319 results on '"A V, Moorman"'
Search Results
2. Targeted treatment options for paediatric B-cell precursor acute lymphoblastic leukaemia patients with constitutional or somatic chromosome 21 alterations
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Naomi Michels, Femke M. Hormann, Aurélie Boeree, Edwin Sonneveld, Anthony V. Moorman, Gabriele Escherich, Rosemary Sutton, H. Berna Beverloo, Rob Pieters, C. Michel Zwaan, Monique L. den Boer, and Judith M. Boer
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Acute lymphoblastic leukemia ,RAS ,JAK ,Paediatric ,Chromosome 21 ,Down syndrome ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Chromosome 21 is affected in ∼60% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients and includes somatic and constitutional gains, intrachromosomal amplification of chromosome 21 (iAMP21), and the translocation t(12;21) resulting in the ETV6::RUNX1 gene fusion. Methods: Since these numeric and structural chromosome 21 alterations are not targetable, we studied the type and frequency of yet-proven targetable events co-occurring with chromosome 21 alterations. Results: Among 307 primary paediatric BCP-ALL cases, JAK/STAT pathway lesions were most frequent in patients with constitutional gain of chromosome 21 (Down syndrome ALL; 35/71, 49%) and iAMP21 (9/22, 41%). RAS pathway lesions were most frequent in high hyperdiploidy (62/108, 57%) and FLT3 lesions were most frequent in iAMP21 (7/22, 32%). Virtually all cases expressed CD19 and CD22 at the cell surface. Positivity for CD20 surface expression ranged from 67% in iAMP21 (8/12) to 20% in ETV6::RUNX1 (26/129). Conclusion: Activated JAK/STAT, RAS or FLT3 signalling, and CD marker surface expression may provide targetable treatment options for the majority of chromosome 21-altered BCP-ALL cases.
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- 2024
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3. Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia
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Hayden L. Bell, Helen J. Blair, Mankaran Singh, Anthony V. Moorman, Olaf Heidenreich, Frederik W. van Delft, John Lunec, and Julie A. E. Irving
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WEE1 ,Inhibitors ,Leukemia ,High-risk ,Relapse ,Translational ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated. Methods Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively. Results Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL. Conclusions Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.
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- 2023
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4. The Prognostic Effect of IKZF1 Deletions in ETV6::RUNX1 and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia
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Anna Østergaard, Amir Enshaei, Rob Pieters, Ajay Vora, Martin A. Horstmann, Gabriele Escherich, Bertil Johansson, Mats Heyman, Kjeld Schmiegelow, Peter M. Hoogerbrugge, Monique L. den Boer, Roland P. Kuiper, Anthony V. Moorman, Judith M. Boer, and Frank N. van Leeuwen
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
IKZF1 deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely ETV6::RUNX1 and high hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of IKZF1 deletions in 939 ETV6::RUNX1 and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups. Only 3% of ETV6::RUNX1 cases (n = 26) were IKZF1-deleted; this adversely affected survival combining all trials (5-year event-free survival [EFS], 79% versus 92%; P = 0.02). No relapses occurred among the 14 patients with an IKZF1 deletion treated on a minimal residual disease (MRD)-guided protocols. Nine percent of HeH cases (n = 85) had an IKZF1 deletion; this adversely affected survival in all trials (5-year EFS, 76% versus 89%; P = 0.006) and in MRD-guided protocols (73% versus 88%; P = 0.004). HeH cases with an IKZF1 deletion had significantly higher end of induction MRD values (P = 0.03). Multivariate Cox regression showed that IKZF1 deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (hazard ratio of relapse rate [95% confidence interval]: 2.48 [1.32-4.66]). There was no evidence to suggest that IKZF1 deletions affected outcome in the small number of ETV6::RUNX1 cases in MRD-guided protocols but that they are related to higher MRD values, higher relapse, and lower survival rates in HeH ALL. Future trials are needed to study whether stratifying by MRD is adequate for HeH patients or additional risk stratification is necessary.
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- 2023
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5. Clinical and Prognostic Impact of Copy Number Alterations and Associated Risk Profiles in a Cohort of Pediatric B-cell Precursor Acute Lymphoblastic Leukemia Cases Treated Under ICiCLe Protocol
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Sanjeev Kumar Gupta, Minu Singh, Pragna H. Chandrashekar, Sameer Bakhshi, Amita Trehan, Ritu Gupta, Rozy Thakur, Smeeta Gajendra, Preity Sharma, Sreejesh Sreedharanunni, Manupdesh S. Sachdeva, Deepam Pushpam, Neelam Varma, Deepak Bansal, Richa Jain, Srinivasan Peyam, Anthony V. Moorman, and Prateek Bhatia
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Copy number alteration (CNA) status and CNA risk profiles of IKZF1plus, UK-ALL CNA risk groups and MRplus scores, were evaluated for clinical and prognostic impact in a cohort of 493 B-cell acute lymphoblastic leukemia cases diagnosed and treated under the Indian Collaborative Childhood Leukemia group (ICiCLe) protocol trial. Overall CNA frequency was 59% with 60% of cases showing 2-loci deletion. CDKN2A/B deletion was most common CNA (36.3%), while IKZF1 deletion and IKZF1plus profile were noted in 19.5% and 13.4% of cases, respectively. IKZF1 deletions and other CNA risk profiles were significantly associated with poor (PR)/high risk (HR) clinical and genetic profile parameters (P < 0.001). In addition, the 3-year OS, event-free survival (EFS) was significantly poor with high relapse rate (RR) of 38.6%, 46.5%, and 35.2% for IKZF1 deletions, IKZF1plus profiles, and UK-ALL CNA-intermediate risk (IR)+PR risk groups, respectively (P < 0.001). Integrated evaluation of UK-ALL CNA risk profile with ICiCLe trial risk stratification groups revealed a worse overall survival, EFS, and RR of 63.3%, 43.2%, and 35.2% for CNA-IR+PR profile compared to CNA-good risk profile (81.3%, 65.0%, and 21.0%; P < 0.001). Hence, routine CNA testing in our setting is must to identify standard risk and IR cases likely to benefit from HR treatment.
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- 2022
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6. Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement
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Simon Bomken, Amir Enshaei, Edward C. Schwalbe, Aneta Mikulasova, Yunfeng Dai, Masood Zaka, Kent T.M. Fung, Matthew Bashton, Huezin Lim, Lisa Jones, Nefeli Karataraki, Emily Winterman, Cody Ashby, Andishe Attarbaschi, Yves Bertrand, Jutta Bradtke, Barbara Buldini, G.A. Amos Burke, Giovanni Cazzaniga, Gudrun Gohring, Hesta A. de Groot-Kruseman, Claudia Haferlach, Luca Lo Nigro, Mayur Parihar, Adriana Plesa, Emma Seaford, Edwin Sonneveld, Sabine Strehl, Vincent H.J. van der Velden, Vikki Rand, Stephen P. Hunger, Christine J. Harrison, Chris M. Bacon, Frederik W. van Delft, Mignon L. Loh, John Moppett, Josef Vormoor, Brian A. Walker, Anthony V. Moorman, and Lisa J. Russell
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin- MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.
