Leukaemias in down syndrome


Transient leukaemia of Down Syndrome (TL-DS) (BSH 2018)



Transient Leukaemia of Down Syndrome (TL-DS) is synonymous with Transient Abnormal Myelopoeisis (TAM). The BSH guidance prefers TL-DS, as TAM is felt to give a misleading impression of a benign disorder.




5-30% of children with Down Syndrome (DS) are born with TL-DS


There is a wide spectrum of clinical outcomes and although it often resolves spontaneously:

  • 15-20% of cases result in early death

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

  • —> 65% event-free survival for all cases of TL-DS




TL-DS / TAM (WHO 2008) = Increased peripheral blood blast cells in a neonate with Down Syndrome


TL-DS (BSH 2018) = 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.


Silent TL-DS / Silent TAM = the presence of a GATA1 mutation in a neonate with no increase in peripheral blood blasts (<10%) in the first week of life




TL-DS occurs in the presence of a GATA1 mutation + Trisomy 21


Evidence for GATA1 as the driving mutation for TL-DS

  • GATA1 is a haematopoietic transcription factor --> mutations in exon 2 or 3 of the gene result in the production of a shortened protein

  • All patients with clinically diagnosed TL-DS have detectable GATA1 mutations by next generation sequencing

  • Paired analysis of TL-DS and ML-DS cases shows that these are clonally linked disorders.

  • In addition, GATA1 mutations are no longer detectable in remission samples and they are not present in other DS or Non-DS leukaemias (e.g. ALL in DS)


TL-DS originates from abnormal megakaryocytic-erythroid precursors in the fetal liver, and circulate from there. As a result, there may or may not be bone marrow involvement.


Clinical Features



Skin rash – papular or vesicopustular lesions, more rarely skin nodules

Pericardial and/or Pleural effusions





Or maybe asymptomatic




Blood film

  • Perform in first 3 days of life – see below for details

  • Blasts are pleomorphic with prominent nucleoli and basophilic cytoplasm.


PB Immunophenotype, variable expression of:

  • Stem cell markers - CD34+/-, CD117+/-

  • Myeloid - CD33+/-, CD13+/-

  • Megakaryocytes - CD36+/-, CD42+/-, CD61+/-

  • Aberrant markers – CD56+, CD7+


Bone Marrow Biopsy is unlikely to be helpful – see pathophys


Next Generation Sequencing (NGS) to detect GATA1 mutation


Significance of the peripheral blood blast count


No internationally agreed definition or threshold for ‘increased PB blasts’


Timing of assessment important – differential count should be performed in first 3 days of life. Counts made after first week of life may underestimate blast % leading to a neonate not being recognised as at risk of ML-DS.

Note: neonates who have suffered placental insufficiency have lower blast % even in the presence of GATA1 mutation --> false reassurance.


>10% - will identify all cases of clinical cases of TL-DS (sensitivity 74%, specificity 81%)

>20% - all neonates with blasts >20% have a GATA1 mutation

Suggests GATA1 testing is of particular importance for neonates with blasts between 10-20%




Although most cases resolve sponatnously, TL-DS can be fatal, and early mortality (6-12 months) is among the highest of any childhood malignancy in the UK.


In severe cases progressive hepatopathy --> fulminant hepatic fibrosis, DIC and multi-organ failure


The strongest poor prognostic factor is hyperleukocytosis, --> WBC >100 associated with early death




Low dose cytarabine (1-1.5mg/kg/day) is highly effective and increases survival in neonates with life-threatening symptoms (WBC>100, DIC, Liver failure, Need for ITU care etc)


TAM-10 Study – One year OS for neonates with WBC >100:

  • 78% for those treated with cytarabine

  • 38% for those treated with supportive care only


Who to treat and when?

  • Complicated decision, possibly some thresholds set too high out of a concern for over treating a condition that may spontaneously remit. See BSH Guideline for detailed discussion.


Current Questions


Minimal disease monitoring to detect early relapse/development of ML-DS?

  • Could use Flow / Molecular. Not enough data yet to know if this is of value.



aml in down syndrome (ML-DS)




Peak incidence is in 2nd year of life, and is rare after 4 years old.

Onset is usually indolent with a gradual, MDS-like decline in counts over a number of months

As all cases progress if left untreated, patients should be treated once ML-DS seen to be developing


Monitoring for ML-DS post TL-DS


FBC every 3 months to the age of 2 years, then less frequently until 4 years, then stop




Based on reduced-dose anthracycline regimens, such as the CCLG 2007 protocol.




Good long-term survival rates of 80-90%



Acute Lymphoblastic Leukaemia


12-fold increase in ALL in Down Syndrome


Mostly precursor type – i.e. CD79a+, CD10+, CD19+

Clinical features similar to children without Down


Worse outcomes than in children without Down, due to higher rates of poor risk cytogenetics



Reduced intensity treatment due to an increased TRM with intensive treatment in Down