Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation

Arm Based on LEg blood pressures (ABLE-BP): can systolic leg blood pressure measurements predict systolic brachial blood pressure? Protocol for an individual participant data meta-analysis from the INTERPRESS-IPD Collaboration

International audienceIntroduction Blood pressure (BP) is normally measured on the upper arm, and guidelines for the diagnosis and treatment of high BP are based on such measurements. Leg BP measurement can be an alternative when brachial BP measurement is impractical, due to injury or disability. Limited data exist to guide interpretation of leg BP values for hypertension management; study-level systematic review findings suggest that systolic BP (SBP) is 17 mm Hg higher in the leg than the arm. However, uncertainty remains about the applicability of this figure in clinical practice due to substantial heterogeneity. Aims To examine the relationship between arm and leg SBP, develop and validate a multivariable model predicting arm SBP from leg SBP and investigate the prognostic association between leg SBP and cardiovascular disease and mortality. Methods and analysis Individual participant data (IPD) meta-analyses using arm and leg SBP measurements for 33 710 individuals from 14 studies within the Inter-arm blood pressure difference IPD (INTERPRESS-IPD) Collaboration. We will explore cross-sectional relationships between arm and leg SBP using hierarchical linear regression with participants nested by study, in multivariable models. Prognostic models will be derived for all-cause and cardiovascular mortality and cardiovascular events. Ethics and dissemination Data originate from studies with prior ethical approval and consent, and data sharing agreements are in place—no further approvals are required to undertake the secondary analyses proposed in this protocol. Findings will be published in peer-reviewed journal articles and presented at conferences. A comprehensive dissemination strategy is in place, integrated with patient and public involvement. PROSPERO registration number CRD42015031227

The cost-effectiveness of mycophenolate mofetil (MMF) as firstline therapy in active lupus nephritis

Objectives. Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect any system of the body. Involvement of the kidneys, lupus nephritis (LN), affects up to 50% of SLE patients during the course of their disease, and is characterized by periods of active disease (flares) and remission. For more severe nephritis, an induction course of immunosuppressive therapy is recommended. Options include intravenous cyclophosphamide (IVC) or mycophenolate mofetil (MMF), followed by a maintenance course, typically of azathioprine. The objective of this study is to determine which therapy results in better quality of life (QoL) for patients and which represents best value for money for finite health service resources. Methods. A patient-level simulation model is developed to estimate the costs and quality-adjusted life-years (QALYs) of a patient treated with IVC or MMF for an induction period of six months. Efficacy, QoL, resource use and cost data are extracted from the literature and standard databases and supplemented with expert opinion where necessary. Results. On average, the model predicts MMF to result in improved QoL compared with IVC. MMF is also less expensive than IVC, costing pound1600 (euro2400; US$3100) less over the period, based on 2005 NHS prices. The major determinant and cost driver of this result is the requirement for a day-case procedure to administer IVC. Sensitivity analysis shows an 81$58 500) per QALY gained. Conclusion. MMF is likely to result in better QoL and be less expensive than IVC as induction therapy for LN

Arm Based on LEg blood pressures (ABLE-BP): can systolic leg blood pressure measurements predict systolic brachial blood pressure? Protocol for an individual participant data meta-analysis from the INTERPRESS-IPD Collaboration

Introduction Blood pressure (BP) is normally measured on the upper arm, and guidelines for the diagnosis and treatment of high BP are based on such measurements. Leg BP measurement can be an alternative when brachial BP measurement is impractical, due to injury or disability. Limited data exist to guide interpretation of leg BP values for hypertension management; study-level systematic review findings suggest that systolic BP (SBP) is 17 mm Hg higher in the leg than the arm. However, uncertainty remains about the applicability of this figure in clinical practice due to substantial heterogeneity.Aims To examine the relationship between arm and leg SBP, develop and validate a multivariable model predicting arm SBP from leg SBP and investigate the prognostic association between leg SBP and cardiovascular disease and mortality.Methods and analysis Individual participant data (IPD) meta-analyses using arm and leg SBP measurements for 33 710 individuals from 14 studies within the Inter-arm blood pressure difference IPD (INTERPRESS-IPD) Collaboration. We will explore cross-sectional relationships between arm and leg SBP using hierarchical linear regression with participants nested by study, in multivariable models. Prognostic models will be derived for all-cause and cardiovascular mortality and cardiovascular events.Ethics and dissemination Data originate from studies with prior ethical approval and consent, and data sharing agreements are in place—no further approvals are required to undertake the secondary analyses proposed in this protocol. Findings will be published in peer-reviewed journal articles and presented at conferences. A comprehensive dissemination strategy is in place, integrated with patient and public involvement.PROSPERO registration number CRD42015031227

