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Featured research from recent issues of Blood
Duvelisib Bests Ofatumumab in Relapsed and Refractory CLL/SLL
In the phase III DUO trial, treatment with the
oral phosphoinositide 3-kinase (PI3K) dual
inhibitor duvelisib improved progression-free
survival (PFS) and overall response, compared
with ofatumumab, in patients with relapsed
and refractory chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL), ac-
cording to results published in Blood.
The findings from this study supported the
U.S. Food and Drug Administration’s approval
of duvelisib for the treatment of patients with
relapsed or refractory CLL/SLL who have
received at least two prior therapies.
In this global, multicenter, randomized,
open-label trial, Ian W. Flinn, MD, PhD, from
Sarah Cannon Research Institute and Ten-
nessee Oncology, and authors compared the
efficacy and safety of single-agent duvelisib or
ofatumumab in 319 patients (median age = 69
years; range = 39-90 years). Participants were
enrolled between January 2014 and Decem-
ber 2015. All patients were required to have
active disease necessitating treatment that had
progressed during or relapsed after at least
one previous CLL/SLL therapy. People who
received prior treatment with a Bruton tyrosine
kinase or PI3K inhibitor or who were refracto-
ry to prior ofatumumab therapy were excluded
from the analysis.
Patients were randomized 1:1 to receive
either:
• oral duvelisib 25 mg twice daily (n=160)
• intravenous ofatumumab at a starting dose
of 300 mg, then weekly and monthly doses
of 2,000 mg (n=159)
The median number of prior therapies was two
in each arm (range not reported), and most
patients had previously received an alkylating
agent (93% in the duvelisib arm and 95% in
the ofatumumab arm), a monoclonal antibody
(78% and 83%, respectively), and/or a purine
analog (60% and 71%, respectively).
Approximately one-third of patients in each
arm had del17p and/or TP53 mutation (31%
and 33%), while approximately two-thirds had
unmutated IGHV status (69% and 73%).
At a median follow-up of 22.4 months (range
not provided), the median PFS, determined by
TABLE.
blinded independent review committee (IRC),
was significantly longer in the duvelisib group:
13.3 months vs. 9.9 months (hazard ratio [HR]
= 0.52; p<0.001). Duvelisib also was associated
with higher six- and 12-month PFS rates:
• 6-month PFS: 78% for duvelisib vs. 72%
for ofatumumab
• 12-month PFS: 60% for duvelisib vs. 39%
for ofatumumab (p values not reported)
Duvelisib treatment also extended PFS in mul-
tiple predefined CLL/SLL subgroups, including
patients with high-risk cytogenetic markers
( TABLE ).
More patients in the duvelisib group re-
sponded to treatment, compared with those
in the ofatumumab group, on IRC assessment:
73.8 percent vs. 45.3 percent (p<0.0001). In the
duvelisib arm, nearly all of these were partial
responses (PR; 72.5%), except for one patient
achieving a complete response (CR) (0.6%) and
another achieving a PR with lymphocytosis
(0.6%).
Responses on the ofatumumab arm were
also predominantly PRs (44.7%), with one CR
(0.6%).
“Duvelisib treatment was particularly effective
in targeting the lymph node disease compart-
ment, with a lymph node response by IRC
assessment of 85.0 percent, compared to 15.7
percent in the ofatumumab arm (p<0.001),” the
investigators reported.
Median overall survival was not reached on
either treatment arm, with a 12-month OS rate
of 86 percent in both groups (HR=0.99; 95% CI
0.65-1.50; p value not provided).
Median treatment exposure was twice as long
in the duvelisib-treated patients than in the
ofatumumab-treated patients (median duration
= 50 weeks vs. 23 weeks), which resulted in a
longer adverse event (AE)–reporting period for
duvelisib.
AEs led to treatment discontinuation in 43
patients in the duvelisib arm and six patients in
the ofatumumab arm.
The most common hematologic AEs with
duvelisib and ofatumumab included: neutro-
penia (33% and 21%, respectively), anemia
(23% and 10%), and thrombocytopenia (15%
and 6%). The most common nonhematologic
AEs included: diarrhea (51% and 19%), pyrexia
(29% and 10%), nausea (23% and 11%), and
cough (21% and 14%).
Eighty-seven percent of duvelisib-treated
patients experienced a grade ≥3 AE (most
commonly neutropenia, diarrhea, pneumonia,
and anemia), while 48 percent of ofatumumab-
treated patients experienced a grade ≥3 AE. In
the ofatumumab arm, only neutropenia (17%)
occurred in more than 10 percent of patients.
“Incidences of neutropenia, diarrhea, colitis,
transaminase elevations, pneumonitis, and
rash with duvelisib therapy were moderate and
manageable with early intervention and dose
modification as required per protocol,” the
researchers wrote, adding that these immune-
mediated toxicities infrequently led to duvelisib
discontinuation.
There were 19 fatal AEs on the duvelisib arm,
four of which were deemed treatment-related; in
the ofatumumab arm, seven patients had fatal
AEs, although none were attributed to treat-
ment.
“Given the unfortunate reality that many
patients have or acquire resistance or intolerance
to currently available, targeted therapies or have
comorbidities that may preclude their safe use,
there remains a … need for additional, novel,
targeted therapies for patients with relapsed/
refractory CLL/SLL, especially those with del17p/
TP53 mutations,” wrote the study authors. “These
combined safety and efficacy results suggest that
duvelisib monotherapy may offer an effective
treatment for CLL/SLL patients in need of ad-
ditional therapeutic options.”
However, the researchers noted that while
duvelisib compared favorably with single-agent
ofatumumab, “ofatumumab for the treatment
of relapsed CLL has diminished in recent years,
being supplanted by newer agents that target the
B-cell receptor pathway,” they wrote, which may
limit the applicability of this study’s findings.
The authors report financial relationships with
Verastem Oncology and Infinity Pharmaceuticals,
which supported the trial. ●
REFERENCE
Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib versus
ofatumumab in relapsed and refractory CLL/SLL. Blood.2018;132:2446-55.
Progression-Free Survival in Select Subgroups
Median PFS
6-Month PFS, %
12-Month PFS, %
Hazard Ratio p Value
0.40 0.0002
0.41 0.0003
IRC Assessment
Duvelisib 12.7 months 73 55
Ofatumumab 9.0 months 63 30
Duvelisib 13.8 months 77 66
Ofatumumab 9.5 months 53 33
Investigator Assessment
IRC = independent review committee; PFS = progression-free survival
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ASH Clinical News
January 2019