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- 2022
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7. Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials
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Thomas Creasey, Emilio Barretta, Sarra L. Ryan, Ellie Butler, Amy A. Kirkwood, Daniel Leongamornlert, Elli Papaemmanuil, Pip Patrick, Laura Clifton-Hadley, Bela Patel, Tobias Menne, Andrew K. McMillan, Christine J. Harrison, Clare J. Rowntree, Nick Morley, David I. Marks, Adele K. Fielding, and Anthony V. Moorman
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and
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- 2021
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8. A fully computational and reasonable representation for karyotypes.
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Jennifer D. Warrender, Anthony V. Moorman, and Phillip Lord
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- 2019
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9. Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement
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Simon Bomken, Amir Enshaei, Edward C. Schwalbe, Aneta Mikulasova, Yunfeng Dai, Masood Zaka, Kent T.M. Fung, Matthew Bashton, Huezin Lim, Lisa Jones, Nefeli Karataraki, Emily Winterman, Cody Ashby, Andishe Attarbaschi, Yves Bertrand, Jutta Bradtke, Barbara Buldini, G.A. Amos Burke, Giovanni Cazzaniga, Gudrun Gohring, Hesta A. De Groot-Kruseman, Claudia Haferlach, Luca Lo Nigro, Mayur Parihar, Adriana Plesa, Emma Seaford, Edwin Sonneveld, Sabine Strehl, Vincent H.J. Van der Velden, Vikki Rand, Stephen P. Hunger, Christine J. Harrison, Chris M. Bacon, Frederik W. Van Delft, Mignon L. Loh, John Moppett, Josef Vormoor, Brian A. Walker, Anthony V. Moorman, Lisa J. Russell, Immunology, Bomken, S, Enshaei, A, Schwalbe, E, Mikulasova, A, Dai, Y, Zaka, M, Fung, K, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, G, Cazzaniga, G, Gohring, G, De Groot-Kruseman, H, Haferlach, C, Nigro, L, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, Van der Velden, V, Rand, V, Hunger, S, Harrison, C, Bacon, C, Van Delft, F, Loh, M, Moppett, J, Vormoor, J, Walker, B, Moorman, A, and Russell, L
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B900 ,B-cell precursor acute lymphoblastic leukemia (BCP-ALL) ,B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) immunoglobulin-MYC rearrangement (IG-MYC-r) ,MYC rearrangement (IG-MYC-r) ,C100 ,Burkitt lymphoma/leukemia ,Hematology ,C500 - Abstract
Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin- MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.
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- 2023
10. The EBF1-PDGFRB T681I mutation is highly resistant to imatinib and dasatinib in vitro and detectable in clinical samples prior to treatment
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Thai Hoa Tran, Jonathan V. Nguyen, Adrian Stecula, Jon Akutagawa, Anthony V. Moorman, Benjamin S. Braun, Andrej Sali, Charles G. Mullighan, Neil P. Shah, Yunfeng Dai, Meenakshi Devidas, Kathryn G. Roberts, Catherine C. Smith, and Mignon L. Loh
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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11. Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia
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Paul B. Sinclair, Ruth E. Cranston, Prahlad Raninga, Joanna Cheng, Rebecca Hanna, Zoe Hawking, Steven Hair, Sarra L. Ryan, Amir Enshaei, Sirintra Nakjang, Vikki Rand, Helen J. Blair, Anthony V. Moorman, Olaf Heidenreich, and Christine J. Harrison
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Cancer Research ,Oncology ,Hematology - Abstract
A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID50
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- 2023
12. Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia
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Sarra L. Ryan, John F. Peden, Zoya Kingsbury, Claire J. Schwab, Terena James, Petri Polonen, Martina Mijuskovic, Jenn Becq, Richard Yim, Ruth E. Cranston, Dale J. Hedges, Kathryn G. Roberts, Charles G. Mullighan, Ajay Vora, Lisa J. Russell, Robert Bain, Anthony V. Moorman, David R. Bentley, Christine J. Harrison, and Mark T. Ross
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Cancer Research ,Oncology ,Hematology - Abstract
Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies. Using current techniques, accurate detection of such aberrations can be challenging, due to the rapidly expanding list of key genetic abnormalities. Whole genome sequencing (WGS) has the potential to improve genetic testing, but requires comprehensive validation. We performed WGS on 210 childhood B-ALL samples annotated with clinical and genetic data. We devised a molecular classification system to subtype these patients based on identification of key genetic changes in tumour-normal and tumour-only analyses. This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients. Novel genetic variants, including fusions involving genes in the MAP kinase pathway, were identified. WGS results were concordant with standard-of-care methods and whole transcriptome sequencing (WTS). We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes. Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.
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- 2023
13. Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial
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Claire Schwab, Ruth E. Cranston, Sarra L. Ryan, Ellie Butler, Emily Winterman, Zoe Hawking, Matthew Bashton, Amir Enshaei, Lisa J. Russell, Zoya Kingsbury, John F. Peden, Emilio Barretta, James Murray, Jude Gibson, Andrew C. Hinchliffe, Robert Bain, Ajay Vora, David R. Bentley, Mark T. Ross, Anthony V. Moorman, and Christine J. Harrison
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Cancer Research ,Oncology ,Hematology - Abstract
Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.
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- 2022
14. Time to Cure for Childhood and Young Adult Acute Lymphoblastic Leukemia Is Independent of Early Risk Factors: Long-Term Follow-Up of the UKALL2003 Trial
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Anthony V. Moorman, Grace Antony, Rachel Wade, Ellie R. Butler, Amir Enshaei, Christine J. Harrison, John Moppett, Rachael Hough, Clare Rowntree, Jeremy Hancock, Nicholas Goulden, Sujith Samarasinghe, and Ajay Vora
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Young Adult ,Cancer Research ,Neoplasm, Residual ,Oncology ,Recurrence ,Acute Disease ,Humans ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Child ,Prognosis ,Disease-Free Survival ,Follow-Up Studies - Abstract
PURPOSE The aim of the randomized trial, UKALL2003, was to adjust treatment intensity on the basis of minimal residual disease (MRD) stratification for children and young adults with acute lymphoblastic leukemia. We analyzed the 10-year randomized outcomes and the time for patients to be considered cured (ClinicalTrials.gov identifier: NCT00222612 ). METHODS A total of 3,113 patients were analyzed including 1,054 patients who underwent random assignment (521 MRD low-risk and 533 MRD high-risk patients). Time to cure was defined as the point at which the chance of relapse was < 1%. The median follow-up time was 10.98 (interquartile range, 9.19-13.02) years, and survival rates are quoted at 10 years. RESULTS In the low-risk group, the event-free survival was 91.7% (95% CI, 87.4 to 94.6) with one course of delayed intensification versus 93.7% (95% CI, 89.9 to 96.1) with two delayed intensifications (adjusted hazard ratio, 0.73; 95% CI, 0.38 to 1.40; P = .3). In the high-risk group, the event-free survival was 82.1% (95% CI, 76.9 to 86.2) with standard therapy versus 87.1% (95% CI, 82.4 to 90.6) with augmented therapy (adjusted hazard ratio, 0.68; 95% CI, 0.44 to 1.06; P = .09). Cytogenetic high-risk patients treated on augmented therapy had a lower relapse risk (22.1%; 95% CI, 15.1 to 31.6) versus standard therapy (52.4%; 95% CI, 28.9 to 80.1; P = .016). The initial risk of relapse differed significantly by sex, age, MRD, and genetics, but the risk of relapse for all subgroups quickly coalesced at around 6 years after diagnosis. CONCLUSION Long-term outcomes of the UKALL2003 trial confirm that low-risk patients can safely de-escalate therapy, while intensified therapy benefits patients with high-risk cytogenetics. Regardless of prognosis, the time to cure is similar across risk groups. This will facilitate communication to patients and families who pose the question “When am I/is my child cured?”
