Alan K Burnett

Cardiff University, Cardiff, Wales, United Kingdom

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Publications (314)2372.76 Total impact

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    ABSTRACT: To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation). DNMT3A mutations (DNMT3A(MUT)) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3A(MUT) had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3A(MUT) was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3A(MUT) did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A. These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 05/2015; DOI:10.1200/JCO.2014.59.2022 · 17.88 Impact Factor
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    ABSTRACT: Many older patients with acute myeloid leukaemia (AML) that receive standard intensive chemotherapy fail to achieve complete remission (CR). Upfront identification of patients unlikely to benefit from standard induction chemotherapy would be important for exploration of novel therapies. This study evaluated if a flow cytometric assay measuring pre-treatment CD34(+) CD38(low) blast frequency could predict therapeutic-resistance in 736 AML patients entered into the UK National Cancer Research Institute AML16 trial. High peripheral blood CD34(+) CD38(low) blast frequency (>7% of leucocytes), present in 18% of assessable patients, conferred significantly reduced CR rates (38% vs. 76%, P < 0·0001) and poor survival, and was independently prognostic for all endpoints of treatment resistance by multivariate analysis. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; DOI:10.1111/bjh.13398 · 4.96 Impact Factor
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    ABSTRACT: Modifying induction therapy in AML may improve the remission rate and reduce the risk of relapse thereby improving survival. Escalation of the daunorubicin dose to 90mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45mg/m(2) and has been recommended as a standard of care. However 60mg/m(2) is widely used and has never been directly compared to 90mg/m(2). As part of the UK NCRI AML17 trial 1206 adults with untreated AML or high risk MDS, mostly under 60 years of age, were randomised to a first induction course of chemotherapy which delivered either 90mg/m(2) or 60mg/m(2) on days 1,3 and 5 combined with cytosine arabinoside. All patients then received a second course which included daunorubicin 50mg/m(2) on days 1,3 and 5. There was no overall difference in complete remission rate (CR) (73% vs 75%, OR1.07 (0.83-1.39), p=0.6) or in any recognised subgroup. The 60 day mortality was increased in the 90mg/m2 arm (10% vs 5% (HR 1.98(1.30-3.02) p=0.001)), which resulted in no difference in overall 2 year survival (59% vs 60%, HR 1.16(0.95-1.43), p=0.15). In exploratory subgroup analysis there was no subgroup which showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. The trial is registered to www.isrctn.com as ISRCTN55675535. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; DOI:10.1182/blood-2015-01-623447 · 9.78 Impact Factor
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    ABSTRACT: HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML). Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p<0.001). Dose dependant cytotoxicity was observed with an apoptotic response coordinate with the loss of pro-survival signaling through the client protein AKT. Combination treatment of primary blasts with ganetespib and cytarabine showed good synergistic interaction (combination index (CI): 0.47) across a range of drug effects with associated reduction in HSP70 feedback and AKT signaling levels. In summary, we show ganetespib to have high activity in primary AMLs as a monotherapy and a synergistic relationship with cytarabine when combined. The combination of cytotoxic cell death, suppression of cytoprotective/drug resistance mechanisms such as AKT and reduced clinical toxicity compared to other HSP90 inhibitors provide strong rationale for the clinical assessment of ganetespib in AML. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Leukemia research 03/2015; 15. DOI:10.1016/j.leukres.2015.03.016 · 2.69 Impact Factor
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    ABSTRACT: The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was down-regulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P=0.007) and a better overall survival (OS: 46% vs 28%; P<0.001) and event-free survival (EFS: 36% vs 21%; P<0.001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene expression profiling, lower CXXC5 expression was associated with up-regulation of cell cycling genes and co-down-regulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to impact the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; DOI:10.1182/blood-2014-12-613703 · 9.78 Impact Factor
