Rachel Wade

Worldwide Clinical Trials, Nottigham, England, United Kingdom

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Publications (41)363.94 Total impact

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    ABSTRACT: Despite the substantial outcome improvements achieved in paediatric acute lymphoblastic leukaemia (ALL), survival in teenage and young adult (TYA) patients has remained inferior. We report the treatment outcomes and toxicity profiles observed in TYA patients treated on the UK paediatric ALL trial, UKALL2003. UKALL2003 was a multi-centre, prospective, randomized phase III trial, investigating treatment intensification or de-escalation according to minimal residual disease (MRD) kinetics at the end of induction. Of 3126 patients recruited to UKALL2003, 229 (7·3%) were aged 16-24 years. These patients were significantly more likely to have high risk MRD compared to 10-15 year olds (47·9% vs. 36·6%, P = 0·004). Nonetheless, 5-year event-free survival for the TYA cohort (aged 16-24 years) was 72·3% [95% confidence interval (CI): 66·2-78·4] overall and 92·6% (95% CI: 85·5-99·7) for MRD low risk patients. The risk of serious adverse events was higher in patients aged ≥10 years compared to those aged 9 or younger (P < 0·0001) and novel age-specific patterns of treatment-related toxicity were observed. TYA patients obtain excellent outcomes with a risk- and response-adapted paediatric chemotherapy protocol. Whilst those aged 10 years and older have excess toxicity compared with younger patients, the age association is specific to individual toxicities.
    No preview · Article · Dec 2015 · British Journal of Haematology
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    ABSTRACT: https://ash.confex.com/ash/2015/webprogram/Paper84403.html Background: Overall survival (OS) for childhood ALL treated on contemporary protocols is now > 90%. For low risk patients the risk of treatment related mortality (TRM) is now similar to the risk of death due to disease relapse. The only way to improve TRM and morbidity in this group is to identify even lower risk patients and reduce therapy. We analysed outcomes for patients with low risk MRD at end of induction (EOI) therapy treated on UKALL 2003, to identify a very low risk group who could potentially benefit from protocols that further reduce TRM. Methods: UKALL 2003 trial recruited 3126 patients aged 1-25 years with Philadelphia-negative ALL between Oct 1, 2003, and June 30, 2011. Treatment was initially stratified based on NCI risk and cytogenetic results. Subsequent treatment was directed by MRD from bone marrow (BM) measured using EuroMRD approved real-time quantitative PCR method for immunoglobulin and T-cell receptor gene rearrangements at EOI therapy. Analysis was performed on the 2666 patients with available MRD results and focused on patients with low risk MRD combined with other patient characteristics – cytogenetic risk group, white cell count (WCC) and age to identify those subgroups with extremely good event free survival (EFS). Low risk MRD at EOI was defined a level <0.005%. Patients with MRD ≥ 0.005% were considered high risk. Good risk cytogenetics included the presence of ETV6-RUNX1 or high hyperdiploidy. Results: Overall 52% (n=1391) of patients had MRD < 0.005% with the remaining 48% (n=1275) of patients with MRD ≥ 0.005%. 5yr OS 97.6 (95% CI 96.6-98.3) vs. 89.1% (87.2-90.7, p<0.0001) and 5yr EFS 94.4 (93.1-95.6) vs. 83.6% (81.4-85.5, p<0.0001). 53% (n=1407) of the patients with MRD results available had good risk cytogenetics, of which 60% (n=843) had MRD <0.005%. This group (with low risk MRD and good risk cytogenetics) makes up 31.6% of the whole trial cohort and has 5yr EFS 96.0% (94.5-97.3) and 5yr OS 98.9% (97.9-99.4). The outcome was similar irrespective of NCI high risk features (i.e. WCC>50 / age>10yrs). Long term survival remained excellent with 10 year EFS 93.9% (OS 98.2%). There were 32 relapses in the low risk MRD/ good risk cytogenetics group (relapse sites: 11 BM, 7 combined BM and central nervous system (CNS), 3 BM + other site, 6 isolated CNS and 5 other site, non BM/CNS), giving an overall relapse rate of 3.8% with a salvage rate of 81%. The relapse death rate was 0.7% (n=6) with TRM of 0.8% (n=7). The low risk group can be further sub divided into a group of 442 patients (16.6% of whole trial) with undetectable MRD at EOI and good risk cytogenetics who have a 5yr EFS of 97.4% (5yr OS 99.5%). Conclusion: This excellent long term outcome for a third of all patients with childhood ALL, low risk MRD and good risk cytogenetics in a large multi-center randomized controlled trial supports exploration of further reduction of therapy in this group to reduce TRM. This strategy is further supported by the observation that the rate of TRM is now similar the relapse death rate in this group, coupled with the very high salvage rates for those patients who do relapse. The superior OS for patients with undetectable MRD and good risk cytogenetics further highlights the additive strength of MRD to accurately predict outcome in the low risk cytogenetic group.
    No preview · Conference Paper · Dec 2015