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- 2022
15. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia
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Jayaram Vijayakrishnan, James Studd, Peter Broderick, Ben Kinnersley, Amy Holroyd, Philip J. Law, Rajiv Kumar, James M. Allan, Christine J. Harrison, Anthony V. Moorman, Ajay Vora, Eve Roman, Sivaramakrishna Rachakonda, Sally E. Kinsey, Eamonn Sheridan, Pamela D. Thompson, Julie A. Irving, Rolf Koehler, Per Hoffmann, Markus M. Nöthen, Stefanie Heilmann-Heimbach, Karl-Heinz Jöckel, Douglas F. Easton, Paul D. P. Pharaoh, Alison M. Dunning, Julian Peto, Frederico Canzian, Anthony Swerdlow, Rosalind A. Eeles, ZSofia Kote-Jarai, Kenneth Muir, Nora Pashayan, The PRACTICAL Consortium, Mel Greaves, Martin Zimmerman, Claus R. Bartram, Martin Schrappe, Martin Stanulla, Kari Hemminki, and Richard S. Houlston
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Science - Abstract
While GWAS have uncovered susceptibility loci for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), much of the heritable risk remains undiscovered. Here, the authors perform a meta-analysis of two existing BCP-ALL GWAS together with an unpublished GWAS to identify risk loci at 8q24.21 and 2q22.3.
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- 2018
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16. Author Correction: Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia
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Jayaram Vijayakrishnan, James Studd, Peter Broderick, Ben Kinnersley, Amy Holroyd, Philip J. Law, Rajiv Kumar, James M. Allan, Christine J. Harrison, Anthony V. Moorman, Ajay Vora, Eve Roman, Sivaramakrishna Rachakonda, Sally E. Kinsey, Eamonn Sheridan, Pamela D. Thompson, Julie A. Irving, Rolf Koehler, Per Hoffmann, Markus M. Nöthen, Stefanie Heilmann-Heimbach, Karl-Heinz Jöckel, Douglas F. Easton, Paul D. P. Pharaoh, Alison M. Dunning, Julian Peto, Frederico Canzian, Anthony Swerdlow, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth Muir, Nora Pashayan, The PRACTICAL consortium, Mel Greaves, Martin Zimmerman, Claus R. Bartram, Martin Schrappe, Martin Stanulla, Kari Hemminki, and Richard S. Houlston
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Science - Abstract
The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
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- 2019
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17. Genetic Profiles and Risk Stratification in Adult De Novo Acute Myeloid Leukaemia in Relation to Age, Gender, and Ethnicity: A Study from Malaysia
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Angeli Ambayya, Anthony V. Moorman, Jameela Sathar, Jeyanthy Eswaran, Sarina Sulong, and Rosline Hassan
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cytogenetic ,karyotype ,acute myeloid leukaemia ,genetics ,ELN 2017 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hitherto, no data describing the heterogeneity of genetic profiles and risk stratifications of adult acute myeloid leukaemia (AML) in Southeast Asia are reported. This study assessed genetic profiles, Moorman’s hierarchical classification, and ELN 2017-based risk stratifications in relation to age, gender, and ethnicity in Malaysian adult AML patients. A total of 854 AML patients: male (52%), female (48%) were recruited comprising three main ethnic groups: Malays (59%), Chinese (32%) and Indians (8%). Of 307 patients with abnormal karyotypes: 36% exhibited translocations; 10% deletions and 5% trisomies. The commonest genotype was FLT3-ITD-NPM1wt (276/414; 66.7%). ELN 2017 risk stratification was performed on 494 patients, and 41% were classified as favourable, 39% as intermediate and 20% as adverse groups. More females (47%) were in the favourable risk group compared to males (37%), whereas adverse risk was higher in patients above 60 (24%) of age compared to below 60 (18%) patients. We observed heterogeneity in the distribution of genetic profiles and risk stratifications between the age groups and gender, but not among the ethnic groups. Our study elucidated the diversity of adult AML genetic profiles between Southeast Asians and other regions worldwide.
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- 2021
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18. Detection of constitutional mismatch repair deficiency in children and adolescents with acute lymphoblastic leukemia
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Richard, Gallon, Rachel, Phelps, Leigh, Betts, Christine, Hayes, Dino, Masic, Julie A E, Irving, Ciaron, McAnulty, Vaskar, Saha, Ajay, Vora, Katharina, Wimmer, Jayashree, Motwani, Christine, Macartney, John, Burn, Michael S, Jackson, Anthony V, Moorman, and Mauro, Santibanez-Koref
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Cancer Research ,Oncology ,Hematology - Published
- 2022
19. The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia
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David O'Connor, Jonas Demeulemeester, Lucia Conde, Amy Kirkwood, Kent Fung, Foteini Papaleonidopoulou, Gianna Bloye, Nadine Farah, Sunniyat Rahman, Jeremy Hancock, Caroline Bateman, Sarah Inglott, Jon Mee, Javier Herrero, Peter Van Loo, Anthony V. Moorman, Ajay Vora, and Marc R. Mansour
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Cancer Research ,Human Biology & Physiology ,Oncology ,Ecology,Evolution & Ethology ,Tumour Biology ,Genetics & Genomics ,Computational & Systems Biology - Abstract
PURPOSE Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF). METHODS We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape. RESULTS IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients ( P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents. CONCLUSION The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.
