Papers by Rosemary Sutton
Bone Marrow Transplantation, 2016
Cancer Research, 2016
Introduction: Despite the improved survival of patients with T-cell acute lymphoblastic leukemia ... more Introduction: Despite the improved survival of patients with T-cell acute lymphoblastic leukemia (T-ALL), therapy-resistant or refractory T-ALL remains a major clinical challenge. Recently, we and others reported promising therapeutic activity for ABT-199, a highly specific inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), especially in immature T-ALL. Nevertheless, the occurrence of dose-limiting toxicities and the emergence of therapy resistance provides a rationale for the evaluation of ABT-199 as part of combination therapies. Indeed, previous studies have shown that ABT-199 can synergize with conventional chemotherapeutic agents in human T-ALL. BRD4 is an important bromodomain and extra-terminal (BET) protein that facilitates the recruitment of the transcriptional apparatus to acetylated chromatin. Small molecule inhibitors that target BET-bromodomain proteins, such as JQ1, can broadly affect oncogenic gene transcription and have recently emerged as powerful an...
Leukemia, 2015
Deletions in IKZF1 are found in~15% of children with B-cell precursor acute lymphoblastic leukemi... more Deletions in IKZF1 are found in~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P o0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P = 0.03), DEL 2-8 (P = 0.002) and DEL-Other (P o0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
Journal of Clinical Oncology, 2011
Purpose Relapse of childhood T-cell acute lymphoblastic leukemia (T-ALL) often occurs during trea... more Purpose Relapse of childhood T-cell acute lymphoblastic leukemia (T-ALL) often occurs during treatment, but in some cases, leukemia re-emerges off therapy. On the basis of previous analyses of T-cell receptor (TCR) gene rearrangement patterns, we hypothesized that some late recurrences of T-ALL might in fact represent second leukemias. Patients and Methods In 22 patients with T-ALL who had late relapses (at least 2.5 years from diagnosis), we studied TCR gene rearrangement status at first and second presentation, NOTCH1 gene mutations, and the presence of the SIL-TAL1 gene fusion. We performed genome-wide copy number and homozygosity analysis by using oligonucleotide- and single nucleotide polymorphism (SNP) –based arrays. Results We found evidence of a common clonal origin between diagnosis and relapse in 14 patients (64%). This was based on concordant TCR gene rearrangements (12 patients) or concordant genetic aberrations, as revealed by genome-wide copy number analysis (two patie...
Leukemia, 2013
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with hig... more Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (B90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL,
Leukemia, 2021
Fusions of NUTM1 (15q14) define a novel subtype of B-cell precursor acute lymphoblastic leukemia ... more Fusions of NUTM1 (15q14) define a novel subtype of B-cell precursor acute lymphoblastic leukemia (B-ALL) that is mutually exclusive with sentinel leukemia-driving aberrations based on RNA-sequencing in children [1-5] and infants [3, 6]. NUTM1 fusions are characterized by increased expression of almost the complete open reading frame of NUTM1 fused to one of several fusion partners. Downstream effects of NUTM1 fusions include upregulation of the proto-oncogene BMI1 [3]. In addition, specific NUTM1 fusions are associated with HOXA gene cluster upregulation [1, 3]. The incidence of NUTM1-rearranged ALL appears to be low, but reported series are small. The subtype may be more prevalent in infants without KMT2A rearrangement, suggested by RNA-sequencing [3, 6] and 15q aberrations [7]. Since not all NUTM1 fusions are obvious from the karyotype [8], the estimated frequency could be higher. We determined the frequency, characteristics, and outcome of NUTM1-rearranged BALL in a large series of 85 cases in a Ponte di Legno Childhood ALL Working Group study. Interfant-related study groups provided NUTM1 screening results for KMT2A-wildtype infants from the Interfant-99 [9] and-06 [10] cohorts (2000-2016) with a karyotypic 15q aberration, a normal karyotype, or missing karyotype (Supplementary Fig. S1).