Multicentre Genome Wide Association Study Identifies Risk Alleles for Progressive Chronic Lymphocytic Leukaemia [Conference Abstract]

The increased incidence of chronic lymphocytic leukemia (CLL) in first-degree relatives of affected patients indicates an element of genetic susceptibility to this malignancy, borne out in large scale genome-wide association studies (GWAS), which have identified over 40 constitutional risk alleles. Given the important genetic contribution to CLL susceptibility we hypothesized that constitutional genetic variants also affect disease progression. We employed GWAS methods in a large United Kingdom multi-center cohort study of well-characterized predominantly early-stage CLL cases to identify risk alleles for progressive CLL. We conducted six GWAS for single nucleotide polymorphisms (SNPs) associating with progressive CLL incorporating a total of 774 cases of European ancestry recruited to 6 clinical centers across the United Kingdom. CLL cases were genotyped on the Illumina OmniExpress platform and genotypes were determined using Illumina GenomeStudio software. After imputation, we combined the association test statistic for 5,199,911 autosomal SNPs common to all 6 GWAS after exclusion of those with an imputation quality score of <0.9 and a minor allele frequency (MAF) of < 2.5%, and conducted a meta-analysis under a fixed-effect model. The primary outcome assessed was time to first treatment (TTFT), defined as the interval between CLL diagnosis and first treatment or last follow-up. Pooling data from the 6 GWAS identified 5 SNPs at two genomic locations that surpassed genome-wide significance (P ≤ 5 x 10-8) for association with TTFT. The strongest statistical evidence for an association with progressive disease was for rs736456 (hazard ratio (HR) = 1.76, 95% confidence interval (CI) = 1.45-2.14; P = 1.26 x 10-8), which maps to chromosome 10q26.13. The second strongest association with progressive disease was for rs3778076 (HR = 2.03, 95% CI = 1.58-2.62; P = 3.89 x 10-8) which maps to chromosome 6p. Both markers showed consistent direction and magnitude of effect sizes across all six GWAS with no evidence of heterogeneity, and retained prognostic significance in multivariate models for disease progression, particularly in models restricted to Binet A patients. Whilst not as powerful as IGVH status, rs736456 and rs3778076 had prognostic utility equivalent to CD38 status, and are particularly powerful when considered together, identifying 5% of CLL patients carrying 2 or more risk alleles at high risk of progressive disease (Figure). To identify cis-regulated genes at each locus associated with progressive disease we interrogated gene expression data derived from a meta-analysis of 31,624 blood samples collated by the eQTLGen consortium. Of the thirteen genes annotated to within 1Mb of the chromosome 10 association signal rs736456 is eQTL for the PLEKHA1 gene (TAPP-1)(Benjamini-Hochberg corrected P-value [P BH] = 1.29 x 10-15). Of the 27 genes annotated to within 1Mb of the chromosome 6 signal, rs3778076 is eQTL for 5 genes including UHRF1BP1 (PBH = 6.73 x 10-139) and C6ORF106 (PBH = 3.54 x 10-64). Annotated genes at both loci have been implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. Data on post-treatment survival were available on 390 CLL cases, with 231 deaths and 159 censored at last follow-up, and neither the lead SNP at chromosome 10 or chromosome 6 were significantly associated with post-treatment survival in patients primarily treated with regimens that included chlorambucil, fludarabine or cyclophosphamide. It will be important to determine whether these markers predict overall survival in patients treated with novel targeted therapies. Taken together, these data identify rs736456 and rs3778076 as prognostic in early stage CLL patients demonstrating that progression of CLL from asymptomatic to symptomatic disease is determined by constitutional genetic variation as well as the more established somatic drivers. Constitutional genetic markers have the advantage of being easy to perform, highly reproducible and inexpensive making them ideal for incorporation into multivariate prognostication models for early stage CLL. Figure Disclosures Fegan: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Other: Conference attendance sponsorship. Forconi: Gilead Sciences: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Honoraria; Menarini: Consultancy; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Honoraria. Schuh: AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Verastem: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Kite: Speakers Bureau. Hillmen: Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Pratt: Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation