Jennifer Woyach, MD
A number of therapeutic options have become available in the frontline setting for patients with chronic lymphocytic leukemia (CLL), most recently the second-generation BTK inhibitor acalabrutinib (Calquence).
The November 2019 approval of acalabrutinib, which is indiciated for adult patients with CLL or small lymphocytic lymphoma, was based on 2 phase III randomized trials: ELEVATE-TN and ASCEND. In ELEVATE-TN, investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab (Gazyva) versus chlorambucil/obinutuzumab in 535 treatment-naïve patients with CLL.
Results showed that the median progression-free survival (PFS) was 22.6 months (95% CI, 20-28) in the control arm, but was not yet reached in the acalabrutinib/obinutuzumab arm (HR, 0.10; 95% CI, 0.06-0.17; P <.0001) or the single-agent acalabrutinib arm (HR, 0.20; 95% CI, 0.13-0.30 P
In ASCEND, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or rituximab (Rituxan) in combination with idelalisib (Zydelig) or bendamustine. Data showed that the median PFS with acalabrutinib was not reached compared with 16.5 months in the control arms (HR, 0.31; 95% CI, 0.20-0.49; P <.0001), translating to a 69% reduction in the risk of progression or death with the BTK inhibitor.2
Beyond acalabrutinib, ibrutinib (Imbruvica) is the other BTK inhibitor currently available in the frontline setting. In addition, physicians can use venetoclax (Venclexta) with obinutuzumab. Although chemoimmunotherapy is still available, in the form of fludarabine, cyclophosphamide, and rituximab (FCR), it is more commonly used in the setting of patients with IGHV-mutant CLL.
However, the frontline space of CLL continues to be redefined, Woyach added, with combination strategies of BTK inhibitors, targeted therapies, and chemoimmunotherapy being explored in clinical trials.
In an interview with OncLive
during the 24th Annual
International Congress on Hematologic Malignancies, Woyach, an associate professor, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center–James, discussed the advances in the frontline setting for patients with CLL, and other strategies that are under investigation in this space.OncLive: What are the frontline treatment options for patients with CLL?Woyach
: For CLL, we have a number of frontline options. We have ibrutinib, which can be used by itself and it usually is used on its own. We have acalabrutinib that can be used with or without obinutuzumab, and we have venetoclax plus obinutuzumab in terms of our targeted agents. We also still have chemoimmunotherapy options, such as FCR, which is to be considered especially for those young, fit patients who IGVH-mutated disease. We also have bendamustine/rituximab and chlorambucil/obinutuzumab still available, although there are not a lot of scenarios where you would use those.What are the toxicity concerns with these agents?
With the BTK inhibitors, specifically ibrutinib, we know a lot about long-term safety profiles. The toxicity that are of concern with ibrutinib include atrial arrythmias, which happen in about 10% to 15% of patients. You can see grade 3 or higher hypertension, and that is something that actually happens more commonly with a longer duration of therapy. You can also see other adverse events that are more common, and less dangerous, such as arthralgias, fatigue, and upper-respiratory infections.
With acalabrutinib, it seems like you probably see some atrial arrythmias, although it seems to be much less frequent than with ibrutinib. You tend to see less bruising with acalabrutinib, as well as less arthralgias. You do see headache with acalabrutinib, although that is predominantly low grade and goes away over time.
With venetoclax, you can see neutropenia—especially early on—and you can see risk of tumor lysis syndrome, especially with the first ramp-ups. With chemoimmunotherapy, our primary concerns are cytopenias, both during and prolonged cases after [the treatment]. With FCR, more specifically, patients have almost a 5% risk of myelodysplastic syndrome or acute myeloid leukemia.Could you discuss the impact of the ELEVATE-TN trial?