Mystery of treatment resistant childhood leukaemia uncovered

Researchers at Wellcome Sanger Institute, Great Ormond Street Hospital (GOSH), University College London (UCL), Addenbrooke's Hospital Cambridge, and collaborators, discovered a new type of cancerous T-cell that does not respond to current treatments and could be responsible for the high mortality rate of this type of childhood cancer.

Published in Nature Communications, experts pinpointed the gene that is switched on in these cells, and how to identify them. This genetic marker can be identified by adapting tests that are already used routinely by clinicians and could therefore be easily adapted into routine clinical care.

Being able to identify children whose cancer will not respond to treatment could allow clinicians to tailor their treatment plan to avoid any chemotherapies that have been proven to be ineffective against resistant cancers and prioritise other treatments.

Acute lymphoblastic leukaemia (ALL) affects the blood and bone marrow and is the most common type of childhood cancer, with 400 children being diagnosed in the UK each year. There are two different groups depending on which cells are affected - B-cell leukaemia (B-ALL) and T-cell leukaemia (T-ALL). T-cells and B-cells are types of white blood cell that play an important role in the immune system.

Outcomes for B-ALL have improved over the past few decades due to the development of new immunotherapies and being able to tailor treatment.

However, T-ALL makes up around 15% of total cases and is a more aggressive condition. It has higher rates of treatment failure, which occur in about 10% of children with T-ALL.

Unlike B-ALL, there is no way to identify which T-ALL cancers are more likely to be aggressive or high risk at diagnosis, meaning that clinical care cannot be adapted at the outset. Instead, children have four weeks of chemotherapy and then undergo further tests to see if there are cancer cells remaining in the bone marrow.

Being able to predict whether chemotherapy will work is of utmost importance to understand which children need less, and which children need more and different treatment from the outset.

The researchers analysed bone marrow samples from 58 children, including 21 children with T-ALL, and identified genes that were more active in cancer cells that did not respond to the initial treatment.

The team identified a new cancer cell type in children whose cancer did not respond to initial treatment, and these cells are not found in children with treatment-responsive T-ALL. They then validated this finding by looking at wider data sets from patients with T-ALL.

The gene, ZBTB16, is switched on in these new, treatment-resistant T-ALL cancer cells. By analysing genomic data from hundreds of patients with ALL, they found that this genetic switch can happen at any point during T-cell development.

If included in clinical tests, this gene could be used as a marker to identify these cells from the day of diagnosis, by adding an additional panel on a flow cytometry test - which is a test currently used during cancer care. The team suggests that this could be used to enable clinicians to closely monitor and adapt the treatment of children with T-ALL when possible.

The discovery also suggests a new avenue for future drug development, as treatments that switch off this gene could potentially stop cancer cell growth.

Three-year-old Jacob was diagnosed with T-ALL leukaemia in December last year after his parents took him to their local A&E after noticing he had dark-coloured bruises on his arm, a rash on his face and was vomiting. A blood test showed his white cell count was extremely high (850 compared to a normal range of 5-15) and he was immediately transferred to Great Ormond Street Hospital for treatment.

Jacob’s parents, Alexandria and Animesh, from Chelmsford in Essex, said: “Since Jacob was diagnosed with leukaemia last December, it’s been a complete whirlwind of a journey. Luckily, he responded amazingly well to the first blocks of chemotherapy despite having a very aggressive form of leukaemia, which meant he could continue the standard treatment and did not need to have a bone marrow transplant.

“All of the staff, from the doctors and nurses to porters and play specialists, have been fantastic during our time in hospital.”

Jacob is now in remission and continuing along the standard T-ALL leukaemia chemotherapy protocol, which lasts for just over a total of two years.

Jacob’s parents continued: “Research like this is so important to help move towards a future where children can have the right cancer treatment more quickly. While we were fortunate that Jacob responded really well to his chemotherapy, we spent a number of months waiting for his bone marrow test results to come back to confirm that he could continue on a chemotherapy-only protocol rather than having to try another treatment, as the tests have to be done at specific timepoints.

“If we had known from the beginning that this would likely be the case it would have provided us with some reassurance in what was a difficult time, and we truly hope that these new developments will help other parents who find themselves in the same position.”

Dr David O’Connor, co-senior author, Consultant in Paediatric Haematology at Great Ormond Street Hospital and Honorary Associate Professor at UCL, said: “Until now, it has not been possible to tailor treatment for T-cell acute lymphoblastic leukaemia in the same way as we can for B-cell leukaemia. Being able to identify children who have T-cell leukaemia that will not respond to initial treatment on the day of their diagnosis is of great importance. While further clinical research is needed, the genetic marker we have discovered can also be identified using an already widely used test, meaning that it could be easily adopted into clinical care if proven effective.”

Professor Sam Behjati, co-senior author at the Wellcome Sanger Institute and honorary Consultant Paediatric Oncologist at Addenbrooke's Hospital, said: “The discovery of this new type of cancerous T-cell is one of the most exciting findings of my career so far, and warrants urgent investigation so that it can be translated into clinical impact as soon as possible. Using genomics to understand the origins of cancer allows us to find new ways to identify it and opens up avenues for being able to treat it. For example, targeting these newly discovered cancer cells could lead to effective therapies for T-cell leukaemia that currently don’t respond to first-line treatment, something that children, and adults, living with this cancer urgently need.”

GOSH is developing a new Children’s Cancer Centre, putting children at the front and centre, with their needs as the very heart of the design. The new facility will also make it easier for clinical teams to combine the very best care with the latest research and innovation - working together to deliver a step change for children with cancer. Find out how you can support the CCC.

All research at GOSH is underpinned by support from the National Institute for Health and Care Research GOSH Biomedical Research Centre.