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    ABSTRACT: The development of new treatments for older patients with Acute Myeloid Leukaemia (AML) is an active area, but has met with limited success. Vosaroxin, a quinolone derived intercalating agent has several properties which could prove beneficial. Initial clinical studies showed it to be well tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with Ara-C. To evaluate vosaroxin, we performed two randomised comparisons within the "Pick A Winner" Programme. 104 patients were randomized to vosaroxin vs low dose Ara-C (LDAC) and 104 to vosaroxin+LDAC vs LDAC. When comparing vosaroxin with LDAC neither response rate (CR/CRi), (26% vs 30%; odds ratio (OR) 1.16 (0.49-2.72) p=0.7) nor 12-month survival (12% vs 31%; hazard ratio (HR) 1.94 (1.26-3.00) p=0.003) showed benefit for vosaroxin. Likewise, in the vosaroxin+LDAC vs LDAC comparison, neither response rate (CR/CRi 38% vs 34%; OR 0.83 (0.37-1.84) p=0.6), nor survival (33% vs 37%, HR 1.30 (0.81-2.07) p=0.3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin+LDAC arm, most obviously in the second month following randomisation. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms as a clinically relevant benefit was unlikely. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(19). DOI:10.1182/blood-2014-10-608117 · 9.78 Impact Factor
  • Leukemia 03/2015; DOI:10.1038/leu.2015.62 · 9.38 Impact Factor
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    ABSTRACT: Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3-internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD-negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD-negative status in older patients with AML. Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD-negative genotype. Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD-negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. NPM1-positive/FLT3-ITD-negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 02/2015; 33(10). DOI:10.1200/JCO.2014.58.0571 · 17.88 Impact Factor
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    ABSTRACT: The development of new treatments for older patients with Acute Myeloid Leukaemia (AML) is an active area, but has met with limited success. Sapacitabine is a novel orally administered nucleoside analogue which has shown encouraging activity in unrandomised early stage trials. We randomised 143 untreated patients with AML or high risk Myelodysplastic Syndrome (>10% marrow blasts) between Sapacitibine and Low Dose Ara-C (LDAC) in our "Pick a Winner" trial design. At the planned interim analysis there was no difference between LDAC and Sapacitibine in remission rate (CR/CRi, 27% vs 16% HR 1.98(0.90-4.39) p=0.09), relapse free-(10% vs 14% at 2 years, HR 0.73(0.33-1.61) p=0.4) or overall survival (12% vs 11% at 2 years, HR 1.24(0.86-1.78) p=0.2). Sapacitibine was well tolerated apart from more grade 3/4 diarrhoea. Based on these findings sapacitibine did not show sufficient evidence of benefit over LDAC for the trial to be continued.Leukemia accepted article preview online, 13 February 2015. doi:10.1038/leu.2015.38.
    Leukemia 02/2015; DOI:10.1038/leu.2015.38 · 9.38 Impact Factor
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    ABSTRACT: It is postulated that disease relapse in patients with acute myeloid leukaemia (AML) is consequent upon chemoresistance within leukaemic stem/progenitor cell (LSC) populations from which bulk blasts arise.1 In adults with high-risk AML, allogeneic haematopoietic cell transplantation (HCT) has become a central component of the treatment algorithm to overcome this chemoresistance, as it delivers maximal anti-leukaemic activity through both dose intensification and by the genesis of a potent graft-versus-leukaemia (GVL) effect.2, 3, 4 However, relapse still occurs in a significant proportion of allografted patients and now represents the major cause of treatment failure, particularly with reduced intensity conditioning (RIC) regimens.5 Although minimal residual disease (MRD) from the bulk leukaemic population is known to be prognostic, more accurate predictors of relapse risk might be developed from detection of putative LSC populations pre- or post transplant. However, to date an association between LSC and transplant outcome remains uncertain.
    Leukemia 11/2014; 29(4). DOI:10.1038/leu.2014.327 · 9.38 Impact Factor
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    ABSTRACT: Allogeneic stem cell transplantation (SCT) provides the best mechanism of preventing relapse in acute myeloid leukaemia (AML). However non-relapse mortality (NRM) negates this benefit in older patients. Reduced intensity conditioning (RIC) permits SCT with reduced NRM, but its contribution to cure is uncertain. In the MRC AML15 Trial, patients in remission without favourable risk disease could receive SCT from a matched sibling or unrelated donor (MUD). If aged >45 years, a RIC was recommended and in patients aged 35-44 years, either RIC or myeloablative conditioning was permitted. The aim was to determine which approach improved survival and within which prespecified cytogenetic groups. RIC transplants significantly reduced relapse (adjusted hazard ratio (HR) 0.66 (0.50-0.85), P=0.002) compared to chemotherapy The 5-year overall survival from a sibling RIC (61%) was superior to a MUD RIC (37%; adjusted HR 1.50 (1.01-2.21), P=0.04) due to lower NRM (34 vs 14%, P=0.002) In adjusted analyses, there was a survival benefit for sibling RIC over chemotherapy (59 vs 49%, HR 0.75 (0.57-0.97), P=0.03), with consistent results in intermediate and adverse-risk patients. In patients aged 35-44 years, best outcomes were seen with a sibling RIC transplant, although a comparison with chemotherapy and myeloablative transplant was not significant in adjusted analyses (P=0.3).Leukemia advance online publication, 5 December 2014; doi:10.1038/leu.2014.319.
    Leukemia 11/2014; DOI:10.1038/leu.2014.319 · 9.38 Impact Factor
  • Alan K. Burnett
    Leukemia Research 10/2014; 38:S2. DOI:10.1016/S0145-2126(14)70008-6 · 2.69 Impact Factor
