More Medical Issues in Down's Syndrome. A conference held under the auspices of the Royal Society of Medicine BLOOD DISORDERS Forum on Learning Disability and The Down's Syndrome Medical Interest Group. Royal Society of Medicine, London, Thursday 26th April 2001 Chaired by Dr Patricia Jackson, Edinburgh and Dr Liz Marder, Nottingham Blood disorders in children with Down's syndrome: overview and update Summary of a presentation by Professor Judith Chessells Leukaemia Research Fund Professor of Haematology and Oncology, Institute of Child Health and Honorary Consultant, Hospital for Sick Children, Great Ormond Street, London Blood disorders are more common in children with Down's syndrome than in other children. Not only are there differences in the blood count, but leukaemia and Leukaemia and leukaemia-like disorders in children with Down's syndrome leukaemia-like disorders also occur in excess. The overall risk of developing leukaemia is about 18 · Transient abnormal myelopoeisis (TAM) times greater for children with Down's syndrome than ­ affects 10% of newborns ­ morphologically indistinguishable from for other children. It has become apparent in recent megakaryoblastic leukaemia years that children with Down's syndrome respond well ­ asymptomatic and usually resolves to the intensive treatments used for other children. It is spontaneously without treatment important therefore to ensure that children with Down's ­ 25% develop AML later in childhood. syndrome and leukaemia are entered into national · Overall childhood leukaemia risk (AML and ALL) leukaemia trials and are managed according to full treat- ­ increased risk maximal in the first 4 years ment protocols. ­ overall risk approximately 1/100 (18 times greater then in the general population). Blood count abnormalities · Acute myeloid leukaemia (AML) ­ very rare in other children (~60­70 new cases There are differences in blood counts between children annually in children aged 0­15 years in the with Down's syndrome and others particularly in the UK) first year of life. It is important to take this into consid- ­ the most common leukaemia seen in children eration when interpreting the results of laboratory inves- with Down's syndrome aged 1­4 years tigation (Panel 1). ­ usually the megakaryoblastic variant of AML ­ 150 times greater risk than in the general When investigating iron deficiency anaemia, it population. should be noted that the baseline mean corpuscular · Acute lymphoblastic leukaemia (ALL) ­ the most common childhood leukaemia (300­400 new cases annually overall in Panel 1: Blood count abnormalities in children children aged 0­15 years in the UK) with Down's syndrome ­ occurs in excess in those with Down's syndrome; highest risk aged 1­4 years. · 64% are polycythemic for up to 2 months · No difference between babies with and without heart disease · Haemoglobin levels sometimes raised volume (MCV) may differ from the general population. · Levels of haematinics (e.g. iron, folate) normal at all ages Baseline platelet count is increased, for no known rea- · Age 9­12 months MCV and MCH elevated ­ son. This is interesting as acute myeloid leukaemia normal erythropoetin levels (AML) in Down's syndrome often appears to be a · WBC and neutrophil counts in the low normal leukaemia of platelet precursors (megakaryoblastic). range · Platelet counts raised from age 6 weeks © Down's Syndrome Medical Interest Group · Children's Centre · City Hospital Campus · Nottingham NG5 1PB · www.dsmig.org.uk T: 0115 962 7658 ext 45667 · F: 0115 962 7915 · info@dsmig.org.uk Transient abnormal myelopoesis (TAM) occur in any type of leukaemia ­ and yet they get better · TAM is almost unique to Down's syndrome, and without any treatment. The reason for this is unknown. probably occurs in about 10% of newborn infants. This condition, where blast cells are found in the Childhood leukaemias blood and bone marrow, is morphologically indistin- The issue of leukaemia in children with Down's syn- guishable from megakaryoblastic leukaemia. TAM is drome is interesting not least because it illustrates the usually asymptomatic and often resolves spontaneous- dramatic change over the past 20 years or so in the ly without treatment but may occasionally persist for perception of families and paediatricians as to what is several months. On rare occasions, low doses of cyto- appropriate and what standard of treatment is required. toxic drugs may be required to reduce the blood count Contemporary UK practice is not only that these chil- (Panel 2). dren should be treated, but that they should be intensive- · Most neonates with TAM recover and remain well, ly treated and also entered into all national trials. however, about 20­25% subsequently develop AML. The overall risk of childhood leukaemia (AML and A very small proportion of children with TAM may ALL) is around 1/100, which is 18 times higher than in die in utero from hydrops or perinatally due to liver other children. It is greatest in children aged 0­5 years, fibrosis. The reasons for this are still not understood. with no cases over 29 years. There is a very specific risk · Following diagnosis, the blood count is usually of myeloid leukaemia which for under fives is 150 times checked monthly for 2­3 months ­ if normal, no that