Written in Blood
The ORR was 61 percent (95% CI 44.5-75.8%), with 25 patients
achieving a partial response and three achieving a nodal response.
However, no patients achieved a complete response. Thirteen patients
had stable disease, and one had progressive disease.
“Therapeutic targeting of BCR signaling kinases has proven to
be an effective strategy in CLL and select B-cell malignancies,” Dr.
Sharman told ASH Clinical News. “Our research shows that inhibition
of Syk kinase with entospletinib results in significant clinical activity
approximately comparable to idelalisib.”
In the CLL cohort, 15 patients (36.6%) experienced adverse events,
14 (34.1%) had disease progression, and one patient died (2.4%) due to
septic pneumonia that was unrelated to entospletnib therapy.
For the entire 186-patient cohort treated with entospletinib,
nearly all (96.8%) experienced at least one treatment-emergent
adverse event; for 54 patients (29%), those events were deemed
“serious” and included dyspnea, pneumonia, febrile neutropenia,
dehydration, and pyrexia.
“Entospletinib was considerably better tolerated than fostamatinib,
Ibrutinib-Chemoimmunotherapy
Combo Adds to CLL Therapy
In chronic lymphocytic leukemia
(CLL), combining two effective
treatments may enhance the
clinical activity seen with each
agent individually, according
to early study results published
recently in Blood.
While treatment-naïve CLL
patients will generally have a
good response to their first round
of therapy, eventual relapse
is guaranteed, necessitating
subsequent treatment. Pairing
ibrutinib, a selective inhibitor
of Bruton’s tyrosine kinase
(BTK), with conventional
chemoimmunotherapy (CIT) may
improve response rates and lead to
longer remissions.
Because single-agent ibrutinib
has demonstrated good tolerability
in previous studies, lead author
Jennifer Brown, MD, PhD, and
colleagues combined the agent
with the two most standard
CIT regimens with the goal of
achieving more prolonged disease
control.
“The safety and efficacy
observed in this study suggest
that the addition of ibrutinib may
substantially enhance the clinical
benefit of standard CIT treatments
for patients with CLL or small
lymphocytic leukemia,” Dr. Brown,
from the Dana-Farber Cancer
Institute in Boston, noted.
Dr. Brown and colleagues
enrolled relapsed/refractory CLL/
SLL patients into two parallel
cohorts: a bendamustine and
rituximab (BR) with ibrutinib
group (n=30) or a fludarabine,
26
ASH Clinical News
cyclophosphamide, and rituximab
(FCR) with ibrutinib group (n=3).
Enrollment to the FCR-ibrutinib
arm closed early due to a lack of
fludarabine-naïve patients.
Eligible patients had between
one and three prior treatment
regimens for a confirmed diagnosis
of either CLL or SLL. All patients
received ibrutinib (420 mg, once
daily) after their CIT (a maximum
of six cycles) on each day of a
28-day therapy cycle. Treatment
continued until disease progression
or unacceptable toxicity. Ibrutinib
monotherapy could continue
indefinitely until progression or
unacceptable toxicity.
Single-agent
ibrutinib
combined
with the two
most standard
CIT regimens
may lead to
prolonged
disease
control.
the first Syk kinase inhibitor studied, although significant liver function
test abnormalities were noted in some patients,” Dr. Sharman observed.
“Development of entospletinib is currently focused on optimizing
the formulation and dose,” he added. “Pivotal phase 3 studies are
currently being considered but have not yet started accrual.”
As to whether enstospletinib could have a role as first-line therapy
for CLL, or as an alternative to other agents to which these patients are
intolerant, Dr. Sharman offered cautious encouragement.
“If entospletinib were studied prior to either ibrutinib or
idelalisib – other key BCR signal inhibitors – it would be considered
a remarkable breakthrough,” he said. “With the emergence of several
new effective therapies that have already obtained FDA approval,
the route to regulatory approval for entospletinib will require
demonstration of efficacy in unique patient populations. This could
include CLL and other B-cell malignancies.” ●
Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective Syk inhibitor,
in chronic lymphocytic leukemia. Blood. 2015 February 18. [Epub ahead of print.]
There were no incidents of
prolonged hematologic toxicity
starting in cycle 1, or a grade ≥3
thrombocytopenia lasting for ≥8
weeks (the study’s primary safety
endpoint).
“Treatment-related
lymphocytosis was less frequent
and less pronounced when
ibrutinib was administered in
combination with BR than as
monotherapy,” the researchers
noted. In addition, they found
hematologic improvement in the
majority of patients who were
cytopenic at baseline.
After a median treatment duration of 15.7 months, the objective
response rate, one of the phase 1b
study’s secondary clinical endpoints, was 93.3% (n = 28) for patients in the ibrutinib-BR cohort.
Five patients (16.7%) achieved a
complete response, and 20 (66.7%)
achieved a partial response.
When Dr. Brown and investigators included data from the extended follow-up period (a median
of 3 years), the rate of complete response increased to 40 percent (12
patients), with 14 patients (46.7%)
achieving a partial response and
two patients (6.7%) achieving a
nodular partial response.
A majority of patients in the
ibrutinib-BR cohort remained
progression-free at 12 months
(86.3%), as well as at 24 months
(78.6%) and 36 months (70.3%).
Rates of treatment-emergent
adverse events were similar to
those observed when ibrutinib
or BR were administered
individually; the majority of these
events were designated as grade
1 or 2 by the researchers. “The
adverse event profile of ibrutinib
in this population is pretty similar
to what was seen previously,” Dr.
Brown told ASH Clinical News.
“Typical issues included diarrhea,
fatigue, nausea, arthralgia, and
ecchymosis, as well as a small risk
of more significant bleeding and
atrial fibrillation.”
In the FCR with ibrutinib
cohort, the ORR response rate
was 100 percent – but this only
included three patients, the
investigators noted. All three
patients were able to complete
six cycles of FCR with only one
serious adverse event (gastritis
with gastrointestinal bleeding
requiring hospitalization).
Commenting on the FCR
with ibrutinib cohort, Dr. Brown
explained that “our ongoing study
has almost reached the safety
pause at 10 patients. Thus far, there
have been no issues and the study
is proceeding well.”
Compared with other BTK
inhibitors, such as CC-292 or
ONO-4059, the safety profile
of ibrutinib held its own in
treatment, she added. “With CC292, the safety profile was fairly
similar; there was less ecchymosis,
bleeding, and atrial fibrillation
than with ibrutinib, but CC-292
has been given to many fewer
patients than ibrutinib,” Dr. Brown
said. “The reported number of
patients who have received ONO4059 is, in my opinion, too small
to compare, but again, the safety
profile looks roughly similar to
ibrutinib.” ●
Brown J, Barrientos J, Barr P, et al. The Bruton’s
tyrosine kinase (BTK) inhibitor, ibrutinib, with
chemoimmunotherapy in patients with chronic lymphocytic
leukemia. Blood. 2015 March 9. [Epub ahead of print.]
April 2015