Evaluating sixty years of UK trials research in acute myeloid leukaemia: lessons for trial design, past, present and future.

Since the launch of their first trial in Acute myeloid leukaemia (AML) in 1959, the Medical Research Council (and latterly National Cancer Research Institute) has conducted randomised trials in AML uninterrupted for six decades. These sixty years have seen a transformation in the way we diagnose, characterise and treat the disease, (and indeed a sea change in clinical trial regulations) and a continuing improvement in outcomes. The increasing refinement of diagnosis, leading to the advent of tailored therapies, and the use of disease monitoring both have the potential to improve outcomes further, but the associated complexities will require an evolution in our approach to trial design. This article looks at the extent to which the guiding principles of the first AML trials remain relevant today, and the challenges facing the next generation of trials methodologists.

The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target.

The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real-time benefit for AML patients.

Incidence, Survival, and Risk Factors for Adults with Acute Myeloid Leukemia Not Otherwise Specified and Acute Myeloid Leukemia with Recurrent Genetic Abnormalities: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database, 2001-2013.

BACKGROUND/AIM: As the knowledgebase of acute myeloid leukemia (AML) has grown, classification systems have moved to incorporate these new findings. METHODS: We assessed 32,941 patients with AML whose records are contained in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Half of all patients diagnosed between 2001 and 2013 did not have a World Health Organization (WHO) classification. Acute promyelocytic leukemia and acute panmyelosis with myelofibrosis were associated with the longest leukemia-specific survival (110 and 115 months, respectively), and AML with minimal differentiation and acute megakaryoblastic leukemia with the shortest (30 and 28 months, respectively). For patients in the WHO groups AML not otherwise specified (AML-NOS) and AML with recurrent genetic abnormalities (AML-RGA), the risk of death was greater for older patients and less for married patients. Black patients with any type of AML-NOS also had a higher risk of death. Patients whose case of AML did not receive a WHO classification were older and this group had a higher risk of death when compared to patients with a WHO type of AML-NOS. CONCLUSION: Our findings highlight the divergent outcomes of patients with AML and the importance of using the WHO classification system and demographic factors to gauge their prognosis.

How can one optimize induction therapy in AML?

Induction therapy for acute myeloid leukemia has not changed much since 1973, when the 7 + 3 regimen of cytarabine and daunorubicin was born. Since then, various strategies have been evaluated to improve patient response, including dose intensification, the incorporation of additional agents into the regimen, the development of novel agents, and modified approaches for older patients. Recently, two novel agents, CPX-351 and gemtuzumab ozogamicin, have been approved by the US Food and Drug Administration. This review discusses each of the induction strategies and their impact on patient outcomes.

Continued improvement in survival of acute myeloid leukemia patients: an application of the loss in expectation of life.

We evaluated temporal trends in survival of Swedish acute myeloid leukemia (AML) patients diagnosed between 1973 and 2011 using relative survival ratios (RSRs) and a measure called the loss in expectation of life (LEL). RSRs increased most for patients <60 years at diagnosis during the first calendar periods, but between 1997-2005 and 2006-2011 the most pronounced increase was for those aged 61-70 years at diagnosis; RSR changed from 0.16 (95% confidence interval (CI): 0.13-0.19) to 0.28 (95% CI: 0.23-0.33), respectively. The LEL for males aged 35 years at diagnosis was 41.0 (95% CI: 40.1-41.8) years in 1975 and 19.5 (95% CI: 16.4-22.5) years in 2011. For males aged 65 years, the corresponding figures were 13.8 (95% CI: 13.7-14.0) and 12.0 (95% CI: 11.3-12.8). Conditional LEL estimates suggested that patients who survive 5 years postdiagnosis have shorter remaining lifespan than the general population. The proportion of expected life lost (PELL) suggested that male 65-year-old patients lost 75% of their life expectancy in 2005 and 66% if they were diagnosed in 2011. Survival continued to increase to 2011, with larger improvements in those aged 61-70 years at diagnosis. The LEL and PELL are intuitive measures that may be useful in communicating survival statistics to patients, clinicians and health-care providers.

Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia.

Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.

Cancer coverage: the public face of childhood leukaemia in 1960s Britain.

In the 1960s, stories of children fighting cancer, previously absent from the British news, started to feature ever more prominently in the national press. Conventional treatments could not keep children alive for many months, so the promise of a cure through the use of an alternative anti-cancer 'serum' was not easily dismissed as quackery. The Ministry of Health and cancer research organisations struggled to find a fair and honest way to inform the public and affected families about childhood leukaemia without raising or crushing hope.

Milestones in the development of pediatric hematopoietic stem cell transplantation--50 years of progress.

In the 1950s, the first infusions of hematopoietic stem cells were given as a form of treatment for childhood leukemia. This heralded the beginning of a field that has expanded to include the treatment of immune deficiencies, a variety of leukemias and solid tumors, and then genetic diseases. A number of milestones are highlighted, particularly in regard to the use of alternative sources of hematopoietic stem cells such as unrelated donors, peripheral blood stem cells and umbilical cord stem cells. In addition, newer techniques of using non-myeloablative preparative regimens helped to reduce the toxicity and long-term consequences of hematopoietic stem cell transplant. Many diseases now benefit from the replacement of the marrow stem cells and the provision of a new immune system and improved immune surveillance.

The Children Leukemia Group: 30 years of research and achievements.

The EORTC Children Leukemia Group (CLG) is part of the offspring of the EORTC Hemopathies Working Party which in 1978 split into a paediatric and to an 'adult' branch. At that time, the Berlin-Frankfurt-Munster (BFM) designed by H. Riehm for acute lymphoblastic leukaemia (ALL) appeared much more efficacious than all others and the CLG decided to adapt that treatment strategy for its own clinical trials. The main results of these may be summarised as follows:for standard risk patients, the deletion of cyclophosphamide from consolidation and reconsolidation courses does not jeopardise the patient's outcomefor medium- and high-risk patients receiving high-dose methotrexate (MTX), cranial radiotherapy is superfluouswith the dose scheduling of the BFM regimen, E-Coli L-Asparaginase is more efficacious than Erwinia L-Asparaginasethe addition of monthly intravenous (i.v.) 6-mercaptopurine to conventional maintenance chemotherapy is detrimentalthe assessment by quantitative polymerase chain reaction (PCR) of minimal residual disease at completion of induction is feasible in a cooperative setting and can be used as a powerful and independent prognostic factor. The CLG also conducted clinical studies of acute myeloblastic leukaemia. Since 1989, lymphoblastic non-Hodgkin's lymphomas have been treated within the ALL trials. The CLG collaborates with other Groups within the I-BFM Study Group and participants in the meta-analytic studies conducted by the Oxford team by the Oxford Children ALL Collaborative Group.