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- 2023
20. The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21
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Qingsong Gao, Sarra L Ryan, Ilaria Iacobucci, Pankaj S Ghate, Ruth E Cranston, Claire J Schwab, Abdelrahman H. Elsayed, Lei Shi, Stanley B Pounds, Shaohua Lei, Pradyumna Baviskar, Deqing Pei, Cheng Cheng, Matthew Bashton, Paul B Sinclair, David R Bentley, Mark Ross, Zoya Kingsbury, Terena James, Kathryn G Roberts, Meenakshi Devidas, Yiping Fan, Wenan Chen, Ti-Cheng Chang, Gang Wu, Andrew J. Carroll, Nyla A. Heerema, Virginia Valentine, Marcus B Valentine, Wenjian Yang, Jun J. Yang, Anthony V Moorman, Christine J Harrison, and Charles G. Mullighan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remain incompletely understood. Here, using integrated whole genome and transcriptome sequencing of 124 iAMP21-ALL patients, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL according to patterns of copy number alteration and structural variation. This large dataset enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which are differentially expressed compared to non-iAMP21-ALL cases, and including multiple genes implicated in the pathogenesis of acute leukemia: CHAF1B, DYRK1A, ERG, HMGN1 and RUNX1. Using multimodal single cell genomic profiling, including single cell whole genome sequencing of two cases, we documented clonal heterogeneity and genomic evolution, formally demonstrating that acquisition of the iAMP21-chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.
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- 2023
21. Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia?
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Claire Schwab, Karin Nebral, Lucy Chilton, Cristina Leschi, Esmé Waanders, Judith M. Boer, Markéta Žaliová, Rosemary Sutton, Ingegerd Ivanov Öfverholm, Kentaro Ohki, Yuka Yamashita, Stefanie Groeneveld-Krentz, Eva Froňková, Marleen Bakkus, Joelle Tchinda, Thayana da Conceição Barbosa, Grazia Fazio, Wojciech Mlynarski, Agata Pastorczak, Giovanni Cazzaniga, Maria S. Pombo-de-Oliveira, Jan Trka, Renate Kirschner-Schwabe, Toshihiko Imamura, Gisela Barbany, Martin Stanulla, Andishe Attarbaschi, Renate Panzer-Grümayer, Roland P. Kuiper, Monique L. den Boer, Hélène Cavé, Anthony V. Moorman, Christine J. Harrison, and Sabine Strehl
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Specialties of internal medicine ,RC581-951 - Published
- 2017
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22. Unmatched Whole-Genome Sequencing As a Clinical Tool for Hematological Neoplasms with Significant Utility in Cases with Tumor-in-Normal Contamination
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Jesús Gutiérrez-Abril, Daniel Leongamornlert, Neerav N Shukla, Maria Luisa Sulis, Yangyu Zhou, Max F. Levine, Emilio Barretta, SooWah Lee, Juan E. Arango-Ossa, Gunes Gundem, Juan S. Medina-Martínez, Bela Patel Wrench, Anthony V. Moorman, Adele K. Fielding, Andrew L. Kung, and Elli Papaemmanuil
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
23. Reduced Intensity Reinduction Followed By Blinatumomab Achieves Excellent MRD Clearance with Reduced Toxicity and Facilitates Timely Transplant in Children and Young People with Relapsed B-Precursor Acute Lymphoblastic Leukemia
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Angus Hodder, Avijeet K Mishra, Katherine Clesham, Susan Baird, Kaljit Bhuller, Ismail Bisho, Denise Bonney, Anna Castleton, Michelle Cummins, Emmy Dickens, Lindsay George, Sara Ghorashian, Brenda Gibson, Chris Hasley, Nicholas Heaney, Rachael E Hough, Danielle Ingham, Galina Jigoulina, Katherine Lindsay, Donna Lancaster, Majid Madni, Andrea Malone, Bethany Mitchell, Anthony V. Moorman, John Moppett, Vanessa McLelland, Jayashree Motwani, Emma Nicholson, Caroline Osborne, Katharine Patrick, Lamia Samrin, Sanjay Tewari, Indu Rakesh Thakur, Sujith Samarasinghe, Ajay Vora, and David O'Connor
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia
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Zhaohui Gu, Michelle Churchman, Kathryn Roberts, Yongjin Li, Yu Liu, Richard C. Harvey, Kelly McCastlain, Shalini C. Reshmi, Debbie Payne-Turner, Ilaria Iacobucci, Ying Shao, I-Ming Chen, Marcus Valentine, Deqing Pei, Karen L. Mungall, Andrew J. Mungall, Yussanne Ma, Richard Moore, Marco Marra, Eileen Stonerock, Julie M. Gastier-Foster, Meenakshi Devidas, Yunfeng Dai, Brent Wood, Michael Borowitz, Eric E. Larsen, Kelly Maloney, Leonard A. Mattano Jr, Anne Angiolillo, Wanda L. Salzer, Michael J. Burke, Francesca Gianni, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Anthony V. Moorman, Bella Patel, Adele K. Fielding, Jacob M. Rowe, Selina M. Luger, Ravi Bhatia, Ibrahim Aldoss, Stephen J. Forman, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Steven Kornblau, Hagop M. Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L. Willman, Mignon L. Loh, Stephen P. Hunger, and Charles G. Mullighan
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Science - Abstract
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
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- 2016
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25. Data from Sequential Influences of Leukemia-Specific and Genetic Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the National Cancer Research Network Acute Myeloid Leukemia 14 and 15 Trials
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Monica Pallis, Alan Burnett, Nigel Russell, Terence Hoy, Anthony V. Moorman, Darya Yakunina, Janet Fisher, Yun Li, Paul White, Martin Grundy, and Claire H. Seedhouse
- Abstract
Purpose: P-glycoprotein (Pgp) is a major prognostic factor for chemotherapy failure in acute myeloid leukemia (AML). This study compared the influence of genetic and leukemia-specific factors on Pgp.Experimental Design: Eight hundred and seventeen samples were studied prospectively for Pgp protein expression and function and G1199A, G2677T, and C3435T polymorphisms in the encoding gene ABCB1.Results: Age, low WBC count, high bcl-2, secondary AML and myelodysplastic syndrome, and adverse cytogenetics all correlated strongly with high Pgp (MRK16) protein expression. However, ABCB1 3435TT homozygosity was negatively correlated with Pgp. Pgp protein is only expressed in 41% of samples such that the negative effect of the polymorphism was not seen at baseline Pgp levels but was marked in the upper 41% of samples (MRK16 Δmean fluorescence intensity of 75th centile sample = 9 units for TT variant samples and 26 units for CC/CT; P = 0.003). However, no association was found between genetic factors and Pgp function using rhodamine 123 accumulation.Conclusions: The genetic polymorphism 3435TT (which results in unstable mRNA) has a significant effect on Pgp expression, but this is only seen in ∼40% of cases in which mRNA and protein are detectable. Moreover, leukemia-specific factors, such as low WBC count and poor risk cytogenetics, have a much greater effect than genetic polymorphisms on Pgp expression in AML blasts.
