Title: The clinical development and service implementation of molecular monitoring to direct treatment of acute myeloid leukaemia
Funder: Department of Health and Social Care

Abstract: Acute myeloid leukaemia (AML) affects around 2,000 people a year in the UK, with an increasing incidence as the population ages. Curative treatment is highly intensive, which is arduous for the patient, expensive (over £50k/patient) and requires prolonged hospital admissions, representing a significant cost to the NHS. The UK runs the largest AML clinical trials in the world which have led to major improvements in survival, but still at least half of patients die, mostly due to relapse, but also treatment-related toxicity. Allogeneic stem cell transplantation (alloSCT) provides a powerful approach to reduce relapse, but is costly (£40-80k/ transplant) and associated with significant toxicity, with a mortality rate of 10-25%. AlloSCT is currently widely applied in standard and poor risk AML. However, it is becoming clear that some patients subject to transplant could have been cured with chemotherapy alone, whilst standard AML therapy represents overtreatment for a proportion with favourable disease. Therefore, to improve quality of care, survival rates and cost-effectiveness there is a critical need to define more precisely the optimal consolidation therapy for any given AML patient, particularly identifying those most (and least) likely to benefit from transplant. Over the last 20 years there have been major advances in understanding the molecular basis of AML with identification of an increasing number of prognostically and therapeutically relevant mutations. This information has been embraced in the recently updated WHO classification, which carries significant implications for guidance on the optimal diagnostic work-up and management of AML. This places demands on the NHS to develop a standardized validated panel of laboratory assays and to evaluate their clinical utility. Better molecular and immunophenotypic characterisation of AML also offers the opportunity to define markers in individual patients which can be used to monitor disease, to identify very low levels of leukaemic cells (minimal residual disease, MRD) before any conventional method.The potential of molecular diagnostics and MRD monitoring has prompted a number of service laboratories to develop their own assays, which are now being applied around the UK in a piecemeal non-standardized fashion, such that the clinical utility of these expensive technologies has not been validated. However, work pioneered by this research team in the MRC/NCRI AML trials involving 155 UK hospitals has shown that rigorous evaluation of standardized quantitative polymerase chain reaction (Q-PCR) assays in the acute promyelocytic leukaemia (APL) subtype of AML can be used to guide treatment according to the needs of the individual patient. Molecular diagnostics and monitoring in APL have been approved as cost-effective in a health economic report commissioned by the Australian Government and are recommended in national and international guidelines. Accordingly, this has been implemented as an NHS service by Blood Sciences at Guy’s and St. Thomas’ acting as the national reference centre performing high-throughput monitoring to direct management of APL patients across the UK. In APL (accounting for ~12% of AML), where effective molecularly targeted therapies are available, MRD monitoring has produced tangible benefits, reducing rates of disease relapse through early treatment intervention and determining the extent to which chemotherapy can be safely reduced, thereby substantially decreasing treatment toxicity and inpatient care. Having established proof of principle and technology transfer in APL in which over 80% of patients are now cured, this programme will develop a comprehensive panel of molecular diagnostic assays for the other subtypes of AML encompassing the new WHO classification, evaluating their predictive value in patients recruited to the NCRI AML17 trial (http://aml17.cardiff.ac.uk). This will be complemented by systematic evaluation of standardized MRD assays to establish whether immunophenotyping and Q-PCR approaches can more reliably predict relapse than conventional criteria, informing the most appropriate consolidation therapy and improving survival. For patients receiving alloSCT, MRD monitoring will be evaluated to predict relapse and to direct the use of donor lymphocyte infusions as a strategy to reduce risk of disease recurrence. This programme is likely to shape the future management of AML and based on the experience with APL and the size of the UK AML trials is likely to provide the necessary evidence base to reliably determine the range of molecular assays required as a standard of care within the next five years. Within this timeframe, we will have implemented standardized robust assays available nationally for molecular diagnostics and MRD monitoring to develop a more rational personalized medicine approach, providing a model for other cancers as these become better defined at the molecular level.

Lay abstract: Acute myeloid leukaemia (AML) is one of the commonest forms of blood cancer, affecting ~2000 people a year in the UK. To cure the disease demands highly intensive therapy, which is arduous for the patient and expensive (over £50k/patient), requiring frequent prolonged hospital admissions. The UK runs the largest clinical trials for AML in the world which have led to major improvements in survival, but still at least half of patients die, mostly due to disease recurrence stemming from residual AML cells surviving therapy. One strategy shown to be effective at reducing risk of relapse is transplantation using stem cells from a sibling or other donor; however, this is a risky and expensive procedure (~£40-80k), associated with high rates of toxicity with a 10-25% risk of death. To improve outcomes for AML patients still further, it is important to tailor intensity of therapy more precisely to the needs of the individual, including identification of those most (and least) likely to benefit from a transplant. Over the last 20 years there have been significant advances in understanding of the genetic changes that transform normal bone marrow cells into leukaemia. Moreover, in addition to these genetic changes, AML cells can typically be distinguished from normal bone marrow cells through detection of different patterns of protein markers at the cell surface. These features of AML cells can be exploited as targets in established laboratory tests that provide a much more precise measure of treatment response capable of detecting low levels of residual leukaemic cells (Minimal Residual Disease", MRD) being 100-10,000-fold more powerful than the microscope. MRD monitoring has been shown to provide a valuable independent predictor of relapse in AML affording the opportunity to prevent clinical relapse through early treatment intervention, which in the acute promyelocytic subtype of AML has already been shown to improve outcome. This research programme will be linked to the NCRI AML17 trial to secure samples from over 2000 patients to investigate whether more sophisticated diagnosis and disease monitoring can yield worthwhile improvements in quality of care and outcome. Within 5 years, we will have implemented standardized robust tests available nationally for diagnosis and MRD monitoring of AML to develop a more rational personalized medicine approach, providing a model for other cancers as these become better defined at the genetic level."

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS