CLINICAL NEWS
On Location 2018 ASH Annual Meeting
TABLE 1.
Grade ≥3-5 Treatment-Related Adverse Events
Adverse Event
Ibrutinib plus
Rituximab
(n=352) Fludarabine,
Cyclophosphamide,
Rituximab (n=158) p Value
Neutropenia 22.7% 43.7% <0.001
Anemia 2.6% 12% <0.001
Thrombocytopenia 2.9% 13.9% <0.001
Infection 7.1% 19% <0.001
Atrial fibrillation 2.9% 0% 0.04
Bleeding 1.1% 0% 0.32
Hypertension 7.4% 1.9% 0.01
Diarrhea 2.6% 0.6% 0.19
and 58 in the FCR group (ranges not provided).
After a median follow-up of 33.4 months (range not reported), the
researchers recorded a total of 77 PFS events – 37 in the ibrutinib group
and 40 in the FCR group. Fourteen patients died – four in the ibrutinib
group and 10 in the FCR group.
This translated to a 65-percent reduction in the risk of disease pro-
gression or death (primary endpoint) with ibrutinib compared with FCR
(hazard ratio [HR] = 0.35; 95% CI 0.22-0.5; p<0.001). There also was
an OS advantage with ibrutinib (secondary endpoint; HR=0.17; 95% CI
0.05-0.54; p<0.003).
The improvement in PFS was seen across subgroups, Dr. Shanafelt
noted. For example, for the 329 patients with IGHV mutation status
available, 71.1 percent had IGHV-unmutated disease; within this group,
ibrutinib lowered the risk of disease progression or death by 74 percent,
compared with FCR (HR=0.26; 95% CI 0.14-0.5; p<0.0001). However,
the impact of treatment did not differ significantly in the patients with
IGHV-mutated disease (HR=0.44; 95% CI 0.14-1.36; p=0.07).
Dr. Shanafelt commented that the ibrutinib-rituximab regimen was
“less toxic than our historical therapy,” with more patients in the FCR
group experiencing a grade ≥3 treatment-related adverse event (72% vs.
58%; p=0.0042; TABLE 1 ).
Together, these results “establish ibrutinib-based therapy as the most
effective treatment … for untreated patients,” Dr. Shanafelt concluded.
“In cancer trials, [we want] to improve the effectiveness of treatment or
reduce its side effects. This trial is one of the rare circumstances where
we’ve done both.”
The younger age of this patient group represents a potential limita-
tion of this finding, as these results may not be generalizable to the larger
CLL population, which generally consists of patients older than 65 years.
The results of this trial also should be interpreted in light of results
from the ALLIANCE trial presented as a plenary abstract at the ASH
annual meeting, which showed that ibrutinib alone was superior to che-
moimmunotherapy with bendamustine and rituximab in older patients
with treatment-naïve CLL. Adding rituximab to ibrutinib did not result
in improved outcomes. When asked if rituximab was necessary in this
setting, Dr. Shanafelt advised caution about cross-trial comparisons –
adding that the ECOG-E1912 trial enrolled a younger population.
Each trial demonstrated ibrutinib’s superiority over standard che-
moimmunotherapy, however, and the results represent “a paradigm shift
from a six-month course of intravenous chemotherapy to chronic treat-
ment with a pill,” which raises questions about the pharmaco-economics
of long-term targeted therapy.
The authors report financial relationships with Celgene, GlaxoSmith-
Kline, Roche, Genentech, Janssen, and Pharmacyclics.
REFERENCE
Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludara-
bine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic
leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Abstract # LBA-4. Presented at the 2018 ASH Annual
Meeting, December 4, 2018; San Diego, CA.
New Tool Provides Simple Approach
to Interrupting Direct Oral
Anticoagulants for Surgery
Researchers have developed a “simple,
standardized, easy-to-use” strategy to
guide decisions about interrupting
direct oral anticoagulants (DOACs)
in patients with atrial fibrillation (AF)
scheduled to undergo an elective surgery
or procedure. The approach was safe
and associated with a low incidence of
perioperative major bleeding and arterial
thromboembolism.
