Molecular tracking of treatment response in childhood AML

14 September 2015
Professor David Grimwade, King’s College London

The use of MRD testing has helped improve the outlook for children with ALL by enabling treatment to be tailored to each individual child. The technique has been less successful in AML, with detectable genetic changes identifiable in only 60 per cent of children. The key aim of this project is to characterise the genetic mutations present in the remaining 40 per cent of cases, who currently have a worse prognosis. This will enable improved treatment strategies.

This project is being funded with the support of The Aila Coull Foundation.

Amount of grant: £238,325 | Date of award: May 2015

Overview

Acute myeloid leukaemia (AML) is the second most common form of childhood leukaemia and has a substantially worse outlook than acute lymphoblastic leukaemia (ALL), the most common childhood form of the disease.

Treatment of AML is guided by analysis of the chromosomal make-up of the leukaemic cells and by detection of defects (mutations) in particular genes as these are known to affect a patient’s risk of relapse. Further information about a patient’s relapse risk can be obtained using sensitive laboratory tests that can detect sub-microscopic levels of leukaemic cells remaining in patients’ bone marrow as treatment progresses (called ‘minimal residual disease’ or ‘MRD’).

MRD tests rely on the identification of specific genetic changes in leukaemic cells; the number of cells with these changes is measured relative to the number of normal blood cells.

In ALL, measurement of MRD is possible in almost all patients and MRD testing is now part of standard therapy. It has been one of the most important developments in treatment in recent decades, enabling children’s treatment to be tailored according to their risk of relapse. Not only has this driven up the survival rate, but it has reduced the risk of treatment-related harm in low-risk patients.

In AML, progress has been less good. Whilst studies have suggested that MRD tests are a powerful predictor of relapse risk in AML (as for ALL), genetic changes that can be detected by available MRD tests have been identified in only 60 per cent of cases.

The key aim of this project is to investigate the genetic make-up of the remaining 40 per cent of childhood AML cases.

The project will be linked to the first ever national clinical trial for AML in children and adolescents (called the MyeChild01 trial), which will recruit around 300 patients over five years from 2015. As part of the trial, DNA from diagnostic cell samples will be analysed (sequenced) to identify the faulty genes. This will be particularly useful in the 40 per cent of patients for whom we currently have no MRD test as these are the patients whose leukaemia we know least about.

Professor Grimwade will use this information to compile lists of genes that are commonly abnormal and will then re-sequence each diagnostic sample using a technique that will enable him to determine which mutations are present in all of the leukaemic cells and which are only found in a proportion of the cells.

The aim is to determine whether identifying the pattern of mutations in each patient could be used to improve prediction of disease prognosis. The team proposes to develop MRD tests for the mutations that they find to be present in all of a patient’s leukaemic cells. Tests must be individually developed for each mutation.

About the research team

The research team has an excellent track record and within the UK they are the right persons to undertake this project.
External reviewer

This project brings together key leaders in four respective fields, critical to the success of MyeChild01.

David Grimwade, Professor of Molecular Haematology at King’s College London, has an international reputation in molecular diagnostics and MRD testing in AML. He coordinates MRD monitoring in the UK NCRI AML trials, which are now the largest AML trials in the world. He will lead the molecular MRD testing in MyeChild01.

Professor Brenda Gibson, Lead Clinician for Haematology/Oncology Service at Glasgow Royal Hospital for Sick Children, is an international authority on paediatric AML trials and is Chief Investigator on MyeChild01.

Christine Harrison, Professor of Childhood Cancer Cytogenetics at the Northern Institute for Cancer Research, is an internationally recognised leader in the genetics of childhood leukaemias.

Paresh Vyas, Professor of Haematology and Honorary Consultant Haematologist at Weatherall Institute of Molecular Medicine/ Oxford University Hospitals NHS Trust, is a leading authority on leukaemic stem cells in AML, which will be evaluated in MyeChild01.

What difference will this project make?

MyeChild01 provides a huge opportunity to gain further insights into the genetic make-up of large numbers of diagnostic samples from children treated under a common protocol.

This project will focus on the 40 per cent of childhood AML where the early genetic abnormality at the root of the leukaemia is not known and will provide for the first time a detailed catalogue of the genetic changes present in these leukaemias.

This is likely to improve the panel of routine genetic tests performed on AML samples at diagnosis, to predict risk of relapse and select the best therapy. The current panel is very limited; it can distinguish broad groups of patients with good, intermediate and poor prognosis, but does not accurately identify which patients are destined to relapse and those most and least likely to benefit from a stem cell transplant (SCT). Whilst SCT can reduce risk of AML relapse, it is a high-risk procedure that carries a risk of death, long-term complications and loss of fertility.

The team will also use the genetic information from this study to develop an extended panel of MRD tests which will then be evaluated in follow-up samples being collected in the MyeChild01 trial. If successful these will enable doctors to monitor more reliably each child’s response to therapy and allow further development of more individualised treatment approaches for children with AML.

Read more: About acute myeloid leukaemia | Other leukaemia projects | Patient story: Louisa

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