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Real world venetoclax experience
(>3 chromosomal abnormalities) and 26.8% (n=15/56) had a NOTCH1 mutation. Thirty-one patients (22%) had del(17p) and TP53 mutation, and 16 patients (11%) had del(17p), TP53 mutation, and complex karyotype.
Venetoclax dosing and adverse events
All patients underwent 5-week dose escalation of vene- toclax. During dose-escalation, 85% (n=120/141) of patients achieved a maximum dose of 400 mg daily, with 75% of the cohort (n=103/137) maintaining 400 mg daily as a long-term stable dose. Dose interruptions occurred in 30% of patients and 21% required dose reduction. Details are available in Online Supplementary Table S1. Reasons for interruptions were not available. Hematologic events were the most common AEs with neutropenia (defined as ANC < 1000 cells/microL) occurring in almost half of patients (47.4%, n=65/137) and thrombocytopenia (defined as platelets < 50,000 cells/microL) occurring in over one-third of patients (36.0%, n=49/136). Other AEs included TLS (13.4%, n=18/134), neutropenic fever (11.6%, n=16/138), and grade ≥ 2 diarrhea (7.3%, n=10/138). Opportunistic infections (OI) while on veneto- clax were reported in 11 patients (7.8%) with the three most common being pneumocystis jirovecii pneumonia (PJP) (n=6), invasive fungal (n=2), and toxoplasmosis (n=2). Nine OI events occurred in patients with prior exposure to any kinase inhibitor, 8 OI events occurred in patients with prior exposure to ibrutinib, and 6 OI events occurred in patients with prior exposure to two prior kinase inhibitors. The median time from venetoclax start to OI event was 5 months (0.2 – 16 months).
TLS: prophylaxis and hospitalization practice patterns
Of 134 patients with TLS data, 44.8% were low-risk (n=60), 35.8% were intermediate risk (n=48), and 19.4% were high risk (n=26). Eighty-nine of 131 patients (64.3%) had pre-venetoclax lymph node assessment by CT scan to inform TLS risk. To minimize the occurrence of TLS, allopurinol was used in almost all cases regardless of risk category (93.1% low risk, 87.5% intermediate risk, 100.0% for high risk), as was intravenous normal saline (82.1% low risk, 91.7% intermediate risk, 100.0% high risk). Rasburicase use as TLS prophylaxis varied by risk category: 17.2% of low risk, 31.3% of intermediate risk, and 46.2% of high risk patients. TLS risk stratification, prophylaxis patterns, and incidence are summarized in Table 2.
Most patients had one or more planned hospitalizations during dose escalation regardless of risk category (Online Supplemental Table S2). Twenty-seven patients were not hospitalized at any point, including 20 of 58 (34.5%) low risk patients and 7 of 48 (14.6%) intermediate risk patients. All high-risk patients were hospitalized at least once for TLS monitoring and prophylaxis during the dose escalation phase. Among high-risk patients, 32.0% (n=8 of 25) were hospitalized for all five dose escalations. The mean number of days hospitalized during the 5-week dose escalation period for low risk, intermediate risk, and high-risk patients were 1.5, 1.7, and 3.1, respectively.
Overall, the incidence of TLS events (laboratory and clinical) was 13.4% (n=18/134) with 5 events (3.7%) reported in low-risk, 4 (3.0%) in intermediate-risk, and 9 (6.7%) in high-risk patients. Of these events, 6 were recorded as clinical TLS events (2 low risk patients, 1 inter- mediate risk patient, and 3 high risk patients), and the
Table 1. Baseline characteristics of 141 patients treated with veneto- clax.
Patient characteristics
Median age at diagnosis, years
Median age at venetoclax start, years Median prior lines of therapy
Follow up, months*
CLL characteristics
Relapsed/Refractory
Treatment naive CLL genetics
Del(17p) Del(11q) TP53 mutation
NOTCH1 mutation
Complex karyotype, ≥ 3 mutations Unmutated IGHV
Prior ibrutinib exposure Ibrutinib resistance mutations
Venetoclax and ibrutinib
Venetoclax and obinutuzumab
Venetoclax and rituximab
*Median follow up calculated using overall survival.
BTK mutation
Median (range)
59 (30-88)
67 (37-91) 3 (0-11) 7 (0.1-38.4)
Frequency
(n with characteristic/ total n with available data)
ì98.6% (139/141)
1.4% (2/141)
44.9% (61/136) 26.0% (34/131) 44.2% (42/95) 26.8% (15/56) 26.8% (52/130) 83.3% (60/72) 81.6% (115/141)
35.3% (12/34) 12.5% (4/32) 18.4% (26/141) 36% (9/26) 32% (8/26) 24% (6/26)
PLCγ2 mutation
Venetoclax administered in combination
remainder were laboratory events (n= 12). Of the clinical TLS patients, 4 of 6 achieved 400 mg venetoclax dosing. No TLS patient required hemodialysis. One TLS death was reported in a patient who was re-challenged with venetoclax after a delayed interruption without utilizing a dose escalation schedule or hospitalization for venetoclax re-escalation. We were unable to correlate TLS events with a threshold dose of venetoclax.
Outcomes
The reported ORR and CR rate, stratified by selected risk factors, are summarized in Table 3. The ORR for the entire cohort was 72.1% and 19.4% of patients achieved a CR. The median time to best response was 2.1 months. Venetoclax had a similar ORR across several high-risk groups including patients with age ≥ 65 (ORR = 74.3%), del(17p) (71.4%), prior ibrutinib therapy (69.1%), BTK mutation (91.6%), and PLCγ2 mutation (75.0%). At a median follow up of 7 months, the median PFS and OS have not been reached for the entire cohort (Figure 1a and 1b). The projected PFS and OS for the entire cohort at 12 months were 68% and 88%, respectively. Patients with a TP53 interruption (del(17p) and/or TP53 mutation) had significantly shorter PFS than those with intact TP53 (Figure 1c), though OS for the two groups was not signif- icantly different (Online Supplementary Figure S1).
In univariate analyses, we identified TP53 interruption as a predictor of inferior PFS (HR 2.7, 95% CI 1.08-6.7, P=0.034) but not OS (HR 1.78, 95% CI .55-5.74, P=.332).
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