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Novel agents in CLL
Although the addition of kinase inhibitors to conven- tional chemoimmunotherapy regimens yields significant undetectable MRD and CR rates in selected populations of patients, these combinations have not yet been tested against kinase inhibitor monotherapy. This limits the practical relevance of these observations in the light of the impressive outcomes of single agent ibrutinib. In addition, toxicity rates with these more intensive combinations cannot be neglected. Treatment of elderly patients with comorbid conditions, in particular, is probably more diffi- cult due to the toxicity rates.
Novel agents plus anti-CD20 antibodies
While idelalisib is specifically approved in combination with anti-CD20 antibodies, ibrutinib has so far not been approved as part of a combination treatment due to ambiguous study results.4,10,63 The combination of ibrutinib plus rituximab has been tested in randomized settings in phase II and phase III trials.10,63 Burger and colleagues con- ducted a randomized trial of ibrutinib versus ibrutinib plus rituximab in 208 CLL patients of whom 181 had r/r CLL.63 The other 27 patients included were treatment-naïve, but had high-risk, unfavorable genetics, defined by del(17p) or TP53 mutation. The study showed no difference between ibrutinib plus rituximab and ibrutinib in either PFS (3-year PFS: 86.9% vs. 86%), ORR (92.3% for both) or CR rate (26% vs. 20.2%). However, patients treated with ibrutinib plus rituximab showed higher rates of undetectable MRD and achieved their remissions faster than patients treated with ibrutinib only. A phase III trial (ALLIANCE) that test- ed ibrutinib and ibrutinib plus rituximab against ben- damustine plus rituximab in older patients showed almost identical efficacy data for both ibrutinib-containing arms.10 While these data support the conclusion that there is no clear benefit of adding rituximab to ibrutinib, no random- ized comparison has been performed so far comparing obinutuzumab plus ibrutinib versus ibrutinib monothera- py. The iLLUMINATE trial evaluated ibrutinib plus obinu- tuzumab in comparison to chlorambucil plus obinu- tuzumab. The combination of ibrutinib plus obinutuzum- ab was significantly superior to the chemoimmunothera- py regimen with a PFS at 30 months of 79% versus 31% (P<0.0001), but unfortunately a third arm with ibrutinib monotherapy was missing. Hence the benefit of the addi- tion of obinutuzumab is not clear, particularly because no treatment stop was planned in the case of CR, which was achieved in 19% of the patients receiving ibrutinib plus obinutuzmab. First data from a phase Ib/II study combin- ing acalabrutinib and obinutuzumab were impressive with an ORR of 93%, but also in this trial there was no direct comparison to acalabrutinib monotherapy.64
Two identically designed phase II trials evaluated the use of ibrutinib plus obinutuzumab and ibrutinib plus ofa- tumumab after an optional debulking with bendamustine including a planned termination of treatment if peripheral blood samples showed undetectable MRD at two consec- utive time-points. While 48% of all ibrutinib plus obinu- tuzumab-treated patients had undetectable MRD at the final restaging, only 14% achieved this status after ibruti- nib plus ofatumumab treatment.65,66
In contrast to ibrutinib, the addition of rituximab to venetoclax has produced unprecedented MRD-negative response rates in r/r CLL leading to its broad approval in the r/r setting.31 In the pivotal MURANO trial comparing bendamustine plus rituximab versus 24 months of veneto-
clax plus rituximab 64% of the patients treated with the latter combination had no detectable MRD after 24 months of treatment and this status was sustained in the majority, with a median follow-up of approximately 10 months.35 This study was the first to establish a chemotherapy-free time-limited treatment regimen in CLL.
Even higher response rates were observed when veneto- clax was combined with obinutuzumab. The CLL2-BAG trial combined an optional upfront debulking with ben- damustine with an 8-month induction treatment and a MRD-guided maintenance phase, both consisting of vene- toclax and obinutuzumab.67 At the end of induction treat- ment, 60 of 63 patients (95%) had responded to treatment and 87% of the patients had no detectable MRD below 10-4. The remissions seem durable after undetectable MRD-triggered end of treatment even in patients with high-risk genetic features.68 The recently published phase III CLL14 trial confirmed the efficacy of this combination treatment in a comorbid patient collective when tested against chlorambucil plus obinutuzumab. A 12 month fixed-duration treatment with venetoclax and obinu- tuzumab produced an unprecedented uMRD rate of 76% and an estimated 2-year PFS of 88%.69 In a recent phase Ib study, venetoclax and obinutuzumab were combined for 6 months and followed by venetoclax treatment for either 1 year in the first-line cohort or until disease progression in the r/r cohort.70 The overall best response rate was 95% in r/r CLL patients and 100% in those treated first-line. Undetectable MRD rates in the peripheral blood were 64% and 91%, respectively, ≥3 months after the last dose of obinutuzumab.
Inhibitors in combination, including triple combinations
Considering the impressive single agent activity of kinase inhibitors and venetoclax in CLL and their ability to induce deep and durable remissions when combined with an anti-CD20 antibody, it seems obvious to test novel- novel combinations to further increase efficacy by syner- gistically tackling the CLL cell in different vital pathways (Figure 1).
The phase II CLARITY trial tested a time-limited and MRD-guided oral combination treatment of ibrutinib and venetoclax in 40 patients with r/r CLL.71 After 8 weeks of ibrutinib treatment, venetoclax was added with the estab- lished 5-week dose escalation scheme. All patients responded to treatment (CR/CRi rate: 58%) and 23 of 40 patients (58%) had no detectable MRD in peripheral blood after 12 months of combined therapy. The same combination in a fixed-duration 24-month strategy was investigated in 80 treatment-naïve patients with CLL.72 After 12 months of combined venetoclax and ibrutinib the CR/CRi rate was 96% and 69% of the patients had no detectable MRD in the bone marrow. In both trials, the rates of undetectable MRD increased during the course of treatment, promising higher rates with longer follow-up.
Rogers and colleagues recently reported the preliminary outcomes of their phase II trial investigating the triple combination of obinutuzumab, ibrutinib and venetoclax in treatment-naïve and r/r CLL.73 In the first month of treatment, only obinutuzumab was administered. Ibrutinib was added in month 2 and venetoclax was added in month 3. After 12 months of combined treatment, the
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