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Impact of discontinuation/modifications on outcome
longest consecutive number of days per person). Treatment interruption, regardless of duration (≥1, ≥8, ≥14 and ≥21 consecutive days of missed venetoclax treatment) had no statistically significant effect on clinical outcomes (Table 6) compared with no treatment interruption.
Thirty-six (18.6%) patients who had treatment interrup- tions later discontinued venetoclax prior to completion of therapy. Previous treatment interruptions did not predict likelihood of prematurely discontinuing venetoclax; dis- continuation rate was 26.3% in patients who previously interrupted treatment versus 31.6% in patients who did not interrupt treatment (statistically similar; P=0.4842).
Overall, 134 patients (69.1%) required treatment inter- ruption for AE (a total of 344 AE). The most common types of AE leading to treatment interruption were blood and lymphatic system disorders (49.0%), infections and infes- tations (24.2%), gastrointestinal disorders (8.2%) and investigations (7.7%; Table 4). The most common individ- ual AE resulting in treatment interruption were neutrope- nia (84 of 194; 43.3%), thrombocytopenia (nine of 194; 4.6%) and diarrhea (nine of 194; 4.6%). Notably, 116 of 134 (86.6%) patients interrupted treatment due to veneto- clax related AE (Online Supplementary Table S2). Number of prior regimens was the only variable found to be statisti- cally significant (P=0.0048) from the logistic regression model for interruption due to venetoclax related AE (Online Supplementary Table S4). Baseline covariates were not sig- nificantly associated with treatment interruption due to AE that were not related to venetoclax (Online Supplementary Table S4). Median time to first onset of AE leading to vene- toclax dose interruption was 1.6 months (range, 0.0–22.8).
Dose reduction
Of the 194 patients receiving VenR, 45 (23.2%) required dose reductions for venetoclax. A total of 76 dose reduc- tions were required, with some patients having multiple dose reductions (for different reasons); 64 due to AE (in 40 patients), seven due to unknown reasons (six patients), two due to medication error (two patients), two due to patient choice (one patient) and one due to a medical decision (one patient). Venetoclax dose was reduced to 300 mg for three of 76 (3.9%) dose reductions (n=3), 200 mg for 44 of 76 (57.9%) dose reductions (n=36), 100 mg for 23 of 76 (30.3%) dose reductions (n=20), 50 mg for two of 76 (2.6%) dose reductions (n=2) and 20 mg for four of 76 (5.3%) dose reductions (n=4). Forty-five dose reductions (in 30 patients) occurred during the combination treatment phase, compared with 31 dose reductions (in 19 patients) during the monotherapy treatment phase.
Dose reduction had no statistically significant effect on PFS (n=165; HR 1.19, 95% CI: 0.65–2.18; P=0.5765) or OS (n=192; HR 0.91, 95% CI: 0.35–2.38;P=0.8519) compared with patients with no dose reduction. Following the first dose reduction, 26 (57.8 %) patients returned to the origi- nal dose; median duration from the first dose reduction before returning to the original dose was 16.5 days (range, 1–293). Of the 19 patients (42.2%) who never returned to the original dose, one patient subsequently discontinued venetoclax, eight interrupted venetoclax treatment, three interrupted and then discontinued venetoclax treatment and seven remained on the reduced dose (200 mg for six patients [85.7%] and 100 mg for one patient [14.3%]) until treatment completion.
Although the reason for dose reduction was AE for 40 patients, information on type of AE and onset of AE was only available for 28 patients (37 AE). Dose reductions in 25 of 28 (89.3%) patients were due to venetoclax related AE (Online Supplementary Table S2). The most common types of AE and the most common individual AE resulting in dose reduction (neutropenia [16 of 194; 8.2%], febrile neutropenia [two of 194; 1.0%] and diarrhea [two of 194;
Table 5. MURANO: best overall response and minimal residual disease status (ASO-PCR – peripheral blood) for patients who discontinued venetoclax due to adverse events.
Patients who discontinued due to AE (n=29)
Best overall response (investigator-assessed), n (%) Objective response rate
Complete response
Complete response with incomplete
bone marrow recovery Partial response Nodular partial response
Stable disease Progressive disease Missing
Best MRD response, n (%) Undetectable
Positive
Missing
MRD response at end of combination treatment response visit,* n (%)
Undetectable Positive Missing
23 (79.3) 3 (10.3)
2 (6.9) 17 (58.6) 1 (3.4) 2 (6.9) 1 (3.4) 3 (10.3)
18 (62.1) 3 (10.3) 8 (27.6)
14 (48.3) 6 (20.7) 9 (31.0)
Table 6. MURANO: impact of interruption of venetoclax treatment versus no interruption on outcomes for all patients.
≥1 days 137 (70.6%)
49 (35.8) 0.67 (0.38-1.19) 0.1709
17 (12.4) 0.97 (0.43-2.21) 0.9474
Duration of treatment interruption (n=194 patients)
*At the 9-month time point. AE: adverse event; ASO-PCR: allele-specific oligonu- cleotide polymerase chain reaction; MRD: minimal residual disease.
Patients, n
Progression-free survival Events, n (%)
HR (95% CI)
P-value
Overall survival Events, n (%) HR (95% CI) P-value
≥8 days 76 (39.2%)
29 (38.2) 1.01 (0.59-1.71) 0.9741
11 (14.5) 1.35 (0.60-3.02) 0.4646
≥14 days 50 (25.8%)
20 (40.0) 0.92 (0.51-1.65) 0.7671
8 (16.0) 1.47 (0.63-3.45) 0.3730
≥21 days 34 (17.5% )
13 (38.2) 0.82 (0.41-1.65) 0.5753
5 (14.7) 1.31 (0.46-3.73) 0.6193
CI: confidence interval; HR: hazard ratio.
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