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Acalabrutinib in ibrutinib-intolerant R/R CLL patients
get effects of ibrutinib on other kinases.2,5,7 Some toxicities can be managed with supportive care and some require ibrutinib discontinuation, especially if more severe. For example, current guidelines recommend careful monitor- ing in the case of atrial fibrillation, and potential use of non-warfarin anticoagulation, although consideration should be given to alternate therapies if the atrial fibrilla- tion is uncontrolled.8 Rates of ibrutinib discontinuation due to adverse events during extended follow-up in a clin- ical trial population are approximately 20%.9 In CLL patients treated outside of clinical trials at academic and community sites, discontinuation rates due to adverse events were as high as 50%, which may better capture tolerability in a general practice setting.6 This means that patients who cannot take ibrutinib due to toxicity may not be able to realize the potential benefit of BTK inhibi- tion on their disease, thereby reducing therapeutic options available for CLL treatment.
Acalabrutinib is an oral covalent inhibitor of BTK approved for treatment of patients with CLL.10 Acalabrutinib binds to BTK at the cysteine 481 residue, which is the same binding site as that for ibrutinib.11 Compared with ibrutinib, acalabrutinib is a more selec- tive BTK inhibitor.12,13 Fewer off-target effects potentially provide an improved safety profile compared with ibruti- nib.5,14 A low frequency of adverse events of interest, specifically atrial fibrillation and severe bleeding, has been reported with acalabrutinib.11 In a phase III trial in patients with relapsed/refractory CLL (ASCEND), atrial fibrillation occurred in eight of 154 patients (5%) receiv- ing acalabrutinib monotherapy, seven of whom had a his- tory of ongoing hypertension. Bleeding and infections (any grade), also events of clinical interest, occurred in 40 (26%) and 87 (57%) patients, respectively. In that trial, 11% of patients receiving acalabrutinib monotherapy dis- continued this treatment because of adverse events.15
Given the improved selectivity of acalabrutinib relative to ibrutinib, we hypothesized that acalabrutinib would be effective and tolerable in patients with CLL who dis- continued ibrutinib due to adverse events. This hypothe- sis is supported by a previous study in which the overall response rate (ORR; i.e., partial response [PR] or better) to acalabrutinib was 61% in patients with relapsed/refracto- ry CLL who were previously unable to continue ibrutinib treatment because of adverse events.16 However, the pre- vious study did not objectively define events classified as ibrutinib-intolerant and analyzed a cohort of patients added to the open-label, phase II, dose-expansion portion of the phase I/II study.16 We therefore conducted a dedi- cated phase II study of acalabrutinib in patients with relapsed/refractory CLL who were intolerant to ibrutinib treatment as defined by specific criteria, including event grade, persistence, and recurrence.
Methods
Study design and participants
This multicenter, single-agent, phase II study (ClinicalTrials.gov identifier NCT02717611; ACE-CL-208) enrolled adults with CLL who were intolerant to ibrutinib and for whom purine analogue-based therapy was not an option. Ibrutinib intolerance was defined as: (i) having discontinued ibrutinib treatment due to grade 3 or 4 adverse events that per- sisted despite optimal supportive care; or (ii) having experienced
grade 2 adverse events related to ibrutinib treatment that persist- ed for at least 2 weeks or recurred at least twice, whether the dose of ibrutinib was reduced or interrupted, despite optimal supportive care. Patients had to have had at least one prior attempt at ibrutinib treatment for CLL and not be appropriate for treatment or retreatment with purine analogue-based thera- py (e.g., fludarabine). After discontinuing ibrutinib, patients had to meet the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2008 criteria for progressive disease (PD)17 as a sign of continued disease activity and not have received other CLL therapy.
To meet the eligibility criteria, patients’ most recent systemic anticancer therapy was required to be ibrutinib; those who received an alternative anticancer therapy after ibrutinib discon- tinuation were excluded. Patients were excluded if they had an ongoing grade 3 or 4 adverse event attributed to ibrutinib. Other patients who were excluded were those with evidence of active Richter transformation or any evidence of PD on ibrutinib; patients who had previously received a BCL-2 inhibitor; patients who had significant cardiovascular disease, such as uncontrolled or symptomatic untreated arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classification or QTc >480 ms at screen- ing (except for controlled, asymptomatic atrial fibrillation during screening, which was allowed); and patients who were receiving anticoagulation with warfarin or equivalent vitamin K antago- nists within 7 days of the first study drug dose. Patients taking other anticoagulants could be included.
All patients signed written informed consent before enroll- ment into the study, which was approved by the institutional review board/independent ethics committee of each participat- ing institution and conducted in accordance with the principles of the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice.
Procedures
Eligible patients were treated with acalabrutinib 100 mg orally twice a day on days 1 to 28 of 28-day cycles until disease pro- gression, as long as treatment was tolerated. Response was assessed according to modified iwCLL 2008 criteria,17 with the first assessment occurring 3 months after starting acalabrutinib. Adverse events were collected and graded according to Common Terminology Criteria for Adverse Events version 4.03.
An exploratory analysis of molecular resistance to BTK inhibitors was performed retrospectively using deep sequencing of BTK and PLCG2 in patients with pretreatment samples18,19 (details in the Online Supplementary Methods).
Outcomes
The primary endpoint was investigator-assessed ORR accord- ing to iwCLL 2008 criteria.17 ORR was defined as the proportion of patients achieving a best overall response of either complete remission (CR), complete remission with incomplete bone mar- row recovery (CRi), nodular partial remission (nPR), or PR at or before initiation of subsequent anticancer therapy. Secondary efficacy endpoints were duration of response (DOR; defined as the time from the initial response [CR, CRi, nPR, or PR] until documented PD), progression-free survival (PFS; defined as the time from first dose to first documented PD or death), time to next treatment (TTNT; defined as the time from first dose to institution of subsequent anticancer therapy for CLL or death), and overall survival (OS; defined as the time from first dose to death). Safety was assessed via laboratory assessments and adverse events by their frequency, and causal attribution.
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