Adriana Izz Ishak, a six-year-old girl with Down syndrome (DS), sits in the waiting room of the haematology clinic with her dad and younger sister.
She appears spritely in her pushchair; her sister plays with the other children who are also waiting to see the doctor.
Just three years ago, Adriana was diagnosed with acute myeloid leukaemia (AML), a type of leukaemia commonly seen in children with DS.
She received chemotherapy over the course of three months – a journey complicated by mouth ulcers, invasive procedures and bloodstream infections, which required prolonged hospitalisation.
Unfortunately, just a year after completion of treatment, her leukaemia relapsed.
Hopes to salvage a cure were slim as children with DS are inherently more sensitive to chemotherapy and withstand its effects poorly.
Administering more intensive chemotherapy to treat the relapse carried the risk of significant toxicities – some of which could be fatal.
However, after deliberation and many discussions, a decision was made to administer two courses of second-line (and stronger) chemotherapy.
Following this, she would undergo bone marrow transplantation, with her younger sister, who was four years old at the time, as the stem cell donor.
The transplant – a first for children with DS in Malaysia – would also be challenging, as Adriana’s sister was only “half-matched” with her.
The treatment plan, however, proved to be a success.
More than a year has passed since Adriana’s bone marrow transplant and she is likely cured of her leukaemia.
She is back to her usual sociable self, and especially enjoys singing, drawing and colouring.
Higher numbers, better outcome
DS is the most common chromosomal disorder, with an estimated incidence of one in every 700-1,000 live births.
Individuals with DS have an extra copy of chromosome 21 instead of the usual two, hence the chosen date of 21.3 (three copies of chromosome 21 or Trisomy 21) for World Down Syndrome Day.
Characteristic facial features of the syndrome include upslanting of the eyes, a flat nasal bridge and protruding tongue, although not every individual with DS has all these features.
Medical conditions associated with DS include structural defects in the heart, gastrointestinal abnormalities, hormone problems, learning impairment and blood disorders.
A wide range of blood disorders may occur in those with DS, commonly developing during childhood.
The incidence of leukaemia, or cancer of the blood cells, is significantly higher in individuals with DS, compared to the general population.
Leukaemia occurs when there is an abnormal production of immature cells termed “blasts” in the bone marrow.
These blasts crowd the bone marrow space and cause decreased production of other blood cell types, namely, red blood cells and platelets.
When this occurs, patients present with symptoms such as lethargy, easy bruising or bleeding, and poor feeding in infants.
These blasts may also infiltrate other organs, including the liver, spleen and brain.
There are two main types of leukaemia in children with DS: AML and acute lymphoblastic leukaemia (ALL).
The incidence of AML in children with DS is 150 times higher than in non-DS children.
AML in children with DS is associated with better outcomes compared to AML in children without DS, due to lower rates of leukaemia recurrence and better sensitivity to standard chemotherapy.
However, in the small population of children with DS who experience disease relapse after initial AML therapy – as in the case of Adriana – the outcome can be very poor.
Higher numbers, worse outcome
Meanwhile, children with DS have a 20-fold increased risk of developing ALL, compared to the general population.
ALL in DS presents similarly to ALL in children without DS.
It can occur any time throughout childhood, but usually in children older than four years of age.
Unlike in AML, the outcome for ALL in children with DS is less favourable compared to ALL in other children.
Additionally, children with DS are more susceptible to the toxic effects of chemotherapy, resulting in increased overall illness and death.
In contrast to treatment for AML, which is usually completed in three months, treatment for ALL takes two years.
Amani Faridah Rustam, a teenage girl with DS, was 11 years old when she was diagnosed with ALL in June 2019.
She also had other medical conditions, including a “hole-in-the-heart” and low thyroid function.
Her mother, Sarah Shukor, recalls her extreme grief upon learning of her daughter’s diagnosis.
She was saddened that Amani had to endure yet another hardship, having already dealt with her other medical conditions.
Being the “baby” of the family, Amani’s three older sisters, who dote on her, rallied together to support her in whatever it was that she needed.
Amani received chemotherapy over 24 months, mostly delivered in the outpatient daycare setting.
Fortunately, she did not experience any major complications and successfully completed treatment last August.
She has remained disease-free since then.
