Ibrutinib Plus Obinutuzumab Superior to Standard Chemoimmunotherapy in Treatment-Naïve Chronic Lymphocytic Leukemia

Treatment with the regimen of ibrutinib plus obinutuzumab improved outcomes for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), compared with treatment with a standard chemoimmunotherapy regimen of chlorambucil plus obinutuzumab. The benefit was observed even among patients with high-risk disease features, according to findings from the phase III iLLUMINATE study published in Lancet Oncology.

“To our knowledge, the iLLUMINATE study is the first prospective, head-to-head clinical trial comparing firstline chemoimmunotherapy with a chemotherapy­free regimen in [this patient population], including patients with del17p or TP53 mutation,” Carol Moreno, MD, from the Hospital de Sant Pau i Santa Creu, Autonomous University of Barcelona in Spain, and colleagues wrote.

The open-label, randomized iLLUMINATE trial enrolled patients with treatment-naïve CLL/SLL from 74 academic and community hospitals in seven countries. Eligible patients were 65 years or older and were considered unsuitable for fludarabine­based chemoimmunotherapy; people younger than 65 years were permitted to enroll if they had one or more of the following coexisting conditions:

  • Cumulative Illness Rating Scale (a composite measures of illness severity and comorbidity) score >6
  • creatinine clearance of <70 mL/min
  • Presence of del17p confirmed by FISH
  • TP53 mutation

After stratifying patients according to Eastern Cooperative Oncology Group performance status and cytogenetics, the investigators randomized patients to receive six treatment cycles of either:

  • continuous once-daily ibrutinib 420 mg plus intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8 and 15 of the first cycle and on day 1 of subsequent 28-day cycles; n=113)
  • chlorambucil 0.5 mg/kg on days 1 and 15 of each 28-day cycle plus intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8 and 15 of the first cycle and on day 1 of subsequent 28-day cycles; n=116)

Median age in the entire study population was 71 years (range = 66-77 years), and nearly two-thirds of patients (n=148; 65%) had high-risk genomic features, including del17p, TP53 mutation, del11q, or unmutated IGHV. These characteristics were well balanced between the treatment groups, the authors noted.

The primary endpoint of this study was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints included safety outcomes in all patients who had received one or more doses of their assigned therapy.

After a median follow-up of 31.3 months (interquartile range = 29.4-33.2 months), the median PFS was significantly longer in the ibrutinib-treated patients, compared with the chlorambucil-treated patients: not reached (95% CI 33.6 months to nonestimable) versus 19.0 months (95% CI 15.1-22.1 months; p<0.0001). In addition, the estimated rates of 30-month PFS was higher in the ibrutinib group (79% vs. 31%; p value not reported). This translated to a significantly lower risk of disease progression or death with the ibrutinib-based combination (hazard ratio [HR] = 0.23; 95% CI 0.15-0.37; p<0.0001).

“The PFS benefit in the ibrutinib plus obinutuzumab group was particularly notable in patients considered to be in the high-risk group,” the authors reported. The median PFS among patients with high-risk genomics was not reached in the ibrutinib-treated group and was 14.7 months (range = 12.4-16.9 months) in the chlorambucil-treated group (HR=0.15; 95% CI 0.09-0.27; p<0.0001). The estimated PFS rate at 30 months in this high-risk population was similar to that reported in the larger population, although chlorambucil appeared to be less effective in this segment (77% vs. 16%; p value not reported).

The proportion of patients achieving minimal residual disease (MRD)–negative status (in either the bone marrow or peripheral blood) was higher in the ibrutinib group: 35 percent (n=39/113) versus 25 percent (n=29/116), although the p value was not reported. This relationship also was observed in the high-risk population: 27 percent (n=20/73) and 15 percent (n=11/75; p value not reported).

“Overall safety findings were consistent with the known safety profiles of the individual drugs, with no new safety signals identified,” the researchers noted. A higher proportion of ibrutinib-treated patients experienced serious adverse events (AEs), compared with chlorambucil-treated patients (58% vs. 35%; p value not reported), and the most common grade 3 or 4 AEs in each group were neutropenia and thrombocytopenia.

Infusion-related reactions were more frequent in the chlorambucil than the ibrutinib group (58% and 25%), but no patients in the ibrutinib group discontinued treatment because of this AE, while 6 percent in the chlorambucil group discontinued due to these reactions. One patient in each group experienced treatment-related death.

Taken together, the authors concluded, these results support the use of ibrutinib plus obinutuzumab for patients with treatment-naïve CLL/SLL, “particularly in patients with high-risk or bulky disease.  Although not directly addressed in this study, understanding which patients might benefit from the combination of ibrutinib with obinutuzumab over single­agent ibrutinib is of interest.”

Limitations of this study include its small sample size, the inability to mask investigators and patients to allocated treatment, as well as the lack of a single-agent ibrutinib group to compare differences between monotherapy and dual treatment.

The authors report financial relationships with Pharmacyclics, AbbVie, and Janssen, which provided support for the trial.


Reference

Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2018 November 30. [Epub ahead of print]

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