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    ABSTRACT: Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver operator characteristic curves (AUC) to quantify our ability to predict therapeutic resistance in individual patients where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4,601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in MRC/NCRI, HOVON, SWOG, and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk, and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ("primary refractoriness"). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival (RFS), was even more difficult. Our ability to forecast resistance based on routinely available pre-treatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and post-treatment data to optimize resistance prediction in AML.Leukemia accepted article preview online, 12 August 2014; doi:10.1038/leu.2014.242.
    Leukemia 08/2014; 29(2). DOI:10.1038/leu.2014.242 · 9.38 Impact Factor
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    ABSTRACT: Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia.
    The Lancet Oncology 07/2014; 15(9). DOI:10.1016/S1470-2045(14)70281-5 · 24.73 Impact Factor
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    ABSTRACT: Some studies have suggested that cases of acute myeloid leukemia (AML) with low levels of FLT3 internal tandem duplications (FLT3(ITD)) do not have a worse prognosis if there is a concomitant NPM1 mutation, although this is controversial. To clarify this therapeutically important issue, we have analyzed FLT3(ITD) and NPM1(MUT) levels in 1609 younger adult cases of cytogenetically intermediate-risk AML. The cumulative incidence of relapse was increased in NPM1(MUT) cases by the presence of a FLT3(ITD), but did not differ markedly according to FLT3(ITD) level. This remained true when allowance was made for poor leukemic cell purity by adjustment of the FLT3(ITD) level to the measured NPM1(MUT) level. If consolidation therapies are to be determined by relapse risk, then NPM1(MUT) cases with low-level FLT3(ITD) should not be considered as good risk without further studies. AML12 and AML15 are registered at http://www.controlled-trials.com under ISRCTN17833622 and ISRCTN17161961 respectively.
    Blood 05/2014; 124(2). DOI:10.1182/blood-2014-02-554667 · 9.78 Impact Factor
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    ABSTRACT: Although the prognostic impact of mutations of FLT3 and NPM1 have been extensively studied in younger patients with acute myeloid leukaemia, less is known in older patients whether treated intensively or non-intensively, or in the context of existing prognostic scores. In 1312 patients 16% and 21% respectively had a FLT3 and NPM1 mutation. A FLT3 mutation did not affect remission rate in intensively or non-intensively treated patients but was associated with an inferior survival. All patients with an NPM1c mutation had a significantly higher remission rate irrespective of treatment approach but survival was not improved, overall, or in any genotype except as in younger patients, in the FLT3 WT NPM1c mutant subgroup. When incorporated into an established multi-parameter prognostic risk score the molecular information provided additional prognostic definition in 11% of patients.Leukemia accepted article preview online, 27 February 2014; doi:10.1038/leu.2014.90.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2014; 28(10). DOI:10.1038/leu.2014.90 · 9.38 Impact Factor
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    Imran Mohamed, Robert K Hills, Alan K Burnett
    British Journal of Haematology 12/2013; DOI:10.1111/bjh.12705 · 4.96 Impact Factor
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    ABSTRACT: PDK1 is a master kinase that activates at least six protein kinase groups including AKT, PKC and S6K and is a potential target in the treatment of a range of malignancies. Here we show overexpression of PDK1 in over 40% of myelomonocytic acute leukaemia patients. Overexpression of PDK1 occurred uniformly throughout the leukaemic population, including putative leukaemia initiating cells. Clinical outcome analysis revealed PDK1 overexpression was associated with poorer treatment outcome. Primary acute myeloid leukaemia blasts overexpressing PDK1 showed improved in vitro survival and ectopic expression of PDK1 promoted the survival of myeloid cell lines. Analysis of PDK1 target kinases revealed that PDK1 overexpression was most closely associated with increased phosphorylation of PKC isoenzymes and inhibition of PKC strongly inhibited the survival advantage of PDK1 overexpressing cells. Membrane localization studies implicated PKCα as a major target for PDK1 in this disease. PDK1 overexpressing blasts showed differential sensitivity to PDK1 inhibition (in the low micromolar range) suggesting oncogene addiction, whilst normal bone marrow progenitors were refractory to PDK1 inhibition at effective inhibitor concentrations. PDK1 inhibition also targeted subpopulations of leukaemic blasts with a putative leukaemia initiating cell phenotype. Together these data show that overexpression of PDK1 is common in acute myelomonocytic leukaemia and is associated with poorer treatment outcome, probably arising from the cytoprotective function of PDK1. We also show that therapeutic targeting of PDK1 has the potential to be both an effective and selective treatment for these patients and is also compatible with current treatment regimes.
    Haematologica 12/2013; DOI:10.3324/haematol.2013.096487 · 5.87 Impact Factor

