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Body and mind

Ninety-nine percent of children and adolescents with leukaemia have abnormal blood lipids at diagnosis

Danish researchers wanted to discover whether they could predict which people with leukaemia are at high risk for very serious side-effects when they undergo chemotherapy. They could not. Instead, they found that virtually all young people with leukaemia already have abnormal levels of blood lipids when diagnosed.

Sometimes researchers begin investigating one topic and then discover something very different.

This applied to researchers from Rigshospitalet when they set out to discover out whether they could predict, at diagnosis, which children and adolescents with leukaemia would later experience severe side-effects associated with chemotherapy.

The researchers found no link between having abnormal levels of blood lipids at diagnosis and the risk of having very elevated blood lipid levels during treatment, resulting in severe side-effects.

By contrast, they discovered, very surprisingly, that the blood lipids of 99% of all children and adolescents with leukaemia are already out of balance at diagnosis.

“We think that both results are interesting. The fact that 99% of all children and adolescents with leukaemia have abnormal levels of blood lipids before starting treatment is very surprising. We will examine this further, because it provides insight into how leukaemia affects the mechanisms of the body. The fact that we cannot use the levels of blood lipids at diagnosis to identify the people with leukaemia who will later experience severe side-effects later in the course of treatment is disappointing, but it is also interesting because it shows that another unknown mechanism must be involved,” explains an author, Thomas Leth Frandsen, PhD and Consultant, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen.

The new study, with Pernille Rudebeck Mogensen as the first author and funded directly by the Danish Childhood Cancer Foundation and the Danish Diabetes Academy, has been published in PLOS One.

Leukaemia treatment is toxic

There is generally great success in treating children and adults younger than 45 years who have acute lymphoblastic leukaemia, the most common type of cancer among children.

From 2008 to 2016, the departments of child and adolescent cancer in Denmark used a new joint Nordic treatment protocol that has increased the survival rate to 93–94%.

However, the treatment is prolonged and leads to severe toxicity, and many patients experience side-effects during the 2.5 years of treatment and afterwards.

Some of these side-effects are horrible and include thromboembolism (blood clot), severe pancreatitis, transient diabetes and the special side-effect of osteonecrosis, in which the bones of young adults crumble and fall apart around the bone’s growth zones.

Previous research from Rigshospitalet has shown that people with very high levels of triglyceride fat in their blood during chemotherapy often have these side-effects.

“The blood of some patients treated for leukaemia is completely white and sticky because the blood contains so much triglyceride: hypertriglyceridaemia. Of course, this is not healthy and increases the risk of the various side-effects. For example, it is easy to imagine that sticky blood has greater difficulty in passing through the blood vessels, and this can create a blood clot. This may be what happens in osteonecrosis: the fine blood vessels in the joints of the growth zones of young adults are blocked, causing the bones to die,” explains Thomas Leth Frandsen.

Blood samples from 127 children and adolescents recently diagnosed with leukaemia

In the new study, the researchers wanted to investigate whether they could identify at an early stage which children and adolescents with leukaemia would later develop very elevated levels of triglyceride in the blood and thus be at high risk of the various side-effects.

“This would be helpful, because then we could use this information to monitor the people who showed early signs of hypertriglyceridaemia,” says Thomas Leth Frandsen.

The researchers very specifically did this by examining blood samples from 127 children and adolescents at Rigshospitalet at diagnosis and determining the concentrations of several blood lipids: HDL, LDL, total cholesterol and triglycerides.

“We especially focused on children and adolescents who already had hypertriglyceridemia at diagnosis. We thought they might be the ones who developed side-effects related to this later, but this was not the case. There was no association,” says Thomas Leth Frandsen.

Various abnormal blood lipids

Thomas Leth Frandsen says that Rigshospitalet often finds that people develop hypertriglyceridaemia when treated with large quantities of glucocorticoids. Glucocorticoids are very good at combatting leukaemia but cause other problems, such as the blood becoming greasy, white and sticky.

This is especially true for intense therapy with glucocorticoids and L-asparaginase, another anti-leukaemia drug.

The idea behind the research project was that this medicine would reinforce an already underlying tendency to develop hypertriglyceridaemia, but this was ultimately a dead end.

Nevertheless, the researchers found that virtually all 127 children and adolescents with leukaemia had abnormal blood lipid levels.

• 98% had low HDL.

• 61% had mild hypertriglyceridaemia.

• 5% had mild hypercholesterolaemia (high blood cholesterol).

• 14% had mild hypocholesterolaemia (low blood cholesterol).

• 13% had low LDL.

• 1% had high LDL.

• Those with either high og low levels of blood cholesterol at diagnosis had an increased risk of thrombosis during treatment.

A stressed body knocks lipid levels out of balance

Based on the results, Thomas Leth Frandsen speculates that the reason leukaemia is so strongly linked with abnormal blood lipid levels is that the people with leukaemia are already very ill when they come to the clinic for the first time and are diagnosed.

Leukaemia, which often develops over a long period, stresses the body, but remains undetected because it initially does not cause any particular symptoms other than fatigue, leg pain or flu-like symptoms.

“Their bodies have been stressed for a long time, and that, we think, explains why their blood lipids are out of balance,” explains Thomas Leth Frandsen.

Focus on improving survivors’ quality of life

Although Thomas Leth Frandsen did not achieve the desired new way of predicting who is at risk of the side-effects of chemotherapy, he is nevertheless satisfied with the result.

He is especially pleased that the researchers have focused on the fact that 99% of the people with leukaemia have abnormal blood lipids, and he is confident that the research team at Rigshospitalet will not be the only ones examining this association more closely.

Other research groups will too, and in the long term this may improve our understanding of leukaemia and the side-effects of chemotherapy.

“The results also confirm the fact that people with leukaemia are successfully being treated in both Denmark and the rest of the world, so we can now start looking at the potential for reducing the side-effects and not simply enabling people to survive. We want to find out how we can improve the quality of life of the children and adolescents who survive leukaemia,” says Thomas Leth Frandsen.

Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia” has been published in PLOS One. The Danish Diabetes Academy and the Novo Nordisk Foundation have supported Pernille Rudebeck Mogensen’s research.

Thomas Leth Frandsen
MD PhD
The Department of Paediatrics and Adolescent Medicine (DPAM) aims to improve cure rates and quality of life for children with medical disorders. This includes recruitment of young researchers, targeted training of clinicians and researchers, interdisciplinary and international research, specialised clinical facilities for adolescents, and register-based long-term follow-up. In addition to offering the best standards of care, innovative treatment approaches are tested in clinical trials including vaccine trials and phase 1 and phase 2 clinical trials for children with cancer and inborn errors of metabolism. To explore health among Danish children in general, DPAM perform population-based register studies to determine rates of and risk factors for hospitalizations, drug use, and mortality among Danish children. We also address strategies for improving quality of life for school children and older adolescents with life-threatening or chronic diseases, which include exploring how healthy peers can be involved in the support of patients.