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Superior clinical outcomes with ibrutinib-obinutuzumab compared to chlorambucil-obinutuzumab in the first-line treatment of chronic lymphocytic leukemia

Results of the phase III ILLUMINATE trial demonstrate that the combination of ibrutinib (ibr) and obinutuzumab (G) is associated with better outcomes than chlorambucil (clb)-G in patients with untreated chronic lymphocytic leukemia (CLL). Compared to clb-G, ibr-G was associated with a 77% reduction in the risk of disease progression or death, increasing to 85% in the subgroup of high-risk patients. In addition, the ibr combination also led to higher response rates, with more patients obtaining a minimal residual disease (MRD) negative state. As such, the combination of ibr with G represents an effective chemotherapy-free treatment option for the first-line treatment of CLL patients.

The recommended first-line treatment options for older CLL patients or for patients with comorbidities include single-agent ibr (based on the RESONATE-2 trial) and clb-G (based on the CLL11 study). ILLUMINATE was the first study to prospectively evaluate a chemotherapy-free regimen (ibr-G) with clb-G in the first-line treatment of CLL patients (including patients with high-risk cytogenetic features). In total, ILLUMINATE included 229 patients with previously untreated CLL/SLL requiring treatment per iwCLL criteria aged 65 years or older, or patients younger than 65 years with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation). Patients in the trial were randomized (1:1) to receive ibr (420 mg once daily continuously) combined with G (1,000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles, for a total of 6 cycles), or clb (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles) combined with G (as above). The primary study endpoint was progression-free survival (PFS) assessed by independent review committee (IRC), with secondary objectives including PFS in high-risk population (del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV), rate of undetectable MRD, overall response rate (ORR), overall survival (OS), and safety. Of note, patients with IRC-confirmed progression on clb-G could cross over to next-line therapy with single-agent ibr.

The median age of patients in the trial was 71 years; just over half of the patients had advanced stage disease (Rai III or IV), and about a third had bulky disease (≥5 cm). In total, 65% of patients had high-risk cytogenetic features. At a median follow-up of 31.3 months, ibr-G significantly prolonged the IRC-assessed PFS compared with clb-G (median not reached [NR] vs. 19.0 months; HR[95%CI]: 0.231[0.145-0.367]; p<0.0001), representing a 77% reduction in risk of progression or death. PFS rates at 30 months were 79% and 31% with ibr-G and clb-G, respectively. Similar findings were reported when the PFS was assessed by the investigators (median NR vs. 21.9 months; HR[95%CI]: 0.260[0.163-0.415]; p<0.0001). The PFS benefit observed with ibr-G was consistently seen across all investigated subgroups, irrespective of age, Rai stage, ECOG performance status and of the presence of bulky disease. Specifically in the subgroup of patients with high-risk cytogenetics, ibr-G was associated with an even more pronounced benefit in PFS. High-risk patients treated with ibr-G had a 85% lower risk of disease progression or death compared to those treated with clb-G (HR[95%CI]: 0.154[0.087-0.370]; p<0.0001). The IRC-assessed ORR was 88% with ibr-G as compared to 73% with clb-G. Also the percentage of patients with a complete response (CR) was higher with ibr-G than with clb-G (19% vs. 8%). In the high-risk population, the IRC-assessed ORR was 90% with ibr-G compared to 68% with clb-G. MRD was undetectable in blood and/or bone marrow in 35% of patients treated with ibr-G and in 25% of patients who received clb-G. The 30-month OS rates were 86% and 85% in the ibr-G and clb-G arms, respectively, with 40% of pts randomized to clb-G receiving single-agent ibr as second-line therapy. Ibr-G also significantly prolonged the time to next treatment compared to clb-G (medians not reached, HR[95%CI]: 0.063[0.023-0.175]; p<0.0001).

The median treatment duration was 29.3 months with ibr-G, which was substantially longer than the 5.1 months median treatment duration with clb-G. The most common (≥3%) serious adverse events (AEs) were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) with ibr-G, and infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%) with clb-G. Of note, IRRs were less frequent with ibr-G than with clb-G for both any grade (25% vs. 58%) and for grade ≥3 or serious IRRs (3% vs. 9%). AEs leading to discontinuation of ibr or clb occurred in 18 (16%) and 11 patients (9%), respectively; AEs leading to discontinuation of G occurred in 10 patients (9%) in the ibr-G arm and in 15 patients (13%) randomised to the clb-G arm.

In summary, first-line Ibr-G resulted in a superior PFS compared with clb-G in CLL patients, regardless of high-risk genomic features. Also the response rates and the depth of remission (CR and undetectable MRD) was better with ibr-G and this combination proved to be tolerable. As such, ibr-G represents an effective chemotherapy-free treatment option for first-line CLL patients, including patients with high-risk cytogenetic features.



Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. Presented at ASH 2018; Abstract 691.

Speaker Carol Moreno


Carol Moreno, MD, PhD, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain


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