Page 110 - Haematologica Vol. 107 - September 2022

ARTICLE - iLLUMINATE: final analysis
C. Moreno et al.
mustine plus rituximab.6 With up to 7 years of follow-up (median: 74.9 months; range, 0.1‒86.8) in the phase III RESONATE-2 study in patients with CLL aged ≥65 years, single-agent ibrutinib provided sustained PFS with ex- tended follow-up, with a PFS of 61% at 6.5 years.4,7 No- tably, in patients with high-risk genomic features such as del(17p)/TP53 mutation, del(11q), and unmutated immuno- globulin heavy-chain variable region gene (IGHV), which are known to be associated with inferior outcomes with chemoimmunotherapy,8 ibrutinib-based regimens have consistently achieved superior PFS versus established chemotherapy/chemoimmunotherapies and appear to confer comparable outcomes to those of ibrutinib-treated patients without these high-risk features.4,5,9,10
The multicenter, randomized, phase III iLLUMINATE study was initiated to compare the efficacy of ibrutinib com- bined with obinutuzumab versus chlorambucil combined with obinutuzumab as first-line therapy for patients with CLL/SLL. Results from the primary analysis with a median follow-up of 31 months demonstrated that ibrutinib plus obinutuzumab significantly prolonged PFS compared with chlorambucil plus obinutuzumab as assessed by an inde- pendent review committee (median not reached vs. 19 months) as well as by the study investigators (median not reached vs. 22 months) in both the intention-to-treat population and in patients with high-risk genomic fea- tures.3
Here we report the final analysis of iLLUMINATE with a median follow-up of 45 months.
Methods
Study design
iLLUMINATE was a multicenter, randomized, open-label, phase III study that enrolled patients at 71 sites in Aus- tralia, New Zealand, Canada, Israel, Turkey, Russia, the European Union, and the USA (ClinicalTrials.gov identifier: NCT02264574). The study was conducted in accordance with the Declaration of Helsinki, the International Confer- ence on Harmonisation Guidelines for Good Clinical Prac- tice, and local regulations. The protocol was approved by the institutional review boards, research ethics boards, or independent ethics committees of participating institu- tions. All patients provided written informed consent. Full details of the study methodology have been published previously3 and are briefly described below.
Participants
Eligible patients had previously untreated CLL/SLL requi- ring treatment according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria11 and were aged ≥65 years or <65 years with at least one of the fol- lowing co-existing conditions: a cumulative illness rating
score >6, creatinine clearance <70 mL/min, del(17p) con- firmed by fluorescence in situ hybridization analysis, or TP53 mutation confirmed by next-generation sequencing. Additional eligibility criteria included an Eastern Cooper- ative Oncology Group (ECOG) performance status 0-2, measurable lymph node disease (longest diameter >1.5 cm), adequate hematologic function (absolute neutrophil count ≥1×109 cells/L; platelet count >50×109 cells/L), and adequate hepatic and renal function.
Treatments
Patients were randomized 1:1 to receive ibrutinib plus obi- nutuzumab or chlorambucil plus obinutuzumab, as strat- ified by geographic region (North America vs. rest of world), ECOG performance status (0-1 vs. 2), and cytogen- etic status (del[17p] vs. del[11q] without del[17p] vs. others [neither del11q nor del[17p]). Patients received oral ibruti- nib 420 mg once daily until disease progression or unac- ceptable toxicity or oral chlorambucil 0.5 mg/kg body weight on days 1 and 15 of each 28-day cycle for six cycles. Intravenous obinutuzumab (100 mg on day 1 and 900 mg on day 2, and 1,000 mg on days 8 and 15 of cycle 1, followed by 1,000 mg on day 1 of each subsequent 28- day cycle) was administered for up to six cycles.
Outcomes
The primary endpoint for the final analysis was PFS by in- vestigator assessment based on iwCLL 2008 criteria with subsequent clarifications to account for treatment-related lymphocytosis.11 Secondary endpoints included overall re- sponse rate (ORR; defined as complete response [CR], CR with incomplete bone marrow (BM) recovery [CRi], nodular partial response [nPR], or partial response [PR]), rate of un- detectable minimal residual disease (MRD) (<1 CLL cell per 10,000 leukocytes in peripheral blood (PB) and/or BM aspi- rate, as measured by central laboratory flow cytometry), OS, sustained hematologic improvement (continuous ≥2 g/dL increase in hemoglobin levels from baseline, or ≥50% increase in platelet counts from baseline for ≥56 days without blood transfusion or growth factors), and safety. Responses were assessed by the investigator for the final analysis. Non-hematologic adverse events were graded using National Cancer Institute Common Terminology Crite- ria for Adverse Events, version 4.03; hematologic adverse events were assessed using iwCLL criteria.11 Because the additional follow-up since the primary analysis extends beyond the adverse event reporting period for the chlo- rambucil plus obinutuzumab arm, safety findings are pres- ented only for the ibrutinib plus obinutuzumab arm.
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