Drug therapy can be successfully used to treat sickle cell anaemia in very young children, BBC News has reported. The website said that the drug, hydroxycarbamide, was able to reduce pain and other complications in a trial in 200 babies.
This two-year study compared the use of hydroxycarbamide against an inactive placebo in babies aged 9-18 months with sickle cell anaemia. This hereditary condition occurs when red blood cells are an abnormal, inflexible crescent shape and get stuck in blood vessels, causing complications that include severe pain, infections and organ damage. There is no cure, and treatment is usually aimed at reducing symptoms.
The chemotherapy drug hydroxycarbamide is licensed in the UK for the treatment of sickle cell anaemia as it has been observed to reduce the risk of complications in older children and adults. However, this is reportedly the first trial of this type in babies. It was primarily intended to determine whether hydroxycarbamide safely prevents early damage to the spleen and kidneys in babies with sickle cell anaemia. However, the trial found the drug did not prevent their decline in function any more than the placebo did.
The trial did find that the hydroxycarbamide reduced pain and other complications, and was relatively safe, with the only side effect being a reduction in levels of certain white blood cells.
This well-designed study has produced promising results on the short-term use of hydroxycarbamide, and will continue to follow the participants to provide important information about longer-term use.
Where did the story come from?
The study was carried out by researchers from St Jude Children’s Research Hospital, Memphis, and other institutions in the US. It was funded by the US’s National Heart, Lung and Blood Institute; the National Institutes of Health; the National Institute of Child Health and Human Development, and the Best Pharmaceuticals for Children Act Program. The study was published in the peer-reviewed medical journal The Lancet.
BBC News has reported on this study in a balanced way, mentioning that although some outcomes were improved by the drug, others were not.
What kind of research was this?
This was a double-blind randomised placebo-controlled trial investigating the effects of a drug called hydroxycarbamide on organ dysfunction and clinical complications in babies with sickle cell anaemia.
Sickle cell anaemia is an inherited genetic disorder of red blood cells that primarily affects people of African and Caribbean descent. Red blood cells contain a substance called haemoglobin that carries oxygen around the body.
Red blood cells normally have a disc-like shape that is quite flexible, allowing them to flow within extremely small blood vessels. However, in sickle cell anaemia, the haemoglobin within the cell is abnormal, causing the red blood cells to form a rigid, inflexible crescent shape. These crescent, or sickle-shaped, cells cannot circulate freely through the blood vessels in the body and get stuck, causing complications such as severe pain, infections and organ damage. The severe pain of sickle cell anaemia resulting from a blockage to the circulation is known as a crisis.
The sickle cells also do not last long and die earlier than normal, causing the person to become anaemic. There is no cure for sickle cell anaemia and management usually revolves around treatment aimed at reducing symptoms through restoring fluids, pain-relief, blood transfusions and sometimes the use of bone marrow transplants.
Hydroxycarbamide (also called hydroxyurea) is a chemotherapy drug used mainly in the treatment of a type of blood cancer called chronic myeloid leukaemia. The drug is also currently licensed for use in sickle cell anaemia at specialist centres treating the disease in the UK, as it is known to reduce the frequency of crises, complications and need for transfusions in adults. This current trial compared hydroxycarbamide with a placebo in young babies with sickle cell anaemia.
What did the research involve?
This was a multicentre trial (called the Pediatric Hydroxyurea in Sickle Cell Anemia - BABY HUG trial) conducted at 13 centres in the US between 2003 and 2009. Eligible children were aged between 9 and 18 months, and carried two abnormal beta globin genes (mutations in beta globin cause sickle cell anaemia). Ninety-six babies were randomised to receive liquid hydroxycarbamide (20mg/kg a day) for two years, and 97 were randomised to receive an identical-looking placebo liquid.
In early life, those with sickle cell anaemia usually experience an abnormal increase in their kidney filtration rate. This can lead to progressive kidney dysfunction. Spleen function is also adversely affected. The main outcomes of interest were the function of the spleen (measured by scanning the spleen’s uptake of a radioactively labelled chemical) and kidney function (assessed by measuring filtration rate of the kidneys). A decrease in uptake of the radioactively labelled chemical by the spleen would indicate poorer spleen function.