in other children. The response to treatment of both further action is needed. If AML develops sub- AML and ALL is good. sequently, it will declare clinically in the usual Increased susceptibility to infection leads to manner. increased morbidity and mortality during treatment for · All information must be shared with parents. The leukaemia. The infection risk may be linked to underly- unpredictability is hard for them to cope with. They ing immunological deficits. can be told that 75% of children do not develop AML. All children in the UK who acquire any type of can- If it does develop, it will be within the first two years. cer have their health records flagged and the data It is very chemosensitive and treatment is more suc- entered on the register at the Childhood Cancer cessful than for other children (see later). Research Group in Oxford. The UK Children's Cancer · Recent research suggests that leukaemias are associated Study Group (UKCCSG) can then link data from the not only with genetic changes, but also with cytogenetic register with records held by specialist paediatric oncol- changes. Clonal cytogenetic abnormalities can occur in ogy centres. Hence, levels of referral can be determined. children with Down's syndrome and TAM just as they When children with Down's syndrome who had leukaemia were investigated in this way, it was revealed that many fewer than expected were being referred to Panel 2: TAM case studies specialist services. Therefore information as to how they The most common TAM scenario involves a baby were faring was sought from the MRC National AML with Down's syndrome who has had a blood trials (AML 10, 1987­95 and AML 12) which were count for some other reason. Although the actual examining the role of short term very intensive cytotox- blood count values are normal, numerous odd ic chemotherapy and from the MRCALL trials (UKALL blast cells are seen on the film. The baby is com- X, 1985­90, and UKALL XI, 1990­97). pletely well. No intervention is needed. The blood count returns to normal within a few months. Acute myeloid leukaemia (AML) A more unusual scenario is illustrated by an infant AML is the most common leukaemia seen in children who was born at 37 weeks gestation with Down's with Down's syndrome. Panel 3 summarises findings syndrome and perimembranous VSD. The leuko- from the UK trials AML 10 and 12. cyte count was found to be very high (471x109/l), The risk of increased deaths from infection during and 90% of the count were blast cells indistin- induction and remission means that there has to be very guishable from AML blast cells. The baby was unstable and there were problems with hydration good supportive and nursing care. There must also be and ventilation. In order to avoid thrombotic prob- extreme vigilance as these children are vulnerable to lems, cytotoxic treatment with a very small dose life-threatening infections during their treatment of cytarabine was given, and the count slowly although they do have a very good chance of cure and a improved. The cardiac defect was repaired and very low risk of relapse. the infant has been well ever since with no sign AML in children with Down's syndrome is quite an of acute leukaemia. indolent disease. Clinical problems may be slow to BMT should no longer be necessary for any child with Panel 3: Review of findings from AML 10 and 12 Down's syndrome. · Fewer children with Down's syndrome entered In summary, children with Down's syndrome get a than expected, suggesting continued reluctance unique form of myeloid leukaemia ­ megakaryoblastic to enter children with Down's syndrome into leukaemia ­ which is extremely rare in other children. It national trials. is very sensitive to agressive chemotherapy, which gives · Initial remission rate following induction slightly a high chance of cure. BMT is not needed as these chil- poorer (not significant) in children with Down's syndrome compared to others (83% vs 92%). dren do very well on chemotherapy. · Deaths during induction significantly increased (17% vs 4%). Acute lymphoblastic leukaemia (ALL) · Overall 5-year survival the same for children Modern treatment for ALL extends for much longer that with and without Down's syndrome (59% vs for AML. It comprises: 60%). · Induction and intensification therapy to achieve stable · Relapse risk significantly less than for children without Down's syndrome (8% vs remission 39%). · Intrathecal methotrexate to prevent leukaemic relapse · Risk of death in remission significantly greater in the spinal fluid than for children without Down's syndrome · Then at least two years of outpatient immunosuppres- (21% vs 8%) because of increased vulnerability sive treatment with oral mercaptopurine and to infection during intensive chemotherapy. methotrexate. · Different morphological type (megakaryoblastic) in Down's syndrome than in other children A review of the findings from two recent national (usually monoblastic or myeloid). MRC trials, UKALL X (1985­90) and UKALL XI · Chromosome 15;17 and 8;21 translocations in (1990­97) is shown in Panel 5. leukaemic cells, which are known to have good Although the relapse risk in most reports is similar, prognoses, do not occur in children with Down's the overall survival for children with Down's syndrome