Objective: To compare disease presentation and outcome in Aboriginal and non-Aboriginal children ... more Objective: To compare disease presentation and outcome in Aboriginal and non-Aboriginal children with acute leukaemia and to assess the impact of remoteness and area-based socioeconomic disadvantage. Design: A retrospective review of children treated for acute leukaemia from South Australia (SA), Northern Territory (NT) and Western Australia (WA) between 2009 and 2018. Setting: Women's and Children's Hospital (WCH), Adelaide and Perth Children's Hospital (PCH)-the sole referral sites for paediatric cancer for SA, NT and WA. Participants: Eligible patients, aged between 1 day and <18 years, diagnosed with acute leukaemia. Main Outcome Measures: Leukaemia diagnosis and overall survival. Results: Analysis of 455 children treated for acute leukaemia showed inferior survival outcomes were associated with remote/very remote localities (p=0.004). Five-year overall survival was 91.7% (95% CI: 87.9%-94.3%) for children with ALL and 69.8% (56.7%-79.5%) for AML. A large percentage of Aboriginal children from SA/NT were diagnosed with AML compared to others (60.0% vs. 14.4%, p=0.001). A trend towards inferior overall survival was seen for Aboriginal children with ALL compared to non-Aboriginal children (82.4% vs. 92.2%, p=0.07) and 55.6% were high-risk by study criteria; however, MRD testing did not identify any high MRD cases. Aboriginal children were less likely to be enrolled on clinical trials (34.5% vs. 53.1%, p=0.03) and more likely to be lost to follow-up (41.4% vs. 13.2%, p<0.001). Conclusion: Aboriginal ethnicity and geographic remoteness of residence are adverse prognostic factors for Australian children with leukaemia. Additional strategies are required to ensure improvements in follow-up and survival of these children.
Cancers, 2020
Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lym... more Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p < 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10−7) that has been previously as...
Blood Advances, 2020
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of... more Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of risk-adapted therapy has been instrumental in the dramatic improvements in clinical outcomes. A key to risk-adapted therapies includes the identification of genomic features of individual tumors, including chromosome number (for hyper- and hypodiploidy) and gene fusions, notably ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 in B-cell ALL (B-ALL). RNA-sequencing (RNA-seq) of large ALL cohorts has expanded the number of recurrent gene fusions recognized as drivers in ALL, and identification of these new entities will contribute to refining ALL risk stratification. We used RNA-seq on 126 ALL patients from our clinical service to test the utility of including RNA-seq in standard-of-care diagnostic pipelines to detect gene rearrangements and IKZF1 deletions. RNA-seq identified 86% of rearrangements detected by standard-of-care diagnostics. KMT2A (MLL) rearrangements, although usually identified, were ...
Blood, 2019
Background - Conventional chemotherapy for adults with Acute Lymphoblastic Leukaemia (ALL) is ass... more Background - Conventional chemotherapy for adults with Acute Lymphoblastic Leukaemia (ALL) is associated with considerable treatment-related toxicity. Blinatumomab is a CD19/CD3 targeting bi-specific T-cell engager that has demonstrated promising efficacy in relapsed/refractory ALL, and in combination with chemotherapy in newly diagnosed patients. Preliminary studies also suggest less toxicity and good efficacy (CR/CRh 66%) when delivered as induction to older adults (median age 75) with newly diagnosed B-ALL (Advani, ASH 2018). Of responders, Minimal Residual Disease (MRD) negativity in this trial was achieved in 92%. Given this, the Australasian Leukaemia & Lymphoma Group (ALLG) has explored the potential for upfront Blinatumomab as induction for younger adults with Ph- B-lineage Acute Lymphoblastic Leukaemia, alternating with CNS-directed chemotherapy cycles. Aim - To assess response to therapy of the first 10 patients enrolled on this study by molecular MRD analysis as a surroga...