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- 2023
26. Supplementary Data from Sequential Influences of Leukemia-Specific and Genetic Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the National Cancer Research Network Acute Myeloid Leukemia 14 and 15 Trials
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Monica Pallis, Alan Burnett, Nigel Russell, Terence Hoy, Anthony V. Moorman, Darya Yakunina, Janet Fisher, Yun Li, Paul White, Martin Grundy, and Claire H. Seedhouse
- Abstract
Supplementary Data from Sequential Influences of Leukemia-Specific and Genetic Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the National Cancer Research Network Acute Myeloid Leukemia 14 and 15 Trials
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- 2023
27. Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia
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Daniel Leongamornlert, Jesús Gutiérrez-Abril, Soo Wah Lee, Emilio Barretta, Tom Creasey, Gunes Gundem, Max Fine Levine, Juan Esteban Arango Ossa, Konstantinos Liosis, Juan Santiago Medina-Martinez, Krisztina Zuborne Alapi, Amy A Kirkwood, Laura Clifton-Hadley, Pip Patrick, David Jones, Laura J O'Neill, Adam P Butler, Christine J Harrison, Peter J Campbell, Bela Patel, Anthony V Moorman, Adele K Fielding, and Elli Papaemmanuil
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Hematology - Abstract
Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41). Complex karyotype by cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL.
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- 2023
28. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial
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David I Marks, Amy A Kirkwood, Clare J Rowntree, Melanie Aguiar, Katharine E Bailey, Brendan Beaton, Paul Cahalin, Anna Z Castleton, Laura Clifton-Hadley, Mhairi Copland, Anthony H Goldstone, Richard Kelly, Emma Lawrie, SooWah Lee, Andrew K McMillan, Mary Frances McMullin, Tobias F Menne, Rachel J Mitchell, Anthony V Moorman, Bela Patel, Pip Patrick, Paul Smith, David Taussig, Deborah Yallop, Krisztina Zuborne Alapi, and Adele K Fielding
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Adult ,Male ,Precursor Cells, B-Lymphoid ,Induction Chemotherapy ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,State Medicine ,Young Adult ,SDG 3 - Good Health and Well-being ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Rituximab ,Aged - Abstract
BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia.METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617.FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient.
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- 2022
29. Activity and toxicity of intramuscular 1000 <scp>iu</scp> /m 2 polyethylene glycol‐ E. coli <scp>L‐asparaginase</scp> in the <scp>UKALL</scp> 2003 and <scp>UKALL</scp> 2011 clinical trials
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Jasmeet Sidhu, Ashish Narayan Masurekar, Manash Pratim Gogoi, Caroline Fong, Tasos Ioannou, Taha Lodhi, Catriona Parker, Jizhong Liu, Amy A. Kirkwood, Anthony V. Moorman, Kiranmoy Das, Nicholas J. Goulden, Ajay Vora, Vaskar Saha, and Shekhar Krishnan
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Hematology - Published
- 2022
30. Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials
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Christine J. Harrison, Elli Papaemmanuil, Ellie Butler, Emilio Barretta, Anthony V. Moorman, Daniel Leongamornlert, Andrew McMillan, Nick Morley, Thomas Creasey, Laura Clifton-Hadley, Tobias Menne, Amy A Kirkwood, Clare J. Rowntree, Bela Patel, Adele K. Fielding, Sarra Ryan, David I. Marks, and Pip Patrick
- Subjects
Gene Rearrangement ,Oncology ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Single-nucleotide polymorphism ,Genomics ,Hematology ,Disease ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Cohort Studies ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Internal medicine ,Cohort ,medicine ,Humans ,Hypodiploidy ,SNP ,Hyperdiploidy ,Child ,business ,Aged ,SNP array - Abstract
Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and
- Published
- 2021
31. Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
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John Moppett, Ajay Vora, Anthony V. Moorman, Amir Enshaei, and Christine J. Harrison
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medicine.medical_specialty ,Multivariate analysis ,business.industry ,Cytogenetics ,Articles ,Hematology ,Minimal residual disease ,Clinical trial ,Internal medicine ,medicine ,Lymphoblastic leukaemia ,Hyperdiploidy ,Young adult ,business ,Survival analysis - Abstract
Summary Background High hyperdiploidy is the most common genetic subtype of childhood acute lymphoblastic leukaemia and is associated with a good outcome. However, some patients relapse and, given its prevalence, patients with high hyperdiploidy account for a large proportion of all relapses. We aimed to evaluate putative risk factors and determine the optimal pattern of trisomies for predicting outcome. Methods We used discovery and validation cohorts from consecutive trials—UKALL97/99 (n=456) and UKALL2003 (n=725)—to develop the prognostic profile. UKALL97/99 recruited patients aged 1–18 years between Jan 1, 1997, and June 15, 2002, and UKALL2003 recruited children and young adults aged 1–24 years between Oct 1, 2003, and June 30, 2001, from the UK and Ireland who were newly diagnosed with acute lymphoblastic leukaemia. Cytogenetic and fluorescence in-situ hybridisation testing was performed on pre-treatment bone marrow samples by regional UK National Health Service genetic laboratories or centrally by the Leukaemia Research Cytogenetics Group, and results were reported using established nomenclature and definitions. We examined the prognostic effect of previously proposed genetic and non-genetic risk factors among patients with high hyperdiploid acute lymphoblastic leukaemia treated on UKALL2003. We used Bayesian information criterion, targeted projection pursuit, and multivariate analysis to identify the optimal number of trisomies, and best subset regression and multivariate analysis to identify the optimal combination. Survival analysis considered three endpoints, as follows: event-free survival, defined as time to relapse, second tumour, or death, censored at last contact; relapse rate, defined as time to relapse for those reaching complete remission, censored at death in remission or last contact; and overall survival, defined as time to death, censored at last contact. Findings The median follow-up time for UKALL97/99 was 10·59 years (IQR 9·25–12·06) and 9·40 years (8·00–11·55) for UKALL2003. UKALL97/99 included 208 female patients and 248 male patients, and UKALL2003 included 345 female patients and 380 male patients. We deduced that the trisomic status of four chromosomes provided the optimal information for predicting outcome. The good risk profile comprised karyotypes with +17 and +18 or +17 or +18 in the absence of +5 and +20. All remaining cases were classified in the poor risk profile. The ratio of patients with good risk and poor risk was 82:18 and 80:20 in the discovery and validation cohorts, respectively. In the validation cohort, patients with the high hyperdiploid good risk profile had an improved response to treatment compared with other patients with high hyperdiploidy at 10 years (relapse rate 5% [95% CI 3–7] vs 16% [10–23]; p
- Published
- 2021
32. Prognostic impact of the absence of biallelic deletion at the TRG locus for pediatric patients with T-cell acute lymphoblastic leukemia treated on the Medical Research Council UK Acute Lymphoblastic Leukemia 2003 trial
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Nadine Farah, Amy A Kirkwood, Sunniyat Rahman, Theresa Leon, Sarah Jenkinson, Rosemary E. Gale, Katharine Patrick, Jeremy Hancock, Sujith Samarasinghe, David C. Linch, Anthony V Moorman, Nicholas Goulden, Ajay Vora, and Marc R. Mansour
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
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33. Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21
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Paul. B. Sinclair, Helen H. Blair, Sarra L. Ryan, Lars Buechler, Joanna Cheng, Jake Clayton, Rebecca Hanna, Shaun Hollern, Zoe Hawking, Matthew Bashton, Claire J. Schwab, Lisa Jones, Lisa J. Russell, Helen Marr, Peter Carey, Christina Halsey, Olaf Heidenreich, Anthony V. Moorman, and Christine J. Harrison
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by in-vivo and ex-vivo luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia-initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumor suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-cell acute lymphoblastic leukemia. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-cell acute lymphoblastic leukemia and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.
