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Real world venetoclax experience
TP53 interruption was significantly associated with inferi- or PFS, OS was not compromised. Complex karyotype was not associated with inferior PFS, despite being shown to be a risk factor for progression in patients receiving venetoclax in a recent study by Anderson et al.2 It is possi- ble that our shorter follow up accounts for this discrepan- cy. Interestingly, del(11q) did not adversely affect PFS. Similar findings were reported by Kipps et al. in 620 patients treated with ibrutinib stratified by del(11q) status (HR 0.73, P=0.08).18 In subgroup analysis, the response rate for patients previously treated with ibrutinib was 69.1%, similar to the 65% demonstrated by Jones et al. in patients who were treated with venetoclax following ibrutinib.5 Finally, we did not observe a difference in PFS whether venetoclax was given alone or in combination.
TLS has been suggested as the most critical toxicity with venetoclax, contributing to early treatment-related deaths in clinical trials, particularly before the current dose ramp- up schedule was implemented in trials to minimize TLS risk. In our study, TLS rates were higher than those report- ed in most recent trials. In this cohort, 18 patients (13.4%) had TLS; 12 (9.0%) cases were laboratory TLS events and 6 (4.5%) cases were clinical events. In the initial phase I venetoclax study, 18% of patients experienced TLS (12.5% laboratory, 5.6% clinical). However, once the dos- ing schedule was modified to minimize TLS risk, 1.7% of patients had laboratory TLS and none had clinical TLS.3 More recently reported clinical trials using the standard dose ramp-up protocol have shown laboratory TLS rates of 2.2%5 and 4.7%3 and clinical TLS rates of 0%.3-5 Despite the higher rates of TLS observed in our study, only 19.4% of patients were deemed high risk for TLS versus 25-49% of patients classified as high risk in the clinical trials set- ting.3-5
Overall, adherence to TLS prophylaxis recommenda- tions was excellent. The majority (92%) received allopuri- nol, which is recommended for all patients regardless of risk category.13 Guidelines per the US venetoclax prescrib- ing information document also recommend oral hydration and intravenous normal saline for high risk patients, which was followed for all patients in our cohort. Similarly, rasburicase is recommended for patients with elevated baseline uric acid. This was used in over one- quarter of all cases and almost half of the high-risk cases. All high-risk patients had at least one planned hospitaliza- tion during dose escalation. Three of 25 high-risk patients forwent the second recommended hospitalization given lack of TLS development during the first hospitalization.
Most low and intermediate-risk patients were hospital- ized at least once, suggesting a conservative approach was utilized in this series during the dose ramp-up as outpa- tient dosing, with close monitoring. As per United States Food and Drug Administration (FDA) label guidelines, low and intermediate-risk patients can also be managed in the outpatient setting without hospitalization and we suspect future real-world series will demonstrate a higher propor- tion of low and intermediate-risk patients managed in the clinic during the dose ramp-up period.
Potential reasons for increased TLS events may include difficulty in adhering to the exact dose-ramp up schedule or lack of physician/patient education surrounding impor- tance of suggested prophylaxis, laboratory monitoring, and interventions for all patients. Patients may have had differences in comorbidities, such as impaired renal func- tion, which would have made them ineligible for a vene- toclax clinical trial and possibly at increased risk for TLS. Deviations in clinical practice initiation of venetoclax from that recommended in the FDA label, in particular the lim- ited use of CT assessment (64.3%) to establish TLS risk prior to venetoclax initiation, could have led to risk mis- classification. Additionally, while investigators were asked to use the Howard criteria to define TLS, it is possible that this mandate was not strictly followed when capturing data, leading to misclassification bias.
To date, little is known regarding reasons for venetoclax discontinuation in clinical practice. In our study, 28% of all patients discontinued therapy; 53.8% of these patients discontinued due to progression of CLL excluding Richter’s transformation (RT) and 20.5% discontinued due to toxicity. As in clinical trials, we found CLL progression to be the most common reason for venetoclax discontinu- ation. In the phase I study of venetoclax for R/R CLL, the overall discontinuation rate of 56%, with 35% of discon- tinuations due to CLL progression (non RT) and 20% due to toxicity.1 In the phase II study of patients treated with prior B-cell receptor signal transduction inhibitors, the dis- continuation rate was 49.5% at 14 months median follow up. CLL progression represented 49% of these discontin- uations and AEs represented 11% of discontinuations.5 In this same series, RT was reported in 5% of patients who discontinued venetoclax. The median time to CLL pro- gression was 8.4 months, and median time to RT was approximately one year.19 Anderson et al. reported that, in a group of heavily pretreated patients, 37% of patients progressed on venetoclax at a median follow up of 23 months, and that 8.2% of patients discontinued therapy
Table 3. Response rates. Overall population Age
Age <65 years n=47
68%
21.2% 46.8% 19.1%
12.7%
Del 17p present n=56
71.4%
25.0% 46.4% 16.1%
12.5%
Del 17p absent n=69
72%
16.0%
56.5%
18.8%
8.7%
Prior ibrutinib therapy n=107
69.1%
17.7%
51.4%
19.6%
11.2%
No prior ibrutinib therapy n=22
86.2%
27.2%
59.0%
9.0%
4.5%
BTK BTK mutation mutation present absent n=12 n=22
91.6% 72.6%
8.3% 18.1% 83.3% 54.5% 8.3% 18.1%
0% 9.0%
PLCγ2 mutation present n=4
75.0%
0.0% 75.0% 25.0% 0%
PLCγ2 mutation absent n=28
78.6%
14.3% 64.3% 14.3% 7.1%
n=129
ORR 72.1%
CR 19.4% PR 52.7% SD 17.8%
PD 10.1%
>65 years n=82
74.3%
18.3% 56.0% 17.1%
8.5%
CR: complete response; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease. .
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