Title: Developing precision medicine in acute lymphoblastic leukaemia

Abstract: Acute lymphoblastic leukaemia (ALL) is defined by a wide spectrum of chromosomal, genetic and genomic abnormalities which drive the initiation and progression of the disease. Numerous chromosomal abnormalities, gene fusions, copy number alterations (CNA) and point mutations have been described in ALL; many of which are pathognomonic of the disease, prognostic or predictive biomarkers. Recent and ongoing studies are revealing the full genomic landscape of the disease and a number of important themes are emerging which impact on how these abnormalities can be used to improve therapeutic decisions and therefore the outcome of patients. Firstly, the total number of genetic alterations per patient is in the “tens” rather than the “hundreds” - as observed in solid tumours. Secondly, an initiating or founder mutation/abnormality can be identified in the majority of cases. Thirdly, this founder mutation is accompanied by a distinctive spectrum of cooperating lesions. Finally, the frequency of founder and cooperating abnormalities is often low with the majority occurring in <10% cases. The frequency of these genetic and genomic abnormalities is strongly age-specific and those associated with a good outcome tend to be more prevalent among children whereas those associated with high risk disease are more frequent among adults.

Response to initial therapy is an important risk factor and virtually all modern protocols assess the level of disease during treatment and assign slow responders to receive intensive chemotherapy. Minimal residual disease (MRD) is widely recognised to be the single most powerful prognostic factor in paediatric and adult ALL. However MRD alone is not sufficient to predict outcome. Recent studies have shown that the prognostic effect of MRD is modulated by the genetic make-up of the leukemic clone and that the prognostic effect of some genetic abnormalities varies by MRD risk group. As a result, risk algorithms integrating risk factors have emerged.

In this talk, I will review the major genomic abnormalities that are currently being used tailor therapy in both paediatric and adult ALL. I will outline and compare the different strategies and algorithms used by some of the major clinical study groups; in particular integrating MRD and genetics. Finally, I will discuss the options for the future risk stratification of patients with ALL.

 

Research

The central philosophy of my research is based on the premise that the genetic heterogeneity of cancer is the key to furthering our understanding of the disease and to improving patient management and outcome. During my research career, I have focused on integrating high quality genetic information into the analysis of clinical trials and aetiological studies of acute leukaemia. Over the past 20 years, I have been involved in the development of an innovative research network which interfaces the Leukaemia Research Cytogenetics Group (LRCG) with clinicians, trial coordinators and geneticists. The establishment, maintenance and development of this innovative framework have enabled the curation and genetic annotation of samples from clinical trial patients diagnosed with acute leukaemia. Currently, the LRCG holds genetic, demographic and clinical data on more than 27,000 patients treated on over 15 National Cancer Research Institute (NCRI) clinical trials. This research infrastructure is unique because it encompasses two major haematological cancers (acute lymphoblastic and myeloid leukaemia) and is not restricted by the age of the patient.

We conduct comprehensive, pertinent and meticulous assessments of the clinical relevance of genetic markers within the context of national and international clinical trials. The objective is to provide clinicians with pertinent and reliable evidence to enable them to decide on the most effective course of treatment for their patients. The ultimate test of our work – at the interface between evidence-based genetic research and clinical practice - is its translational impact. Two major achievements with a direct impact on patient outcome have been: (1) the identification of a novel marker of poor outcome in childhood ALL [Blood, 2007, 109:2327]. This led directly to a protocol modification in the subsequent paediatric trial, so patients with this abnormality were transferred to the more intensive treatment arm. This change in treatment has reduced the risk of relapse in this subgroup of patients from >75% to <10%; (2) the comprehensive assessment of the clinical relevance of cytogenetics in adult ALL [Blood, 2007, 109:3189; Blood, 2009, 113:4489; Blood, 2009, 114:5136]. The results of this study led directly to patients with one of three chromosomal abnormalities being classified as high risk and treated differentially in the new adult ALL trial, UKALL14. The results of this study have also been used by other clinical groups to risk-stratify patients.

 

Institutional Profile: Staff Profile - Faculty of Medical Sciences - Newcastle University (ncl.ac.uk)

 

A 'Tea with the Speaker' will follow this seminar, where Pathway 2/PGR staff and students are warmly encouraged to join in an informal discussion with the speaker following their talk. 

Professor Anthony Moorman, Newcastle University