Acute myeloid leukaemia trials: long-term follow-up, analysis and reporting

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

In recent years there have been substantial advances in our understanding of the underlying disease processes that lead to acute myeloid leukaemia (AML) and the biology of the disease. Treatment has also improved dramatically (40 years ago AML was invariably fatal, nowadays 40% of younger adults and 60% of children can be cured). This major improvement in outcome has generally been achieved by a series of small steps, not by dramatic breakthroughs. Many new treatments for AML have been proposed but only a minority of these will be better than standard therapy, so large randomised trials with adequate follow-up are needed to evaluate these new treatments in order to determine reliably whether there is a benefit. The reliable results produced by the MRC trials allow doctors and patients to make informed decisions about treatment that balance benefits against side-effects.

AML is a variable disease. Patients with some subtypes now have a relatively favourable prognosis. Others still have a very poor outlook with conventional therapy (including stem cell transplant) and novel treatments are urgently needed for these patients. On the other hand, survival for the best prognosis subtype of AML (acute promyelocytic leukaemia, APL) has improved so much that we are now asking whether equally good outcome can be achieved with less intensive treatment that has fewer side-effects. Some treatments, such as bone marrow transplant from a sibling donor, have a high risk associated with them, but may still offer survival benefit in the long term if they are effective against the disease, so careful comparisons are needed to determine which types of patients, if any, benefit. New laboratory techniques are helping to identify relevant risk groups, but national coordination is needed to address these questions of prognosis in appropriately large cohorts.

The MRC AML trials have already provided definite information about the effects of certain treatments, which has now been incorporated into clinical decision making. This application seeks support to continue the follow-up of over 3000 surviving patients after the current trial funding expires. Included in this initiative is the modernisation of the IT support systems that will make data collection for future trials more efficient. Continuous statistical analysis is needed to compare treatments within the trials, to correlate laboratory research findings derived from material in the tissue bank with outcome, and to inform the design of new trials which we have traditionally based on the long-term findings of previous trials.

Technical Summary

In the last 14 years, the national trials in acute myeloid leukaemia (AML) have recruited over 8000 patients into the portfolio supervised by the former MRC Adult and Childhood Leukaemia Working Parties. The trials concerned (AML10, AML11, G-CSF, ATRA, AML-R, AML12, AML-HR and AML15) were sponsored by the MRC or the Leukaemia Research Fund (LRF) (AML14). These represent the largest AML trials ever conducted (AML12 accrued 3459 patients), and recruitment is consistently better than that achieved by any other collaborative group. The use of efficient factorial designs, either as part of the main trial or through add-on protocols (e.g. G-CSF, ATRA), means that every recent trial has addressed at least three different questions, with a total of 24 randomised comparisons, thereby making them extremely cost-effective. The large size of these trials makes them uniquely reliable and hence more informative than most other studies. The patients are fully characterised by demographics, more than 80% are cytogenetically characterised, and about 98% have up to date follow-up information. Diagnostic material (DNA, RNA, cells) is stored in the AML Tissue Bank which is supported by the MRC and LRF (Professor D Linch, Professor Burnett).

This represents a unique database, unparalleled anywhere in the world, with approximately 3000 surviving patients still on long-term follow-up. The aim of this proposal is to: 1) continue long-term follow-up of surviving patients; 2) analyse and report the treatment comparisons in recent trials, and update those from the older trials; 3) conduct further analyses on distinct biological entities (e.g. core binding factor leukaemias, 11q23 disease, verification of the new WHO classification, etc); 4) correlate outcome newly identified disease-related features using material in the AML cell bank; 5) contribute to meta-analyses either conducted by CTSU in Oxford, under the current proposal under EU framework 6, or with the Cochrane Haematological Malignancies Group (CHMG); 6) to inform the design of future phase II and phase III trials to be conducted by the AML network under the auspices of the National Cancer Research Institute (NCRI). Thus, all of the recent trials require further detailed follow-up, analysis and writing up over the next five years.

Publications

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British Committee For Standards In Haematology (2006) Guidelines on the management of acute myeloid leukaemia in adults. in British journal of haematology

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Burnett AK (2010) Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Burnett AK (2006) Long-term results of the MRC AML10 trial. in Clinical advances in hematology & oncology : H&O

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Grimwade D (2009) Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Harrison CJ (2010) Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

 
Description BCSH AML Guidelines
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Provided evidence-based guidelines for treatment of AML