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Visiting Professor of Haematology
Department of Haematology
Anglia Ruskin Medical School
Department of Haematology
Cambridge University Hospitals
Cambridge, United Kingdom
George Follows, BM, BCh, PhD, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, Celgene, Janpix, Janssen, Karyopharm, Kite, and Roche; has received fees for non-CME/CE services from AbbVie, AstraZeneca, Janssen, and Roche; and has ownership interest in Janpix.
In this commentary, George Follows, BM, BCh, PhD, provides his thoughts on updated data from key studies in chronic lymphocytic leukemia (CLL) that were presented at the 2021 meetings of the American Society of Clinical Oncology (ASCO), European Hematology Association (EHA), and International Conference on Malignant Lymphoma (ICML). These conferences have provided reassuring updates and new data for hematologists who treat patients with CLL and certainly for the patients themselves. For the first time in CLL, there are comparative data showing how one BTK inhibitor may differ from another, and there has been extended follow-up of some of the landmark trials of BTK inhibitors. In addition, there are new data on BTK inhibitors combined with venetoclax, a new way of taking doublet therapy forward into the future.
Head-to-Head Phase III Trials of BTK Inhibitors in Relapsed/Refractory CLL
Interim analysis data from the randomized phase III ALPINE trial were reported at EHA 2021. In this noninferiority trial, zanubrutinib, a novel irreversible BTK inhibitor, was compared with ibrutinib for treating patients with relapsed/refractory CLL (N = 415 at this interim analysis). The primary endpoint was investigator-assessed overall response rate (ORR). A significantly higher ORR was observed for patients who received zanubrutinib vs ibrutinib (78.3% vs 62.5%, respectively; P = .0006). Of importance, ORR in this trial included partial and complete responders and excluded partial responders with residual lymphocytosis.
Although the choice of endpoint (ORR vs progression-free survival [PFS] or overall survival) and very early presentation of data for this trial have been points of discussion, perhaps the most interesting results from this early analysis are those comparing common adverse events and patient discontinuation rates between the 2 BTK inhibitors. With a lower rate of atrial fibrillation and fewer discontinuations with zanubrutinib, the trial does appear to support the theme that second-generation, more targeted inhibitors have a better adverse event profile, which will undoubtedly be of key interest for both patients and clinicians.
ELEVATE-RR is a head-to-head phase III trial comparing acalabrutinib with ibrutinib in 533 patients with previously treated high-risk relapsed/refractory CLL. In this trial, the definition of high-risk disease was the presence of del(17p) or del(11q). The primary endpoint was noninferiority of independent review committee–assessed PFS, with secondary endpoints including any-grade atrial fibrillation/flutter, grade ≥3 infection, Richter transformation, and overall survival. The patients enrolled had had a median of 2 lines of therapy (range: 1-3 vs ≥4 lines), and the trial only included those with del(17p) or del(11q). ELEVATE-RR compared PFS as the primary endpoint and both of these BTK inhibitors did well, with a median PFS of 38.4 months for both agents. The HR was 1.00 (95% CI: 0.79-1.27), demonstrating that the efficacy of acalabrutinib was noninferior to that of ibrutinib in this study.
The trial was also designed to specifically look at adverse events in a clever statistical design to analyze all the events sequentially and showed quite clearly that incidence of any-grade atrial fibrillation was lower in patients receiving acalabrutinib vs ibrutinib. The rate of any-grade atrial fibrillation/flutter in the acalabrutinib arm was 9.4% vs 16.0% (P = .02) in the ibrutinib arm, which was statistically significantly different. In addition, other adverse events, such as hypertension, were lower over time with acalabrutinib. These are adverse events of clinical significance to routine practice, and these comparative data may influence the choice between the different BTK inhibitors for both healthcare professionals and patients alike when there is a choice in the clinic. In my own practice, these data will be even more important when choosing therapy for our older patients and with comorbidities. Cardiovascular health and risk correlate well with both quality and duration of life, and being able to minimize this risk, particularly with our frailer patients, is increasingly important.
Long-term Outcomes With BTK Inhibitor Therapy in Previously Untreated CLL
RESONATE-2 is a phase III trial of ibrutinib vs chlorambucil in older treatment-naive patients (65 years of age or older) with CLL/small lymphocytic leukemia (SLL) that led to the frontline approval of ibrutinib. Patients with del(17p) were not included in this trial. Seven-year follow-up data from RESONATE-2 were recently presented. Significant benefit of the primary endpoint — PFS — with single-agent ibrutinib was sustained with an 84% reduction in the risk for disease progression or death compared with chlorambucil (HR: 0.160). At 6.5 years of follow-up, median PFS in the ibrutinib treatment arm was not reached. PFS benefit was observed in ibrutinib-treated patients across all subgroups, including in patients with high-risk genomic features of unmutated immunoglobulin heavy chain variable (IgHV) (HR: 0.109) or del(11q) (HR: 0.033). This long-term follow-up is reassuring because it shows that 61% of patients are still progression free even at 78 months on ibrutinib treatment. From a more detailed data analysis, we see both patients with unmutated and mutated IgHV have similar PFS outcomes with this long, ongoing follow-up. This is reassuring for the whole class of BTK inhibitors.
The phase III ELEVATE-TN study assessed acalabrutinib vs acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil in treatment-naive CLL. After a median follow-up of approximately 4 years, acalabrutinib-based combination therapy and acalabrutinib monotherapy maintained significantly improved PFS and consistent safety profiles vs chemoimmunotherapy in adults with treatment-naive CLL. Although with a shorter follow-up compared with the RESONATE-2 trial, we are seeing similar data coming out of the ELEVATE-TN study with patients treated with acalabrutinib. In this trial, however, patients with del(17p) were allowed to enroll, making this a potentially more challenging group of patients to treat vs those in the RESONATE-2 trial. Nevertheless, the data at 4 years were reassuring, with 78% of patients treated with acalabrutinib monotherapy still without disease progression. For the patients who received acalabrutinib along with obinutuzumab, the percentage of patients without disease progression at 4 years was even higher at 87%. Again, when we looked at the patients with unmutated IgHV compared with those with mutated IgHV, the PFS was similar. As we would expect, treatment does not do quite as well for patients with del(17p), but there are still quite impressive figures with approximately 75% of patients still in remission and progression free 4 years since starting their treatment.
Emerging Combination Therapy With BTK Inhibitors and BCL2 Inhibitors in CLL
The phase II CAPTIVATE trial was a first-line study of ibrutinib plus venetoclax in patients with previously untreated CLL/SLL. In this trial, 2 treatment cohorts were planned: The first cohort included a fixed duration of treatment with 3 cycles of ibrutinib during a lead-in phase and 12 cycles of ibrutinib plus venetoclax. The second cohort included measurable residual disease (MRD)–guided randomization after the fixed duration of therapy. In this MRD-guided cohort, patients with confirmed undetectable MRD were randomized to placebo or additional cycles of ibrutinib, and patients who did not meet criteria for confirmed undetectable MRD were randomized to continue combination therapy with ibrutinib plus venetoclax vs ibrutinib alone.
At EHA 2021 and ICML 2021, Ghia and colleagues presented data from the fixed-duration cohort of ibrutinib plus venetoclax. Nearly all patients responded (96% ORR), and three quarters of patients achieved undetectable MRD assessed in peripheral blood. These data support the use of a fixed duration of therapy with ibrutinib plus venetoclax, allowing some patients to stop therapy after 1 year of the combination and potentially avoid IV medications and long-term complications of continuous therapy. This combination strategy from the CAPTIVATE trial is very exciting, with the recently presented fixed-duration cohort showing remarkably good data. Of importance, these data were comparable to the data from the MRD-directed cohort, which was presented previously at the 2020 American Society of Hematology annual meeting. It is important to keep in mind that this study enrolled a younger patient group with treatment-naive CLL, with a median age of 60 years. But in this younger, fitter patient population, the reported 24-month PFS rate was 95% in all patients, 97% in patients with mutated IgHV, 93% for unmutated IgHV, and 84% even in those patients with del(17p)/TP53 aberrations, which are the most difficult to treat in clinical practice.
The phase III GLOW trial, which followed the CAPTIVATE trial, is looking at fixed-duration ibrutinib plus venetoclax treatment in older or unfit adults with previously untreated CLL using the same dosing schedule. When the data mature, they will provide more insights into the combination of ibrutinib with venetoclax in this patient population. However, for the younger patients enrolled on the CAPTIVATE trial, the data, along with other venetoclax and BTK inhibitor combinations, look very hopeful for the way forward in the future.
What are your thoughts on the new data in CLL presented at ASCO 2021, EHA 2021, and ICML 2021? What investigational agents and combinations are you most excited about? Please answer the polling question and join the conversation by posting a comment in the discussion section
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