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    ABSTRACT: https://ash.confex.com/ash/2015/webprogram/Paper81104.html igh hyperdiploidy (HeH) in acute lymphoblastic leukaemia (ALL) is defined by the non-random acquisition of multiple chromosomes, resulting in a modal number of 51-65 chromosomes. HeH is the most common primary abnormality in paediatric ALL and is associated with an excellent outcome. However, relapses do occur and prevalence of the subgroup means that they account for a sizeable proportion of relapsed cases. Hence identifying risk factors within this subtype remains important. Numerous studies have identified specific trisomies, modal numbers and structural rearrangements as prognostic factors. Despite these efforts, a consensus of the key risk factors has failed to emerge. We present a comprehensive analysis of 1181 children with HeH ALL, comprising discovery and validation cohorts: ALL97/99 (n=456) and UKALL2003 (n=725). The event-free survival (EFS), relapse risk (RR) and overall survival (OS) of HeH patients were: 84%/13%/93% and 91%/6%/95%, respectively. Initially, we examined previously reported risk factors in both cohorts separately. We did not observe any impact on outcome when patients were sub-divided using our copy number alteration (CNA) risk profile, which is based on the deletion status of the 8 most often affected genes. Similarly, there was no relationship between modal number and outcome whether we examined modal number as a continuous variable or in categories (51-53 v 54-57 v 58-65). Although the EFS hazard ratios (HZR) for patients with a double (+4, +10) or triple trisomy (+4, +10, +17) were <1, the difference was not statistically significant in either cohort. HeH karyotypes harbour 5-19 additional chromosomes and although some chromosomes are more likely to be gained than others, there are thousands of combinations. In order to assess the optimal number of chromosomes required for predicting outcome, we used the discovery cohort to calculate the area under the curve (AUC) associated with each individual trisomy as well as all possible combinations of 2-6 chromosomes. This analysis revealed that the average AUC (an estimate for predictive power) increased with the number of chromosomes, but only up to 4, suggesting that there was no advantage in considering 5 or more chromosomes. Next, we derived EFS HZR from univariate Cox regression models for each chromosome and ranked them in order of p value. The HZR for the top 4 chromosomes were +18 (0.43, p<0.001), +20 (2.33, p=0.01), +17 (0.68, p=0.09) and +5 (1.52, p=0.09). Therefore, patients with +17 and +18 but not +5 or +20 (HeH good risk, HeHgr) are predicted to have a better outcome compared to HeH poor risk (HeHpr) patients. This was true for patients in the discovery cohort but also, more importantly, in the validation cohort (table). In UKALL2003, the HeHpr group was associated with a higher incidence of end of induction (EOI) MRD (>0.01%) (56% v 47%, p=0.04) and IKZF1 deletions (12% v 2%, p=0.002). Factoring in EOI MRD, revealed that all UKALL2003 HeH patients had an excellent outcome except those with EOI MRD plus a poor risk HeH profile (table). This subset represented 33% of HeH patients but captured 71% (15/21) of the relapses recorded among UKALL2003 patients. In conclusion, we demonstrate that with the exception of EOI MRD the most important risk factor in HeH is the pattern of chromosomal gain. This result is in keeping with recent genomic studies, which have failed to identify a common underlying mutation, suggesting that the key driving event is disordered gene expression caused by the pattern of chromosomal gain. It is reassuring that the trisomies identified in this study have all previously been proposed as risk factors, providing a framework for further investigations aimed at elucidating precisely which genes are determining treatment response in HeH.
    No preview · Conference Paper · Dec 2015
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    ABSTRACT: https://ash.confex.com/ash/2015/webprogram/Paper84454.html Background: Overall survival (OS) for children with ALL treated on contemporary protocols is now > 90%. To further improve outcomes, stratification must direct intensive treatment to those patients with the highest risk of relapse. Whilst minimal residual disease (MRD) has emerged as the most powerful predictor of outcome, its use in isolation is insufficient to identify those patients with the greatest risk. To address this, we performed a detailed analysis of the entire patient cohort from the recently reported large multi-center randomized controlled trial, UKALL 2003. Integration of end of induction (EOI) MRD with other predictive factors - cytogenetics, age and white cell count (WCC) - allowed the identification of very high risk groups that are likely to benefit from early treatment intensification or novel therapies. Methods: The UKALL 2003 trial recruited 3126 patients aged 1-25 years with Philadelphia-negative ALL between Oct 1, 2003, and June 30, 2011. Treatment was initially stratified based on NCI risk and cytogenetic results. Subsequent treatment was directed by EOI MRD measured using EuroMRD approved real-time quantitative PCR for immunoglobulin and T-cell receptor gene rearrangements. Analysis was performed on 2666 patients with available MRD results and focused on the systematic integration of MRD results with other patient characteristics to identify subgroups with a very poor OS (<75% at 5 years). MRD was considered positive at a level ≥0.005% and low risk if <0.005% unless otherwise stated. Results: Both MRD and cytogenetic risk group were independently predictive of survival. In particular, patients with high risk (HR) genetic abnormalities - low hypodiploidy, near haploidy, KMT2A (MLL) rearranged, iAMP21 and t(17;19)(q23;p13) (n=100) had a poor outcome with 5 yr OS of 76.0%. Combining these factors showed that MRD could stratify the HR cytogenetic subgroup with a significant difference in survival between those with low risk MRD and positive MRD (5yr OS 93.0 vs. 63.1%, p=0.002, n=43 vs. 57). Crucially, this demonstrates that HR cytogenetics are only truly poor risk in the context of poor treatment response. Importantly, there were almost no survivors following relapse in the HR cytogenetic/MRD positive group, whilst 50% of those with low risk MRD could be salvaged after relapse. In addition, whilst t(1;19)(q23;p13)was not considered a HR cytogenetic factor in this trial, combination with positive EOI MRD identified an additional subgroup of 20 patients with a 5yr OS of only 74.7% (vs. 96.7% in MRD low risk patients, p=0.003). Whilst