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- 2018
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34. Genetic characterisation of childhood B‐other‐acute lymphoblastic leukaemia in UK patients by fluorescence in situ hybridisation and Multiplex Ligation‐dependent Probe Amplification
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Christine J. Harrison, James W. Murray, Sarra Ryan, Zoe Hawking, Claire Schwab, Ruth E. Cranston, Daniel Murdy, Anthony V. Moorman, Emily Winterman, Grace Antony, Emilio Barretta, Amir Enshaei, Ellie Butler, and Ajay Vora
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Adolescent ,DNA Copy Number Variations ,Oncogene Proteins, Fusion ,medicine.drug_class ,Fusion Proteins, bcr-abl ,ZNF384 ,Tyrosine-kinase inhibitor ,Young Adult ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Multiplex ,Multiplex ligation-dependent probe amplification ,Child ,In Situ Hybridization, Fluorescence ,business.industry ,Surrogate endpoint ,Disease Management ,Infant ,Hematology ,Minimal residual disease ,United Kingdom ,Child, Preschool ,Karyotyping ,Lymphoblastic leukaemia ,Female ,business ,Multiplex Polymerase Chain Reaction ,Erg - Abstract
While next-generation sequencing technologies provide excellent strategies to screen for newly defined genetic abnormalities of prognostic or therapeutic significance in patients with B-other-acute lymphoblastic leukaemia (ALL), they are not widely available. We used a dual screening approach, incorporating fluorescence in situ hybridisation (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA), to establish the frequency and long-term outcome of a representative cohort of specific subgroups of B-other-ALL recruited to the childhood ALL trial, UKALL2003. We focussed on abnormalities of known prognostic significance, including ABL-class fusions and ERG deletions, as a surrogate marker for DUX4-rearranged ALL. ABL-class fusions accounted for ~4% of B-other-ALL and were associated with high levels of minimal residual disease (MRD; 14/23 with MRD >5%) and a high relapse rate (55·7%) following treatment without tyrosine kinase inhibitor (TKI), confirming the importance of prospective screening with a view to incorporating TKI into therapy. Patients with deletions of ERG (~10% of B-other-ALL) had a 10-year event-free-survival of 97·2%, validating previous reports of their excellent outcome. Rearrangements of ZNF384, MEF2D and NUTM1 were observed at low frequencies. Here, we estimate that approximately one third of B-other-ALL patients can be reliably classified into one of the known genetic subgroups using our dual screening method. This approach is rapid, accurate and readily incorporated into routine testing.
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- 2021
35. Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study
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Elli Papaemmanuil, Amy A Kirkwood, Andrew McMillan, Eleanor J. Ward, David I. Marks, Amir Enshaei, Claire Schwab, Daniel Leongamornlert, Pip Patrick, Ellie Butler, Emilio Barretta, Christine J. Harrison, Clare J. Rowntree, Laura Clifton-Hadley, Tom Creasey, Bela Patel, Adele K. Fielding, Anthony V. Moorman, Tobias Menne, and Katie Twentyman
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Hematology ,ETV6 ,KMT2A ,medicine.anatomical_structure ,CDKN2A ,hemic and lymphatic diseases ,Internal medicine ,Complex Karyotype ,Cohort ,biology.protein ,Medicine ,Hypodiploidy ,business ,BTG1 ,B cell - Abstract
Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients.
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- 2021
36. Minimal residual disease, long-term outcome, and IKZF1 deletions in children and adolescents with Down syndrome and acute lymphocytic leukaemia
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C. Michel Zwaan, Gisela Barbany, Toby Trahair, Naomi Michels, Monique L. den Boer, Rosemary Sutton, Rob Pieters, Sabine Ebert, Marta Fiocco, Hester A. de Groot-Kruseman, Ajay Vora, Udo zur Stadt, Gabriele Escherich, Luciano Dalla-Pozza, Mats Heyman, Kjeld Schmiegelow, Amir Enshaei, Judith M. Boer, Anthony V. Moorman, Vincent H.J. van der Velden, Pediatrics, and Immunology
- Subjects
Male ,medicine.medical_specialty ,Down syndrome ,Neoplasm, Residual ,Adolescent ,Disease-Free Survival ,Cohort Studies ,Ikaros Transcription Factor ,SDG 3 - Good Health and Well-being ,Internal medicine ,Humans ,Medicine ,Child ,Proportional hazards model ,business.industry ,Hazard ratio ,Articles ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Minimal residual disease ,Pediatric cancer ,Regimen ,Child, Preschool ,Cohort ,Female ,Down Syndrome ,business ,Gene Deletion ,Cohort study - Abstract
Background: Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome. Method: Patients (aged 1–23 years) with Down syndrome and acute lymphocytic leukaemia and matched non-Down syndrome patients with acute lymphocytic leukaemia (matched controls) from eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) done between 2002 and 2018 across various countries (the Netherlands, the UK, Australia, Denmark, Finland, Iceland, Norway, Sweden, and Germany) were included. Participants were matched (1:3) for clinical risk factors and genetics, including IKZF1 deletion. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low [cs] 4·3 [1·6–11·0]; p=0·0028), but not in the IKZF1 wild-type group (relapse at 5 years 5·8% [2·1–12·2] vs 8·1% [5·1–12·0]; HRcs 1·0 [0·5–2·1]; p=0·99). In addition to increased induction deaths (15 [6%] of 251 vs 69 [0·8%] of 8426), Down syndrome and acute lymphocytic leukaemia was associated with a higher risk of post-induction TRM compared with matched controls (TRM at 5 years 12·2% [7·0–18·9] vs 2·7% [1·3–4·9]; HRcs 5·0 [2·3–10·8]; p
- Published
- 2021
37. IKZF1 alterations are not associated with outcome in 498 adults with B-precursor ALL enrolled in the UKALL14 trial
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Pip Patrick, Clare J. Rowntree, Andrew McMillan, Emma Lawrie, Krisztina Zuborne Alapi, Bela Patel, Laura Clifton-Hadley, Emilio Barretta, Adele K. Fielding, Rachel J. Mitchell, Anthony V. Moorman, Tobias F. Menne, Elli Papaemmanuil, David I. Marks, Soo Wah Lee, Amy A Kirkwood, Daniel Leongamornlert, and Nahid Zareian
- Subjects
Adult ,medicine.medical_specialty ,Population ,Fusion Proteins, bcr-abl ,Subgroup analysis ,Polymerase Chain Reaction ,law.invention ,Ikaros Transcription Factor ,law ,Internal medicine ,Genotype ,medicine ,Humans ,Multiplex ,Multiplex ligation-dependent probe amplification ,education ,Polymerase chain reaction ,Aged ,education.field_of_study ,Lymphoid Neoplasia ,business.industry ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Burkitt Lymphoma ,Minimal residual disease ,business ,Burkitt's lymphoma - Abstract
IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1− B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420). Although patients with BCR-ABL1− ΔIKZF1 were more likely to have minimal residual disease at the end of induction, we did not find any impact of ΔIKZF1 (including subgroup analysis for DN or loss-of-function lesions) or the IKZF1plus genotype on event-free, overall survival, or relapse risk by univariable or multivariable analyses. Consistent with the technical approach, MLPA not only detected a wider range of deletions than PCR but also failed to detect some PCR-detected lesions. The main difference between our study and others reporting an association between ΔIKZF1 and outcome is the older age of participants in our population. The impact of ΔIKZF1 in ALL may be less marked in an older population of patients. Our study underscores the need for analyses in large, harmonized data sets. This trial was registered at www.clinicaltrials.gov as #NCT01085617.
