On Location 2018 ASH Annual Meeting
When the authors compared out-
comes in patients enrolled in arms B
and C, they found that the addition of
rituximab did not significantly improve
response or survival rates, compared
with ibrutinib alone. When asked if there
was a patient population that might
benefit from ibrutinib plus rituximab,
Dr. Woyach commented, “all the data
suggest that there probably are not pa-
tients – especially in the older population
– who would benefit from the combina-
tion.” However, she added anecdotally
that those with autoimmune hemolytic
anemia or with a higher white blood
cell count might be candidates for this
approach.
Grade ≥3 hematologic adverse events
(AEs), including anemia, neutropenia,
and thrombocytopenia, were more com-
mon in the BR group (61%) compared
with the ibrutinib-alone or ibrutinib-
rituximab group (41% and 38%, respec-
tively; p<0.001). However, grade ≥3 non-
hematologic AEs were more prevalent
in the ibrutinib-containing arms (74%
for both), compared with the BR group
(63%)
The researchers observed grade 5 AEs
in five (2.8%), 14 (7.8%), and 14 (7.7%)
patients, respectively, in each arm; two
(1.1%), seven (3.9%), and four (2.2%)
patients died in each arm, respectively.
The safety profile might limit the use
of ibrutinib in the entire population of
older patients, the authors cautioned.
“BTK inhibition is not without toxicity in
this age group, including significant tox-
icity, so close monitoring is important,”
Dr. Woyach said. “Strategies to limit
toxicity through the use of more selective
BTK inhibitors or potentially limiting the
duration of therapy are also important
areas to explore.”
The authors report financial relation-
ships with Pharmacyclics, Janssen, Genen-
tech, and Teva Pharmaceuticals.
REFERENCE
Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in
combination with rituximab produces superior progression free
survival (PFS) compared with bendamustine plus rituximab in
untreated older patients with chronic lymphocytic leukemia (CLL):
results of Alliance North American Intergroup Study A041202.
Abstract #6. Presented at the 2018 ASH Annual Meeting, December 2,
2018; San Diego, CA.
18
ASH Clinical News
Alan F. List, MD, presents results from the MEDALIST trial.
Luspatercept Reduces the Need for Transfusions
in Patients With Beta Thalassemia and MDS
In two separate phase III trials presented at the 2018 ASH
Annual Meeting, luspatercept, a first-in-class recombi-
nant fusion protein, was found to be safe and effective at
reducing transfusion burden in patients with myelodys-
plastic syndromes (MDS) and beta thalassemia, when
compared with patients receiving placebo.
MEDALIST
In the MEDALIST trial, which enrolled patients with
lower-risk MDS who were anemic, required regular red
blood cell (RBC) transfusions, and had ring sideroblasts,
more than half of participants treated with luspater-
cept had a reduction in transfusion burden. More than
one-third (38%) of patients achieved the study’s primary
endpoint of at least eight weeks without the need for a
transfusion, coauthor Alan F. List, MD, from the Mof-
fitt Cancer Center in Tampa, Florida, noted during his
presentation of the findings during a Plenary Scientific
Session.
Luspatercept works by binding to select TGF-beta
superfamily ligands to reduce aberrant Smad2/3 signal-
ing and enhance late-stage erythropoiesis, Dr. List
explained. By interfering with the signals that suppress
RBC production, the drug improves patients’ ability to
manufacture their own RBCs – therefore reducing the
need for transfusions.
“This is an agent that targets the pathobiology of
anemia in MDS,” Dr. List told ASH Clinical News. “We’ve
known for years that the TGF-beta signaling pathway was
implicated in the pathogenesis of the anemia in lower-
risk MDS, but we didn’t have any agents that could target
that. Luspatercept does just that.”
The trial included 229 patients with MDS with ring
sideroblasts classified as very low-, low-, or intermediate-
risk disease per the Revised International Prognostic
Scoring System scale. Dr. List explained that the MEDALIST
trial included patients with MDS with ring sideroblasts
based on results from a previous phase II trial in which
luspatercept yielded a high frequency of transfusion
reduction or transfusion independence in this patient
population.
All patients either had not responded to or were ineli-
gible to receive erythropoiesis-stimulating agents (ESAs)
and required an average of at least two RBC transfusions
every eight weeks. ESA-naïve patients had a low probabil-
ity of benefit from ESAs, “by virtue of RBC transfusion
dependence and serum erythropoietin levels greater than
200 U/L,” Dr. List noted.
Patients were randomized 2:1 to receive either luspa-
tercept 1 mg/kg every 21 days (titrated up to 1.75 mg/kg;
n=153) or placebo (n=76). Patient characteristics were well
balanced between the luspatercept and placebo arms: Forty-
three percent of patients in each group were “heavily trans-
fused” (defined as requiring ≥6 units every eight weeks) and
the median hemoglobin (Hb) level at baseline was 7.6 g/dL.
As of May 8, 2018 (data cutoff), 70 luspatercept-
treated patients (45.8%) and six placebo-treated patients
(7.9%) were still receiving treatment. The most common
reason for treatment discontinuation in both groups was
lack of clinical benefit (33.3% and 65.8%, respectively; p
value not provided).
During the first 24 weeks of treatment, 58 patients
in the luspatercept group (37.9%) achieved the primary
endpoint of RBC transfusion independence for at least
eight weeks, compared with 10 patients in the placebo
group (13.2%; p<0.0001). The benefit with luspatercept
was observed across all subgroup analyses, the authors
reported, including according to average baseline
January 2019 Annual Meeting Edition