Blood, 2019
Eighty-six newly diagnosed Philadelphia-negative ALL pts were enrolled from 2012 to 2018, from 14... more Eighty-six newly diagnosed Philadelphia-negative ALL pts were enrolled from 2012 to 2018, from 14 Australian centres; 82 pts were evaluable. Pts were stratified and treated as per the pediatric ANZCHOG Study 8 protocol based on BFM 2000. Response was assessed on day 33 and 79 by morphology, flow cytometry and RQ-PCR measurable residual disease (MRD) at a central lab according to EuroMRD criteria. Allogenic stem cell transplantation was permitted for high and very high-risk disease groups. Detailed genomic analysis was performed in 47 pts (to date), using whole transcriptome sequencing (mRNA Seq) and multiplex ligation-dependent probe amplification (MLPA) for recurrent ALL related gene deletions. Median age of the study was 24 (16 - 38) years; 28% were female; 59/82 (72%) had B-ALL. Median follow up was 36 (range 3-73) months. Induction mortality was 3.6%. CR rate at day 33 was 90.4% and day 79 (time point 2, TP2) 97.6%. Relapse free survival (RFS) at 2 years was 75.6% (95%CI 65.6 - ...
Blood Advances, 2019
Key Points Low or nondetectable MRD pre-HCT leads to similar outcomes, suggesting that MRD negati... more Key Points Low or nondetectable MRD pre-HCT leads to similar outcomes, suggesting that MRD negativity is not an absolute prerequisite for HCT. MRD post-HCT is more important than pre-HCT, and monitoring with sensitive techniques can detect very high-risk patients early.
British Journal of Haematology, 2018
Blood, 2010
3303 Introduction: Despite improvement in frontline therapy in childhood acute lymphoblastic leuk... more 3303 Introduction: Despite improvement in frontline therapy in childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) relapse remains a significant clinical problem. The ALLR3 trial (ISCRTN 45724312) was designed specifically to address this issue with the use of drugs known to penetrate the CNS. The trial incorporated a randomization between Mitoxantrone and Idarubicin during induction. Mitoxantrone showed an early benefit in all patients resulting in closure of the randomization in December 2007 (ASH Annual Meeting Abstracts, Nov 2009; 114:3390). Subsequently all patients now receive Mitoxantrone. Here we report on the outcome of patients with isolated CNS relapse (iCNSr) or combined CNS relapse (involvement of CNS and bone marrow, cCNSr). Methods: CNS involvement was defined as ≥5 WBC/μl with morphological evidence of blasts in the cerebrospinal fluid (CSF). Combined relapse (cCNSr) was defined as CNS disease with ≥ 5% blasts in the bone marrow. Time to relaps...
Translational Oncology, 2019
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell p... more IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of BALL with COBL rearrangements (COBL-r). Patients with BALL and IKZF1 deletion (n = 133) were included. IKZF1 1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%),
Biology of Blood and Marrow Transplantation, 2018
Blood Advances, 2019
Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymp... more Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)–CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide...
British journal of cancer, 2018
Zinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lympho... more Zinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) and here we further characterised their prevalence, survival outcomes and transcriptome. Bone marrow mononuclear cells from 274 BCR-ABL1-negative pre-B-ALL patients were immunophenotyped and transcriptome molecularly characterised. Transcriptomic data was analysed by principal component analysis and gene-set enrichment analysis to identify gene and pathway expression changes. We exclusively detect E1A-associated protein p300 (EP300)-ZNF384 in 5.7% of BCR-ABL1-negative adolescent/young adult (AYA)/adult pre-B-ALL patients. EP300-ZNF384 patients do not appear to be a high-risk subgroup. Transcriptomic analysis revealed that EP300-ZNF384 samples have a distinct gene expression profile that results in the up-regulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) and cell adhesion pathways and down-regulation of cell cycle and DN...
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Papers by Rosemary Sutton