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Ibrutinib Leads to Better Overall and
Progression-Free Survival Than Chlorambucil
in Older Patients with CLL/SLL
Chronic lymphocytic leukemia
(CLL) is a disease of older adults,
many of whom have other medical problems in addition to their
cancer. Chlorambucil is a standard
first-line therapy for older patients
with CLL or those with co-existing
conditions.
Ibrutinib, a first-in-class oral
Bruton’s tyrosine kinase inhibitor, is approved for the treatment
of patients with CLL who have
received at least one prior therapy.
In the phase III RESONATE trial,
single-agent ibrutinib prolonged
overall survival (OS) compared
with ofatumumab in older patients
with previously treated CLL.
To further examine whether
single-agent ibrutinib has a role as
initial treatment in CLL patients,
Jan A. Burger, MD, PhD, from the
University of Texas MD Anderson
Cancer Center, and colleagues conducted the phase III, international,
open-label, randomized RESONATE-2 trial, which compared
treatment with ibrutinib versus
chlorambucil in older patients with
previously untreated CLL or small
lymphocytic lymphoma (SLL).
A total of 269 patients 65 years
old or older (median age = 73
years) were included in the study
and randomized to receive:
• Ibrutinib: 420 mg once daily
(n=135)
• Chlorambucil: 0.5 mg/kg of
body weight on days 1 and
15 of each 28-day cycle and
increased to 0.8 mg/kg if there
was no toxicity (n=132)
Eligibility criteria included patients
aged 65 years or older, who had
previously untreated CLL or SLL,
with an Eastern Cooperative Oncology Group performance status
score of <2, an absolute neutrophil count of ≥1,000 cells/mm3, a
platelet count of ≥50,000/mm3, and
adequate liver and kidney function.
Patients were ineligible if they had
chromosome 17p13.1 deletion.
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ASH Clinical News
Patients were treated until
disease progression, unacceptable
toxicity, or an observed lack of
efficacy and were followed for a
median of 18.4 months starting in
March 2013. Eighty-seven percent
of patients taking ibrutinib were
still receiving treatment at the time
of analysis.
The rate of progression-free
survival (PFS) at 18 months, the
study’s primary endpoint, was significantly higher in patients treated
with ibrutinib than with chlorambucil: 90 percent versus 52 percent
(p<0.001). At the time of last
follow-up, the overall PFS had not
been reached for ibrutinib and was
18.9 months for chlorambucil. The
response rate (assessed by an independent review committee) was
86 percent in the ibrutinib cohort
and 35 percent in the chlorambucil
cohort (p<0.001).
The relative risk of progression
or death was 84 percent lower for
patients receiving ibrutinib compared with chlorambucil (hazard
ratio [HR] = 0.16; 95% CI 0.090.28; p<0.001).
In addition, ibrutinib significantly prolonged OS. At 24
months, the estimated survival
rate was 98 percent in the ibrutinib cohort and 85 percent in
the chlorambucil group, with a
relative risk of death that was 84
percent lower for those treated
with ibrutinib (HR=0.16; 95% CI
0.05-0.56; p=0.001). At the latest
time of follow-up, the OS had not
been reached in either cohort.
“Furthermore, ibrutinibtreated patients had a restoration of bone marrow function,
with a significantly higher rate of
sustained improvement in hematologic variables,” Dr. Burger and
colleagues added. “This finding
has particular clinical relevance
because bone marrow failure is a
common cause of complications
in patients with CLL, with anemia
and thrombocytopenia being
frequent indications for initiating
treatment in this population.”
Three patients in the ibrutinib
group died during follow-up, compared with 17 in the chlorambucil
group. The most common adverse
events (AEs) in the ibrutinib and
chlorambucil cohorts included:
• Diarrhea: 42% vs. 17%, respectively
• Fatigue: 30% vs. 38%
• Cough: 22% vs. 15%
• Nausea: 22% vs. 39%
• Peripheral edema: 19% vs. 9%
• Dry eye: 17% vs. 5%
• Arthralgia: 16% vs. 7%
• Neutropenia: 16% vs. 23%
• Vomiting: 13% vs. 20%
“Treatment exposure and AE
follow-up was nearly 2.5 times as
long with ibrutinib as with chlorambucil,” the authors wrote. Nine
percent of patients in the ibrutinib
cohort discontinued treatment due
to AEs, compared with 23 percent
in the chlorambucil group.
“Compared with chlorambucil,
a standard cytotoxic chemotherapy,
ibrutinib was associated with significantly longer progression-free
survival and overall survival and
with higher rates of response and
improvement in hematologic variables among patients with previously
untreated CLL or small lymphocytic
lymphoma,” the authors concluded.
The median PFS with chlorambucil (18.9 months) observed
in this study appears to be generally longer than that reported in
previous trials with chlorambucil
in previously untreated patients.
“The relatively strong performance of chlorambucil in the
current study may have been
influenced, in part, by a generally longer exposure to involving
previously untreated patients with
CLL or by the exclusion of patients with chromosome 17p13.1
deletion,” the authors wrote, noting one possible limitation.
“Better results with ibrutinib
might be obtained when it is used
as first-line treatment rather than
for later relapses or in patients with
refractory disease,” Dr. Burger and
colleagues reported, since chlorambucil-treated patients with disease
progression who were allowed to
cross over to ibrutinib treatment
experienced prolonged OS.
Chlorambucil may be considered by some as a suboptimal
comparison group, which is a
limitation of the study. In addition,
some patients could have tolerated
a more aggressive therapy. ●
REFERENCE
Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial
therapy for patients with chronic lymphocytic leukemia. N
Engl J Med. 2015;373:2425-37.
March 2016