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Director of CLL Program
Hematologic Malignancies Section
Department of Medicine
New York-Presbyterian/Columbia University Medical Center
New York, New York
Nicole Lamanna, MD, has disclosed that she has received consulting fees from AbbVie, AstraZeneca, Celgene, Genentech, Gilead Sciences, Janssen, and Pharmacyclics.
The introduction of BTK inhibitor therapy has truly transformed the treatment landscape in chronic lymphocytic leukemia (CLL). Clinical data with the first-in-class BTK inhibitor ibrutinib have shown its long-term efficacy in both the frontline and relapsed/refractory settings as well as in high-risk patients with del(17p). In addition, findings from recent phase III trials of ibrutinib vs chemoimmunotherapy have solidified its position as a standard-of-care frontline therapy. Despite its efficacy, certain adverse events can lead to dose reductions or discontinuation of therapy in many patients with CLL receiving ibrutinib, including fatigue, arthralgias, cardiac arrythmias such as atrial fibrillation, hypertension, and increased risk of bleeding. "Second-generation" BTK inhibitors such as acalabrutinib and zanubrutinib were developed with the hope of similar or possibly improved efficacy and reduced toxicity compared with ibrutinib. Early phase I/II studies of acalabrutinib in CLL indeed suggested that this agent appears to have fewer adverse events than its predecessor. In November 2019, acalabrutinib gained FDA approval for the treatment of CLL or small lymphocytic lymphoma (SLL) based on results from the phase III ELEVATE-TN and ASCEND trials.
Phase III Data of Acalabrutinib in CLL
The ELEVATE-TN trial evaluated acalabrutinib plus obinutuzumab vs acalabrutinib alone vs chlorambucil plus obinutuzumab in 535 patients with treatment-naive CLL who were 65 years of age or older or younger than 65 years with coexisting conditions (CIRS score > 6 or creatinine clearance < 70 mL/min). At a median follow-up of 28.3 months, acalabrutinib with or without obinutuzumab significantly prolonged PFS compared with chlorambucil plus obinutuzumab, resulting in a 90% and 80% reduction of the risk of disease progression or death, respectively (P < .0001). The PFS benefit of acalabrutinib was observed across subgroups including patients with del(17p) and mutated IGHV. With more than 2 years of follow-up, 79% of patients in both acalabrutinib-containing arms remained on single-agent acalabrutinib. Special grade ≥ 3 adverse events of interest in acalabrutinib-containing arms included 1 case of atrial fibrillation and 6 patients with major bleeding, each totaling an incidence of < 2%. The rates of grade ≥ 3 hypertension were similar between the acalabrutinib-containing arms and the control arm.
The ASCEND trial investigated acalabrutinib monotherapy vs idelalisib plus rituximab or bendamustine plus rituximab in 310 patients with relapsed/refractory CLL who received at least 1 previous therapy excluding BCL-2 or B-cell receptor inhibitors. Median age of enrolled patients was 68 years in the acalabrutinib arm and 67 years in the control arm. Acalabrutinib significantly prolonged median PFS compared with idelalisib or bendamustine plus rituximab (not reached vs 16.5 months; HR 0.31; P < .0001). The PFS benefit was consistently observed across patient subgroups including those with high-risk disease. Acalabrutinib was also associated with higher ORR as well as more durable responses. The discontinuation rate due to adverse events was lower with acalabrutinib and it was generally better tolerated compared with the control regimens.
Considering BTK Inhibitors in Clinical Practice
These 2 large phase III studies support the use of acalabrutinib in patients with CLL/SLL. It remains to be seen whether acalabrutinib will have a lower incidence of adverse events vs ibrutinib with continued long-term follow-up. In addition, the phase III ELEVATE-RR trial of acalabrutinib vs ibrutinib in previously treated patients with high-risk CLL has been fully accrued and results from this study are eagerly awaited. If this head-to-head study shows a better safety profile with acalabrutinib vs ibrutinib, there is little doubt that acalabrutinib usage will continue to increase. While we await these data, if clinicians are deciding to use a BTK inhibitor for treating CLL, I may recommend acalabrutinib in patients who have severe cardiac issues/arrhythmia or anticoagulation needs. In addition, there are patients with CLL intolerant to ibrutinib who have been successfully treated with acalabrutinib without worsening of adverse events. If a patient has progressive disease on ibrutinib, however, there are currently no data to suggest that the patient would respond to acalabrutinib, and another agent from a different class should be considered altogether.
To summarize, it is an amazing time for our patients with CLL and the advent of many active therapies is refreshing. BTK inhibitors are now a mainstay therapy for our patients with CLL in both frontline and relapsed/refractory settings. Ultimately, we will need to await long-term clinical data to further guide us on how to best incorporate available therapies into optimal management strategies for our individual patients with CLL (ie, sequential monotherapy vs combination therapy, and/or which patient subgroups might benefit from certain therapies vs other subgroups). Stay tuned!
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