Publication Stats

15k Citations
2,372.76 Total Impact Points

Institutions

  • 2005–2015
    • Cardiff University
      • • School of Medicine
      • • Institute of Cancer & Genetics
      Cardiff, Wales, United Kingdom
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 2007–2014
    • University of South Wales
      Понтиприте, Wales, United Kingdom
    • Erasmus MC
      • Department of Hematology
      Rotterdam, South Holland, Netherlands
  • 2013
    • University of Cambridge
      Cambridge, England, United Kingdom
    • University of Birmingham
      • Cancer Research UK Clinical Trials Unit (CRCTU)
      Birmingham, England, United Kingdom
  • 2012
    • Institute of Cancer Research
      • Division of Molecular Pathology
      Sutton, ENG, United Kingdom
  • 2009–2012
    • King's College London
      • Department of Medical and Molecular Genetics
      London, ENG, United Kingdom
    • Hospital Universitari i Politècnic la Fe
      Valenza, Valencia, Spain
    • Sapienza University of Rome
      • Department of Cellular Biotechnology and Hematology BCE
      Roma, Latium, Italy
  • 2001–2010
    • University College London
      • Department of Haematology
      London, ENG, United Kingdom
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 1992–2009
    • University of Wales
      • College of Medicine
      Cardiff, Wales, United Kingdom
  • 2006
    • Technion - Israel Institute of Technology
      • Rambam Medical Center
      Haifa, Haifa District, Israel
    • Case Western Reserve University
      • Case Comprehensive Cancer Center
      Cleveland, OH, United States
  • 2003
    • St. Jude Children's Research Hospital
      Memphis, Tennessee, United States
  • 1997–2000
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
    • Oxford University Hospitals NHS Trust
      • Department of Haematology
      Oxford, England, United Kingdom
  • 1999
    • Erasmus Universiteit Rotterdam
      • Department of Hematology
      Rotterdam, South Holland, Netherlands
  • 1996–1998
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
    • Cancer Research UK
      Londinium, England, United Kingdom