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• Many children with MDS have a monocytosis which results in their being classified as CMML, also the clinical features and outlook for

486 childhood CMML are quite different.

• RARS is virtually never seen in children.

Individual disorders

Refractory anaemia: Children with a clonal genetic marker in the marrow who present with refractory anaemia usually progress to RAEB and AML. Those without such a marker probably do not have MDS but some other cause of erythropoietic failure.

RAEB and RAEB-t: Many of the RAEB syndromes in children arise in those with pre-existing disease like Down syndrome, trisomy 8, neurofibromatosis type 1, Fanconi's anaemia, Kostmann's syndrome, DiamondBlackfan anaemia and Shwachman-Diamond syndrome (see previous section). All these diseases predispose to leukaemia, and RAEB is merely part of the evolution of AML. A substantial proportion of childhood MDS in the RA or RAEB category is also induced by previous chemotherapy as a prodrome to secondary AML. In other words all paediatric cases of RAEB/RAEB-t are best regarded as AML and treated as such if the diagnosis is not in any doubt.

• Down syndrome children have a particular predisposition to develop M7 (megakaryoblastic) AML in the first few years of life. This is commonly preceded by a RAEB prodrome where the marrow is hard to aspirate through secondary sclerosis. The decision when to start therapy is difficult, but the overall outlook is potentially good with EFS >50%.

Transient abnormal myelopoiesis (TAM):Down children also have a predisposition to develop a transient blast cell overgrowth in infancy that looks like frank leukaemia with blasts in the peripheral blood. It is completely self-limiting within days or weeks and is not associated with marrow failure, arising alongside normal haemopoiesis. There is no genetic abnormality in the marrow apart from trisomy 21. It is important that chemotherapy is withheld in what is regarded as a temporary stem cell instability. Rarely the problem can arise in non-Down children, where trisomy 21 is found in the bone marrow only.

JCMML (juvenile chronic myelomonocytic leukaemia): Originally called juvenile chronic myeloid leukaemia to distinguish it from adult type chronic myeloid leukaemia (see below), this pernicious disease still has a high mortality. It is now recognised to be a clonal disorder, with all marrow cell lines involved. It has several distinctive clinical and haematological features.

• Stigmata of fetal erythropoiesis; high HbF, 4 red cell i antigen expression and carbonic anhydrase activity, 4 MCV.

• Modest 4 WBC; average 30-40 x 109/L, with evident monocytosis, blasts 5-10%, and occasionally a basophilia.

• Marrow appearances unremarkable; modest 4 blasts.

• Thrombocytopenia; sometimes profound.

• Skin rashes; butterfly distribution on face. 487

• Increasing hepatosplenomegaly.

• Associated with neurofibromatosis type 1. May be present in >10% of cases.

• Poor outlook with progression associated with wasting, fever, infections, bleeding and pulmonary infiltrations.

Monosomy 7 syndrome: Conventional cytogenetic analysis of the marrow in JCMML shows no abnormality in the classic syndrome, though there is a subvariety (or similar condition that may nevertheless be biologically distinct) where monosomy 7 is found. Whether this is a different disorder is not clear. Apart from the different genetics, monosomy 7 syndrome and JCMML have several features in common. However, monosomy 7 children may have:

• A longer prodrome with RA or RAEB and no monocytosis.

• They may respond to AML chemotherapy (JCMML responds poorly and seldom remits).

• They may remain stable for years without therapy.

• They respond better to BMT (JCMML achieve <40% EFS even with BMT).

Adult-type chronic myeloid (granulocytic) leukaemia (ATCML, see Adult CML p164): More common than JCMML, though still rare, ATCML arises in around 1 in 500,000 children per year (20 in whole of UK). Tends to affect older children (60% >6 years) though it has been reported in a 3 month old infant.

• Associated with Ph chromosome and t(9;22) BCR-ABL fusion gene in all haemopoietic cells exactly as seen in adults.

• Natural history exactly the same as the disease in adults with benign phase and eventual progression to accelerated acute phase.

• Only curative therapy is allogeneic BMT, but impressive remissions of so far unknown length are now being achieved with novel tyrosine kinase inhibitor, STI571 (imatinib). This is set to replace the conventional management of the chronic phase with a-interferon or hydroxyurea, but at present is reserved for those who fail to respond to IFN or those entering the accelerated phase.

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