Richter's transformation: Transforming the clinical landscape.

Richter transformation (RT) represents an aggressive histological transformation from chronic lymphocytic leukaemia, most often to a large B cell lymphoma. It is characterised by chemo-resistance and subsequent short survival. Drug development has struggled over recent years in light of the aggressive kinetics of the disease, lack of pivotal registrational trials and relative rarity of the phenomenon. In this review we will highlight the diagnostic and therapeutic challenges of managing patients with RT as well as taking a look to the future therapeutic landscape. Highly active therapies developed across B cell malignancies are starting to impact this field, with T-cell activation therapies (CAR-T, bispecific antibodies), antibody-drug conjugates, and novel small molecule inhibitor combinations (e.g. BTKi-BCL2i) being actively studied. We will highlight the data supporting these developments and look to the studies to come to provide hope for patients suffering from this devastating disease.

Correction: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.

Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

This corrects the article DOI: 10.1038/leu.2017.177.

Targeted deep sequencing reveals clinically relevant subclonal IgHV rearrangements in chronic lymphocytic leukemia.

The immunoglobulin heavy-chain variable region gene (IgHV) mutational status is considered the gold standard of prognostication in chronic lymphocytic leukemia (CLL) and is currently determined by Sanger sequencing that allows the analysis of the major clone. Using next-generation sequencing (NGS), we sequenced the IgHV gene from two independent cohorts: (A) 270 consecutive patient samples obtained at diagnosis and (B) 227 patients from the UK ARCTIC-AdMIRe clinical trials. Using complementary DNA from purified CD19+CD5+ cells, we demonstrate the presence of multiple rearrangements in independent experiments and showed that 24.4% of CLL patients express multiple productive clonally unrelated IgHV rearrangements. On the basis of IgHV-NGS subclonal profiles, we defined five different categories: patients with (a) multiple hypermutated (M) clones, (b) 1 M clone, (c) a mix of M-unmutated (UM) clones, (d) 1 UM clone and (e) multiple UM clones. In population A, IgHV-NGS classification stratified patients into five different subgroups with median treatment-free survival (TFS) of >280(a), 131(b), 94(c), 29(d), 15(e) months (P<0.0001) and a median OS of >397(a), 292(b), 196(c), 137(d) and 100(e) months (P<0.0001). In population B, the poor prognosis of multiple UM patients was confirmed with a median TFS of 2 months (P=0.0038). In conclusion, IgHV-NGS highlighted one quarter of CLL patients with multiple productive IgHV subclones and improves disease stratification and raises important questions concerning the pre-leukemic cellular origin of CLL.

Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia.

Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome-wide array based study of pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies.

ASTI: a guideline-based drug-ordering system for primary care.

Existing computer-based ordering systems for physicians provide effective drug-centered checks but offer little assistance for optimizing the overall patient-centered treatment strategy. Evidence-based clinical practice guidelines have been developed to disseminate state-of-the-art information concerning treatment strategy but these guidelines are poorly used in routine practice. The ASTI project aims to design a guideline-based ordering system to enable general practitioners to avoid prescription errors and to improve compliance with best therapeutic practices. The " critic mode " operates as a background process and corrects the physician's prescription on the basis of automatically triggered elementary rules that account for isolated guideline recommendations. The " guided mode " directs the physician to the best treatment by browsing a comprehensive guideline knowledge base represented as a decision tree. A first prototype, applied to hypertension, is currently under development.

Identification of patients at high cardiovascular risk: a critical appraisal of applicability of statistical risk prediction models.

Assessment of cardiovascular risk is widely proposed as a basis for taking management decisions about patients presenting with hypertension or hypercholesterolemia. Our aim was to critically assess the use of risk equations derived from epidemiological studies for the purpose of identifying high-risk patients. Risk equations were retrieved from the MEDLINE database and then applied to a data set of 118 patients. This data set was an evaluation study of the clinical value of the World Health Organization 1993 hypertension guidelines for the decision to treat mild hypertensive patients. We calculated agreement: 1) between equations and 2) between equations and the decision to treat taken by the physician. Most models were not applicable to our population, mainly because the original population had a narrow age range or comprised only males. Between-model agreement was better for the lower and upper risk quintiles than for the three other risk quintiles (0.58, 0.33, 0.34, 0.45, 0.70, from the lower to the upper risk quintile). When using an arbitrary threshold for defining high-risk patients (i.e. > 2% per year), we observed a huge variation of the proportion of patients classified at high risk (from 0 to 17%). There was a poor agreement between risk models and the decision to treat taken by the physician. These results suggest that risk-based guidelines should be validated before their diffusion.

A critical appraisal of the use of Internet for calculating cardiovascular risk.

This paper aims to retrieve and evaluate the quality of the Internet sites providing information on cardiovascular risk. We searched web pages related to risk prediction using six search engines. Sites proposing a cardiovascular risk prediction were selected for evaluation. The quality of each site was checked against criteria testing the validity, type and potential usefulness of information for physicians or patients. Search engines retrieved about 50 10(6) web pages. Eight sites were included. Only 2 of them provided calculation of cardiovascular risk based on Framingham equation. The others proposed algorithms, guidelines, or general information on cardiovascular health. Most sites lacked details to ensure quality of information. Present search engines are inefficient to retrieve precise and valid information. Facing the inflation of medical information, a systematic approach to validate the quality of a site is mandatory. Application of Evidence Based Medicine concepts gives a solution for evaluation of internet-based medical information.

[Arterial hypertension and cerebrovascular accident: the need for improved prevention strategies]. / Pression artérielle et accident vasculaire cérébral: nécessité d'améliorer les stratégies de prévention.

It is well demonstrated that the antihypertensive treatment is effective, particularly for the primary prevention of stroke. However, benefits of treatment are rather small in certain groups of patients. The explicit assessment of absolute cardiovascular risks and likely treatment benefits in patients with hypertension can usefully guide treatment decisions and provide a more rational basis for initiating therapy than blood pressure levels alone. This approach highlights the generally greater cardiovascular risk and potential treatment benefits in older compared with younger hypertensive patients. Some specific questions remain still unanswered. Evidence is accumulating concerning protective effect of antihypertensive treatment against dementia. Trials are in progress to investigate the effect of treatment on stroke incidence in hypertensive patients over the age of 80 years. Finally, despite the worldwide use of calcium antagonists and converting enzyme inhibitors, solid evidence of their safety and efficacy compared with the references drugs (beta-blockers and diuretics) is still lacking.