Rachel Wade

Worldwide Clinical Trials, Nottigham, England, United Kingdom

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Publications (35)338.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild-type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event-free survival (EFS) between the TPMT genotypes. The 5-year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild-type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5-year EFS 53%) was not seen in ALL2003 (5-year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high-risk MRD patients 4·22, 95% confidence interval 2·97-5·99, P < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol. © 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.
    British Journal of Haematology 05/2015; DOI:10.1111/bjh.13469 · 4.96 Impact Factor
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    ABSTRACT: The impact of thiopurine methyltransferase (TPMT) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia (ALL) trial ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild-type patients although the average dose range was similar for both genotypes. Event-free survival (EFS) for patients heterozygous for the more common TPMT*1/*3A variant allele (n = 99, 5-year EFS 88%) was better than for both wild-type TPMT*1/*1 (n = 1206, EFS 80%, P = 0·05) and TPMT*1/*3C patients (n = 17, EFS 53%, P = 0·002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS (P = 0·02) and such non-compliance may have contributed to the poorer outcome for TPMT*1/*3C patients. Patients prescribed escalated doses had a worse EFS (P = 0·04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT*1/*3A heterozygotes had a better EFS than TPMT wild-type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.
    British Journal of Haematology 11/2014; 169(2). DOI:10.1111/bjh.13240 · 4.96 Impact Factor
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    ABSTRACT: Background No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy. Methods Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1–24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 109/L vs ≥50 × 109/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119. Findings 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52–91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9–93·3]) than in the standard group (82·8% [78·1–87·5]; odds ratio [OR] 0·61 [95% CI 0·39–0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8–96·0]) than in the standard therapy group (88·9% [85·0–92·8]; OR 0·67 [95% CI 0·38–1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]). Interpretation Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen. Funding Medical Research Council and Leukaemia and Lymphoma Research.
    The Lancet Oncology 07/2014; 15(8). DOI:10.1016/S1470-2045(14)70243-8 · 24.73 Impact Factor
  • A. Vora, N. Goulden, R. Wade
    The Lancet Oncology 07/2014; 15(8):E308-E308. · 24.73 Impact Factor
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    ABSTRACT: Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia and increased the number of potential prognostic markers. Therefore we integrated copy number alteration data from the eight most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a two-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 UKALL2003 patients. Good risk genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy number status for all eight genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk. Three-quarters of UKALL2003 patients had a good risk genetic profile and a significantly improved event-free survival (94%) compared to patients with a poor risk genetic profile (79%). This difference was driven by a lower relapse rate (4% v 17%), was seen across all patient subgroups and was independent of other risk factors. Even genetic good risk patients with minimal residual disease (>0.01%) at day 29 had an event-free survival in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines two subgroups with distinct responses to treatment, and identifies a large subset of children suitable for treatment de-intensification.
    Blood 06/2014; 124(9). DOI:10.1182/blood-2014-03-562918 · 10.43 Impact Factor
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    ABSTRACT: Although infection is the major cause of treatment-related mortality (TRM) in childhood ALL, factors associated with infection-related mortality (IRM) are poorly understood. To address this we report an analysis of all 75 cases of IRM on the UKALL2003 trial. The 5-year cumulative incidence of IRM was 2.4% (95% confidence interval (CI) 1.9-3.0%) accounting for 75/249 (30%) trial deaths and 75/117 (64%) TRM deaths. Risk of IRM as a proportion of TRM was greater in induction than other phases (77% vs. 56%, p=0.02). Sixty-eight percent of cases were associated with bacterial infection (64% gram negative) and 20% with fungal infection. Down syndrome (DS) was the most significant risk factor for IRM (odds ratio (OR) 12.08; 95% CI 6.54-22.32; p<0.0001). In addition there was a trend towards increased IRM in girls (OR 1.63; 95% CI 1.02-2.61; p=0.04) and increasing treatment intensity (regimen B vs. A: OR 2.11; 95% CI 1.24-3.60; regimen C vs. A: OR=1.41; 95% CI 0.76-2.62; p=0.02). Importantly, DS patients were at significantly higher risk of IRM during maintenance (p=0.048). Our results confirm DS as a major risk factor for IRM. Enhanced supportive care and prophylactic antibiotics should be considered in high-risk patient groups and during periods of increased risk. This study was registered at http://www.controlled-trials.com/, identifier: ISRCTN07355119.
