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K.A. Rogers et al.
grade (Online Supplementary Table S4). Only one event (4% [n=1/27] events in 1 patient) was of a higher grade during acalabrutinib treatment than during prior ibrutinib treatment. This event was increased liver function test (grade 2 on ibrutinib and grade 3 during acalabrutinib treatment). Two patients treated with acalabrutinib had recurrence of the same ibrutinib-intolerance adverse event of atrial fibrillation, both of whom had atrial fibril- lation events with a lower severity grade on acalabrutinib treatment (grade 3/2 and grade 2/1 during ibrutinib/acal- abrutinib treatment). One of the two patients had a med- ical history of atrial fibrillation and hypertension and dis- continued acalabrutinib treatment due to pneumonia that started the same day as atrial fibrillation. The second patient had a medical history of atrial fibrillation; at the time of data analysis, treatment with acalabrutinib was ongoing in the presence of ongoing atrial fibrillation (the dose was not changed and no other action was taken).
Among 60 enrolled patients, during ibrutinib treatment, 41 patients had the following ibrutinib-intolerance adverse events: arthralgia, atrial fibrillation, bleeding, diarrhea, or rash (Table 3, Online Supplementary Table S5). Of the 74 ibrutinib-intolerance adverse events in the 60 enrolled patients, 42 (57%) did not recur during acalabru- tinib treatment. Eighteen (30%) patients treated with acalabrutinib had recurrence of the same ibrutinib-intol- erance adverse event. The most common ibrutinib-intol- erance adverse events recurring with acalabrutinib were diarrhea (n=5) and bleeding events (n=5), all of which had the same or lower severity grade with acalabrutinib treat- ment. Among the five patients with recurrent bleeding events, only one patient had the same type of bleeding event reported with ibrutinib and acalabrutinib (recurrent hematuria); the other four patients had bleeding events with ibrutinib that were different from those reported on acalabrutinib (Online Supplementary Table S4).
Eleven deaths occurred during the study; the causes included pneumonia (n=3), Richter transformation (n=2), bronchopulmonary aspergillosis, ventricular fibrillation, squamous cell carcinoma of lung, multiple organ dysfunc- tion syndrome, disease progression, and death (n=1
each). Of the seven deaths due to adverse events, two occurred while the patient was receiving study treatment (1 each, pneumonia and subdural hematoma), and the remainder occurred following acalabrutinib discontinua- tion. Of note, an 85-year-old male patient with multiple cardiac morbidities died of ventricular fibrillation 27 days after acalabrutinib was discontinued due to stomatitis. The other event of interest which resulted in death occurred in a 76-year-old female patient with a medical history of herpes zoster who died of bronchopulmonary aspergillus 7 days after discontinuation of acalabrutinib due to pneumonia.
Analysis of mutations associated with resistance to BTK inhibitors
To determine whether mutations associated with resistance to BTK inhibitors were present before acal- abrutinib treatment, purified B-cell samples at the start of acalabrutinib treatment were tested for mutations in BTK and PLCG2. Mutations in BTK and PLCG2 have been associated with clinical disease progression during ibruti- nib treatment and with resistance to acalabrutinib because both bind to BTK at the same site.18-22
Samples were available for 55 of 60 (92%) patients. Pretreatment samples were available for 52 patients; sam- ples were taken at later time-points for three patients (cycle 1, day 28, n=1; cycle 6, day 28, n=2). Three (5%) were found to have a mutation in at least one gene. Two patients had multiple mutations associated with ibrutinib resistance in BTK or BTK and PLCG2, while one patient had a PLCG2 mutation of uncertain significance (Online Supplementary Table S6).18,19,23,24 All mutations were found in pretreatment samples.
Of the two patients with mutations associated with BTK and/or PCLG2, one was electively taken off acal- abrutinib after just over 2 months of exposure due to the presence of these mutations and was not evaluable for evaluation of response to acalabrutinib. The other patient received acalabrutinib and had PD after 15 months, hav- ing achieved a best response of SD during acalabrutinib treatment and at CLL progression, the major BTK C481S
Figure 2. Response to acal- abrutinib. Patients who dis- continued study treatment before evaluation for response (n=6) or who were not available for response assessment (n=2) were classified as not evaluable. CR: complete remission; Cri: CR with incomplete bone marrow recovery; ORR: over- all response rate; PD: pro- gressive disease; PR: partial remission; PRL: partial remission with lymphocyto- sis; SD: stable disease.
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