Page 119 - Haematologica Vol. 107 - September 2022

ARTICLE - iLLUMINATE: final analysis
C. Moreno et al.
demonstrated that first-line treatment with ibrutinib plus rituximab resulted in significantly longer PFS (3-year rate 89% vs. 73%) and OS (3-year rate 99% vs. 92%) compared with FCR.5 With additional follow-up (median: 45 months), PFS favored ibrutinib plus rituximab over FCR (HR=0.39; 95% CI: 0.26-0.57; P<0.0001).18
With additional follow-up since the primary analysis of iL- LUMINATE, the percentage of patients treated with ibruti- nib plus obinutuzumab achieving undetectable MRD increased (from 34.5% at primary analysis to 38.1% at final analysis), demonstrating deepening of remission with con- tinued ibrutinib treatment. Furthermore, fewer patients in the ibrutinib arm experienced MRD relapse, with approxi- mately 60% of patients maintaining undetectable MRD at a median follow-up of 2 years after first attaining unde- tectable MRD status. Due to the small numbers of pa- tients in the subgroups, the association between MRD status and PFS was not further studied.
Few patients discontinued treatment during the additional 13 months of follow-up after the primary analysis (n=14), and no new safety signals were reported with ongoing ibrutinib treatment. This is consistent with prior reports that rates of most adverse events are highest during the first year of ibrutinib-based treatment and decrease in frequency thereafter.4,9,19,20 Most patients had improvement or resolution of adverse events following dose reduction, suggesting that many such events are managed effectively by dose modification, allowing patients to stay on therapy and continue to maintain disease control. The discontinu- ation rate due to adverse events (22%) is comparable to that for first-line, single-agent ibrutinib after 4 years of follow-up in the RESONATE-2 study (19%)4 and is sup- ported by real-world studies showing that treatment dis- continuation is similar in patients with CLL/SLL receiving single-agent ibrutinib or ibrutinib-based combination therapy.21
Overall, first-line ibrutinib plus obinutuzumab was well tolerated, which is important given that the median age at diagnosis of CLL is over 70 years,22 a demographic that often presents with comorbidities that preclude the use of chemotherapy-containing regimens. In patients receiv- ing concomitant medications, ibrutinib was well tolerated. Notably, ibrutinib can be co-administered with acid-re- ducing medications, offering an advantage over other ki- nase inhibitors known to have drug‒drug interactions with acid-reducing agents.23 Overall, these results strengthen and build upon the broad experience with ibrutinib. Several studies have assessed whether adding anti-CD20 therapy to ibrutinib results in a clinically relevant improve- ment in efficacy in CLL.5,6,24 Evidence suggests that addi- tion of anti-CD20 therapy to ibrutinib may increase depth of response and decrease the time to absolute lympho- cyte count normalization relative to single-agent ibrutinib therapy, although survival outcomes have not been sig-
nificantly improved over the impressive results with single-agent ibrutinib.6,24,25 The lack of data showing quality of life or survival outcome benefits notwithstanding, the addition of an anti-CD20 agent may nonetheless provide reassurance for patients concerned with increased abso- lute lymphocyte count. In a cross-trial comparison of RESONATE-2 and iLLUMINATE, patients treated with ibrutinib plus obinutuzumab combination therapy had higher CR/CRi rates (44% vs. 27%; P=0.006) and shorter time to absolute lymphocyte count normalization (8 vs. 55 weeks) than patients treated with single-agent ibruti- nib.25 Compared to single-agent ibrutinib, the combination of ibrutinib plus rituximab was demonstrated by Burger et al. to improve CR/CRi rates (particularly in the first-line setting: 50% vs. 20%) and shortened time to absolute lym- phocyte count normalization (24 vs. 48 weeks) in a phase II study with a median follow-up of 36 months.24 In the phase III ALLIANCE 041202 study, the CR rates (12% and 7%) and rates of undetectable MRD (4% and 1%) were slightly higher with ibrutinib plus rituximab than with single-agent ibrutinib.6 The difference in response rates tended to be greater in patients with high-risk disease, suggesting that combination therapy may be most useful for patients with high-risk or bulky disease.24 In the re- lapsed/refractory high-risk setting, the GENUINE study demonstrated significantly higher ORR with ublituximab plus ibrutinib compared to single-agent ibrutinib after a median follow-up of 41.6 months (83% vs. 65%; P=0.02).26 In the setting of other BTK inhibitors, the ELEVATE-TN study reported investigator-assessed CR/CRi rates of 24% with acalabrutinib plus obinutuzumab compared to 8% for acalabrutinib monotherapy and 13% for obinutuzumab plus chlorambucil.27
In terms of PFS, 48-month estimates between RESONATE- 2 and the current study were similar across ibrutinib- based treatment arms (76% vs. 74%), although it is worth noting that the current study included patients with high- risk genomic features whereas RESONATE-2 excluded those with del17p.4,10 Regardless, these broad clinical data clearly refute preclinical hypotheses of ibrutinib negating anti-CD20 efficacy, although anti-CD20 use may be im- portant to optimize efficacy of other BTK inhibitors.27
In conclusion, ibrutinib plus obinutuzumab remains an ef- fective chemotherapy-free regimen for patients with CLL/SLL that provides sustained efficacy and significantly reduces the risk of disease progression or death compared with chlorambucil plus obinutuzumab, including in pa- tients with high-risk genomic features. With ongoing once-daily dosing, long-term ibrutinib therapy was well tolerated with no new safety signals observed.
Disclosures
CM has provided consulting/advisory services for Janssen, AbbVie, AstraZeneca, and BeiGene; has received research
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