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Disease and treatment

Children with leukaemia may avoid permanent damage from chemotherapy

More and more children with leukaemia are surviving. Unfortunately, the side-effects of chemotherapy often affect children for the rest of their life. Danish researchers can now measure how children react to chemotherapy, thereby potentially minimizing permanent damage to organs and life-threatening infections.

Only a few decades ago, the chances of surviving leukaemia were very slim. Today, 90% of children survive the disease. This higher rate of recovery is the result of intensified chemotherapy. However, the price of this increased survival is greater acute toxicity as well as significant late effects of the therapy. Through research that elucidates how chemotherapy harms the immune system Danish researchers are working to reduce the damage caused by chemotherapy.

“We can see that chemotherapy in the blood reduces the level of surfactant protein D, which participates in protecting the mucous membranes against infection. Thus we have gained new insight into how chemotherapy weakens the immune system, and this may help us to monitor the protective capacity of the immune system more precisely during chemotherapy and thereby prevent its side-effects,” explains Klaus Müller, Clinical Professor of Paediatric Oncology at Rigshospitalet and the University of Copenhagen.

Hefty increase in infection

Surfactant protein D is present in the mucous membranes and plays a role in combating invading bacteria to keep infection at bay. The human gut is one of the key places where surfactant protein D functions.

“One of the main problems with chemotherapy is that it damages the mucous membranes of the gut resulting in serious infections. We recently measured the effect of chemotherapy on piglets and saw a change in the production of surfactant protein D in the gut, which suggested a connection.”

In a collaboration between Rigshospitalet in Copenhagen and Odense University Hospital, the researchers therefore decided to monitor 43 children with leukaemia treated with chemotherapy. Through blood tests, they monitored the concentration of surfactant protein D and several other immune-related parameters such as interleukin 6, C-reactive protein and white blood cells.

“Soon after initiation of chemotherapy we saw a reduction in the blood levels of surfactant protein D and, from week 2 we observed a prolonged and major reduction in surfactant protein D that was related to increased inflammation of the mucous membranes and a higher concentration of markers of inflammation in the blood.”

Personalized chemotherapy

Inflammation and acute pain are precisely what characterizes mucositis, inflammation of the mucous membranes, one of the commonest, most painful and disabling conditions caused by chemotherapy. This condition breaks down the cells of the mucous membranes, harming digestion and suppressing the protection against serious infections, increasing the risk of subsequent serious organ damage.

“Thus there appears to be a clear association between the reduction in surfactant protein-D and increasing degrees of mucositis. If this is the case, this discovery suggests that we have found a new and potentially important biomarker that will enable us to continually monitor whether a child has an increased risk of these side-effects and possible accompanying organ damage.”

This knowledge may turn out to be important because it will enable the dosage and composition of chemotherapy to be individualized. These days, medicine is becoming increasingly aware that patients do not react uniformly to the same type of chemotherapy. Research increasingly suggests that individual differences in the sensitivity towards the toxic effects of chemotherapy is not random but is rather dependent on biological differences including genetic differences.

“The differences in people’s genomes may partly explain why people’s healthy tissues react very differently under chemotherapy. We are trying to improve understanding of the biological mechanisms that lie behind the side-effects of chemotherapy. This will enable us to better predict which children are at risk of developing side-effects and subsequent complications. If we understand why exactly these children develop side-effects, we can develop new tools to monitor them during the chemotherapy process and ameliorate or, in the best case scenario, completely prevent serious damage.”

No longer a question of survival

The continual improvement of cancer treatment in the past 20 years has meant that more and more patients survive. The price of this improved survival rate, however, is that more patients develop severe and sometimes life-threatening side-effects. Research has shown that more than half of those successfully treated for cancer in childhood have varying degrees of long lasting side-effects.

“Especially the treatment of leukaemia in children has been an unmitigated success story because, today, 9 of 10 children survive. This means that we have moved from researching mainly how to survive the disease to also strongly focusing on reducing the subsequent complications of treatment so that we can ensure that the disease does not affect children for the rest of their lives and deny them the opportunities that their peers have.”

The researchers do not yet know why chemotherapy reduces the concentration of surfactant protein D, but they hypothesize that the chemotherapy destroys the cells in the mucous membranes that produce surfactant protein D. Understanding the factors that regulate the function of the mucous membranes is therefore significant.

“This research is one aspect of a wider research strategy that aims to improve prophylaxis by increasing understanding of how chemotherapy affects mucous membranes in the gut and the surrounding bacterial flora. We hope to achieve this by developing new drugs but also through nutrients in food that can rehabilitate and strengthen the balance between the protective and the harmful gut bacteria.”

Chemotherapeutic treatment reduces circulating levels of surfactant protein-D in children with acute lymphoblastic leukemia” has been published in Pediatric Blood & Cancer. In 2016, the Novo Nordisk Foundation awarded a grant to co-author Kjeld Schmiegelow for the project 6-Thiopurine Resistance in Childhood Acute Lymphoblastic Leukemia (6-TRIAL).

Klaus Müller
Professor
Klaus Müller is a professor in paediatric oncology at the Department of Paediatrics and Adolescent Medicine at The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Denmark. His main research areas are: Treatment related toxicity in cancer treatment Stem Cell Transplantation Inflammation and immunodeficiency Late effects after chemotherapy during childhood