Myelodysplastic Syndromes (MDS)

Synonyms: MDS, myelodysplasia, refractory anaemia, refractory anaemia with excess blasts (RAEB), refractory anaemia with ringed sideroblasts (RARS), subacute myeloid leukaemia, 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 highly variable.

Although the overall number of marrow cells is increased, their turnover is very rapid due to early cell death and they do not produce adequate peripheral cells to maintain normal blood counts. The abnormal clonal progenitor cells 'take over' the marrow and disturb the function of normal cell lines. Eventually the abnormal cells may become leukaemic and overwhelm the marrow. The disease course is highly variable, from indolent to aggressive with swift progression to acute myeloid leukaemia in 30% of cases.¹

The disease(s) may occur as a primary phenomenon (following viral infection, toxin exposure such as benzene or genetic predisposition).¹ Alternatively, it can be classified as secondary following treatment for other neoplasms/autologous bone marrow transplantation,¹ where there has been exposure to certain drugs (see risk factors below).

• The overall prevalence of the syndromes appears to be increasing due to an ageing population and better diagnosis.²
• Population prevalence in the US is estimated at 30,000–40,000 cases with the majority having indolent (early) MDS.
• There is an annual incidence of 4/100,000 in the general population (0.5/100,000 in the <50 age group, rising to 89/100,000 in the ≥80 age group).³
• There are an estimated >1,000 new cases per year in the US among children.¹
• Thus it appears to be as common or commoner than the major haematological neoplasms of older people such as myeloma/chronic lymphocytic leukaemia.^1,4
• There is a very slight male preponderance.

Risk factors³

• 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 5 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 anaemia and neurofibromatosis type 1 which are all associated with an increased risk.

Problems linked to peripheral blood cytopenias

Anaemia

• Ranges from mild anaemia to profound pancytopaenia. A macrocytic or normocytic anaemia is common (60-80% of cases).³
• 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 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 occurs in 50-60% of cases.³
• If granulocyte depletion occurs patients may present with recurrent or unusual infections or overwhelming sepsis.

Thrombocytopenia

• This occurs in 40-60% of cases but isolated thrombocytopenia is rare.³
• 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. Splenomegaly may also result in easy satiety.

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 mouth for evidence of anaemia and infections such as candidiasis.
• Check for evidence of lymphadenopathy (not present in myelodysplasia but may occur in similarly presenting leukaemias).
• Splenomegaly may occur in chronic myelomonocytic leukaemia.

• Other causes of anaemia e.g. B12 or folate deficiency, renal failure, 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

• Blood film and FBC (useful to see results over time) will show 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 U&E, LFTs, perform a CXR and ECG to assess co-morbidity.
• Bone marrow aspirate/biopsy plus cytogenetics – typically shows hypercellular marrow due to ineffective haematopoiesis and commonly shows 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
• Abnormalities are found in the bone marrow cytogenetic analysis in 40-70% of patients with de novo disease and 80-90% of secondary MDS.³ There are a variety of clonal chromosomal abnormalities including loss of part of a chromosome, monosomy or trisomy, usually affecting chromosomes 5, 7 & 8.

• Chronic myelomonocytic leukaemia (monocytosis with >1000 cells/μl and trilineage dysplasia) appears to be an overlap condition between MDS and myeloproliferative disorders.
• MDS also appears to show overlap features with severe aplastic anaemia and paroxysmal nocturnal haemoglobinuria.¹

Staging

• The classification of myelodysplastic syndrome is continuously evolving;⁶ every new validated classification reflects better understanding of the disease, its pathogenesis and prognosis.⁷
• The traditional classification is the FAB (French-American-British) 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 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.⁷
• Although the newer classifications have not yet been universally accepted, they do provide a helpful diagnostic and predictive framework.

The International Prognosis Scoring System (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 4 groups: low risk, intermediate-1 and intermediate-2 risks and high risk.

Clinical variants of MDS³

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

• Chronic myelomonocytic leukaemia (CMML) is the fifth element in the FAB classification but is a MDS/MPD condition according to the WHO classification (see next section).⁹
• 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:

• Chronic myelomonocytic leukaemia
• Atypical chronic myeloid leukaemia
• Juvenile myelomonocytic leukaemia
• Unclassifiable MDS/MPD

The management of MDS is constantly evolving with new agents being trialled and licensed on a regular basis. On the whole 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 transplantation is the only curative treatment but this is applicable to only a small proportion of these patients.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

This is the mainstay of treatment and may involve transfusions, administration of growth factors or antibiotics:⁹

• 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 Hb value compared to the cyclical fluctuations of blood transfusions. These treatments are efficacious and safe for the treatment of anaemia associated with MDS.¹⁰ 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.³
  • G-CSF treatment of neutropenia, particularly where there are recurrent or antibiotic resistant infections.
• Other low intensity therapy:³
  • 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.¹¹
  • 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 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 co-morbidity, 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) has been used with success in de novo RAEBt.¹²
• 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.¹³
• NICE is currently evaluating azacitidine for the treatment of adults not eligible for haematopoietic stem cell transplantation with high risk (IPSS intermediate-2 and high risk) myelodysplastic syndromes - among others. Guidance is due out in November 2009.⁹

Other therapies

• Allogenic bone marrow 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 of anaemia, thrombocytopenia and low white cell count
• Myelofibrosis may develop and cause increased transfusion dependence and disease progression
• Transformation to acute leukaemia
• Splenomegaly may lead to splenic rupture and intraperitoneal haemorrhage

• On the whole outlook is poor and disease progression, deterioration and increasing transfusion dependence are the norm.
• Haematologists use an International Prognostic Scoring System (IPSS) based on the percentage of bone marrow blast cells and the number of cytopenias to calculate the risk score. This enables them to stratify the patients into 4 risk groups:³
  • Low - median survival 5.7 years
  • Intermediate-1- median survival 3.5 years
  • Intermediate-2 - median survival 1.2 years
  • High - median survival 0.4 years
• Features indicating a relatively good prognosis (mean survival of ≥18–24 months):
  • Patients with single/mild cytopenias
  • Normal cytogenetics
  • Only one cytogenetic abnormality (with the exception of those involving chromosome 7)
  • <10% myeloblasts in the bone marrow
• Poor prognostic indicators (≤6–12 months survival) include:
  • Patients with pancytopenia requiring regular blood or platelet transfusion
  • Patients with multiple cytogenetic abnormalities or single chromosome 7 aberrations⁹
  • >10% myeloblasts in the bone marrow
• Median survival outlook in months for FAB subtypes:
  • RA – 50
  • RARS – 51
  • RAEB – 12
  • RAEBt – 6
• Unfortunately, nearly all patients with RAEBt transform to acute leukaemia within 30 months or so; newer therapies may improve this outlook.