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Novel agents in CLL
Administration (FDA). The efficacy of duvelisib, an oral inhibitor of PI3Kd and PI3Kγ, was demonstrated in a phase I study that included 55 r/r CLL patients of whom 56% responded to treatment.29 The results of the phase III DUO study, which tested the efficacy and safety of duvelisib versus ofatumumab, were recently published: duvelisib was associated with a significantly prolonged PFS com- pared to ofatumumab (13.3 vs. 9.9 months, HR=0.52, P<0.0001) and a superior ORR (74 % vs. 45 %, P<0.0001). The PI3Kd inhibitor umbralisib demonstrated promising activity in an initial phase I trial while showing a more favorable safety profile than other PI3K inhibitors with a lower incidence of autoimmune-like adverse events.30
BCL2 inhibitors
Venetoclax is an oral B-cell lymphoma 2 (BCL2) inhibitor and was recently approved for the treatment of patients with r/r CLL in combination with rituximab.31 Before the approval of the combination therapy, veneto- clax was used as an indefinite monotherapy in patients who relapsed after ibrutinib treatment and patients with TP53 aberrations.7 With the universal approval of veneto- clax plus rituximab as second-line therapy, indefinite venetoclax monotherapy will be less relevant in the near future. Nonetheless, it is worthwhile looking at extended follow-up data of venetoclax monotherapy trials.
The results of a phase II study evaluating venetoclax in 158 mostly r/r CLL patients with 17p deletions was recently published.32 The median duration of venetoclax treatment was 23.1 months (range, 0-44.2 months) and the ORR was 77% (122 of 158 patients; 20% CR) while the 2-year PFS was 54% [95% confidence interval (95% CI): 45% to 62%]. Forty-eight (30%) of the 158 patients achieved a minimal residual disease (MRD) status below 10-4 at least once in the course of the study. More detailed MRD data showed that, in patients receiving venetoclax monotherapy, MRD status was closely associated with PFS. Patients who achieved undetectable MRD during treatment had significantly longer PFS than patients with intermediate or high MRD levels.33 This association had previously only been reported for chemoimmunotherapy
regimens.34 While these results demonstrate the relevance of venetoclax for patients with 17p deletions, venetoclax monotherapy is still only approved in the first-line setting in patients ineligible for ibrutinib treatment.
In relapsed CLL, venetoclax was approved in combina- tion with rituximab based on the data from the MURA- NO study that tested this 24-month long combination treatment against bendamustine plus rituximab in a popu- lation of 389 CLL patients.31 With a median follow-up of 23.8 months, PFS among the patients treated with veneto- clax plus rituximab was clearly superior to that of patients treated with bendamustine plus rituximab (HR=0.17; 95% CI: 0.11-0.25; P<0.0001): the estimated 2-year PFS was 84.9% for patients treated with venetoclax plus rituximab and 36.3% for those treated with bendamustine plus rit- uximab. Venetoclax plus rituximab also produced a signif- icantly prolonged OS (HR=0.48; 95% CI: 0.25-0.90) and an impressive ORR of 93.3% compared to 67.7% with bendamustine plus rituximab (difference= 25.6%; 95% CI: 17.9-33.3%). Venetoclax plus rituximab also led to higher rates of undetectable MRD in peripheral blood (62.4% vs. 13.3% after 9 months). Most importantly, the MURANO study established the feasibility of a time-lim- ited chemotherapy-free treatment regimen by demon- strating that the majority of MRD-negative remissions were sustained after the end of the study treatment.35 With an extended median follow-up of 36 months, 130 (67%) of 194 patients completed the 2-year treatment and with a median observation time of 9.9 months after com- pletion of treatment with venetoclax plus rituximab, only 16 of 130 patients (12%) showed disease progression.
While the occurrence of clinical tumor lysis syndromes was a dreaded and common event in the early experiences with venetoclax, the risk of these syndromes has now been successfully mitigated by introducing a ramp-up schedule and repeated testing of tumor lysis syndrome parameters within the first 24 h after each ramp-up.7 A recent comprehensive safety analysis of three trials using venetoclax monotherapy showed an incidence of labora- tory tumor lysis syndrome of only 1.4% while no clinical tumor lysis syndrome occurred.36 Most adverse events
Ageᵻ ORR 64 83%
63 68%
62 70%
64 45% 55 96% 55 97% 60 100% 60 93%
67 100%
59 95%
Table 2. Trials using novel agents in combination with chemoimmunotherapy as first or further line therapy for CLL.
Treatment
BR + ibrutinib BR
BR + idelalisib
BR
Ibrutinib + FCR
Duvelisib + FCR
Ibrutinib + FCG
Bendamustine + ibrutinib
+ ofatumumab
Bendamustine + ibrutinib + obinutuzumab
Bendamustine + venetoclax
+ obinutuzumab
TN, r/r
r/r (n=289) r/r (n=289)
r/r (n=207)
r/r (n=209)
TN (n=85)
TN (n=32)
TN (n=42)
TN (n=40),
r/r (n=25)
TN (n=30), r/r (n=31)
TN (n=35),
r/r (n=31)
CR %
10% 3%
1%
0 36% 28% 40% 31%
46%
38%
PR %
72% 65%
69%
44% 61% 69% 60% 62%
54%
56%
uMRD % PFS*
26% NR 6% 13.3
NA 20.8
NA 11.1 78% NR 67% NR 100% NR 7% NR
48% NR
87% NR
2 y-PFS
18 m: 79% 18 m: 24%
NA
NA 100% 97% NA NA
15 m: 96%
15 m: 92%
2 y-OS
3 y-OS: 82% 3 y-OS: 73%
NA
NA 100% 97% NA NA
NA
15 m: 95%
Reference
Chanan-Khan et al. 201656 Zelenetz et al. 201758
Davids et al. 201959 Davids et al. 201862 Jain et al. 201860 Cramer et al. 201765
Von Tresckow et al. 201866 Cramer et al. 201867
ᵻmedian, years; *median, months; TN: treatment-naïve; r/r: relapsed or refractory; ORR: overall response rate; CR %: complete response rate; PR %: partial response rate; uMRD %: rate of patients with undetectable minimal residual disease (<10-4) in peripheral blood; PFS: progression-free survival; y: year; m: month; OS: overall survival; BR: bendamustine, rituximab; FCR: fludarabine, cyclophosphamide, rituximab; FCG: fludarabine, cyclophosphamide, obinutuzumab; NR: not reached; NA: not available.
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