A K Burnett

Cardiff University, Cardiff, Wales, United Kingdom

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Publications (295)2158.76 Total impact

  • Leukemia. 11/2014;
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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;
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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; · 25.12 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; · 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; · 10.16 Impact Factor
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    Imran Mohamed, Robert K Hills, Alan K Burnett
    British Journal of Haematology 12/2013; · 4.94 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; · 5.94 Impact Factor
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    ABSTRACT: Regulation of ABCB1 (P-glycoprotein/Pgp) in AML was investigated. In a historical cohort with Pgp and transcriptional regulator expression profiling data available (n=141), FOXO1 correlated with Pgp protein expression. This was confirmed in an independent cohort (n=204). Down-regulation (siRNA) or hyperactivation (nicotinamide) of FOXO1 led to corresponding changes in Pgp. Low FOXO1 expression correlated with FLT3-ITDs (p<0.001) and siRNA inhibition of FLT3-ITD up-regulated FOXO1. As FOXO1 is a key growth regulator, it may underpin biological differences between Pgp-positive clones (low WBC and primary resistant disease) and clones with a FLT3-ITD (associated with a high WBC and early relapse).
    Leukemia research 11/2013; · 2.36 Impact Factor
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    ABSTRACT: Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean >10-fold) in >60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of NOX oxidases. In contrast overproduction of mitochondrial ROS was rarely observed. Elevated ROS was found to be associated with lowered glutathione levels and depletion of antioxidant defense proteins. We also show for the first time that the levels of ROS generated were able to strongly promote the proliferation of AML cell lines, primary AML blasts and to a lesser extent normal CD34(+) cells and that the response to ROS is limited by the activation of the oxidative stress pathway mediated though p38(MAPK). Consistent with this, we observed that p38(MAPK) responses were attenuated in patients expressing high levels of ROS. These data show that overproduction of NOX-derived ROS can promote the proliferation of AML blasts and that they also evolve mechanisms to suppress the stress signaling that would normally limit this response. Together these adaptations would be predicted to confer a competitive advantage to the leukemic clone.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Older patients with acute myeloid leukemia (AML) have a high relapse rate after standard chemotherapy. We investigated whether measuring chemotherapy sensitivity by multiparameter flow cytometric minimal residual disease (MFC-MRD) detection has prognostic value in patients older than age 60 years or is simply a surrogate for known age-related risk factors. Eight hundred ninety-two unselected patients treated intensively in the United Kingdom National Cancer Research Institute AML16 Trial were assessed prospectively for MFC-MRD during treatment. Eight hundred thirty-three patients had leukemia-associated immunophenotypes (LAIPs) identified by pretreatment screening. Four hundred twenty-seven patients entered complete remission (CR) after one or two courses (designated C1 and C2, respectively) and were MFC-MRD assessable by LAIP detection in CR bone marrow for at least one of these time points. MRD positivity was defined as residual disease detectable by LAIP. MFC-MRD negativity, which was achieved in 51% of patients after C1 (n = 286) and 64% of patients after C2 (n = 279), conferred significantly better 3-year survival from CR (C1: 42% v 26% in MRD-positive patients, P < .001; C2: 38% v 18%, respectively; P < .001) and reduced relapse (C1: 71% v 83% in MRD-positive patients, P < .001; C2: 79% v 91%, respectively; P < .001), with higher risk of early relapse in MRD-positive patients (median time to relapse, 8.5 v 17.1 months, respectively). In multivariable analysis, MRD status at the post-C1 time point independently predicted survival, identifying a subgroup of intermediate-risk patients with particularly poor outcome. However, survival benefit from gemtuzumab ozogamicin was not associated with MFC-MRD chemotherapy sensitivity. Early assessment of treatment response using flow cytometry provides powerful independent prognostic information in older adults with AML, lending support to the incorporation of MRD detection to refine risk stratification and inform clinical trial design in this challenging group of patients.
    Journal of Clinical Oncology 09/2013; · 18.04 Impact Factor
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    ABSTRACT: Abstract ASXL1 mutations are recurrent in acute myeloid leukemia (AML) but it is unclear whether ASXL1 genotype might influence patient management. We analyzed frequency and impact in younger (15-59 years) and older (≥60 years) patients with primary or secondary disease. Overall, 9% had truncating mutations. Incidence was significantly lower in younger patients with primary than secondary disease (4%, 12%; P=.03); in older patients it did not significantly differ (11%, 15%; P=.5). In univariate analysis, ASXL1-mutated patients had worse outcome (5-year relapse 83% versus 56%, P=.01; overall survival [OS] 6% versus 22%, P=.02). However in multivariate analysis ASXL1 mutations had no prognostic significance (for OS, P=.3), because age was a major confounding factor. The low incidence of mutations in younger patients with primary disease and the lack of significance in multivariate analysis indicate that there is a limited role for screening at diagnosis for ASXL1 mutations for the purpose of prognostic stratification.
    Leukemia & lymphoma 08/2013; · 2.61 Impact Factor
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    ABSTRACT: PURPOSETreatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. PATIENTS AND METHODS Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227).ResultsOverall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. CONCLUSIONFLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.
    Journal of Clinical Oncology 08/2013; · 18.04 Impact Factor