    Blood 06/2014; 124(7). DOI:10.1182/blood-2014-03-560847 · 10.43 Impact Factor
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    ABSTRACT: To determine the prevalence and prognostic association of immunoglobulin heavy chain (IGH@) translocations in acute lymphoblastic leukemia (ALL). The cohort comprised 3,269 patients treated on either the UKALL2003 trial for children and adolescents (1 to 24 years old) or the UKALLXII trial for adolescents and adults (15 to 59 years old). High-throughput fluorescent in situ hybridization was used to detect IGH@ translocations. We identified IGH@ translocations in 5% of patients with ALL (159 of 3,269 patients), in patients with both B-cell (148 of 2,863 patients) and T-cell (11 of 408 patients) disease. Multiple partner genes were identified including CRLF2 (n = 35), five members of the CEPB gene family (n = 17), and ID4 (n = 11). The level of the IGH@-positive clone varied and indicated that some IGH@ translocations were primary events, whereas others were secondary aberrations often associated with other established aberrations. The age profile of patients with IGH@ translocations was distinctive, with a median age of 16 years and peak incidence of 11% among 20- to 24-year-old patients. Among patients with B-cell precursor ALL who were Philadelphia chromosome negative, those with an IGH@ translocation had an inferior overall survival compared with other patients (UKALL2003: hazard ratio, 2.37; 95% CI, 1.34 to 4.18; P = .003; UKALLXII: hazard ratio, 1.73; 95% CI, 1.22 to 2.47; P = .002). However, this adverse effect was not independent of age or minimal residual disease status and did not seem to be driven by an increased risk of relapse. IGH@ translocations define a genetic feature that is frequent among adolescents and young adults with ALL. Although associated with an adverse outcome in adults, it is not an independent prognostic factor in children and adolescents.
    Journal of Clinical Oncology 04/2014; 32(14). DOI:10.1200/JCO.2013.51.3242 · 17.88 Impact Factor
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    ABSTRACT: We investigated the outcome for children and young people with Early T-precursor acute lymphoblastic leukaemia (ETP-ALL), a recently described poor prognosis sub-group of T-ALL, treated on a contemporary protocol, UKALL 2003. After a median follow-up of 4 years and 10 months, the ETP sub-group, representing 16% of T-ALL patients, had non-significantly inferior 5-year event-free survival (76·7% vs. 84·6%, P = 0·2) and overall survival (82·4% vs. 90·9%, P = 0·1), and a higher relapse rate (18·6% vs. 9·6%, P = 0·1) compared to typical T-ALL. ETP-ALL has an intermediate risk outcome, which does not warrant experimental treatment or first remission allogeneic transplant for the group universally.
    British Journal of Haematology 04/2014; 166(3). DOI:10.1111/bjh.12882 · 4.96 Impact Factor
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    ABSTRACT: We aimed to examine the prognostic influence of gender in chronic lymphocytic leukemia. Data from four randomized trials (n=1821) and three registration studies of stage-A disease (n=1299) were analyzed. Overall survival at 10 years was better for women than men in all trials (27% vs 15%; p=0.0001) and in the registration series (55% vs 43%; p<0.0001). More women than men in the trials were Binet stage A-progressive (26% vs 15%), but gender was an independent predictor of survival in multivariate analysis of clinical variables (p<0.0001). Women responded better to treatment (overall response 83%) than men (71%; p<0.0001), within each stage and age group, although fewer women than men received the full treatment dose (79% vs. 85%; p=0.01). Women were more likely than men to experience toxicity (85% vs 78%, p=0.01), particularly gastro-intestinal toxicity (57% vs 42%, p<0.0001). Laboratory markers in the LRF CLL4 trial showed a significantly lower incidence in women than men of unmutated IGHV genes, raised beta-2 microglobulin, CD38 and Zap-70 positivity and TP53 deletions/mutations and/or 11q deletions. We also highlight the higher male:female ratios in randomized trials vs. studies of early chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Chronic lymphocytic leukemia in women runs a more benign clinical course than in men. Gender was also an independent predictor of response, suggesting that pharmacokinetic differences between the sexes and a possible effect of estrogens may contribute to the better outcome. Understanding the reasons for the different outcome by gender may improve patient management. (LRF CLL4 controlled-trials.com identifier: ISRCTN58585610).
