The third, and final, day of the scientific programme for the 23rd congress of EHA featured a handful of oral abstracts on chronic lymphocytic leukaemia (CLL). Presentations highlighted some remarkable new clinical and biological research findings. The link between genetic mutations and clinical outcomes was a key focus of much of the research conducted, with the ultimate aim of improving therapeutic outcomes for CLL patients.
Dr Lydia Scarfò delivered a presentation of great clinical interest during the morning’s oral abstract session, revealing that half of CLL patients relapsing under ibrutinib carry Bruton’s tyrosine kinase (BTK) and PLCG2 mutations.
Acquired mutations within the BTK gene impacting the ibrutinib binding site (C481), or, more rarely, the PLCG2 gene, whose gene product is activated by BTK, have been reported in ibrutinib-treated CLL patients before and after relapse. Consequently, the European Research Initiative on CLL (ERIC) study was established to determine the prevalence of BTK and PLCG2 mutations in CLL patients relapsing or responding to ibrutinib in a real-world setting.
Preliminary results from 26 patients (N = 79) revealed that 54% of patients relapsing on ibrutinib had BTKC481 mutations that were often also associated with PLCG2 mutations. Importantly, the absence of mutations in these genes was associated with a longer time to progression compared to patients with mutations (32.5 months vs. 13 months, respectively). Dr Scarfò concluded that these results indicate the outgrowth of several resistant clones. She suggested that multiple resistance mechanisms ought to be studied, with the eventual goal of designing an innovative treatment that will improve outcomes in CLL patients who relapse on ibrutinib.
In addition to the talk by Dr Scarfò, several biological and translational research abstracts of clinical relevance were also presented during the day.
Ibrutinib confers its therapeutic benefit by preventing BTK tyrosine phosphorylation, thereby interfering with BCR pathway signalling. This fact was considered by Dr Gregory Vladimer and colleagues in their research on ibrutinib drug synergies. Dr Vladimer explained in his presentation that despite the high responses achieved by ibrutinib important limitations remain and that even among patients who tolerate long-term treatment a considerable percentage develop drug resistance, BTK-independent disease progression, or Richter’s transformation. He went on to describe the value of ibrutinib drug synergies in improving prognosis.
Initial, preclinical results have been promising for the combined use of ibrutinib with carfilzomib, venetoclax, and abexinostat. However, Dr Vladimer explained that because these approaches were largely empirical, they do not have systematic rational. So, in their research, targetable pathways for synergistic combination therapies were mapped using chromatin profiling and drug sensitivity analyses of peripheral blood from CLL patients, collected before and during therapy with ibrutinib. The aim was to find combination therapies that could potentially improve disease control. The approach was determined to be a powerful tool for identifying targetable pathways in CLL, and Dr Vladimer concluded that this methodology may be useful for designing personalised therapies for patients, as well as assisting in the planning of clinical studies.
Although we are in what would widely be considered the era of targeted therapies for CLL, Dr Jonathan Strefford and colleagues concentrated on a different branch of CLL treatment. Dr Strefford started by outlining the clinical value of exploring disease characteristics in chemo-immunotherapy (CIT) trials and their impact on outcomes. He explained that by identifying features that contribute most to long-term outcomes, we can pinpoint the patients likely to benefit from these therapies. One such feature is the CLL DNA methylome. Pyrosequencing analysis of DNA methylation signatures enabled the investigators to divide CLL into three epigenetic subgroups: memory B cells (m-CLL), naive B cells (n-CLL) and a third intermediate epigenetic subgroup (i-CLL) with borderline mutation status. The aim of the study was to validate the clinical utility of identifying these subgroups in patients entering clinical trials. In total, 605 treatment-naïve patients randomised to chemotherapy (CLL4) and chemo-immunotherapy (ARCTIC and ADMIRE) trials, were categorised into the three epigenetic subgroups. Interestingly, the memory CLL signature was identified as an independent marker of survival in both cohorts, while the n-CLL subgroup had a significantly shorter progression-free survival (PFS) and overall survival (OS) than patients in the other two groups.
Attendees heard how these results provide important evidence for the value of DNA methylation analysis in identifying patients likely to demonstrate durable remissions when treated with these agents.
Though numerous recurrent epigenetic mutations have been identified in CLL, their role in the molecular and clinical pathomechanism is only partly understood. Research from Dr Mertens and colleagues helps fill in some of the missing knowledge gaps between the cancer epigenotype and phenotype. Presenter Viola Meyer-Pannwitt explained how the investigators had profiled the chromatin landscape and the transcriptome in the primary peripheral blood cells of untreated CLL patients and age-matched healthy donors. A substantial increase in the partially methylated genome fraction was identified in CLL patients comparted to controls indicating transcriptional deregulation. This deregulated transcription factor network helps establish the link between the epigenetic pathophenotype of CLL and changes in transcription factor activity. Most importantly, it was concluded that understanding the transcriptional dysregulation of the molecular targets of novel therapies will help to personalise treatment, reduce serious adverse events and thereby optimise outcome of CLL patients in future.
Today marks the end of another fascinating EHA Congress. See below to view the previous days’ highlights, featuring abstracts that represent the forefront of CLL research and clinical findings.
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