CLINICAL NEWS
transfusion requirement:
• ≥6 units per 8 weeks: 9.1% vs. 3.0%
(odds ratio [OR] = 3.2; 95% CI 0.37-
27.7; p=0.27)
• <6 units per 8 weeks: 59.8% vs. 20.9%
(OR=5.61; 95% CI 2.4-13.1; p<0.001)
A larger proportion of patients in the lus-
patercept group also achieved the second-
ary endpoint of transfusion-independence
for at least 12 weeks (28.1% vs. 7.9% at
24-week follow-up and 33.3% vs. 11.8%
at 48-week follow-up; p<0.0003 for both).
The median duration of response was 30.6
weeks (range = 20.6-40.6 weeks) in the lus-
patercept group, compared with 13.6 weeks
(range = 9.1-54.9 weeks) in the placebo
group (p value not reported).
Secondary endpoints such as erythroid
response and mean change in Hb levels also
significantly favored luspatercept (p<0.0001
for both), with luspatercept responders
experiencing “a greater sustained rise in Hb
concentration from baseline pre-transfusion
levels, compared with nonresponders or
placebo-treated patients,” he added.
“Overall, approximately 40 percent of
luspatercept-treated patients remained
transfusion-free at one year,” Dr. List
reported.
The proportion of patients discontinu-
ing treatment due to adverse events (AEs)
was comparable in both arms (8.5% and
7.9%, respectively). Treatment-emergent
AEs that were reported more frequently
in the luspatercept arm than the placebo
arm included fatigue, diarrhea, asthenia,
nausea, dizziness, and back pain.
“Of course, with anything that’s going
to promote cell survival, we worry about
leukemia, but there was no difference in the
frequency of acute leukemia,” Dr. List added.
Four luspatercept-treated patients (2%) and
one placebo-treated patient (1.3%) pro-
gressed to acute myeloid leukemia during
the study follow-up period.
The study’s findings are limited to
patients with lower-risk MDS with ring
sideroblasts, and the results may not be
generalizable to patients with higher-risk
MDS or those without ring sideroblasts. Dr.
List noted that the phase III COMMAND
trial is comparing luspatercept with
placebo in patients with and without ring
sideroblasts who are ESA-naïve; results
from this study may provide more answers
about luspatercept’s role in the larger MDS
population.
BELIEVE
In the randomized, double-blind, pla-
cebo-controlled BELIEVE trial, patients
with beta thalassemia who received lus-
patercept had lower transfusion burdens,
compared with those receiving placebo.
The results, presented by lead author
Maria Domenica Cappellini, MD, from
the University of Milan in Italy, suggest
that luspatercept is a potential new thera-
py for “this very demanding disease.”
Luspatercept holds the promise of
alleviating the treatment burden for pa-
tients, she added. “These are young adult
patients [being transfused] three units of
blood every three weeks, so [the reduction
in transfusion burden with luspatercept]
has a substantial impact.”
Patients were included in BELIEVE if
they had beta thalassemia or Hb E/beta
thalassemia and were RBC transfusion-
dependent, defined as requiring regular
transfusions (6-20 RBC units) in the 24
weeks prior to randomization and having
no transfusion-free period ≥35 days during
that time.
Participants were then randomized 2:1
to receive either luspatercept at a start-
ing dose level of 1 mg/kg, with titration
up to 1.25 mg/kg, or placebo adminis-
tered subcutaneously every three weeks
for at least 48 weeks. In both treatment
arms, patients continued to receive RBC
transfusions and iron chelation therapy as
needed. Crossover to the luspatercept arm
was allowed after unblinding.
As of May 11, 2018 (data cutoff), 336
patients were treated: 224 in the luspa-
tercept arm and 112 in the placebo arm.
Participants’ median age was 30 years
(range = 18-66 years), and 58 percent of
patients were female. Most patients (58%
of each arm) had undergone splenectomy
prior to study randomization.
After up to three years of follow-up,
48 of 224 patients (21.4%) in the luspater-
cept arm achieved the primary endpoint
of RBC transfusion reduction (defined
as a ≥33% reduction in RBC transfusion
burden, with a reduction of ≥2 RBC units
from baseline, during weeks 13-24). In
the placebo group, just five of 112 patients
(4.5%) experienced a clinically meaning-
ful reduction in transfusion dependence
(OR=5.79; p<0.001).
In addition, 158 of 224 luspatercept-
treated patients (70.5%) achieved a
≥33-percent reduction in RBC transfu-
sion requirements during any consecutive
12 weeks of treatment, while 33 of 112
placebo-treated patients (29.5%) achieved
the same result (p<0.001).
