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K.A. Rogers et al.
Table 3. Ibrutinib-intolerance adverse events and recurrence after acalabrutinib treatment.
Adverse event Number of patients with ibrutinib intolerancea
Atrialfibrillation 16b
Diarrhea 7
Rash 7
Bleedingc,d 6
Arthralgia 7e
Total 41 24 18
Acalabrutinib experience for same patients
Total Lower grade
Same grade
0 2 0 2 1 6
Higher grade
0 0 0 0 0 1
2 2 5 3 3 3 5 3 2 1
aAmong 60 patients meeting the study enrollment criteria,41 patients had a medical history of one or more (43 events in total) of the following categories of ibrutinib-intolerance events:atrial fibrillation,diarrhea,rash,bleeding,or arthralgia.bIncludes patients with atrial flutter (n=2).cEvents categorized as bleeding included ecchymosis,hemorrhage,epis- taxis, contusion, hematuria, and subdural hematoma. dAll but one patient experienced a different type of bleeding event with acalabrutinib compared with ibrutinib treatment. eIncludes one patient with arthritis.
14.29 months. One patient had low levels of the BTK C481S and the T4741 gatekeeper resistance mutation at baseline as well as the PLCG2 D1140N C2 domain muta- tion detected at progression. The PLCG2 D1140N muta- tion was predominant (indicating many CLL cells in the sample were without a BTK mutation), whereas with ibrutinib, treatment resistance mutations in this PLCG2 domain were more commonly secondary mutations after BTK C481X development.19
This study was designed to determine whether acal- abrutinib is effective in patients intolerant to ibrutinib or unable to continue ibrutinib treatment due to adverse events. However, it is acknowledged that the study had a few limitations, the most significant being that the ibruti- nib experience was not prospectively or rigorously cap- tured. This not only means that a significant portion of these patients’ responses to ibrutinib were unknown, but also that not all of the details were captured for the adverse events on ibrutinib. In addition, subjective report- ing of adverse events by patients prior to enrollment who sought to have access to the study drug could have influ- enced the patients’ enrollment. It is therefore possible that some adverse events occurring at a low grade with ibrutinib may have occurred at a greater severity with acalabrutinib. To partially overcome this limitation, we applied two different approaches to assessing the occur- rence of known adverse events with ibrutinib during acal- abrutinib treatment. However, only a prospective or ran- domized study could fully capture differences in toxici- ties between the two drugs. The other important limita- tion is in understanding differential CLL resistance to acalabrutinib. PD was the most common reason for acal- abrutinib discontinuation, with a relatively high rate of 23%. The direct comparison of acalabrutinib with ibruti- nib is ongoing via a phase III randomized non-inferiority clinical trial in patients with previously treated, high-risk CLL (NCT02477696).
In summary, the results of this study demonstrate that acalabrutinib is a safe and effective option for patients with relapsed/refractory CLL who are not able to tolerate ibrutinib. Acalabrutinib is an important therapeutic option in this population and will allow more CLL patients to benefit from BTK inhibitor treatment.
Disclosures
KAR has received research funding from Genentech, AbbVie, and Janssen, serves on advisory boards for Acerta Pharma, AstraZeneca, and Pharmacyclics, and has received travel sup-
port from Acerta Pharma. PAT has received research funding from Pharmacyclics, AbbVie, Genentech, Pfizer, and Amgen, and has served as a consultant to Pharmacyclics, AbbVie, Genentech, Amgen, Janssen-Cilag, and Gilead. JNA has received research funding from Genentech, Janssen, and Celgene, and has served as a consultant to Pharmacyclics, AbbVie, Genentech, AstraZeneca, Sunesis, and Janssen. MC has stock and other ownership interests in Gilead Sciences and Immunomedics, has served as a consultant to Celgene, Gilead, and Pharmacyclics, serves on the speakers bureau for Gilead, Janssen China R&D, and Pharmacyclics, and has received research funding from Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Merck, Millennium Pharmaceuticals, and Pharmacyclics. JPS has received research funding from Sunesis, Gilead, Acerta Pharma, Pharmacyclics, AbbVie, BeiGene, and TG Therapeutics, and has served as a consultant to Acerta Pharma, Pharmacyclics, AbbVie, BeiGene, and TG Therapeutics. BDC has received research funding from Pharmacyclics/Janssen, AstraZeneca, AbbVie, TG Therapeutics, MorphoSys, and Roche-Genentech, and has served as a consultant to Pharmacyclics/Janssen, AstraZeneca, AbbVie, TG Therapeutics, Karyopharm, and MorphoSys. DJ has received research funding from Acerta Pharma and Pharmacyclics. RI is an employee of Acerta Pharma, has equity ownership in AstraZeneca, and has patents for acalabrutinib. MMF is an employee and stock shareholder of AstraZeneca. CQ, RKR, and MHW are employees of Acerta Pharma. TJK has received research funding from AbbVie and Hoffman- LaRoche.
Contributions
The clinical study was designed by RI and Ahmed Hamdy (both of Acerta Pharma) in collaboration with John C. Byrd (The Ohio State University Comprehensive Cancer Center). Data collection and interpretation were done by the authors, investiga- tors, and study sponsor. Statistical analyses were performed by MHW and DJ, who also oversaw the mutation testing. KAR developed the first draft of the manuscript, for which all authors reviewed and provided important intellectual contributions; all authors approved the final version for publication. All authors had full access to the data and vouch for the completeness and accuracy of the data.
Acknowledgments
The authors acknowledge the Acerta Pharma study team for their commitment to this study. They also thank the patients who participated in this study as well as their friends and family who supported them.
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