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The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression. Synopsis: Combined perturbation by microenvironmental stimuli and drugs of chronic lymphocytic leukaemia cells annotated for genetic alterations reveals distinct response patterns and molecular modulators. CLL samples fall into four subgroups with distinct progression dynamics based on their microenvironmental response.Trisomy 12 enhances the response to microenvironmental stimulation and has a distinct transcription factor activity profile which is inhibited by IBET‐762 treatment.Linear modelling reveals different types of drug ‐ stimuli interactions, the most common being drug resistance induced by microenvironmental stimulation.IL4 and TLR signalling is more active in CLL infiltrated lymph nodes, and higher IL4 signalling activity correlates with faster disease progression. [ABSTRACT FROM AUTHOR]

The article reports on a study which investigated the impact of telomere length on the outcome of allogeneic stem cell transplantation (SCT) for patients with poor risk chronic lymphocytic leukaemia (CLL) based on the German CLL3X trial which included 100 patients. Topics covered include association of telomere length with clinical characteristics, and analysis of telomere length using quantitative polymerase chain reaction.

The best approach for allogeneic haematopoietic stem cell transplantations (allo HCT) in patients with chronic lymphocytic leukaemia ( CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival ( EFS) in a large retrospective study. Data of 684 CLL patients who received a first allo HCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [ CI], 34-42%). Larger numbers of CLL allo HCTs (hazard ratio [ HR] 0·96, P = 0·002), certification of quality management ( HR 0·7, P = 0·045) and a higher gross national income per capita ( HR 0·4, P = 0·04) improved EFS. In vivo T-cell depletion ( TCD) with alemtuzumab compared to no TCD ( HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient ( HR 1·4, P = 0·02) had a negative impact on EFS, but not non-myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL. [ABSTRACT FROM AUTHOR]

Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were most frequently mutated (16-3%, 16-9%, 10-7%). We found evidence for subclonal mutations in 67-5% of CLL cases with mutations of cancer consensus genes. We observed selection of subclones and found initial evidence for convergent mutations in CLL. Our data suggest that assessment of (sub)clonal structure may need to be integrated into analysis of the mutational profile in CLL. [ABSTRACT FROM AUTHOR]