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- 2021
38. Clinical characteristics and outcomes of B-cell precursor ALL with MEF2D rearrangements: a retrospective study by the Ponte di Legno Childhood ALL Working Group
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Kentaro Ohki, Ellie R. Butler, Nobutaka Kiyokawa, Shinsuke Hirabayashi, Anke K. Bergmann, Anja Möricke, Judith M. Boer, Hélène Cavé, Giovanni Cazzaniga, Allen Eng Juh Yeoh, Masashi Sanada, Toshihiko Imamura, Hiroto Inaba, Charles G. Mullighan, Mignon L. Loh, Ulrika Norén-Nyström, Lee-Yung Shih, Marketa Zaliova, Ching-Hon Pui, Oskar A. Haas, Christine J. Harrison, Anthony V. Moorman, and Atsushi Manabe
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Cancer och onkologi ,Cancer Research ,Oncology ,Cancer and Oncology ,Pediatrik ,Hematology ,Pediatrics - Published
- 2022
39. Prognostic value of Oncogenetic mutations in pediatric T Acute Lymphoblastic Leukemia: a comparison of UKALL2003 and FRALLE2000T protocols
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Fanny Alby-Laurent, John Moppett, Lina Hamadeh, Arnaud Petit, André Baruchel, Vahid Asnafi, Marc R. Mansour, Elizabeth Macintyre, Rosemary E. Gale, Mary Taj, Sylvie Chevret, Ajay Vora, and Anthony V. Moorman
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,MEDLINE ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,law.invention ,T Acute Lymphoblastic Leukemia ,Randomized controlled trial ,law ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Child ,Clinical Trials as Topic ,business.industry ,Hematology ,Prognosis ,Combined Modality Therapy ,Survival Rate ,Child, Preschool ,Mutation ,Female ,Neoplasm Recurrence, Local ,business ,Value (mathematics) ,Follow-Up Studies - Published
- 2021
40. DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis
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Kathrine Grell, Lisa Lyngsie Hjalgrim, Anja Möricke, Jacob Nersting, Jaitri Joshi, Bruce Bostrom, Petter Quist-Paulsen, Kim Dalhoff, Bendik Lund, Kristi Lepik, Anthony V. Moorman, Goda Vaitkevičienė, Kjeld Schmiegelow, Daniel Murdy, Jukka Kanerva, Olafur G. Jonsson, Linea Natalie Toksvang, Bodil Als-Nielsen, Martin Zimmermann, Stine Nygaard Nielsen, Ajay Vora, Matilda Degn, Laimonas Griskevicius, and Jonas Abrahamsson
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Maintenance therapy ,Internal medicine ,medicine ,Humans ,Young adult ,Child ,Thioguanine ,Clinical Trials as Topic ,Proportional hazards model ,business.industry ,Hazard ratio ,DNA, Neoplasm ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Minimal residual disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Biomarker (medicine) ,Female ,Methotrexate ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.
- Published
- 2021
41. Single nucleotide polymorphism array‐based signature of low hypodiploidy in acute lymphoblastic leukemia
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Christine J. Harrison, John Moppett, Thomas Creasey, Claire Schwab, Kathryn Watts, Anthony V. Moorman, Oskar A. Haas, Adele K. Fielding, Gavin Cuthbert, Karin Nebral, Amir Enshaei, and Ajay Vora
- Subjects
Genetics ,clone (Java method) ,Cancer Research ,medicine.medical_specialty ,Cytogenetics ,Single Nucleotide Polymorphism Array ,acute lymphoblastic leukemia ,Biology ,cytogenetics ,03 medical and health sciences ,hypodiploid ,0302 clinical medicine ,Polymorphism (computer science) ,030220 oncology & carcinogenesis ,medicine ,Hypodiploidy ,SNP ,Ploidy ,SNP array ,Research Articles ,Research Article - Abstract
Low hypodiploidy (30-39 chromosomes) is one of the most prevalent genetic subtypes among adults with ALL and is associated with a very poor outcome. Low hypodiploid clones can often undergo a chromosomal doubling generating a near-triploid clone (60-78 chromosomes). When cytogenetic techniques detect a near triploid clone, a diagnostic challenge may ensue in differentiating presumed duplicated low hypodiploidy from good risk high hyperdiploid ALL (51-67 chromosomes). We used single-nucleotide polymorphism (SNP) arrays to analyze low hypodiploid/near triploid (HoTr) (n=48) and high hyperdiploid (HeH) (n=40) cases. In addition to standard analysis, we derived log2 ratios for entire chromosomes enabling us to analyze the cohort using machine-learning techniques. Low hypodiploid and near triploid cases clustered together and separately from high hyperdiploid samples. Using these approaches, we also identified three cases with 50-60 chromosomes, originally called as HeH, which were, in fact, HoTr and two cases incorrectly called as HoTr. TP53 mutation analysis supported the new classification of all cases tested. Next, we constructed a classification and regression tree model for predicting ploidy status with chromosomes 1, 7 and 14 being the key discriminators. The classifier correctly identified 47/50 (94%) HoTr cases. We validated the classifier using an independent cohort of 44 cases where it correctly called 7/7 (100%) low hypodiploid cases. The results of this study suggest that HoTr is more frequent among older adults with ALL than previously estimated and that SNP array analysis should accompany cytogenetics where possible. The classifier can assist where SNP array patterns are challenging to interpret. This article is protected by copyright. All rights reserved.
