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A.R. Mato et al.
included patients without missing values for all covariates used in the final multivariate model. All analyses performed were post- hoc and are therefore considered hypothesis-generating, with no statistical adjustment for type-I error. A P-value of <0.05 was considered significant except for in the covariate selection process described above. Data cut-off for this analysis was May 8, 2019.
Results
In total, 194 patients were included in the ITT population for the VenR arm of the MURANO study, of whom 140 completed 2 years of venetoclax therapy. Patient demo- graphics and baseline characteristics have been reported previously.29 Half of the patients were aged <65 years (50.0%), most patients were male (70.1%), white (93.3%) and had Rai stage 0–II at enrollment (71.6%). In total, 46 of 173 patients (26.6%) who were assessed for del(17p) status had this deletion, 48 of 192 patients (25.0%) who were tested for TP53 mutation status had TP53 muta- tions, and 123 of 180 patients (68.3%) who were tested
for immunoglobulin heavy chain variable region (IGVH) mutational status had unmutated IGVH.
Treatment discontinuation
Early discontinuation of venetoclax (<2 years) was reported in 27.8% of patients (54 of 194). The two most common reasons for discontinuation was AE (29 of 54, 53.7%), followed by PD (12 of 54, 22.2%). Two of the remaining 13 patients died, and the other 11 discontinued due to withdrawal by patient (n=5), physician decision (n=3), other reasons (n=2) and non-compliance (n=1). In total, 22 of 28 (79%) deaths reported for the MURANO study were in patients who discontinued venetoclax pre- maturely. Of those, 13 of 22 (59.1%) deaths were in patients who discontinued venetoclax due to AE (two were related to venetoclax), while four of 22 (18.2%) deaths were in patients who discontinued due to PD (Table 2). Two of the remaining five of 22 (22.7%) deaths were in patients who discontinued due to death, and three were in patients who discontinued due to with- drawal by patient (n=1), physician decision (n=1; related to venetoclax) and other reasons (n=1; Table 2).
Table 1. MURANO: stratified time-dependent Cox proportional-hazards regression models used to assess clinical outcomes.
Model 1 Model 2
Model 3
Model 4
Model 5
Model 6
Model 7
Model 8
Time-dependent Clinical indicators outcome
Discontinuation due to any reason excluding PFS patients who discontinued venetoclax due to PD
Discontinuation due to AE PFS Discontinuation due to PD/other
Discontinuation due to venetoclax-related AEs PFS
Covariates included in final multivariate model
TP53 mutation status, number of prior regimens, refractoriness to most recent prior therapy, hepatic impairment status and SAE time-dependent indicator
Age, TP53 mutation status, IGVH mutation status, number of prior regimens, refractoriness to most recent prior therapy, hepatic impairment status and SAE time-dependent indicator
TP53 mutation status, IGVH mutation status, refractoriness to most recent prior therapy and SAE time-dependent indicator
TP53 mutation status, IGVH mutation status, bulky disease, refractoriness to most recent prior therapy and SAE time-dependent indicator
Venetoclax interruption of ≥8 consecutive days PFS
OS TP53 mutation status, number of prior regimens and refractoriness to
most recent prior therapy
Venetoclax interruption of ≥14 consecutive days PFS
OS TP53 mutation status, number of prior regimen and refractoriness to
TP53 mutation status, IGVH mutation status, bulky disease, refractoriness to most recent prior therapy and SAE time-dependent indicator
most recent prior therapy
Venetoclax interruption of ≥21 consecutive days PFS
OS TP53 mutation status, number of prior regimen and refractoriness to
TP53 mutation status, IGVH mutation status, bulky disease, refractoriness to most recent prior therapy and SAE time-dependent indicator
most recent prior therapy
TP53 mutation status, IGVH mutation status, bulky disease, refractoriness to most recent prior therapy and SAE time-dependent indicator
Venetoclax interruption of ≥1 consecutive days PFS
OS TP53 mutation status, number of prior regimen and refractoriness to
Cumulative treatment (cycle) exposure excluding PFS
most recent prior therapy
TP53 mutation status, IGVH mutation status and SAE time-dependent
patients who discontinued venetoclax due to PD
indicator
OS Chromosome 11q deletion, TP53 mutation status, Rai stage, number of
prior regimen and refractoriness to most recent prior therapy
TP53 mutation status, IGVH mutation status, bulky disease, refractoriness to most recent prior therapy and SAE time-dependent indicator
Time-dependent venetoclax dose reduction PFS indicator (Yes/No)
OS TP53 mutation status, number of prior regimens and refractoriness to most recent prior therapy
AE: adverse event; IGVH: immunoglobulin heavy chain gene; OS: overall survival; PD: progressive disease; PFS: progression-free survival; SAE: serious adverse event.
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