“This is a common clinical problem
that occurs in one in six patients with
atrial fibrillation each year, or six million
patients worldwide, and it is increasing in
prevalence as the population ages,” report-
ed James Douketis, MD, from McMaster
University in Ontario, who presented the
results of the late-breaking trial at the
2018 ASH Annual Meeting. However,
“since the DOACs were introduced nearly
10 years ago, few studies have looked
at how to manage these patients, [lead-
ing to] a lot of variability in clinical
practice and inconsistency in guideline
recommendations.”
The aim of the Perioperative Anti-
coagulant Use for Surgery Evaluation
(PAUSE) study, Dr. Douketis said, was to
establish a simple tool that did not require
perioperative anticoagulant bridging or
coagulation function testing.
Interruption and resumption of
DOACs was dictated by the bleeding risk
associated with the planned procedure
and the type of DOAC: For procedures
with low bleeding risk (e.g., colonoscopy
or hernia repair), DOACs were inter-
rupted for one day before and one day
after surgery; for procedures with high
bleeding risk (e.g., major cancer, heart, or
orthopedic surgery), DOACs were inter-
rupted for two days before and two days
after surgery. Patients on dabigatran with
a creatine clearance <50 mL/min and who
were planned for a procedure with a high
bleeding risk stopped the drug four days
before and two days after surgery.
Researchers evaluated the approach in
3,007 patients with AF receiving apixa-
ban (n=1,257), dabigatran (n=668), or
rivaroxaban (n=1,082). Approximately
one-third of patients in the trial were
scheduled to undergo a high-bleeding-risk
surgery, and the median CHADS 2 scores
(a 1- to 5-point scale measuring stroke
risk based on congestive heart failure,
hypertension, age, diabetes, and previous
TABLE 2.
ASH Clinical News
stroke) were 2.1, 2.2, and 2.0 in the apixa-
ban, dabigatran, and rivaroxaban groups,
respectively.
Participants were followed weekly
for 30 days post-procedure to measure
incidence of major bleeding and arterial
thromboembolism (primary endpoint).
The researchers expected arterial
thromboembolism (including stroke, sys-
temic embolism, and transient ischemic
attack) to occur in 0.5 percent of patients
and major bleeding in 1 percent. They
reported lower-than-expected rates for
arterial thromboembolism in the entire
cohort, but the rates were higher than
expected in the apixaban and rivaroxaban
groups ( TABLE 2 ).
An analysis of preoperative blood
samples indicated that more than 90
percent of patients treated per the PAUSE
protocol had minimal or no residual
DOAC levels. Nearly all patients (98.9%)
undergoing a high-bleeding-risk proce-
dure had DOAC levels <50 ng/L, prompt-
ing the investigators to select 50 ng/L as “a
clinically safe threshold to allow a surgery
to proceed.”
“This is the first study to demonstrate
the safety of a standardized perioperative
management approach in patients with
AF who are taking a DOAC, and we hope
it will establish a standard and will have
an effect on clinical practice guidelines,”
Dr. Douketis concluded.
The authors report financial relation-
ships with Pfizer, Janssen, Merck, Aniara-
Hyphen Biomed, and Sanofi. ●
REFERENCE
Douketis J, Spyropoulos AC, Duncan JM, et al. Perioperative anticoagulant
use for surgery evaluation (PAUSE) study: a perioperative management
plan for patients with atrial fibrillation who are receiving a direct oral an-
ticoagulant. Abstract LBA-5. Presented at the 2018 ASH Annual Meeting,
December 4, 2018; San Diego, CA.
Primary Outcomes
Apixaban
(n=1,257) Dabigatran
(n=668) Arterial thromboembolism 2 (0.16%) 4 (0.60%) 4 (0.37%)
Major bleeding 17 (1.35%) 6 (0.90%) 20 (1.85%)
Outcome
26
James Douketis, MD
Rivaroxaban
(n=1,082)
January 2019