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Novel agents in CLL
CLL patients following the impressive results of the piv- otal RESONATE-2 trial.3,13,14 The phase III trial demonstrat- ed markedly prolonged PFS and overall survival (OS) in ibrutinib-treated patients compared to patients treated with chlorambucil monotherapy. The superiority of ibru- tinib was shown independently of genetic subgroups and a recent follow-up documented an overall response rate (ORR) of 92% and a 2-year PFS of 89% in the ibrutinib arm.15 Data from the first trial investigating indefinite ibru- tinib treatment in young, fit CLL patients versus the stan- dard of care in these patients (fludarabine, cyclophos- phamide and rituximab) were published recently.9 The ECOG-ACRIN E1912 intergroup trial showed significant PFS and OS advantages for patients treated with ibrutinib plus rituximab (Table 1). Improved survival was observed across all analyzed subgroups except for IGHV-mutated patients. In another recently published study, Woyach and colleagues evaluated the efficacy of ibrutinib alone or in combination with rituximab in CLL patients ≥65 years and compared it to that of bendamustine plus rituximab.10 The study showed a clear PFS advantage for both ibrutinib and ibrutinib plus rituximab compared with bendamus- tine plus rituximab. Due to the planned cross-over no sig- nificant survival differences were seen in the IGHV-mutat- ed group or with regards to OS. The addition of rituximab to ibrutinib did not result in an improved survival.
Consequently, the place of ibrutinib in the first-line
treatment of most groups of patients with CLL has been consolidated and the responses seem to be durable as well. A 5-year follow-up of a phase II trial initiated by the National Institutes of Health evaluating ibrutinib as first- line therapy in CLL showed a 5-year PFS of 74.4% in treat- ment-naïve patients with TP53 mutations or deletions and 100% in treatment-naïve patients without TP53 muta- tions.16 Although ibrutinib monotherapy is currently the most and best evaluated novel substance and indisputably yields impressive outcomes, its continued administration is associated with several problems. In the above-men- tioned study in patients with high-risk CLL, the cumula- tive incidence of resistance-conferring BTK or PLCγ2 mutations at 5 years ranged between 22.6% and 66.7% depending on the risk group.16,17 Similar rates were observed in a French real world cohort: after a median of 3.5 years of ibrutinib treatment, BTK mutations were found in 57% of the patients.18 The same study showed that 3 years after initiation of ibrutinib treatment, only 31% of the patients remained on the drug. The incidence of ibrutinib-related toxicities and associated treatment dis- continuation vary significantly between clinical trials and so-called real world experiences. A retrospective analysis reported toxicity-related treatment discontinuations in 128 of 616 patients (21%) with a median follow-up of 17 months in their comprehensive real-world analysis while the toxicity-related treatment discontinuation rate in the
Table 1. Trials using chemotherapy-free combination treatments in chronic lymphocytic leukemia
Treatment
Novel agents + anti-CD20 antibodies
Ibrutinib + rituximab FCR
Ibrutinib
Ibrutinib + rituximab Bendamustine + rituximab
Ibrutinib + obinutuzumab Chlorambucil + obinutuzumab
Idelalisib + rituximab
Rituximab
Acalabrutinib + obinutuzumab
Venetoclax + rituximab
Bendamustine + rituximab
Venetoclax + obinutuzumab CLB + obinutuzumab Venetoclax + obinutuzumab
Novel-novel combinations
Venetoclax + ibrutinib
Venetoclax + ibrutinib
TN, r/r
TN (n=354) TN (n=175)
TN (n=182) TN (n=182) TN (n=183)
TN (n=113) TN (n=116)
r/r (n=110)
r/r (n=110)
TN (n=19) r/r (n=26)
r/r (n=194)
r/r (n=195)
TN (n=216) TN (n=216) TN (n=32) r/r (n=50)
r/r (n=50)
TN (n=80)
CR %
17% 30%
7% 12% 26%
19% 8%
0
PR %
NA NA
NA NA NA
69% 66%
81%
uMRD %
8% 59%
1% 4% 8%
35% 25%
NA
NA NA
62%
13%
PFS*
NA NA
NR NR 41.0
NR 19.0
NR
2 y-PFS 2 y-OS
3y:89% 3y:99% 3y:73% 3y:92%
Reference
Shanafelt et al. 20199 Woyach et al. 201810
Moreno et al. 20188
Furman et al. 20144
Woyach et al. 201764
Seymour et al. 201831
Fischer et al. 201969 Flinn et al. 201970
Hillmen et al. 201871 Jain et al. 201872
Rogers et al. 201873 Davids et al. 201974
Nastoupil et al. 201975
Ageᵻ ORR 58 96%
57 81%
71 93% 71 94% 70 81%
70 88% 72 73%
71 81%
87% 88% 74%
30 m: 79% 30 m: 31%
6 m: 93%
90% 94% 95%
30 m-OS: 86% 30 m-OS: 85%
1 y-OS: 92%
71 13%
61 TN: 95% TN: 16% TN: 79%
6 m: 46%
1 y-OS: 80%
0 r/r: 8%
8%
4%
13% r/r: 85%
84%
69%
5.5 NRNANA
NR 85% 92%
r/r: 92%
65 92%
65 72%
17.0
NR NR NR NR
NR
NR
NR NR
NR
63% 87%
72 85% 50%
71 71% 23%
63 TN: 100% TN:78% TN:22% TN: 91%
88%
64% 93%
35% 48%
76% 35%
92%
61 r/r: 95%
NA 100%
65 100%
59 100% 67 90%
62 100%
r/r:37% r/r:58%
58% 42%
96% 4%
50% 50% 29% 62%
36% 64%
r/r: 64%
58%
69%
70% NA
78%
r/r: 85% NA
TN: 91%
NA
NA
NA
1y:98% 1y:99%
Venetoclax + ibrutinib + obinutuzumab TN (n=25) Umbralisib + ibrutinib r/r (n=21)
NA 90%
NA
NA 95%
NA
Umbralisib + ibrutinib + ublituximab r/r (n=22)
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; FCR: fludarabine, cyclophosphamide, rituximab; NR: not reached, NA: not available..
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