Page 114 - 2018_09-Mondo

A.R. Mato et al.
Complex karyotype (HR 1.36, 95% CI 0.66-2.84, P=0.4), prior ibrutinib therapy (1.74, 95% CI 0.61-5.0, P=0.3), and unmutated IGHV (HR 0.29, 95% CI 0.04-2.3, P=0.25) were not significantly associated with inferior PFS. TP53 interruption remained a significant predictor for inferior PFS in a multivariate analyses which included TP53 inter- ruption, complex karyotype and prior ibrutinib therapy (HR 2.8, CI 1.22-6.4, P=0.03). The presence of del(11q) did not impact OS and had an observed protective effect on PFS (HR 0.31, 95% CI 0.11-0.90, P=0.03).
Venetoclax discontinuations and treatment selection following venetoclax
Venetoclax was discontinued in 41 patients (29%). Progression of disease was the most common reason for discontinuation (53.8%, n=21) followed by toxicity (20.5%, n=9), two-thirds of which were hematologic. Other reasons for discontinuation included death not related to progressive disease (10.25%, n=4), second can- cer (5.1%, n=2), physician/patient preference (2.5%, n=1), Richter’s transformation (2.5%, n=1), and planned alter- nate therapy including CD19 directed chimeric antigen receptor T cells (CAR-T, 2.5%, n=1) and transplantation (2.5%, n=1).
Table 4 summarizes therapy selection and outcomes for individual cases following venetoclax. Notably, 17 of 34 patients (50%) who discontinued venetoclax and remain alive have not required a subsequent therapy. Reasons for discontinuation in the group of patients who have not yet been treated following venetoclax discontinuation
Table 2. Tumor lysis syndrome prophylaxis and events.
TLS prophylaxis
include toxicity (n=6), progression of CLL (n=4), death not secondary to toxicity or progression (n=4), secondary malignancy (n=2), and doctor or patient preference (n=1). Ibrutinib-based therapy was the most common choice after venetoclax; five of 24 (21%) patients receiving ibru- tinib. Three of five of patients treated with ibrutinib had prior ibrutinib exposure. Of these five patients, 1 had a partial response, 2 had stable disease, and 2 had progres- sive disease. Other therapies selected included rituximab monotherapy (12.5%, n=3), anthracycline based regi- mens (12.5%, n=3), allogeneic stem cell transplant (12.5%, n=3), idelalisib-based therapy (8.3%, n=2), and CAR-T (8.3%, n = 2). Subsequent lines of therapies with their corresponding responses are detailed in Online Supplementary Table S3.
Discussion
In the largest series of venetoclax-treated CLL patients treated in the U.S., response rates (ORR 72.1%) and sur- vival data are comparable to those reported in published clinical trials.1,3-5 Toxicities were similar with hematologic toxicities being the most frequently observed. Rates of TLS were higher than prior reports. Collectively, these results suggest that the efficacy and safety profile of vene- toclax demonstrated in the clinical trials setting are com- parable to what has been observed in the real world.
Consistent with previously published data, the ORR for the del(17p) population remained high at 71.4%. Whereas
TLS risk category n=134
Low
44.8% (n=60) Intermediate 35.8% (n=48) High
19.4% (n=26)
Allopurinol Rasburicase Normal saline Total
93.1% 17.2% 82.1% 5 (n=54/58) (n=10/58) (n=46/56)
87.5% 31.3% 91.7% 4
(n=42/48) (n=15/48) (n=44/48)
100.0% 46.2% 100.0% 9
(n=26/26) (n=11/26) (n=25/25)
TLS events
Laboratory Clinical
32
31
63
ABC
HR 2.7, P=0.034
Figure 1. Survival analyses for patients following venetoclax initiation. (A) Progression free survival for the entire cohort. Median PFS has not been reached with median follow up of 7 months. Projected 12-month PFS is 68%. (B) Overall survival for the entire cohort. Median OS has not been reached with median follow up of 7 months. Projected 12-month OS is 88%. (C) Progression free survival by TP53 status. PFS is significantly superior for patients with intact TP53 compared to patients with TP53 interruption, either TP53 mutation or del(17p).
1514
haematologica | 2018; 103(9)