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Impact of discontinuation/modifications on outcome
reduction does not result in inferior PFS (Online Supplementary Table S5).33,34
Our literature review revealed evidence that treatment discontinuation of ibrutinib may be associated with poor survival outcomes; the impact of ibrutinib discontinua- tion may be significantly modified by factors such as the reason for discontinuation and the number of prior ther- apies received (Online Supplementary Table S1). The impact of ibrutinib interruption is harder to quantify from the literature (Online Supplementary Table S1); the phase III RESONATE study reported an impact on PFS with treat- ment interruption ≥8 consecutive days,16 while a phase II trial indicated that outcomes were not compromised by treatment interruption.19 Some real-world datasets also suggest an impact of interruption on outcomes,21,23,28 while others do not.24,26 Similarly the impact of ibrutinib dose reduction is difficult to quantify from the literature (Online Supplementary Table S5); one interventional and one real-world study suggest that there is no survival detriment with dose reduction,19,23 whereas inferior PFS is indicated in two real-world studies.24,28
The current literature consists of a mixture of clinical trials and real-world data; therefore patient characteris- tics, management of AE and the timing of data collec- tion/availability of data may vary significantly. This could explain the inconsistencies in the data, where numerous studies have reported conflicting results, making conclu- sions particularly difficult to draw. In addition to this, it is important to also note the variation in the definitions used for dose reduction. While some studies indicate that data are representative of early dose reductions (e.g., within the first 8 weeks of initiating therapy28), other studies, such as MURANO, look at dose reductions occurring throughout therapy. Furthermore the lack of information indicating the permanence of dose reduc- tions, or whether all dose reductions experienced by a patient were taken into account or not, could provide some explanation for inconsistencies in the data reported.
Literature assessing the impact of discontinuation and interruption on outcomes was limited for both idelalisib and duvelisib. Discontinuation data from clinical trials of idelalisib showed similar OS in one study and reduced PFS in another,35,36 while real-world data indicated an effect on survival dependent upon reason for treatment discontinuation.37 Phase III data suggest an association between idelalisib interruption and longer PFS and OS (with length of interruption potentially having an impact on outcome), but this is difficult to confirm with only one study available (Online Supplementary Table S1).38 Similarly, conclusions are hard to draw for duvelisib treat- ment interruptions with only one study reporting the impact on PFS (which is similar regardless of duration of interruption [>1 week vs. >2 weeks]; Online Supplementary Table S1).39
The analyses presented here are the first to be conduct- ed from MURANO for the impact of venetoclax dose modification or premature discontinuation. Since analy- ses were performed retrospectively, without type-I error control, the results should be interpreted with caution. This manuscript also provides the first literature review on this topic to collate the numerous articles and provide context for the MURANO analyses. Limited published
data for the impact of venetoclax discontinuation and interruption on survival hindered comparison of the MURANO results with other studies of venetoclax. Moreover, the review was further limited by the inability to perform a meta-analysis in order to compare the MURANO results with studies of other targeted thera- pies (ibrutinib, idelalisib and duvelisib).
In conclusion, these analyses provide the first compre- hensive account of the impact of discontinuation, treat- ment interruption and dose reduction of oral targeted treatment on PFS and/or OS in patients with 1L or R/R CLL. These data highlight the importance of prompt treatment modification upon development of AE with venetoclax, as effective management of AE with treat- ment interruption or dose reduction allows patients to continue venetoclax treatment and avoid the negative impact of treatment discontinuations on outcomes.
Disclosure
ARM consults for or advises for AbbVie, AstraZeneca, Celgene, Genentech, Janssen, Loxo, PCYC, Sunesis and TG therapeutics, and has received research funding from AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis and TG Therapeutics; JPS consults for or advis- es for AbbVie, Acerta, AstraZeneca, Bayer Health, Celgene, F. Hoffmann–La Roche, Pharmacyclics and TG Therapeutics, has received research funding from AbbVie, Acerta, AstraZeneca, Celgene, Pharmacyclics and TG Therapeutics, has received travel support from AbbVie, AstraZeneca and Celgene, and has role or activity within Pfizer; JMLB, MW and YM are employ- ees and stockholders of Genentech; SYK is an employee and stockholder of AbbVie, and has received travel support from AbbVie; KH and MB are employees and stockholders of F. Hoffmann–La Roche; QZ is an employee and stockholder of Edwards Life Sciences, and consults or advises for Genentech; JFS has received honoraria from and consults/advises for AbbVie, BMS, Celgene, F. Hoffmann–La Roche, Gilead, Janssen, Mei Pharma, Sunesis and Takeda, has participated in speaker’s bureaus for AbbVie and F. Hoffmann–La Roche, has received research funding from AbbVie, Celgene, F. Hoffmann– La Roche and Janssen, has provided expert testimony for F. Hoffmann–La Roche, and has received travel support from AbbVie, BMS, F. Hoffmann–La Roche and Janssen.
Contributions
All authors were involved in the analysis and interpretation of the data, as well as review and/or revision of the manuscript.
Acknowledgments
The authors would like to thank the patients and their fami- lies, investigators, study coordinators and support staff, and MURANO study team members.
Funding
Venetoclax is being developed in collaboration between Genentech and AbbVie. Genentech and AbbVie provided finan- cial support for the study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writ- ing, review and approval of the manuscript. Medical writing support was provided by Rachel Dobb of Ashfield MedComms, an Ashfield Health company and was funded by F. Hoffmann– La Roche Ltd.
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