WCC at presentation was also predictive of outcome, this difference was significant only in those with B-ALL and not T-ALL. In B-ALL, WCC>100 x109/L was associated with significantly poorer survival (5yr OS 95.1 vs. 84.0%, p<0.0001) whilst high WCC in T-ALL had little effect on survival, even at WCC >200 x109/L (5yr OS 90.2 vs. 86.7%, p=0.283). Integration of MRD results allowed the identification of a very high risk group with B-ALL, WCC>100 and positive EOI MRD (n=80) which had a 5yr OS of only 71.3%. Further breakdown by cytogenetic risk group showed those patients with good risk cytogenetics (ETV6-RUNX1, high hyperdiploidy) (n=19) had a remarkably good survival despite WCC>100 (5yr OS 94%). In contrast, those with intermediate (n=34) or HR cytogenetics (n=15) had a very poor 5yr OS (65.7% and 60.0% respectively). Older age (≥10yr) was also associated with poorer outcomes compared to those <10yr (5yr OS 95.8 vs. 87.4%, p<0.0001). Integration with MRD results further separated these groups but did not identify a very high risk subgroup. However, combining older age with a higher EOI MRD cut-off of 1% successfully identified a subgroup (n=96) with a very poor 5yr OS of 51.3% (vs. 91.4% in those with MRD<1%, p<0.0001). Interestingly, this was independent of cytogenetic risk group. Conclusions: Through the integration of EOI MRD with other risk factors in a large pediatric ALL cohort we have identified a population of patients with a very poor OS. When combined, these criteria select only 6% of all patients, but capture 35% of all deaths suggesting current treatment is suboptimal in this group. This information is essential for the planning of future trials to ensure that treatment intensification and novel therapies are targeted at those patients at greatest risk, whilst avoiding unnecessary treatment in those patients that already experience good outcomes.
    No preview · Conference Paper · Dec 2015
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    ABSTRACT: With 10+ years follow-up in the Leukaemia Research Fund (LRF) CLL4 trial, we report the effect of salvage therapy, and the clinical/biological features of the 10-year survivors treated for chronic lymphocytic leukaemia (CLL). Overall survival (OS) was similar in the three randomized arms. With fludarabine-plus-cyclophosphamide (FC), progression-free survival (PFS) was significantly longer (P < 0·0001), but OS after progression significantly shorter, than in the chlorambucil or fludarabine arms (P < 0·0001). 614/777 patients progressed; 524 received second-line and 260 third-line therapy, with significantly better complete remission (CR) rates compared to first-line in the chlorambucil arm (7% vs. 13% after second-, 18% after third-line), but worse in the FC arm (38% vs. 15% after both second and third-line). OS 10 years after progression was better after a second-line CR versus a partial response (36% vs. 16%) and better with FC-based second-line therapy (including rituximab in 20%) or a stem cell transplant (28%) versus all other treatments (10%, P < 0·0001). The 176 (24%) 10-year survivors tended to be aged <70 years, with a "good risk" prognostic profile, stage A-progressive, achieving at least one CR, with a first-line PFS >3 years and receiving ≤2 lines of treatment. In conclusion, clinical/biological features and salvage treatments both influence the long-term outcome. Second-line therapies that induce a CR can improve OS in CLL patients.
    No preview · Article · Oct 2015 · British Journal of Haematology
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    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.
    Preview · Article · May 2015 · British Journal of Haematology
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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.
    Preview · Article · Nov 2014 · British Journal of Haematology
  • A. Vora · N. Goulden · R. Wade

    No preview · Article · Jul 2014 · The Lancet Oncology
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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.
    Preview · Article · Jul 2014 · The Lancet Oncology
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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.
    Full-text · Article · Jun 2014 · Blood
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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.
    No preview · Article · Jun 2014 · Blood

  • No preview · Conference Paper · May 2014
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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.
    Full-text · Article · Apr 2014 · Journal of Clinical Oncology
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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.
    No preview · Article · Apr 2014 · British Journal of Haematology
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    Daniel Catovsky · Rachel Wade · Monica Else
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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).
    Full-text · Article · Mar 2014 · Haematologica
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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.
    No preview · Article · Jan 2014 · British Journal of Haematology

  • No preview · Conference Paper · Dec 2013
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    Full-text · Article · Jun 2013 · British Journal of Haematology
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    No preview · Article · May 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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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.
    Preview · Article · Feb 2013 · The Lancet Oncology

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1k Citations
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Institutions

  • 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