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, preleukaemia.

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 some cases.¹

The disease(s) may occur as a primary phenomenon, or be classified as secondary following treatment for other neoplasms/autologous bone marrow transplantation,¹ where there has been exposure to ionising radiation, alkylating agents, topoisomerase II inhibitors or colony-stimulating-factors used to stimulate marrow function during chemotherapy.² The injury/insult to the marrow is thought to be from the above factors in secondary cases, or viral infection, toxin exposure (e.g. benzene) or genetic predisposition in primary cases.¹

• The overall prevalence of the syndromes appears to be increasing due to an ageing population and better diagnosis.³
• Rough annual incidence is 22–45 cases per 100,000 people aged >70 years.⁴
• Population prevalence in the US is estimated at 30–40,000 cases with the majority having indolent (early) MDS.
• 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

Risk Factors

• It is mainly a disease of older people with ~80% of cases in those aged >60 years.
• It may however affect all ages with an estimated >1,000 new cases per year in the US among children.¹
• Previous exposure to a variety of agents used in the treatment of other neoplasms (see description section above).
• Viral infections, toxin exposure (benzene, insecticides, fungicides and herbicides) and genetic susceptibility are purported but unproven risk factors.

Symptoms

• 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 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, e.g. angina, CCF.
• 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.
• If granulocyte depletion occurs patients may present with recurrent or unusual infections or overwhelming sepsis.

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, a condition with considerable overlap with the myelodysplastic disorders.

• Anaemia of another cause, e.g. B₁₂/folate deficiency
• Chronic myeloid leukaemia
• Bone marrow failure
• Other causes of thrombocytopenia, e.g. idiopathic thrombocytopenic purpura
• 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.
• Blood film characteristically shows dysplasia evidenced as erythrocytes with anisocytosis (varying sizes) and poikilocytosis (abnormal shape).
• 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
• 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

• The table below indicates the FAB (French-American-British) classification of the myelodysplastic disorder entities.
• It is thought that this system is inadequate in terms of clinical homogeneity and outlook within the groups.⁵
• An International Prognostic Scoring System and a WHO classification have 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.⁶
• The classification of myelodysplastic syndrome is continuously evolving; every new validated classification reflects better understanding of the disease, its pathogenesis and prognosis.⁶

General Measures

• Most asymptomatic patients require no active management but are usually followed up in a haematology clinic.
• In symptomatic anaemia, in those with anaemia-related cardiovascular disease, bleeding episodes and/or high risk of significant bleeds, the mainstay of 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 if necessary (e.g. with desferrioxamine).
• Younger patients may be treated with allogeneic bone marrow transplant.⁷

Chemotherapy

• The management of MDS is constantly evolving with new agents being trialled and licensed on a regular basis.
• A large number of different forms of chemotherapy have been tried, including those used to treat acute myeloid leukaemia, but results are generally disappointing.
• Fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor (FLAG) has been used with success in de novo RAEBt.⁸
• Allogenic bone marrow transplant may be offered to high-risk young patients, usually in a carefully selected group of 55–60 year olds.¹
• Erythropoietin and colony-stimulating-factors have been used to treat cytopenias – although increased blood parameters do not necessarily improve survival.¹
• Recently, immunosuppressive therapies including prednisolone and cyclosporin A have been used in selected patients.⁹
• Modern DNA-anti-methylating agents (azacitidine, decitabine), farnesyl transferase inhibitors (lonafarnib, tipifarnib) and immunomodulators such lenalidomide (a thalidomide analogue) have been shown to have some efficacy in preventing/slowing progression of low-risk or early MDS and decreasing the need for transfusion.¹⁰
• 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.¹

• 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.
• 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 aberrations
  • >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.