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Editorials
Figure 1. A proposed sequencing algorithm for treatment of chronic lymphocytic leukemia following discontinuation of ibrutinib due to intolerance. CLL: chronic lympho- cytic leukemia; iwCLL: International Workshop on CLL; BTKi: Bruton tyrosine kinase inhibitor; PI3K: phosphoinositide 3-kinase.
treatment with ibrutinib.5 These studies clearly estab- lished that intolerance to ibrutinib is a common scenario encountered in clinical practice, which may limit the clin- ical benefit of this drug that has been largely studied as a continuous therapy.
Given the clinical efficacy of BTK inhibition in CLL, for patients who discontinue a BTK inhiibitor due to intoler- ance, an important question is whether treatment with an alternative kinase inhibitor is an acceptable treatment option. This is particularly relevant given the develop- ment of more selective BTK inhibitors with fewer off-tar- get effects. Newer BTK inhibitors include approved ther- apies such as acalabrutinib, as well as emerging covalent and non-covalent BTK inhibitors in clinical development (zanubrutinib, LOXO-305, ARQ-351).
Previously, Awan et al. addressed this key question by conducting a small cohort study of acalabrutinib treat- ment for patients who discontinued ibrutinib due to intolerance (defined by the investigator’s discretion).6 In this study of 33 patients, the efficacy of acalabrutinib fol- lowing ibrutinib was high (overall response rate 76%) with only 9% of patients discontinuing acalabrutinib due to an adverse event.6 However, this study examined only a small number of patients and lacked an objective defini- tion of ibrutinib intolerance.
The study by Rogers et al. is the first prospectively designed study to answer this important sequencing question.1 Intolerance was defined as discontinuation of ibrutinib due to either persistent/recurrent grade 2 adverse events despite dose modification or interruption or persistent grade 3/4 adverse events. Sixty patients with relapsed and/or refractory CLL were treated with acal- abrutinib (median number of prior therapies 2) with a
prior median duration of ibrutinib therapy of 5.7 months. Overall, the approach was well-tolerated, with the most common adverse events being diarrhea (53%), headache (42%) and contusion (40%). Only 40% of patients had ibrutinib-related intolerance adverse events, and 67% of events were lower grade with acalabrutinib than with ibrutinib; only one adverse event (increased levels of liver enzymes) occurred at a higher grade with acalabrutinib treatment than with ibrutinib treatment. Notably, more patients discontinued acalabrutinib because of CLL pro- gression (23%) than because of adverse events (17%). Acalabrutinib following discontinuation of ibrutinib for intolerance was efficacious, with an overall response rate of 73% and a 24-month estimated progression-free sur- vival of 72% (median follow-up, 35 months). It should be noted that the majority (94%) of patients with available pre-treatment sequencing data did not have BTK or PLCG2 mutations prior to initiating treatment with acal- abrutinib.1
In addition to the work presented by Rogers et al., two additional recent studies have also shown that treatment of CLL with an alternative kinase inhibitor following ibrutinib intolerance is safe and efficacious.7,8 A phase II study examined the phosphoinositide 3-kinase (PI3K) inhibitor umbralisib in 51 patients with relapsed/refracto- ry CLL who were intolerant to prior BTK inhibition (n=44) or PI3K inhibition (n=7) and showed a median progression-free survival of 23.5 months, with the major- ity (58%) of patients remaining on umbralisib for longer than on their prior kinase inhibitor therapy.7 Additionally, LOXO-305 (pirtobrutinib), a novel, highly selective, non- covalent BTK inhibitor showed a favorable safety profile in 170 patients with CLL/small lymphocytic leukemia, of
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