Case 107 – summary

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This week we have been looking at Transient Leukaemia of Down Syndrome (TL-DS).


Between 5%- 30% children with Down syndrome (DS) are born with Transient Leukaemia of Down syndrome (TL-DS), aka transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD).

  • A clonal disorder, with circulating megakaryoblasts and dysplastic changes in peripheral blood

  • TL-DS is driven by mutations in the haematopoiesis transcription factor gene GATA1, and is only seen in conjunction with trisomy 21, either constitutional or acquired

  • May present with overt clinical features but some are only identified through blood film and/or by GATA1 mutation analysis

  • Many cases resolve without treatment

  • 15-23% cases result in early death

  • 20-23% survivors will develop acute myeloid leukaemia of Down syndrome (ML-DS) in the first 4 years of life

  • Overall event-free survival 63-68%

  • Those with previous TL-DS has a Risk of ML-DS 150 times greater than non-DS children (AML risk in all DS is about 1-2%)
  • Risk of ALL in previous TL-DS 30 times greater than those without DS (and with poorer outcome)

Definitions, clinical features and diagnosis:

  • A congenital leukaemia unique to neonates with DS or mosaic trisomy 21

  • Clonal disorder

  • TL-DS cells spread throughout the body, infiltrating the liver, pleural and pericardial spaces, skin and to a LESSER extent, the bone marrow

  • Presence of an acquired N-terminal mutation in exon 2 or exon 3 of the key haematopoietic transcription factor gene GATA1, resulting in a truncated GATA1 protein

  • Paired TL-DS and ML-DS samples show the same GATA1 mutations, indicating that they are clonally linked conditions

  • GATA1 mutations are not detected in remission samples after treatment of ML-DS nor are they present in other DS and non DS leukaemias

  • GATA1 mutation(s) are not leukaemogenic in cells that are not trisomic for chromosome 21

  • Studies using next generation sequencing (NGS) indicate that cases classified clinically as TL-DS or by blast >10%, all have detectable GATA1 mutations

  • Of note, in studies, 98% of neonates with DS had circulating blasts, the great majority had no clinical features of TL-DS and no detectable GATA1 mutation

  • Hence TL-DS = the presence of a GATA1 mutation in a neonate with DS or mosaic DS, combined with an increased blast count, or features suggestive of TL-DS

Blast count threshold

  • > 10% peripheral blasts in the first week of life identifies all neonates with clinical features of TL-DS

  • Blast count requires careful examination of a peripheral blood film in the first week of life, ideally in the first 3 days of life, by a haematologist experienced in reviewing neonatal blood films
  • automated blast counts are not accurate
  • Blast count assessment after the first week of life may underestimate the prevalence of disease, as blast% falls rapidly after birth
  • Neonates with intra-uterine growth restriction (IUGR) or other history of placental insufficiency (e.g. maternal hypertension, pre-eclampsia or diabetes mellitus) may have lower blast counts despite large GATA1 clones

Clinical features

  • Clinical features can be variable and may be absent (or present in the absence of TL-DS)
  • they can spread locally, spill into the peripheral blood and infiltrate through the liver as well as distant tissues
  • Hepatomegaly, hepatic fibrosis
  • splenomegaly (30% cases, often due to portal vein obstruction, splenic infiltration is rare)
  • Malignant effusions in pleural and pericardial spaces
  • And/or as papular or vesicopustular rash due to skin deposits of blast cells (skin nodules are rare)
  • Hepatopathy – Jaundice, Abnormal LFTs (raised transaminases with conjugated hyperbilirubinaemia)
  • Hyperleucocytosis
  • Coagulopathy
  • Multi-organ failure
  • Thrombocytopenia (which is common in DS even without TL-DS)
  • Neutrophilia
  • Anaemia


  • Leukaemic cells are megakaryoblastic, originate from abnormal megakaryocyte-erythroid precursors in the fetal liver
  • Blasts are pleomorphic, with prominent nucleoli and basophilic, blebbed cytoplasm, in keeping with erythroid-megakaryocytic origin
  • Megakarycotye fragments often a prominent feature