A pre-leukaemia state
The acronym HANDS has been used to describe blood disorders in newborns with DS, i.e. Haematological Abnormalities in the Newborn with Down Syndrome.
In the majority of cases, these blood disorders do not cause symptoms and resolve spontaneously over time, although some patients may experience persistent changes that can lead to medical problems.
Transient myeloproliferative disorder (TMD) is a condition affecting the white blood cells, which is unique to newborns with DS.
It is also known as transient abnormal myelopoiesis (TAM) or transient leukaemia.
TMD occurs in approximately 10-15% of babies with DS.
It results from the excessive proliferation of immature cells called megakaryoblasts in the fetus’ liver and peripheral blood.
This blood abnormality is usually detected on routine blood screening in the first few weeks of life and does not occur beyond three months of life.
The majority of affected newborns do not have any symptoms, apart from a high white blood cell count and liver enlargement.
In these cases, management is typically supportive.
Less commonly, babies with TMD may present with symptoms such as jaundice, bleeding easily and difficulty breathing.
In severe cases, DS babies with TMD may experience liver failure.
They may also present as hydrops fetalis – a condition of excessive fluid accumulation in the entire body that is often fatal.
Severe forms of TMD are life-threatening and necessitate treatment with a short course of low-dose chemotherapy in order to reduce abnormal cell production and their infiltration into other organs.
Fortunately, for the majority of children with TMD, spontaneous resolution will occur within the first three months of life without the need for any intervention.
However, approximately 20% of those who had TMD during the neonatal period go on to develop a specific type of leukaemia called acute megakaryoblastic leukaemia (AMKL) within four years.
Thus, TMD may be considered a pre-leukaemic syndrome.
AMKL is prevalent in children with DS younger than four years of age, with most developing the disease by two years of age.
This is why babies with DS who have had a history of TMD require close monitoring for the first four years of their life, and should be managed with the input of a paediatric haematologist.
It is presently not possible to accurately predict which babies with DS and TMD will spontaneously recover and which ones will progress to AMKL.
The good news is that the outcome for children with AMKL is excellent, with a cure rate of 80-90%, as these leukaemic cells are very susceptible to chemotherapy.
Ongoing research
The management and follow-up of children with DS requires a multidisciplinary approach, with the involvement of select medical specialities as needed.
Although blood abnormalities in children with DS are common, the majority of these cases are mild, do not have serious symptoms (if any) and will resolve by itself.
Ideally, all newborns with DS should be screened with a complete blood count to identify HANDS as described earlier.
Following this, those who are affected should undergo annual blood count tests to help pick up issues such as anaemia and leukaemia.
Children with DS with pre-cancerous states such as TMD or myelodysplastic syndrome, should be followed-up by a paediatric haematologist.
Active research is also being undertaken to determine the best methods to treat both ALL and AML in children with DS.
These efforts aim to not only minimise the toxic side effects of chemotherapy, but also to prevent leukaemia relapse, which is often difficult to treat effectively in these children.
Multi-country clinical trials are ongoing for ALL in DS patients, where the intensity of chemotherapy is personalised according to treatment response.
Recent research into the molecular basis of leukaemia development in children with DS has discovered that their immune system is not regulated properly (dysregulation) and a phenomenon called clonal haematopoiesis in their blood.
Clonal haematopoiesis is a process where blood stem cells acquire a genetic mutation that leads to abnormal replication and proliferation.
This phenomenon is more often seen in the elderly population, and may explain the increased incidence of leukaemia and Alzheimer’s disease in individuals with DS.
It is hoped that with more understanding of the biological processes underlying blood and other disorders in DS, the current challenges facing these special children can be successfully addressed in the near future.
Dr Syaza Zafirah Ab Rahman is a paediatrician and lecturer, and Dr Hany Ariffin is a senior consultant paediatric oncologist and professor, at University Malaya Medical Centre (UMMC). For more information, email starhealth@thestar.com.my. The information provided is for educational and communication purposes only, and should not be considered as medical advice. The Star does not give any warranty on accuracy, completeness, functionality, usefulness or other assurances as to the content appearing in this article. The Star disclaims all responsibility for any losses, damage to property or personal injury suffered directly or indirectly from reliance on such information.
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