The authors also observed statistically
significant differences in favor of luspater-
cept for all other transfusion burden–related
secondary endpoints, including:
• ≥33% reduction in transfusion burden
at weeks 37-48: 19.6% (44 of 224
luspatercept-treated patients) vs. 3.6%
(4 of 112 placebo-treated patients;
p<0.001)
from Saarland University Medical School in
Germany, who presented the findings at the
2018 ASH Annual Meeting.
The FLYER trial was based on results
from an earlier study in which patients
with an age-adjusted International Prog-
nostic Index (aaIPI) score of 0 without
bulky disease had high rates of three-year
event-free survival (EFS) and progression-
free survival (PFS) with a standard regimen
of rituximab plus CHOP chemotherapy.
“Our aim was to see if we could maintain
efficacy and reduce toxicity in patients
meeting these criteria by reducing the
REFERENCES
• ≥50% reduction in transfusion
burden at weeks 13-24: 7.6% (17/224)
vs. 1.8% (2/112; p=0.03) 1. Fenaux P, Platzbecker U, Mufti GJ, et al. The MEDALIST trial: results
of a phase 3, randomized, double-blind, placebo-controlled study
of Luspatercept to treat anemia in patients with very low-, low-,
or intermediate-risk myelodysplastic syndromes (MDS) with ring
sideroblasts (RS) who require red blood cell (RBC) transfusions.
Abstract #1. Presented at the 2018 ASH Annual Meeting, December
2, 2018; San Diego, CA.
• ≥50% reduction in transfusion
burden at weeks 37-48: 10.3%
(24/224) vs. 0.9% (1/112; p=0.002) 2. Cappellini MD, Viprakasit V, Taher A, et al. The BELIEVE trial: results
of a phase 3, randomized, double-blind, placebo-controlled study
of luspatercept in adult beta thalassemia patients who require
regular red blood cell (RBC) transfusions. Abstract #163. Presented
at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.
Four Cycles as Effective as Six Cycles of Chemotherapy
for Favorable-Risk DLBCL
While young patients with diffuse large
B-cell lymphoma (DLBCL) are typically
treated with six cycles of R-CHOP (ritux-
imab, cyclophosphamide, doxorubicin,
vincristine, prednisone), results from the
FLYER trial suggest that a subgroup of
young patients with favorable-prognosis
disease can achieve the same clinical ben-
efit with four cycles of R-CHOP plus two
cycles of rituximab monotherapy.
“With a shorter duration of chemother-
apy, patients are back to daily life with their
families and back to work more quickly,”
said lead study author Viola Poeschel, MD,
Among all patients, the median number of
RBC units received in the 12 weeks prior to
study treatment was six (range = 3-14), and
the mean reduction in transfusion burden
from baseline to weeks 13 to 24 was 1.35
units (p<0.001), the authors added.
“Luspatercept achieved a reduction
in transfusion burden across any 12- or
24-week period – the most important ob-
servation, because each [patient’s disease]
is different and may respond in a different
time and outside of the fixed observation
period,” Dr. Cappellini stressed.
AEs occurring with luspatercept were
“generally mild to moderate and manage-
able, without requiring dose modifications
or interruptions,” Dr. Cappellini reported.
Common AEs included bone pain and
thrombotic events, including stroke. No
patient deaths were reported for those
treated with luspatercept.
The findings of this placebo-controlled
trial will need to be compared with available
management strategies for beta thalassemia,
including transfusions – as well as gene
therapy options on the horizon. “In my
point of view, to be really efficacious, gene
therapy must be a cure,” Dr. Cappellini said.
“We are not going to perform gene therapy
for reducing transfusion burden – that’s not
the scope of the treatment. There is still a
ways to go to achieve that point.”
The authors of the MEDALIST and
BELIEVE trials report financial relation-
ships with Acceleron, the manufacturer of
luspatercept. Celgene and Acceleron sup-
ported both trials.
number of CHOP cycles,” Dr. Poeschel
explained.
In this trial, the researchers random-
ized patients aged 18 to 60 years who had
an aaIPI of 0 and non-bulky disease (<7.5
cm) to receive either six cycles of R-CHOP
(n=295) or four cycles of R-CHOP plus
two cycles of rituximab (n=293). This was a
“relatively young patient population” with a
median age of 48 years (range not report-
ed), and demographics were well balanced
between each group, the authors noted.
Most patients had stage I or II disease and
were considered to have low-risk disease.
At a median follow-up of 66 months
(range not reported), the rates of three-year
PFS, EFS, and overall survival (OS) were
similar between each group:
• PFS: 94% with 6 cycles vs. 96% with 4
cycles (hazard ratio [HR] = 0.9; 95% CI
0.5-1.6; p=0.8)
• EFS: 89% vs. 89% (HR=1.0; 95% CI
0.7-1.6; p=0.9)
• OS: 98% vs. 99% (HR=0.8; 95% CI
0.4-1.9; p=0.67)
All patients did well with R-CHOP, the re-
searchers noted, with a similar low frequency
of relapses in each arm: 4 percent of patients
in the four-cycle group and 5 percent in the
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