  • Distinct from other leukaemias
  • Variable co-expression of:
  • stem cell markers CD34 & CD117
  • Myeloid markers CD33/CD13
  • Platelet glycoproteins CD36, CD41, CD42, CD61
  • Aberrant expression of CD56, CD7, low expression of CD11a
  • HLA-DR in 30%
  • Negative for MPO, CD15, CD14, glycophorin A
  • Bone marrow examination is NOT useful, since blasts originate in the liver and marrow blasts are variable and lower than in peripheral blood. Bone marrow involvement does NOT correlate with disease severity


  • All neonates with known or a high suspicion of DS should be examined for features suggestive of TL-DS
  • FBC & blood film within first 3 days of life with formal assessment of blast %
  • Those with features of TL-DS should have additional tests:
    • LFTs including conjugated bilirubin
    • CXR
    • ECHO
    • AUSS
  • Those with features of TL-DS and blasts>10% should have peripheral blood tested for GATA1 mutation
  • Those who did not have a peripheral blasts performed in the first 3 days of life or where there was significant IUGR (where blast count may be suppressed) should be considered at risk in first 4-8 weeks of life and be monitored accordingly. Consider GATA1 mutation analysis

Silent TL-DS

  • Recent studies found that at least half of DS neonates with GATA1 mutations have blasts < 10% and have no clinical features of TL-DS.
  • The prevalence of GATA1 mutation in DS neonates with blast % 1-10% is around 20%
  • Where this is a GATA1 mutation and a peripheral blast =< 10% in the first week of life in a neonate with DS or mosaic trisomy 21 is termed Silent TL-DS or Silent TAM
  • These children have a much lower rate of transformation to ML-DS (<3%) compared to those with clinical TL-DS which has a transformation rate of 10-30%
  • Therefore routine screening for GATA1 is not recommended when blast % =<10%, unless blast % was not assessed or unreliable

Risk factors for poor outcome & life threatening symptoms

  • Most TL-DS resolve spontaneously without sequelae
  • Clinical TL-DS has an early mortality of 15-23%. This is in excess of any other childhood cancers in the UK
  • Risk factors/life threatening symptoms leading to early death:
    • Progressive hepatopathy with cholestasis (conjugated bilirubin > 83umol/L, ascites or massive hepatomegaly
    • Hepatosplenomegaly (beyond umbilicus or causing respiratory or feeding compromise)
    • WBC > 100 x 10^9/L or leucostasis
    • Multi-organ failure
    • Hydrops fetalis
    • Pleural or pericardial effusions
    • Renal failure
    • Disseminated intravascular coagulation/coagulopathy with bleeding


  • Those with life threatening symptoms should be considered for treatment with cytarabine
  • TL-DS and ML-DS blasts are extremely sensitive to cytarabine
  • Very low doses of cytarabine can be successfully used
  • Cytarabine should be given urgently at a dose of 1-1.5mg/kg/day for 5-7 days either intravenously or subcutaneously
  • Monitor closely due to risk of neutropenia and sepsis
  • Repeated courses of cytarabine can be considered to achieve control if severe liver dysfunction persists
  • Exchange transfusion and leukapheresis may be used in acute count reduction but is not definitive treatment
  • Cytarabine should NOT be used to prevent later development of ML-DS

Monitoring & Follow up

  • Those without life threatening symptoms can be monitored without treatment, and most will resolve spontaneously
  • Peripheral blasts will disappear in days to months (most by 2 months)
  • Progression to ML-DS 20-23% in those with clinical TL-DS (numbers vary slightly in different studies)
  • FBC & blood film usually return to normal in most
  • TL-DS cases should be monitored with FBC, LFTs until spontaneous resolution
  • If persistent abnormal FBC, GATA1 mutation analysis should be considered
  • All children with previous TL-DS or silent TL-DS should be monitored for progression to ML-DS every 3 months till 2 years of age.
  • If FBC & film are normal, then monitor 6 monthly till 4 years of age, as most ML-DS will develop by the age of 2
  • Any abnormal blood counts should promt early bone marrow aspirate and trephine (as aspirate is frequently difficult due to marrow fibrosis and trephine biopsy is essential in diagnosing ML-DS)


1. WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues

2. Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome – BSH Guidelines. 2018. BJH.

3. GATA factor mutations in Hematologic Disease. Blood Journal 2017

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