J Clin Oncol 2021 Jul 26
Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial.
Abstract
Purpose
Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).
Methods
Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).
Results
Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.
Conclusion
In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.
Related Questions
In a patient who has been receiving 1L Ibrutinib for TP53+ CLL for years with complete hematologic response but detectable MRD, is there any role to switch to the novel BTKi agents given better PFS?
There are a couple of features to this question that need comment. First, the goal of therapy with a single-agent BTKi, regardless of ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib, is NOT to achieve undetectable MRD. Very few patients will achieve this milestone due to the drug's MOA. BTK...
How do you manage severe thrombocytopenia due to splenomegaly and bone marrow involvement in CLL when starting obinituzumab and venetoclax?
This is a tough question without any information about the case. I am assuming the patient is untreated. For this setting, there are really three options supported by randomized phase 3 trials. Venetoclax + Obinuzumab has a single randomized phase 3 trial that showed improved progression free surviv...
Would you extrapolate results from ELEVATE-RR study to favor use of acalabrutinib as first-line therapy in treatment-naive CLL?
The ELEVATE-RR study enrolled patients with a median of 2 prior regimens, with either deletion 11q or deletion 17p. I think one could debate whether selecting this patient population as compared to a less selected treatment naïve population would be more likely to find a difference between the two d...
For frail patients with cardiac co-morbidities and relapsed CLL with high cytogenetic risk, what are some considerations for using continuous acalabrutinib over fixed duration therapies such as venetoclax/rituximab?
This is a complicated question and I evaluate each patient individually. I worry more about patients with reduced cardiac function on BTK inhibitors than I do those with pre-existing atrial fibrillation, and if they are on anticoagulation as well, that is a further concern. If the patient has reduce...
Do you find ELEVATE-RR data and study design compelling to start preferentially using acalabrutinib over ibrutinib?
The inferiority design of the ELEVATE-RR included a 1.429 margin, but the hazard ratio between treatments was 1.0 as related to DFS and 0.82 (favoring acalabrutinib) for OS. This improved OS likely is reflective of lower cardiac events and other adverse events. To me, this is sufficiently beneficial...
Do you routinely offer fungal prophylaxis for patients on BTK inhibitors?
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What is your approach to CLL in patients with atrial fibrillation and/or on anticoagulation?
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Given results of the ELEVATE-RR study, would you consider use of acalabrutinib in all patients with previously treated CLL, or restrict it to certain patient populations?
Efficacy and safety are both important for evaluating new therapies. The ELEVATE-RR study demonstrated equivalent efficacy with a hazard ratio of 1.0 which indicates response duration was identical. Notably, several indications of safety were better which then would tilt the benefit to using an alte...
What factors do you take into account for recommending venetoclax/obtinutuzumab vs BTK inhibitors vs chemotherapy in front line therapy for CLL?
For most patients, either BTK inhibitor or venetoclax/obinutuzumab would be appropriate therapies. I would only consider chemotherapy (fludarabine/cyclophosphamide/rituximab) for those <65 years old with IGHV mutated disease and no high risk genetic markers. And even in these patients, I almost alwa...