MYELODYSPLASTIC SYNDROME (MDS)
infections or bleeding. The blood film shows cytopenias and the dysplastic features indicated above. A bone marrow aspiration should be performed, which is usually hyper¬cellular with evidence of dysplasia. Blast cells may be increased but do not reach the 20% level which indicates acute leukaemia. Chromosome analysis frequently reveals abnormalities, particularly of chromosomes 5 or 7.
Management
For the majority of patients the disease is incurable and supportive care with red-cell and platelet transfusions to maintain quality of life is the mainstay of treatment. A trial of erythropoietin and granulocyte-colony stimulating factor (G-CSF) is recommended in some patients with early disease to improve haemoglobin and white cell counts. Allogeneic stem cell transplants may afford a cure in younger patients. Transplantation should be preceded by intensive chemotherapy in those with more advanced disease.
This syndrome consists of a group of clonal haematopoietic disorders which represent steps in the progression to the development of leukaemia. It affects predominantly older people (median age 69 years); the overall incidence is 4/100 000 rising to more than 30/100 000 in the over-70s. It is characterised by blood cytopenias and abnormal-looking (dysplastic) blood cells, including macrocytic red cells and hypogranular neutrophils with nuclear hyper- or hypo¬segmentation. The marrow is hypercellular with dysplastic changes in all three cell lines. Inevitably it progresses to acute myeloid leukaemia, although the time to progression varies with the subtype of MDS, being slowest in refractory anaemia and most rapid in refractory anaemia with excess of blasts. The WHO classification of MDS is
Box 24.49.
shown in
Clinical features and diagnosis
The most common presentation is due to the consequences of bone marrow failure: symptoms of anaemia, recurrent
Prognosis
The survival in MDS can vary from years in patients with RA and RARS to months in those with RAEB, who rapidly transform to acute myeloid leukaemia. Poor prognostic factors include blasts > 10% in the marrow, certain cyto¬genetic abnormalities and more than one cytopenia in the blood.
APLASTIC ANEMIA
• Cytotoxic drugs-idiosyncratic
• Anti biotics-chloramphenicol, sulphonamides
• Antirheumatic agents-penicillamine, gold, phenylbutazone, indometacin
• Antithyraid drugs • Anticonvulsants
• Immunosuppressives-azathioprine
PRIMARY IDIOPATHIC ACQUIRED APLA5TIC ANAE 1
This is a rare disorder in developed countries, with 2-4 new cases per million population per annum; the disease is much more common in certain other parts of the world-for example, east Asia. The basic problem is failure of the pluripotent stem cells, producing hypoplasia of the bone marrow with a pancytopenia in the blood. Usually no cause is found but careful enquiry should be made for potential causes such as exposure to drugs, chemicals and radiation, a history taken of viral illness, particularly hepatitis, and a search undertaken to exclude rare congenital causes such as Fanconi s anaemia.
Chemicals
• Benzene toluene solvent misuse-glue-sniffing
• Insecticides-chlorinated hydrocarbons (DDT), organophosphates and carbamates (p. 216)
Radiation Viral hepatitis Pregnancy Paroxysmal nocturnal haemoglobinuria
only one cell line, most often the neutrophils. Frequently, this is an incidental finding with no ill health. It probably has an immune basis but this is difficult to prove.
The clinical features and methods of diagnosis are the same as for primary idiopathic aplastic anaemia. An under¬lying cause should be treated or removed but otherwise management is as for the idiopathic form.
1054
Clinical features
Patients present with symptoms of bone marrow failure. usually anaemia or bleeding. and less commonly infections. A full blood count demonstrates pancytopenia, low reticulo¬cytes and often macrocytosis. Bone marrow aspiration and trephine reveal hypocellularity.
Management
All patients will require blood product support and aggressive management of infection. The prognosis of severe aplastic anaemia managed with supportive therapy only is poor and more than 50% of patients die, usually in the first year. The curative treatment for patients under 30 years of age with severe idiopathic aplastic anaemia is allogeneic bone marrow transplantation if there is an available donor. Those with a compatible sibling donor should proceed to transplantation as soon as possible and have a 75-90% chance of long-term cure. In older patients, immunosuppressive therapy with ciclosporin and anti¬thymocyte globulin gives 5-year survival rates of 75%. Such patients may relapse or evolve into other clonal disorders of haematopoiesis, such as paroxysmal nocturnal haemo¬globinuria (PNH), MDS and even AML, and must be followed up long-term.
SECONDARY APLASIA
Causes of this condition are listed in Box 24.61. It is not practical to list all the drugs which have been suspected of causing aplasia. It is important to check the reported side¬effects of all drugs taken over the preceding months. In some instances the cytopenia is more selective and affects
MYELOPROFERTIVE DISODRER
These make up a group of chronic conditions characterised by clonal proliferation of marrow er} throid precursors (pols°cythaemia rubra wera. PRV ). megakaryocytes (primary thrombocythaemia and myelofibrosis) or myeloid cells (chronic myeloid leukaemia). Although the majority of patients are classifiable as having one of these disorders, some have overlapping features. Furthermore, there is often progression from one to another, e.g. PRV to myelofibrosis.
CML is considered in detail above (p. 1044).
Myelofibrosis is characterised by bone marrow fibrosis, extramedullary haematopoiesis (blood cell formation outside the bone marrow) and a leucoerythroblastic blood picture. The marrow is initially hypercellular, with an excess of abnormal megakaryocytes which release growth factors, e.g. platelet-derived growth factor, to the marrow microenvironment, resulting in a reactive proliferation of fibroblasts. As the disease progresses, the marrow becomes fibrosed.
Most patients present over the age of 50 years with lassitude, weight loss and night sweats. The spleen can be massively enlarged due to extramedullary haematopoiesis, and painful splenic infarcts may occur.
The characteristic blood picture is a leucoerythroblastic anaemia, with circulating immature red blood cells (increased reticulocytes and nucleated red blood cells) and
granulocyte precursors (myelocytes). The red cells are shaped like teardrops (teardrop poikilocytes) and giant platelets may be seen in the blood. The white count varies from low to moderately high and the platelet count may be high, normal or low. Urate levels may be high due to increased cell breakdown, and folate deficiency is common. The marrow is often difficult to aspirate and a trephine biopsy shows an excess of megakaryocytes, increased reticulin and fibrous tissue replacement.
Median survival is 4 years from diagnosis but ranges from 1 year to over 20 years. Treatment is directed at control of symptoms, e.g. red cell transfusions for anaemia. Folic acid should be given to prevent deficiency. Cytotoxic therapy with hydroxycarbamide may help control spleen size, the white cell count or systemic symptoms. Splenectomy may be required for a grossly enlarged spleen or symptomatic pancytopenia secondary to splenic pooling of cells and hypersplenism. Bone marrow transplantation may be considered for younger patients.
PRIMARY THR
The malignant proliferation of megakaryocytes results in a raised level of circulating platelets that are often dysfunctional. Prior to making a diagnosis of essential thrombocythaemia it is essential to exclude reactive causes of increased platelets (p. 10 17). Patients present at a median age of 60 years with vascular occlusion or bleeding events, or without symptoms and an isolated raised platelet count. In most individuals the condition is chronic, with the platelet count gradually increasing. A very small percentage may transform to acute leukaemia and others to myelofibrosis.
Low-risk patients (age less than 40 years, platelet count less than 1000 x 109/1 and no bleeding or thrombosis) may require no treatment to reduce the platelet count. Aspirin therapy is often recommended. For those with a platelet count over 1000 x 109/I or those with symptoms, treatment to control platelets should be given. Agents include oral hydroxycarbamide or anagrelide, an inhibitor of mega¬karyocyte maturation. Intravenous radioactive phosphorus (32P) may be useful in old age. Aspirin should be considered for all patients to reduce the risk of thrombosis and is particularly useful therapy for those with digital ischaemia.
THROMBOCYTHAEMIA
BLEEDING DISORDERS
abnormal karyotype may be found in the marrow, and in vitro culture of the marrow demonstrates autonomous growth in the absence of added growth factors.
Venesection gives prompt relief of hyperviscosity symptoms. Between 400 and 500 ml of blood (less if the patient is elderly) are removed and the venesection is repeated every 5-7 days until the haematocrit is reduced to below 45%. Less frequent but regular venesection will maintain this level until the haemoglobin remains reduced because of iron deficiency. The underlying myeloprolifera¬tion can be suppressed by hydroxycarbamide or interferon. Radioactive phosphorus (5 mCi of 32P i.v.) is reserved for older patients, as it increases the risk of transformation to acute leukaemia by six- to ten-fold. Treatment of marrow proliferation may reduce the risk of vascular occlusion, control spleen size and reduce transformation to myelo¬fibrosis. Aspirin reduces the risk of thrombosis.
Median survival after diagnosis in treated patients exceeds 10 years. Some patients survive more than 20 years; however. cerebrovascular or coronary events occur in up to 60% of patients. The disease may convert to another myeloproliferative disorder, with about 15% developing myelofibrosis. Acute leukaemia develops principally in those patients who have been treated with radioactive phosphorus.