- Published
- 2021
42. Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance
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Olga Zimmermannova, Marketa Zaliova, Anthony V. Moorman, Halima Al-Shehhi, Eva Fronkova, Zuzana Zemanova, Tomas Kalina, Ajay Vora, Jan Stary, Jan Trka, Ondrej Hrusak, and Jan Zuna
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2017
- Full Text
- View/download PDF
43. Robust Validation of the UKALL High Hyperdiploid Risk Profile Using Individual Patient Data Collected By the Harmony Alliance
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Amir Enshaei, Javier Martinez Martínez Elicegui, Esther Anguiano, Jude Gibson, Mirella Ampatzidou, Michael Doubek, Adele K. Fielding, Edoardo La Sala, Elizabeth Middleton, Anita W. Rijneveld, Amin T. Turki, Ajay Vora, Martin Zimmermann, and Anthony V. Moorman
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
44. The Clinico-Genomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL)
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David O'Connor, Jonas Demeulemeester, Lucia Conde, Amy A. Kirkwood, Kent Fung, Foteini Papaleonidopoulou, Gianna Bloye, Nadine Farah, Sunniyat Rahman, Jeremy Hancock, Caroline Bateman, Sarah Inglott, Jon Mee, Javier Herrero, Peter Van Loo, Anthony V. Moorman, Ajay Vora, and Marc R. Mansour
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
45. Final Results from UKALL60+ (NCT01616238), a UK National Cancer Research Institute Trial for Older People with De Novo Acute Lymphoblastic Leukaemia
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Bela Patel Wrench, Amy A. Kirkwood, Krisztina Zuborne Alapi, Laura Clifton-Hadley, SooWah Lee, David I. Marks, Anthony V. Moorman, Nicholas J. Morley, Pip Patrick, Zaynab Rana, Clare J. Rowntree, John A. Snowden, and Adele K. Fielding
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
46. Diagnostic Utility of Whole Genome Sequencing in Adults with B-Other Acute Lymphoblastic Leukaemia
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Daniel Leongamornlert, Jesús Gutiérrez-Abril, SooWah Lee, Emilio Barretta, Thomas Creasey, Krisztina Zuborne Alapi, Max F. Levine, Juan E Arango-Ossa, Juan S Medina-Martinez, Amy A. Kirkwood, Laura Clifton-Hadley, Pip Patrick, David Jones, Adam P Butler, Christine J. Harrison, Peter J. Campbell, Bela Patel Wrench, Anthony V. Moorman, Adele K. Fielding, and Elli Papaemmanuil
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
47. Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL
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Selina M. Luger, Richard C. Harvey, Anthony H. Goldstone, Jan Barinka, Mark R. Litzow, Victoria Wang, Charles G. Mullighan, Ross L. Levine, Jacob M. Rowe, Bela Patel, Peter H. Wiernik, Zhaohui Gu, Adele K. Fielding, Kathryn G. Roberts, Zhongshan Cheng, David I. Marks, Ari Melnick, Georgina Buck, Elisabeth Paietta, Yanming Zhang, Omar Abdel-Wahab, Deqing Pei, Janis Racevskis, Gordon W. Dewald, Hillard M. Lazarus, Anthony V. Moorman, Cheng Cheng, Rhett P. Ketterling, Letizia Foroni, Stanley Pounds, Cheryl L. Willman, David Alejos, Lei Shi, Gang Wu, Chunxu Qu, and Martin S. Tallman
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Immunology ,Fusion Proteins, bcr-abl ,BCR/ABL1 Negative ,Risk Assessment ,Biochemistry ,Gastroenterology ,Young Adult ,Molecular classification ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,White blood cell ,Internal medicine ,Genotype ,medicine ,Humans ,Proto-Oncogene Proteins c-abl ,Gene Rearrangement ,Lymphoid Neoplasia ,business.industry ,Cytogenetics ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,Confidence interval ,medicine.anatomical_structure ,Mutation ,Proto-Oncogene Proteins c-bcr ,Cohort ,Female ,Transcriptome ,Risk assessment ,business - Abstract
Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1− B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non–risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.
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- 2021
48. SSBP2-CSF1R is a recurrent fusion in B-lineage acute lymphoblastic leukemia with diverse genetic presentation and variable outcome
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Mignon L. Loh, Zoe Thorn, Richard Dillon, Gabriele Escherich, Christine Macartney, Christine J. Harrison, Monique L. den Boer, Rachael Hough, Claire Schwab, Doris Steinemann, Kathryn G. Roberts, Judith M. Boer, Gudrun Göhring, Ajay Vora, Giovanni Cazzaniga, Anthony V. Moorman, Brigitte Schlegelberger, Schwab, C, Roberts, K, Boer, J, Gohring, G, Steinemann, D, Vora, A, Macartney, C, Hough, R, Thorn, Z, Dillon, R, Escherich, G, Cazzaniga, G, Schlegelberger, B, Loh, M, Den Boer, M, Moorman, A, and Harrison, C
- Subjects
Adult ,Male ,Fusion transcript, B-lineage Acute Lymphoblastic Leukaemia, Outcome ,Lineage (genetic) ,Adolescent ,Oncogene Proteins, Fusion ,Immunology ,Bioinformatics ,Biochemistry ,Outcome (game theory) ,Translocation, Genetic ,Young Adult ,Text mining ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Humans ,Medicine ,Child ,business.industry ,Cell Biology ,Hematology ,DNA-Binding Proteins ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,Child, Preschool ,Lymphoblastic leukaemia ,Female ,Presentation (obstetrics) ,business - Published
- 2021
49. The EBF1-PDGFRB T681I mutation is highly resistant to imatinib and dasatinib in vitro and detectable in clinical samples prior to treatment
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Jonathan V. Nguyen, Mignon L. Loh, Benjamin S. Braun, Neil P. Shah, Kathryn G. Roberts, Thai Hoa Tran, Catherine C. Smith, Anthony V. Moorman, Meenakshi Devidas, Yunfeng Dai, Charles G. Mullighan, Jon Akutagawa, Adrian Stecula, and Andrej Sali
- Subjects
business.industry ,Imatinib ,PDGFRB ,Hematology ,In vitro ,Dasatinib ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Cancer research ,Medicine ,business ,030215 immunology ,medicine.drug - Published
- 2021
50. DNA-TG and risk of sinusoidal obstruction syndrome in childhood acute lymphoblastic leukemia
- Author
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Stine Nygaard Nielsen, Jacob Nersting, Anthony V. Moorman, Ajay Vora, Linea Natalie Toksvang, Daniel Murdy, Kathrine Grell, and Kjeld Schmiegelow
- Subjects
Cancer Research ,chemistry.chemical_compound ,medicine.medical_specialty ,Oncology ,chemistry ,business.industry ,Internal medicine ,medicine ,Hematology ,business ,Childhood Acute Lymphoblastic Leukemia ,Gastroenterology ,DNA - Published
- 2021
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