BRC Clinical Fellow
Unravelling the mutational landscape of acute lymphoblastic leukaemia in older adults to improve treatment.
Thomas Creasey
Genomic characterisation of acute lymphoblastic leukaemia in older adults
The Study
Acute lymphoblastic leukaemia (ALL) is the most frequent cancer of childhood but the disease also becomes more common with age and approximately a third of adults diagnosed with ALL are over the age of 60 years. Despite the excellent advances in the survival of younger patients with ALL, these older adults still fare very poorly and fewer than 20% are alive 5 years from diagnosis. A difference in underlying disease biology and older patients’ reduced ability to tolerate intensive chemotherapy contribute to this dismal survival.
Leukaemic cells have specific genetic abnormalities which make them cancerous. Many of these have been well characterised in children, and younger adults but have not been extensively studied in older patients.
The first part of this research project will aim to characterise the genetic changes that occur in ALL in older adults, involving both rearrangements of specific genes, and losses or gains of genetic material. Characterising these abnormalities and understanding their effects can subsequently inform the use of more targeted and less toxic treatments. This valuable information will most benefit older patients and those with underlying medical conditions which often preclude the use of intensive treatments.
It is well recognised that individual cancers consist of a number of different clones (the clonal architecture) which can evolve with treatment. Understanding the effects of treatment on this clonal architecture will offer an insight into ways of controlling the disease.
The second part of the research project will therefore study a small number of older adults with ALL through their treatment. State of the art and very sensitive genomic techniques (whole exome sequencing and targeted next generation sequencing) will be used to identify the leukaemic clones present at diagnosis and track their mutations at specific time points to better understand how the disease responds and how the clonal architecture varies through treatment. This information will be used to understand whether a) some patients can achieve a state of disease control where the disease is suppressed but certain leukaemic clones are still detectable at very low levels and b) whether ALL in older adults occurs on a background of common mutations that have recently been identified in the blood cells of older adults, a state known as clonal haematopoiesis. These mutations are present in around 10% of healthy individuals over the age of 70 and have been associated with a greater risk of developing other cancerous conditions of the bone marrow (acute myeloid leukaemia and myelodysplastic syndrome) but a link with ALL has not yet been investigated.
This research project will therefore offer a novel insight into the genetic landscape of ALL in older adults and assess how this is affected by treatment. Understanding the dynamic behaviour of low level disease during treatment in this patient population could pave the way for new therapeutic approaches aimed at controlling the disease with less aggressive and more targeted treatments to prolong both quality and quantity of life.
Project milestones
- Complete screening all ‘B-other’ ALL patients for ABL-class fusions and JAK-STAT rearrangements by fluorescence in situ hybridisation
- Full SNP array analysis and copy number profile of up to 200 older adults with ALL
- Complete whole exome sequencing analysis on 8-10 patients
- Targeted amplicon sequencing on serial samples for first 4-5 patients
- Complete amplicon sequencing for all patients including data analysis