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Impact of discontinuation/modifications on outcome
sine kinase [BTK] inhibitors ibrutinib and acalabrutinib, and the phosphatidylinositol 3-kinase [PI3K] inhibitors idelalisib and duvelisib) and the potent B-cell lymphoma- 2 (BCL-2) inhibitor venetoclax.5
Mechanisms of action differ between targeted thera- pies. BTK inhibitors reduce CLL cell chemotaxis toward the chemokines CXCL12 and CXCL13 and block B-cell receptor signaling.6 This drives apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments. PI3K inhibitors impede one or more of the PI3K enzymes, part of the PI3K/AKT/mTOR path- way that regulates many cellular functions (e.g., growth control, metabolism and translation initiation), resulting in tumor suppression.7 Venetoclax is a BH3-mimetic, which blocks the anti-apoptotic BCL-2 protein, leading to programmed cell death of CLL cells.8
Ibrutinib, idelalisib, duvelisib and acalabrutinib are used until progression or toxicity, while venetoclax pro- vides a chemotherapy-free treatment option that allows for a finite duration of therapy.9 Venetoclax has a fixed treatment duration of 1 year when given concomitantly with obinutuzumab for 1L CLL, 2 years when given in combination with rituximab for R/R CLL, and until dis- ease progression (PD) or toxicity as a monotherapy for R/R CLL.10-13
Although targeted therapies have manageable safety profiles and in some instances improve life expectancy for patients with CLL, both premature discontinuations (before PD) and modifications to therapy are reported in a proportion of cases. To date, information on whether premature discontinuations and/or treatment modifica- tions have an impact on survival outcomes in patients with CLL (in both real-world studies and clinical trials) has not been summarized collectively. However, numer- ous publications address this question, with significant literature available on the impact of disruption of ibruti- nib on survival (Online Supplemental Table S1).14-28 In brief, the literature suggests that ibrutinib discontinuation is associated with poor survival outcomes,16,19,21 while the impact of interruption on outcomes seems contradictory (with some indicating an effect on survival and others suggesting a lack of difference in outcomes).14,15,18-20,22,23 Limited data are available for venetoclax; and given the different mechanism of action, more rapid kinetics of response and deeper remissions with venetoclax (espe- cially when used with anti-CD20 antibodies), extrapola- tion of ibrutinib data is unlikely to be valid for venetoclax.
The MURANO phase III, international, randomized, open-label study evaluated the efficacy of six cycles of venetoclax in combination with rituximab (VenR) then venetoclax once daily for 2 years in total compared with six cycles of bendamustine plus rituximab (BR) in patients with R/R CLL.29 VenR was superior to BR; after a median follow-up period of 23.8 months, investigator-assessed progression-free survival (PFS) was significantly longer in the VenR group (32 events in 194 patients) than in the BR group (114 events in 195 patients).29 Additionally, PFS benefit of VenR over BR was sustained (hazard ratio [HR], 0.19 [95% Confidence Interval [CI]: 0.14–0.25]; P<0.0001), with 4-year PFS estimates of 57.3% (95% CI: 49.4–65.3) versus 4.6% (95% CI: 0.1–9.2), respectively.30 While the minimum duration of venetoclax necessary to achieve therapeutic benefit remains unclear, the available data suggest that no substantial further deepening of responses occurs beyond 24 months of therapy.31
This manuscript reports novel venetoclax data from post-hoc analyses of MURANO to assess the impact of dis- continuation/modification on outcomes and provides the first review of the current published literature (for all oral targeted agents approved for use in CLL as of August 2019: ibrutinib, idelalisib and duvelisib; see the Online Supplemental Appendix), to contextualize these data.
Methods
MURANO study methodology
Analyses were performed on data from the VenR cohort of patientsintheMURANOstudy(NCT02005471),whichhasbeen described previously.29
MURANO enrolled patients aged ≥18 years, who had received 1–3 prior lines of therapy (including at least one chemotherapy- containing regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate bone marrow, renal, and hepatic function. Patients received venetoclax over a 5- week dose ramp-up period (to reach the 400 mg daily target dose) followed by six cycles of rituximab (single infusion on day 1 of each 28-day cycle: 375 mg/m2 on day 1, cycle 1 and 500 mg/m2 for day 1, cycles 2–6) with ongoing daily dosing of venetoclax. Patients continued daily venetoclax therapy for a maximum of 2 years (from day 1, cycle 1). All relevant ethical committees approved the MURANO study.
Data and statistical analyses
Efficacy analyses were based on the intention-to-treat popula- tion (all patients who underwent randomization). After trial drug initiation, all adverse events (AE), including those resulting in dis- continuation or treatment modification (including treatment inter- ruption and dose reduction), were reported up to 28 days after the last dose of trial drug (maximum of 2 years) or up to 90 days after the last dose of rituximab, whichever was longer. Discontinuation and modification events were recorded (see the Online Supplementary Appendix). Primary endpoints of the post-hoc analy- ses included investigator-assessed PFS and overall survival (OS). PFS was defined as time from randomization to first occurrence of PD, relapse or death.
In order to determine the effect of treatment discontinuations and modifications on clinical outcomes, eight time-dependent Cox proportional hazards regression models stratified by chromo- some 17p deletion (del(17p)) and disease risk status (high or low risk; see the Online Supplementary Appendix) were used to evaluate investigator-assessed PFS and OS (Table 1). Time-fixed baseline covariates and time-dependent serious AE (SAE) indicators were considered in each model. Time-dependent analyses were per- formed to account for varying time when treatment discontinua- tion/modification occurred, helping to assure that longer PFS and OS were not falsely attributed to patients who simply had treat- ment discontinuation/modification occurring at the later time (i.e., immortal-time bias).
The covariate selection process for the final multivariate model consisted of a bivariate or trivariate time-dependent Cox propor- tional-hazards regression model stratified by del(17p) and risk status with independent time-dependent variable (variables) and the given time-fixed covariate. Covariates were included in the final multivariate model if the P-value of the given time-fixed covariate was <0.1. The final multivariate time-dependent Cox proportional-hazards regression model was then stratified by del(17p) and risk status and included time-dependent covariates in addition to the significant time-fixed covariates (P<0.1; Table 1). The complete-case method was used in the analyses, which
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