syndrome. Despite this patients tend to do well. Panel 5: Review of findings from UKALL X and Panel 4: AML case study UKALL XI Alex was living with his family overseas when, at · More children with Down's syndrome were age 10 months, he was found to have blast cells entered in the UKALL XI trial but it is probably in his blood. His family did not return to the UK the case that not all were entered or adequately until 4 months later by which time he was starting treated. to get anaemic and had some bruising, hence · Significantly more children with Down's syn- intervention was necessary. He was treated drome and ALL were aged between 2­9 years according to the standard full protocol and has compared with other children i.e. fewer infants done very well since. and teenagers. · All children with Down's syndrome who devel- develop. There is plenty of time to investigate and oped leukaemia had early B cell leukaemia ­ common lymphoblastic leukaemia. As shown in discuss treatment options. Intervention is not necessary previous studies, there were no cases of T cell until either symptoms become apparent or blood prod- leukaemia. ucts are needed (Panel 4). Eventually however, the dis- · Cytogenetics were unremarkable with absence ease will progress and without treatment death will of both good (e.g. high-hyperdiploid ALL) and ensue. adverse (e.g. 9/22 translocation) prognostic Children with Down's syndrome and AML respond factors. · The response to treatment showed a steady unusually well to intensive treatment. The need for improvement in the children with Down's syn- aggressive cytotoxic chemotherapy has been questioned drome. The risk of death in the first remission and debated worldwide. Some do well on less intensive during treatment fell from 21% to 8% from regimens but some die. An international trial would be UKALL X to UKALL XI. For children without necessary to establish whether it is indeed safe to use Down's syndrome, the risk fell from 4% to 2%. less intensive protocols. · The overall 5-year survival for children with Down's syndrome was good (73%) but signifi- In the early days of the AML trials, four children cantly worse than for children without Down's with Down's syndrome had bone marrow transplants syndrome (82%). UKALL XI figures are better (BMT). However the excellent response to intensive than UKALL X (Figure 1). cytotoxic therapy which is now reported suggests that DSMIG is indebted to the Down's Syndrome Association who have met all the production costs for this summary. 100 85% 80% 75 78% 53% 50 centage still alive Per X DS XI DS 25 X Non-DS XI Non-DS 0 0 1 2 3 4 5 Years from entry Figure 1: Overall survival for children with Down's syndrome in UKALL X (DS vs non DS p< 0.001) and XI (DS vs non DS p = 0.1). compared with children without Down's syndrome was than in other children. Both respond remarkably well not quite as good as in some reports. Treatment-related to intensive cytotoxic chemotherapy. deaths tended to follow long periods of neutropaenia · Entry into national UK trials should be improved when children had been on long-term antibiotics. They and national treatment protocols followed. tended to be fungal infections, which raises the question · There is a need for maximal supportive care during as to whether aggressive antifungal therapy with ampho- induction and remission because of the increased risk tericin should have been administered earlier. of infection. During oral continuation therapy, patients are at risk of ordinary childhood illnesses such as chicken pox. Further reading As with AML, it is important to deliver chemotherapy as Chessells JM, Harrison G, Richards SM et al. Down's intensively as possible and also to provide very syndrome and acute lymphoblastic leukaemia: clinical good supportive care to reduce the risk of treatment- features and response to treatment. Arch Dis Child related deaths. 2001;85:321­5 Craze JL, Harrison G, Wheatley K, Hann IM, Chessells Other cancers JM. Improved outcome of acute myeloid leukaemia in In contrast to the leukaemias, in Down's syndrome there Down's syndrome. Arch Dis Child 1999;81:32­7 is a significantly decreased risk of solid tumours in all Hasle H, Clemmensen IH, Mikkelsen M. Risks of age groups with the possible exception of testicular and leukaemia and solid tumours in individuals with Down's ovarian cancers. syndrome. Lancet 2000;355:165­9 Summary Levitt GA, Stiller CA, Chessells JM. Prognosis of · Down's syndrome with acute leukaemia. Arch Dis Child Children with Down's syndrome have macrocytosis 1990;65:212­6 and thrombocytosis, which is apparently unrelated to congenital heart disease. Robison LL, Nesbit ME, Sather HN et al. Down's syn- · They have a variable degree of immune deficiency. drome and acute leukemia in children: a 10-year retro- · There is an almost unique risk of transient neonatal spective survey from Children's Cancer Study Group. abnormal myelopoesis (TAM) which usually follows a J Paediatr 1984;105:235­42 benign course. · Acute lymphoblastic and myeloblastic leukaemias A complete transcript of this presentation, together with are more common in children with Down's syndrome references, is available at www.dsmig.org.uk. © 2002 Down's Syndrome Medical Interest Group. Produced by Oxford PharmaGenesisTM Ltd, UK