    Haematologica 03/2014; 99(6). DOI:10.3324/haematol.2013.101378 · 5.87 Impact Factor
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    ABSTRACT: We report the outcome for children and young people with Down Syndrome-associated Acute Lymphoblastic Leukaemia (DS-ALL) treated on a contemporary protocol. Compared with non-DS ALL, patients with DS-ALL had an inferior event-free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment-related mortality - was primarily responsible for the worse outcomes for DS-ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group.
    British Journal of Haematology 01/2014; 165(4). DOI:10.1111/bjh.12739 · 4.96 Impact Factor
  • 55th Annual Meeting and Exposition of the American Society of Hematology (ASH), WASHINGTON; 12/2013
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    British Journal of Haematology 06/2013; 162(5). DOI:10.1111/bjh.12407 · 4.96 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2013; DOI:10.1038/leu.2013.136 · 9.38 Impact Factor
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    ABSTRACT: BACKGROUND: Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. METHODS: Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. FINDINGS: Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). INTERPRETATION: Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. FUNDING: Medical Research Council and Leukaemia and Lymphoma Research.
    The Lancet Oncology 02/2013; 14(3). DOI:10.1016/S1470-2045(12)70600-9 · 24.73 Impact Factor
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    ABSTRACT: AIMS: In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation. METHODS: We measured TPMT (activity as units/ml packed RBCs, and genotype) at diagnosis (n=1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8x10(8) RBCs) during chemotherapy (n=1131) in children randomised to thioguanine or mercaptopurine on the United Kingdom trial ALL97. RESULTS: Median TPMT activity at diagnosis (8.5units) was significantly lower than during chemotherapy (13.8units, median difference 5.1units, 95% confidence interval, CI, 4.8 to 5.4, P<0.0001). At diagnosis genotype-phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754pmol) than wild-type (360pmol) patients; median difference 406pmol, 95% CI 332 to 478, P<0.0001, whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10,650pmol) than heterozygous patients (3,868pmol); P<0.0001. In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366pmol) and MeMPN (median 8590pmol) concentrations were similar to those in wild-type, high activity patients. CONCLUSIONS: In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy.
    British Journal of Clinical Pharmacology 12/2012; 76(1). DOI:10.1111/bcp.12066 · 3.69 Impact Factor
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    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; 27(2). DOI:10.1038/leu.2012.209 · 9.38 Impact Factor
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    ABSTRACT: Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.Leukemia advance online publication, 20 July 2012; doi:10.1038/leu.2012.176.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; DOI:10.1038/leu.2012.176 · 9.38 Impact Factor
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    ABSTRACT: We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84-lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7-64.9%); non-Asp84-Lys69: 67.3% (63.4-71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.
    Blood Cancer Journal 07/2012; 2(7):e80. DOI:10.1038/bcj.2012.25 · 2.88 Impact Factor
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    ABSTRACT: We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.
    Blood 06/2012; 120(4):843-6. DOI:10.1182/blood-2012-03-413591 · 10.43 Impact Factor
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    ABSTRACT: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.
    Clinical Cancer Research 06/2012; 18(15):4191-200. DOI:10.1158/1078-0432.CCR-11-2936 · 8.19 Impact Factor

Publication Stats

846 Citations
338.76 Total Impact Points


  • 2014–2015
    • Worldwide Clinical Trials
      Nottigham, England, United Kingdom
  • 2008–2014
    • University of Oxford
      • Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)
      Oxford, England, United Kingdom
  • 2010
    • Bournemouth University
      Bournemouth, England, United Kingdom
  • 2009
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom