Why these blood cancers?
Platelet precursor (megakaryocytic) cancers are poorly understood, there are no specific therapies and the outcomes of the advanced and acute forms are poor.
The incidence of these blood cancers increases with age but the acute leukaemia is particularly common in children with Down syndrome.
Treatment of these cancers relies on chemotherapy drugs but toxic side effects limit their use in both older patients and children, so there is a real need for new forms of therapy.
Acute megakaryocytic cancers
The most severe form is acute megakaryoblastic leukaemia. This leukaemia is rare, except for children with Down syndrome in whom it is 500 times more common than in other children.
Acute panmyelosis with fibrosis is another very rare form of acute cancer that combines leukaemic features with acute bone marrow fibrosis and abnormal megakaryocytes.
Chronic megakaryocytic cancers
Chronic myeloproliferative neoplasms, also called myeloproliferative disorders, are a spectrum of blood cancers. They include polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF).
ET and PMF are driven by abnormal megakaryocytes. These disorders arise in 2-4 per 100,000 people per year. ET is characterised by very high platelet counts and PMF by anaemia, low platelet counts, large spleen and bone marrow fibrosis. Major complications include blood clots, bleeding and rarely, transformation to acute leukaemia.
Myelodysplastic syndromes are another mixed group of similar blood disorders. Megakaryocyte abnormalities and thrombocytopenia are relatively common in these conditions. The annual incidence of myelodysplasia overall is 3-5 cases per 100,000 people but this increases with age and may be as high as 75 cases per 100,000 people aged over 65 years.
Why are Down syndrome children important?
Down syndrome infants are prone to a unique form of megakaryoblastic leukaemia that can spontaneously reverse within weeks or months. When this happens, the disease is called transient abnormal myeloproliferation (TAM). TAM can frequently only be distinguished from true leukaemia when it goes away. Otherwise, symptoms can be very similar to leukaemia, making it difficult to decide what treatment is required.
In addition, true leukaemia may still develop in up to 30% of these children within the following 3-4 years. Unfortunately, we cannot currently predict which children progress to true leukaemia.
Importantly, the transient nature of TAM indicates that there is a reversible switch between TAM and leukaemia. Defining how this switch works could hold the key to treating these conditions, not only in Down syndrome but also in other patients.
An outline of normal and diseased platelet production
