Day 2 of the 23rd Congress of EHA carried on from where the first day left off with speakers, abstracts and posters covering a diverse range of topics in clinical and translational research in chronic lymphocytic leukaemia (CLL). Interesting evidence-based approaches to diagnosis, prognosis and treatment were presented throughout the day, alongside exciting proposals for novel treatment targets that may be utilised in the future.
As evidenced by a large-scale population study conducted in the Netherlands and presented today by Dr Lina van der Straten et al., improvements in survival time are increasing among CLL patients. The nationwide study suggests advances in supportive care, improved management, and the introduction of novel agents as likely reasons for this. However, CLL follows a heterogenous course, so how can we better predict outcomes in patients? Several of today’s abstracts presented results from different strategies developed to help achieve this goal.
Dr Lodovico Terzi di Bergamo and colleagues delivered their evaluation of a new prognostic model developed for patients with Binet A CLL. Some patients with this subclassification of CLL live for decades without therapy, while others require therapy within months of diagnosis, so determining an accurate prognosis can be tricky. The “Binet A model” was developed to combine routine clinical and genetic variables into an easily applicable prognostic score. Validation results were promising, and investigators suggested it may help in the design of clinical trials testing and to give more accurate counselling for patients regarding the implications of their disease.
Minimal residual disease (MRD) in CLL is an independent predictor of outcome and using MRD to guide treatment duration is under evaluation in several trials. Dr Remi Letestu et al., presented results from their study investigating the prognostic value of high-sensitivity MRD testing. They concluded with the suggestion that blood-sensitive MRD testing could be used as a routine tool in future and thus reduce the need for bone marrow assessment in MRD-driven therapeutic strategies. Minimal residual disease was also the topic of Dr Peter Hillmen’s presentation, in which he explained how the Phase 3 MURANO study, had confirmed the value of blood MRD for correlation with clinical outcome, in patients with relapsed/refractory CLL treated with venetoclax + rituximab.
As described by Dr Carsten Niemann et al., infections are a significant cause of morbidity and mortality in CLL. The clinical importance of identifying patients at high risk of infection prior to treatment is therefore to enable effective pre-emptive and prophylactic measures. By applying machine learning models to baseline characteristics and laboratory values of known prognostic significance (cytogenetics, IGHV mutational status, beta-2 microglobulin, clinical stage and age) the authors of this study identified a sub-population (24%) of CLL patients at high risk of early infection or treatment. More specifically, this group had an estimated 70% risk of infection or CLL treatment within two years of diagnosis. A randomised, pre-emptive trial with targeted therapy for this patient population is now planned.
Ibrutinib, an oral, selective inhibitor of Bruton’s tyrosine kinase (BTK), has been previously to be an effective treatment option for patients with relapsed/refractory CLL, as well as in untreated patients with genetic abnormalities which predict chemoresistance (i.e. TP53 deletion or mutation), and was featured in a few of today’s noteworthy abstracts.
Dr. Paolo Ghia opened his oral presentation by explaining that although ibrutinib as a single-agent results in improved survival, complete response (CR) rates are low, and continuous therapy is required. Delegates then heard how ibrutinib and venetoclax have complementary therapeutic activity, and that early study results from CAPTIVATE (a Phase II, multicentre study of ibrutinib plus venetoclax in first-line CLL), support the safety, activity, and tumour lysis syndrome risk reduction potential of ibrutinib lead-in.
Further to this, results from a multicentre Phase II trial exploring the efficacy of an induction treatment associating obinutuzumab and ibrutinib (followed by immunochemotherapy in case of partial response or detectable MRD) were also presented. The study by Dr Pierre Feugier et al., found that the 9-month, chemotherapy-free induction was associated with a high complete response rate (41%). However, most patients required subsequent immuno-chemotherapy because of detectable bone marrow MRD.
A thought-provoking poster presentation by Dr Giovanni Del Poeta and colleagues, described how NOTCH1 mutations may confer poor response to ibrutinib in CLL. NOTCH1 mutations were confirmed as an independent prognostic factor for CLL.
Of note, it was suggested that venetoclax could be combined with BTK inhibitors, to overcome ibrutinib resistance in some patients, particularly within the CLL subset characterised by NOTCH1 mutation.
Dr Anthony R. Mato delivered an interesting afternoon oral presentation on umbralisib, a novel, highly-specific PI3K-δ inhibitor that also uniquely inhibits CK-1ε (Casein Kinase-1ε). Attendees heard that although kinase inhibitor (KI) therapies such as ibrutinib are generally well tolerated, intolerance is still the most common reason for discontinuation. Research findings highlighted that switching from ibrutinib, acalabrutinib or idelalisib to umbralisib can result in durable responses without recurrence of prior KI intolerance toxicities.
In addition, Dr. Matthew Davids presented his results from a Phase Ib/II study which concluded that duvelisib (a delta/gamma PI3K inhibitor), plus fludarabine, cyclophosphamide, rituximab (FCR) was an effective regimen for the initial therapy of younger, fit CLL patients, leading to a high rate of bone marrow MRD negativity, although it is also important to note that infectious and immune-mediated toxicities were observed.
Read our highlights from the final day of this premier haematology congress for the latest innovations and clinical findings in CLL. See day 3 here.