Further outcomes that were assessed were blood count, fetal haemoglobin (Hb) concentration (fetal Hb is more efficient at carrying oxygen than adult Hb and enables survival in the uterus), other blood chemistry, biomarkers of spleen function, urine concentration, neurodevelopment, ultrasound scan of the head, growth, and chromosome mutations.
Adverse events were also assessed, including known complications such as pain, dactylitis (tenderness and inflammation of the fingers or toes) and acute chest syndrome (a specific respiratory complication of sickle cell anaemia that is often characterised by fever, shortness of breath and a cough).
Babies were monitored for adverse effects every two weeks initially and then every four weeks.
What were the basic results?
A total of 83 babies in the hydroxycarbamide group (86%) and 84 in the placebo group (87%) completed the study. There was no significant difference between hydroxycarbamide and placebo groups for the main study outcomes:
- nineteen out of 70 (27.1%) babies assessed had decreased spleen function in the hydroxycarbamide group versus 28 out of 74 (37.8%) in the placebo group (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.42 to 0.83; p=0.002)
- kidney filtration rate increased by 2ml/min per 1.73m2 of body surface area in the hydroxycarbamide group relative to the placebo group (HR 0.27, 95% CI 0.15 to 0.87; p<0•0001)
However, hydroxycarbamide significantly improved a number of secondary outcomes, including:
- pain events: defined as pain in the body lasting for at least two hours and requiring pain relief. There were 177 pain events in 62 babies in the hydroxycarbamide group compared to 375 events in 75 babies in the placebo group (p=0.002).
- dactylitis: tenderness and inflammation of the fingers or toes. There were 24 events in 14 babies in the hydroxycarbamide group compared to 123 events in 42 babies in the placebo group (p<0•0001).
There was also some evidence for decreased rate of acute chest syndrome, hospitalisation rates, and need for blood transfusion. Hydroxycarbamide was found to increase levels of both adult and fetal haemoglobin and to decrease white blood cell count.
The only frequent observed toxicity of hydroxycarbamide was mild-to-moderate neutropenia (low levels of neutrophils – a type of white blood cell), but there were no severe cases and no increase in the rate of blood infection.
How did the researchers interpret the results?
The authors conclude that based on their study data, hydroxycarbamide can be considered safe and effective for very young children with sickle cell anaemia.
This well-designed study has identified some potential benefits for using hydroxycarbamide to treat very young children with sickle cell anaemia. As well as using a double-blind, placebo-controlled randomised study design, the research benefits from high completion rates and a thorough follow-up of its participants over two years. While hydroxycarbamide is used in adults and has been trialled in older children, this trial is of key importance as it is reportedly the first trial of its type to involve younger children - babies of average age 13.6 months.
The BABY HUG trial was primarily intended to determine whether hydroxycarbamide could safely prevent the early spleen and kidney damage experienced by babies with sickle cell anaemia.
Although the researchers did not find that it prevented decline of kidney and spleen function, the drug was found to improve a number of secondary outcomes, reducing pain, the rate of dactylitis, acute chest syndrome, hospital admission, and transfusion rates, as well as improving blood haemoglobin levels. They also found that it was a relatively safe drug, with the only adverse effect being low neutrophil count, which did not itself translate into an increased risk of blood infection.
Although the trial may seem relatively small, it can be difficult to enrol large numbers of very young children into research studies, particularly for conditions that are not common.
These are promising results of the short-term use of hydroxycarbamide in very young children with sickle cell anaemia, but further research is still needed. Importantly, as the authors in highlight, the risk of cancer from starting hydroxycarbamide treatment early in life is still unknown, and that 'long-term follow-up is crucial'.
Further follow-up of the BABY HUG participants is planned until 2016, when participants will be 9–13 years of age. Longer-term safety and efficacy of the drug will be important, as children could be taking the drug for extended periods.