessary, such as if the patient receives more than 20 units of packed red blood cells.
  • Erythropoietin ± granulocyte colony-stimulating factor (G-CSF) for the treatment of symptomatic anaemia may improve the quality of life, providing a more stable haemoglobin value compared with the cyclical fluctuations of blood transfusions. These treatments are efficacious and safe for the treatment of anaemia associated with MDS.⁹ However, increased blood parameters do not necessarily improve survival.¹
• Neutropenia:
  • Neutropenic sepsis should be treated promptly with empirical broad-spectrum antibiotics but there is no evidence supporting the routine use of prophylactic anti-infective agents.
  • G-CSF treatment of neutropenia, particularly where there are recurrent or antibiotic-resistant infections.
• Other low-intensity therapy:
  • Immunosuppression may be effective for patients with hypoplastic MDS and for patients with low-risk MDS (IPSS ≤intermediate-1). These include prednisolone and ciclosporin A, which have been used in selected patients.¹⁰
  • Non-intensive chemotherapy may be the only tolerable treatment in the more elderly population but there are difficulties associated with this.

High-intensity therapy: chemotherapy

• A large number of different forms of chemotherapy have been tried, including those used to treat acute myeloid leukaemia (AML) but results are generally disappointing.
• Generally, if the patient is otherwise reasonably well, more aggressive treatment can be envisaged, e.g. topotecan. More commonly, the patient is elderly or has some significant comorbidity, in which case less aggressive agents such as arsenic trioxide should be tried. Patients should also be considered for entry into a clinical trial.
• Fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor (FLAG) have been used with success in de novo RAEBt.¹¹
• Modern DNA anti-methylating agents (azacitidine, decitabine), farnesyl transferase inhibitors (lonafarnib, tipifarnib) and immunomodulators such lenalidomide (a thalidomide analogue effectively used in the treatment of 5-q syndrome)⁶ have been shown to have some efficacy in preventing/slowing progression of low-risk or early MDS and decreasing the need for transfusion.¹²
• The National Institute for Health and Clinical Excellence (NICE) recommends azacitidine as a treatment option for adults who are not eligible for haematopoietic stem cell transplantation and have:¹³
  • Intermediate-2 and high-risk MDS according to the IPSS; or
  • CMML with 10-29% marrow blasts without MDP; or
  • AML with 20-30% blasts and multi-lineage dysplasia, according to the WHO classification.

Other therapies

• Allogenic stem cell transplant may be offered to high-risk young patients, usually in a carefully selected group of 55-60 year-olds.¹ Patients need prior chemotherapy or radiotherapy.
• Biological modifiers such as retinoic acid may be considered in certain groups of patients. These are often given with low-dose chemotherapy.

Complications

• Complications of anaemia, thrombocytopenia and low white cell count
• Myelofibrosis may develop and cause increased transfusion dependence and disease progression
• Patients are therefore at risk of transfusional iron overload and iron chelation therapy has been shown to improve organ function and survival.^14,15
• Transformation to acute myeloid leukaemia (AML).
• Splenomegaly may lead to splenic rupture and intraperitoneal haemorrhage.

Prognosis

• On the whole, outlook is poor with disease progression, deterioration and increasing transfusion dependence.
  Older age and comorbidities, such as coronary artery disease, chronic obstructive pulmonary disease and chronic kidney disease, make myelodysplastic syndrome (MDS) more difficult to manage and worsen the prognosis.²
• Relatively good prognosis (mean survival of 18-24 months or longer): single or mild cytopenias, normal chromosomes or a single chromosomal abnormality (except involving chromosome 7), and greater than 10% myeloblasts in the bone marrow.¹
• Poorer prognosis (mean survival of 6-12 months): pancytopenia requiring red cell or platelet transfusions, chromosome 7 or multiple abnormalities, and patients with greater than 10% myeloblasts in the bone marrow.¹

Document references

1. Besa E et al; Myelodysplastic Syndrome, Medscape, Apr 2009
2. Barzi A, Sekeres MA; Myelodysplastic syndromes: a practical approach to diagnosis and treatment. Cleve Clin J Med. 2010 Jan;77(1):37-44. [abstract]
3. Corey SJ, Minden MD, Barber DL, et al; Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer. 2007 Feb;7(2):118-129. [abstract]
4. Dixon N et al; Pediatric Myelodysplasia, Medscape, Aug 2010
5. Hershman D, Neugut AI, Jacobson JS, et al; Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst. 2007 Feb 7;99(3):196-205. [abstract]
6. Maniatis A; Progress in the treatment of myelodysplastic syndromes. Blood Transfus. 2008 Oct;6(4):180-1.
7. Komrokji RS, Bennett JM; Evolving classifications of the myelodysplastic syndromes. Curr Opin Hematol. 2007 Mar;14(2):98-105. [abstract]
8. Estey EH; Current challenges in therapy of myelodysplastic syndromes. Curr Opin Hematol. 2003 Jan;10(1):60-7. [abstract]
9. Ross SD, Allen IE, Probst CA et al.; Database of Abstracts of Reviews of Effects (DARE): Efficacy and safety of erythropoiesis-stimulating proteins in myelodysplastic syndrome: a systematic review and meta-analysis (November 2008).
10. Shimamoto T, Ohyashiki K; Immunosuppressive treatments for myelodysplastic syndromes. Leuk Lymphoma. 2003 Apr;44(4):593-604. [abstract]
11. Jackson G, Taylor P, Smith GM, et al; A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol. 2001 Jan;112(1):127-37. [abstract]
12. Larson RA; Myelodysplasia: when to treat and how. Best Pract Res Clin Haematol. 2006;19(2):293-300. [abstract]
13. Myelodysplastic syndromes - azacitidine, NICE Technology Appraisal Guideline (March 2011)
14. List AF; Iron overload in myelodysplastic syndromes: diagnosis and management. Cancer Control. 2010 Jan;17 Suppl:2-8. [abstract]
15. Leitch HA; Optimizing therapy for iron overload in the myelodysplastic syndromes: recent Drugs. 2011 Jan 22;71(2):155-77. doi: 10.2165/11585280-000000000-00000. [abstract]

Internet and further reading

• Fey MF, Dreyling M; Acute myeloblastic leukaemias and myelodysplastic syndromes in adult patients: Ann Oncol. 2010 May;21 Suppl 5:v158-61.
• Scott BL, Estey E; Management of myelodysplastic syndromes: 2008 update. Oncology (Williston Park). 2008 Nov 15;22(12):1344-52. [abstract]