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    ABSTRACT: Better treatment is required for older patients with acute myeloid leukaemia (AML) not considered fit for intensive chemotherapy. We report a randomised comparison of Low Dose Ara-C (LDAC) versus the novel nucleoside, Clofarabine, in untreated older patients with AML and high risk Myelodysplastic Syndrome (MDS). Four hundred and six patients with de novo (62%), secondary disease (24%) or high risk MDS (>10%marrow blasts)(15%), median age 74 years, were randomised to LDAC 20mg bid for 10 days every 6 weeks or clofarabine 20mg/m(2) days 1-5, both for up to 4 courses. These patients had more adverse demographics than contemporaneous intensively treated patients. The overall remission rate was 28% and 2-year survival was 13%. Clofarabine significantly improved complete remission: 22% vs 12% (HR 0.47(0.28-0.79); p=0.005) and overall response: 38% vs 19% (HR 0.41 (0.26-0.62); p=<0.0001), but there was no difference in overall survival, explained by poorer survival in the clofarabine patients who did not gain CR and also following relapse. Clofarabine was more myelosuppressive and required more supportive care. Although clofarabine doubled remission rates, overall survival was not improved overall or in any subgroup. The treatment of patients of the type treated here remains a major unmet need. (Trial registered with ID: ISRCTN 11036523).
    Blood 07/2013; · 9.78 Impact Factor
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    ABSTRACT: Chromosome gain is frequent in acute myeloid leukemia (AML) and is counted alongside structural abnormalities when determining karyotype complexity. However, there are few studies investigating the cytogenetic profile and outcome of patients with a hyperdiploid karyotype (49-65 chromosomes, HK). We identified 221 (14%) patients with HK out of 1563 patients with three or more chromosomal abnormalities. HK was not associated with sex, white cell count and secondary disease status but was more prevalent among children (22% v 13%). The pattern of chromosomal gain and loss was non-random and chromosomes 8, 13 and 21 were the most frequently gained. Three distinct subgroups (numerical, structural and adverse) were identified with differential outcome: 5 year cumulative incidence of relapse of 52%, 68 and 76%, respectively (P=0.008). Patients in the adverse subgroup had poorer survival compared with patients with only numerical abnormalities (adjusted hazard ratio 2.01 (95% CI 1.43-2.83), P=0.0002). This outcome heterogeneity was similar among children and adults. In conclusion, AML patients with a HK should not automatically be assigned to the adverse cytogenetic risk group on the basis of complexity. Instead they should be assessed for the presence of specific chromosomal abnormalities which are known to harbour an adverse effect.Leukemia accepted article preview online, 1 July 2013; doi:10.1038/leu.2013.198.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2013; · 10.16 Impact Factor
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    ABSTRACT: Several different mutations collaborate with the fusion proteins in core-binding factor acute myeloid leukemia (CBF-AML) to induce leukemogenesis, but their prognostic significance remains unclear. We screened 354 predominantly younger (<60 years) adults with t(8;21) (n=199) or inv(16) (n=155) entered into UK MRC trials for KIT, FLT3 tyrosine kinase domain (FLT3(TKD)), N-RAS, K-RAS and c-CBL mutations and FLT3 internal tandem duplications (FLT3(ITD)) and assessed the impact of relative mutant level on outcome. Overall, 28% had KIT, 6% FLT3(ITD), 10% FLT3(TKD), 27% RAS and 6% CBL mutations. Mutant levels for all genes/loci were highly variable. KIT mutations were associated with a higher cumulative incidence of relapse but in multivariate analysis this was only significant for cases with a higher mutant level of 25% or greater (95% confidence intervals [CI]=1.01-1.52, P=.04). Similarly, only FLT3(ITD-HIGH) was a significant adverse factor for OS (CI=1.27-5.39, P=0.004). Conversely, FLT3(TKD-HIGH) and CBL(HIGH) were both favorable factors for OS (respectively, CI= 0.31-0.89, P=0.01 and CI=0.05-0.85, P=0.02). KIT mutations were frequently lost at relapse, which is relevant to minimal residual disease detection and the clinical use of KIT inhibitors. These results indicate that relative mutant level should be taken into account when evaluating the impact of mutations in CBF-AML.Leukemia accepted article preview online, 20 June 2013; doi:10.1038/leu.2013.186.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2013; · 10.16 Impact Factor
  • Alan K Burnett, Robert K Hills
    Journal of Clinical Oncology 05/2013; 31(13):1700-1; discussion 1701. · 18.04 Impact Factor
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    ABSTRACT: GATA2 mutations have recently been reported in acute myeloid leukaemia (AML) patients with CEBPA-double mutations. To explore their impact on this favourable-risk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ-line CEBPA-mutant family at AML presentation. Overall, 27% (15/55) CEBPA-double, 16% (7/43) CEBPA-single and 0% (0/55) normal karyotype/CEBPA-wild-type patients were GATA2-mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPA-double/FLT3-inernal tandem duplication-negative patients.
    British Journal of Haematology 04/2013; · 4.94 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2013; · 10.16 Impact Factor
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    ABSTRACT: The BCR/ABL1 fusion gene, usually carried by the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11) or variants, is pathognomonic for chronic myeloid leukaemia (CML). It is also occasionally found in acute lymphoblastic leukaemia (ALL) mostly in adults and rarely in de novo acute myeloid leukaemia (AML). Array Comparative Genomic Hybridization (aCGH) was used to study six Ph(+)AML, three bi-lineage and four Ph(+)ALL searching for specific genomic profiles. Surprisingly, loss of the IKZF1 and/or CDKN2A genes, the hallmark of Ph(+)ALL, were recurrent findings in Ph(+)AML and accompanied cryptic deletions within the immunoglobulin and T cell receptor genes. The latter two losses have been shown to be part of 'hot spot' genome imbalances associated with BCR/ABL1 positive pre-B lymphoid phenotype in CML and Ph(+)ALL. We applied Significance Analysis of Microarrays (SAM) to data from the 'hot spot' regions to the Ph(+)AML and a further 40 BCR/ABL1(+) samples looking for differentiating features. After exclusion of the most dominant markers, SAM identified aberrations unique to de novo Ph(+)AML that involved relevant genes. While the biological and clinical significance of this specific genome signature remains to be uncovered, the unique loss within the immunoglobulin genes provides a simple test to enable the differentiation of clinically similar de novo Ph(+) AML and myeloid blast crisis of CML.
    British Journal of Haematology 03/2013; · 4.94 Impact Factor

