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K.A. Rogers et al.
of 35 months, 48% of patients remained on acalabrutinib. The most common reason for discontinuation was dis- ease progression (23%) and the rate of acalabrutinib dis- continuation due to adverse events was 17%. This rate of discontinuation due to adverse events is low considering that 100% of patients had discontinued ibrutinib due to adverse events, suggesting that acalabrutinib is tolerable in a large proportion of patients who are intolerant of ibrutinib.
Comparing the full spectrum of adverse events between ibrutinib and acalabrutinib in this study is diffi- cult because the ibrutinib experience was not captured prospectively. The study was not intended to compare toxicity between two drugs, but rather to determine acal- abrutinib tolerability in patients who discontinued ibruti- nib due to toxicity. When reviewing events of arthralgia, atrial fibrillation, bleeding, diarrhea, and rash leading to ibrutinib intolerance, 24/41 patients experienced recur- rence during acalabrutinib treatment, and recurrence was at a similar (25%) or lower (75%) grade of severity in all patients. Most adverse events (64%) limiting ibrutinib treatment were not experienced during acalabrutinib treatment. Additionally, all adverse events causing ibruti- nib intolerance and recurring with acalabrutinib treat- ment (27 events in total) were reviewed to determine dif-
A
ferences in maximal severity grade experienced. Of these adverse events, only one occurred at a higher grade, while 18 occurred at a lower grade with acalabrutinib, demon- strating that the severity of intolerance adverse events during acalabrutinib treatment may be decreased. This reduction in rate includes hemorrhage events, which have previously been observed to be a class effect of BTK inhibitors,26 but in this study were observed to occur at a lower grade with acalabrutinib than with ibrutinib. Only one patient discontinued acalabrutinib for the same adverse event (diarrhea) that was also the cause reported for ibrutinib discontinuation.
Clinical strategies for patients with ibrutinib intoler- ance, such as switching to alternative kinase inhibitors or combining different therapeutic agents, have been evalu- ated. Real-world data have suggested that ibrutinib-intol- erant patients could be treated successfully with an alter- native kinase inhibitor.27 Early phase clinical trial data have also demonstrated the efficacy and safety of an alternative kinase inhibitor, umbralisib, in ibrutinib-intol- erant patients. There is a potential clinical benefit in switching patients with ibrutinib intolerance to another BTK inhibitor so that venetoclax remains a future treat- ment option. However, depending on the type and sever- ity of the adverse events and their potential for harm of
B
Figure 4. Progression-free survival and overall survival with acalabruti- nib. (A, B) The medians were not reached for progression-free survival (A) or overall survival (B). CI: confi- dence interval; OS: overall survival; PFS: progression-free survival.
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haematologica | 2021; 106(9)