The opening day of the scientific programme for the 23rd Congress of EHA did not disappoint delegates with a keen clinical interest in chronic lymphocytic leukaemia (CLL). Featured abstracts included some of the latest clinical and translational research in the field. Topics in the spotlight were wide-ranging and included updates on patient outcomes for already-available treatments, newly-discovered factors of prognostic significance and targets for future drug development.
Venetoclax is an orally bioavailable BCL-2 inhibitor with demonstrated activity in clinical trials for relapsed/refractory CLL patients, including those with del17p or have failed on a B cell receptor pathway inhibitor. Expanded indications for venetoclax in CLL are under investigation, but additional data are needed to understand its use and outcomes in clinical practice. With this in mind, a wealth of new trial and real-world study data are now emerging, including some promising CLL patient outcome and tolerability findings presented in today’s abstract sessions.
Dr John C. Byrd et al. presented results from an ongoing Phase 2 trial which demonstrated robust activity and good tolerability for venetoclax monotherapy in patients with CLL relapsed or refractory to ibrutinib and/or idelalisib. Outcomes were reported to be durable with undetectable minimal residual disease (MRD). Additionally, investigators retrospectively analysing results from the Phase 3 MURANO study, found venetoclax plus rituximab to be superior to bendamustine plus rituximab in high-risk CLL patients with TP53 alterations.
Interim safety analysis results (the first 30 patients) from the Phase 2 HOVON 139/GIVE trial (Dr Levin et al.) were also presented during the afternoon poster session. Results showed that obinutuzumab pre-induction mitigated tumour lysis syndrome (TLS)-risk in all venetoclax-treated patients. Additionally, the CLL14 Phase 3 trial, designed to compare obinutuzumab and venetoclax vs. obinutuzumab and chlorambucil in patients with previously untreated CLL plus coexisting medical conditions, described long-lasting remissions in 13 elderly patients (median age 75 years), including 2 patients with del17p, following treatment with obinutuzumab and venetoclax.
Real-world data is undoubtedly useful in formulating a clearer picture of clinical outcomes among a more heterogenous patient population than is typically included in clinical trials. With this in mind, the largest study of venetoclax-treated CLL patients in community practice to date was conducted and featured in a poster by Dr Chadi Nabhan and colleagues. The study found comparable progression-free survival (PFS), overall survival (OS) and response rates to those reported in clinical trials, with most clinical factors not impacting response to therapy. Venetoclax was well tolerated by patients and few experienced a TLS or haematologic event.
The standard of care for patients with relapsed/refractory CLL is rapidly changing and chemotherapy-free regimens, that can be safely stopped when necessary, are warranted. To this end, the VISION/HOVON 141 study was designed to evaluate whether treatment with venetoclax plus ibrutinib in patients with relapsed/refractory CLL can lead to MRD negativity, allowing MRD-guided treatment cessation. The pre-planned interim analysis, gave promising results; the first set of eligible patients (n = 15) all responded and 53% had a clinical complete response within the first three cycles of treatment. Consequently, the Data and Safety Monitoring Board has recommended continuing the study.
Promising efficacy and tolerability results have also been seen with ibrutinib versus comparators (ofatumumab, chlorambucil or placebo plus bendamustine and rituximab). Dr William Wierda and colleagues found improved sustained haematologic improvement in haemoglobin and platelet levels with ibrutinib vs. comparators for both first-line and relapsed/refractory patients in a side-by-side presentation of three phase 3 clinical studies (RESONATE, RESONATE-2 and HELIOS). This large analysis included a total of 1,238 patients. Moreover, the overall response rate (ORR) and PFS improvements with ibrutinib were maintained vs. comparators and rates of severe haematologic AEs remained low.
The durability of ibrutinib efficacy was also demonstrated with 4-year follow-up results from the RESONATE‑2 extension study (Dr. Jan A Burger et al.) which illustrated a substantial 86% risk reduction of progressive disease or death versus chlorambucil. Ibrutinib improved the PFS including in patients with high-risk features such as del11q or UM-IGHV and preserved PFS in patients with or without del11q or UM-IGHV.
Complete response rates improved with prolonged follow-up. Regarding tolerability, investigators found that discontinuation due to AEs decreased over time, with 65% of ibrutinib patients continuing daily treatment.
The day’s presidential symposium reported findings from some of the most noteworthy abstracts of the conference. Attendees heard Dr Valentin Goede discuss findings from the Phase 3 CLL11 study evaluating the efficacy and safety of glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab plus chlorambucil in patients with previously untreated CLL and comorbidities.
Dr Goede reiterated the superiority of obinutuzumab + chlorambucil over chlorambucil alone and over rituximab + chlorambucil, that has already been established in previous pre-planned analyses. This final analysis of the CLL11 study, with ~2 years additional follow-up, confirms the clinically meaningful benefits conferred by obinutuzumab + chlorambucil in CLL patients with comorbidities, including prolongation of PFS and OS (compared with chlorambucil alone and rituximab + chlorambucil). An absolute treatment-free duration of approximately four and a half years was also observed. These findings support the use of obinutuzumab plus chlorambucil as first-line treatment for CLL patients with comorbidities.
New mutations of prognostic significance were reported in the poster sessions, including NOTCH1, TP53, SF3B1, ATM or BIRC3, which were found to be associated with shorter overall survival (OS) and time to first treatment (TFT) in 13q- CLL patients, and the IGLV3-21G110R mutation, which also has an unfavourable prognostic impact.
In addition to research conducted on biomarkers that may enable determination of more accurate prognosis for CLL patients, a key focus for many of the abstracts presented was novel therapeutic targets.
In terms of drugs already in development, the Phase 3 DUO extension study, found that duvelisib (an oral dual inhibitor of PI3K-δ, γ) monotherapy achieved robust and durable responses in 89 relapsed/refractory CLL/SLL patients with confirmed progressive disease following ofatumumab treatment, with a longer PFS with duvelisib than prior ofatumumab. In addition, anti-CD19 antibody MOR208 + idelalisib showed promising antitumor activity and acceptable safety and tolerability in patients with relapsed/refractory CLL who fail on ibrutinib.
Each day of EHA, we have written you a blog outlining some of the highlights of the research that is pushing the boundaries of our CLL knowledge. Check our highlights of Day 2 featuring summaries of some of the latest CLL innovations and clinical findings.