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Triplets © CC BY Heather Spears, Wellcome Collection

For Childhood Cancer Awareness Month, Dr Andi Roy explains current challenges in the treatment of Acute Lymphoblastic Leukaemia and how research at the MRC WIMM is trying to tackle them.

 

How far have we come?

Every year, 1,900 children are diagnosed with cancer in the UK. Of these, leukaemia is the most common form of childhood cancer, with approximately 440 children diagnosed every year.

Whilst even thinking of one child with cancer can be disheartening, remarkable progress has been made in treating childhood acute lymphoblastic leukaemia (ALL).  ALL is a type of leukaemia that is caused by an abnormal proliferation of immature lymphoid cells/ precursors and could be of the B or T cell lineage. Precursor B ALL is much more common than T ALL in children, and is usually due to a molecular/ genetic defect in these cells such as chromosomal translocations, gains or deletions and/or genetic mutations.

One of the greatest success stories for cancer care has been the improvement in survival of children diagnosed with ALL. In 1970, only three out of ten children diagnosed with ALL survived. At present, nine out of ten children are cured in the UK. Such a dramatic improvement has been made possible by years of research, which have developed precise diagnostic methods and more sensitive monitoring of residual disease, leading to appropriate risk stratification for treatment.  Better supportive care and novel therapies have also contributed to lives being saved. 

 

Where are we now?

Despite this encouraging progress, it has rapidly become evident that not all childhood ALL is the same. Some children demonstrate a quick and complete response to current treatment approaches, while others remain refractory to treatment with a dismal prognosis. Another interesting feature is how childhood ALL differs from adult ALL. What is it that makes a disease that looks the same to us when looking down a microscope and harbouring the same genetic abnormality (Figure 1a), behave so variably in different patients (Figure 1b)? Answering these questions is essential to develop new treatments that may cure the remaining 10% of children.

 

Image credits: 1a) VashiDonsk, Wikimedia Commons (CC BY-SA 3.0); Wessex Reg. Genetics Centre, Wellcome Collection (CC BY 4.0); and D Ladon (Great Ormond Street Hospital, London) Image credits: 1a) VashiDonsk, Wikimedia Commons (CC BY-SA 3.0); Wessex Reg. Genetics Centre, Wellcome Collection (CC BY 4.0); and D Ladon (Great Ormond Street Hospital, London)

Our research

It is likely that the biology of ALL, including leukaemia initiation, maintenance and progression, depends on the developmental stage and type of cell it originates in. There is growing evidence that many cases of childhood ALL originate before birth. This is especially true for those leukaemias that occur in babies less than a year old (infant ALL) which invariably arise in utero.

Only five out of ten babies with infant ALL are able to survive. While most paediatric leukaemias require a postnatal genetic ‘second hit’ to develop, in infant ALL rearrangement of the MLL gene is often sufficient to cause rapid leukaemic transformation without additional genetic abnormalities.

In the Roberts/Roy lab at MRC MHU, we have hypothesised that the target cell population responsible for in utero initiation of infant and childhood ALL may have specific molecular and/or epigenetic characteristic that make infant ALL particularly aggressive and difficult to treat. These cells are the focus of our research and we have recently shown that B lymphocytes are produced via specific developmental pathways in the human fetus. In my current Wellcome Trust funded project, I now want to examine why these fetal specific progenitors are particularly susceptible to leukaemic transformation and how it progresses, especially compared to postnatal progenitors found in paediatric and adult life. This will help identify the developmental pathways that drive aggressive treatment resistant leukaemia in infants.

In one out of five children with ALL, the disease either does not respond to treatment, or relapses after apparent control despite risk-stratified therapy. Understanding the mechanisms that drive treatment resistance and finding ways to overcome these poses the biggest challenge in paediatric ALL research and treatment in current times. Current treatment protocols for these rare leukaemias are undertaken as part of large international collaborative study groups. They involve intensive chemotherapeutic and stem cell transplantation strategies, with resultant acute and long-term treatment related morbidities that place a significant societal and economic burden. For infant ALL, these treatment strategies have so far failed to improve survival despite collaborative efforts and improvements in supportive care. Hopefully research such as ours into the molecular and developmental basis of the disease, will be able to help these children.

 

Where do we go from here?

For childhood ALL, the focus must now shift to helping those children who do not respond to treatment and those who cannot tolerate the treatment because of toxic side effects. A ‘one size fits all’ approach to treatment is not the right strategy and children deserve the most effective treatment that can be delivered with the least amount of toxicity. We have already begun to tailor personalised anticancer therapy to optimize therapeutic outcomes and minimise side effects for individual children. Research programmes such as ours are now focusing on childhood leukaemias where the need is greatest, by trying to identify new or repurposed drugs for ALL that is resistant to treatment, as well as strategies for therapy reduction in ALL that is sensitive to treatment. Drug development is increasingly focused on targeting specific pathways/ mutations or unique surface proteins on cancer cells using small molecules or antibody/cellular therapies. A particularly promising development had been the emergence of CAR-T therapy whereby the patient’s own T cells are engineered to recognise and eliminate cancerous cells. These treatments have provided new hope for children who have refractory or relapsed ALL, but are also expensive and not without side effects/ failures.

In the coming years we want to expand our understanding of these agents and refine techniques, with the hope that more children will be able to receive these therapies upfront with less toxicity. They have the potential to change the treatment paradigm for newly diagnosed ALL, with a shift from combination chemotherapy treatment based on morphological diagnosis to combination targeted therapy based on leukaemia biology.  All of these will lead to safer and more effective treatments for childhood ALL. We must also focus our energies in helping children with ALL from low and middle-income countries.  85% of children with cancer reside in these countries, and yet survival rates lag far behind resource rich countries. We must strive to close this gap.

 

The bottom line

As a South East Asian saying goes, childhood ALL is ‘same, same but different’ in so many ways and at so many levels. Understanding how they are similar but also different is crucial to help children affected by this condition.

 

 

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