Publication Stats

11k Citations
2,158.76 Total Impact Points

Institutions

  • 1996–2014
    • Cardiff University
      • • School of Medicine
      • • Institute of Cancer & Genetics
      Cardiff, Wales, United Kingdom
    • Cancer Research UK
      Londinium, England, 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
    • Cleveland Clinic
      • Department of Hematologic Oncology and Blood Disorders
      Cleveland, OH, United States
  • 1993–2010
    • University College London
      • Department of Haematology
      London, ENG, United Kingdom
  • 1992–2010
    • University of Wales
      • College of Medicine
      Cardiff, Wales, United Kingdom
  • 2006–2009
    • University of Birmingham
      • Birmingham Clinical Trials Unit
      Birmingham, ENG, United Kingdom
    • Technion - Israel Institute of Technology
      • Rambam Medical Center
      Haifa, Haifa District, Israel
    • Case Western Reserve University
      • Case Comprehensive Cancer Center
      Cleveland, OH, United States
  • 2008
    • University of Dundee
      Dundee, Scotland, United Kingdom
  • 2007
    • Erasmus MC
      • Department of Hematology
      Rotterdam, South Holland, Netherlands
  • 2005
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
    • Newcastle University
      • Northern Institute for Cancer Research
      Newcastle-on-Tyne, England, United Kingdom
  • 1997–2005
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 2004
    • The Royal Marsden NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2002
    • University of Alabama at Birmingham
      • School of Public Health
      Birmingham, AL, United States
  • 2001
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • University College London Hospitals NHS Foundation Trust
      • Department of Haematology
      London, ENG, United Kingdom
  • 2000
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
  • 1997–2000
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 1999
    • Erasmus Universiteit Rotterdam
      • Department of Hematology
      Rotterdam, South Holland, Netherlands