CLINICAL NEWS
Literature Scan
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 chemoim-
munotherapy 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 chemo-
immunotherapy with a chemotherapy-
free 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 chemoimmu-
notherapy; 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 measure 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)
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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.
“The [progression-
free survival]
benefit [with
ibrutinb] was
particularly
notable in patients
considered to be
in the high-risk
group.”
- CAROL MORENO, MD
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 single-agent 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]
January 2019 Annual Meeting Edition