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Acalabrutinib in ibrutinib-intolerant R/R CLL patients
clone identified at baseline expanded from 30.7% to 90.2% allele fraction (Online Supplementary Tables S6 and S7).
The patient with the D993N missense variant in PLCG2 (which has been associated with ibrutinib resist- ance, but not shown to alter drug sensitivity in vitro to date), achieved a CR with acalabrutinib at treatment cycle 18 and had remained on therapy for 25 months at the time of data cutoff.
At the time of this analysis, five patients had relapsed on acalabrutinib and peripheral blood mononuclear cell samples were collected at treatment termination. Three of the five patients were confirmed to have no BTK or PLCG2 mutations; one of these patients experienced a best overall response of PRL on acalabrutinib treatment (DOR, 11.53 months), the second patient had a best overall response of PR (DOR, 15.67 months), and the third patient had SD (Online Supplementary Table S7). The fourth patient who achieved a PR (DOR, 14.29 months) had low levels of BTK C481S and T474I mutations as well as a predominant PLCG2 1140N mutation at treat- ment termination, none of which was detectable at base- line. The fifth patient, described above, had a pre-exist- ing clone with BTK C481S expansion during treatment that was detectable at progression (Online Supplementary Table S7).
A
Discussion
This phase II study of acalabrutinib in patients who were ibrutinib-intolerant demonstrated that acalabrutinib is effective and tolerable in a large proportion of this pop- ulation. The ORR of 73% with a median PFS that was not reached demonstrates durable disease control in this pop- ulation of relapsed/refractory CLL patients. A similar response rate was reported with ibrutinib in the front-line setting in a population of elderly patients with a similar median age (71 years) and follow-up duration (22.1 months).25 In this study, 10% of patients were not evalu- able for response because they discontinued treatment before the first response assessment. As responses to BTK inhibitors tend to improve with longer treatment dura- tion, it is possible that with additional follow-up, the ORR will increase and additional CR will be observed.9 It was not unexpected that acalabrutinib was effective in these patients, as the prior ibrutinib exposure was short for most patients (median, <6 months) and most were assumed to have a response to BTK inhibition (based on disease progressing after discontinuing ibrutinib due to adverse events).
The safety of acalabrutinib in this study is perhaps more helpful than the observed response rate in under- standing the impact of this agent. At a median follow-up
B
Figure 3. Duration of response to acalabrutinib. (A, B) The median duration of response was not reached when patients with partial remission with lym- phocytosis were excluded (A) or when they were included (B). CI: confidence interval; DOR: duration of response; PR: partial remis- sion; PRL: partial remission with lymphocytosis.
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