CLINICAL NEWS
patients died, and the mortality rate was
highest in patients with confirmed PH:
• group A: 21/269 (8%)
• group B: 7/70 (10%)
• group C: 9/23 (39%)
“While an isolated TRV ≥2.5 m/s on
transthoracic echocardiography was found
to be a moderate prognostic factor for
overall survival,” the authors noted, “our
findings reveal highly contrasted outcomes
depending on the mPAP values measured
by RHC.”
Overall survival was significantly lower
in patients with a TRV ≥2.5 m/s (hazard
ratio [HR] = 2.5; 95% CI 1.3-4.7; p=0.006
for groups B and C vs. group A). After
accounting for mPAP levels, though, there
was no statistically significant difference
between patients with a TRV <2.5 m/s
(group A) and those with TRV ≥2.5 m/s
and mPAP <25 mmHg (group B; p=0.54).
Looking at other clinical parameters,
the authors found that biologic markers
of chronic organ damage, when combined
with measures of PH, were associated with
a higher risk of death:
• higher systolic blood pressure
(HR=1.03; 95% CI 1.01-1.05; p=0.002)
• lower estimated glomerular filtration
rate (HR=0.99; 95% CI 0.98-1.00;
p=0.048)
• higher lactate dehydrogenase levels
(HR=1.48; 95% CI 1.05-2.07; p=0.025)
“Surprisingly, there was no difference in
risk of death according to leukocyte count
or percentage of hemoglobin F,” Dr. Barto-
lucci said. There also was no difference in
mortality risk according to sex, history of
veno-occlusive crises, or tobacco use.
Taking these data together, the authors
created a “hyperhemolytic phenotype” of
SCD: Patients with pre- and post-capillary
PH, leg ulcers, chronic kidney disease,
and higher systolic blood pressure have a
poorer chance of survival.
Dr. Bartolucci noted that these results
need to be replicated in other cohorts,
and that future studies should focus on
the role of transfusion in patients with
higher-risk SCD, according to the factors
identified here.
The authors of the first study report no
relevant conflicts of interest. The authors
of the ETENDARD study report relation-
ships with Novartis, Addmedica, and Global
Blood Therapeutics.
REFERENCES
Srisuwananukorn A, Raslan R, Zhang X, et al. Clinical, laboratory, and
genetic risk factors for thrombosis in sickle cell disease. Abstract #9.
Presented at the 2018 ASH Annual Meeting, December 1, 2018; San
Diego, CA.
Savale L, Loko G, Lionnet F, et al. Predictive factors for survival in sickle cell
disease: a cohort study using Etendard data. Abstract #7. Presented at
the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.
ASHClinicalNews.org
Evaluating Imetelstat for Patients With
Relapsed/Refractory Myelofibrosis
In a phase II trial presented at the 2018 ASH Annual
Meeting conducted in patients with higher-risk myelo-
fibrosis (MF) who had relapsed following or had not
responded to JAK inhibitor therapy, approximately
one-third responded to treatment with imetelstat. The
findings were presented by John Mascarenhas, MD,
from Icahn School of Medicine at Mount Sinai in New
York.
“Imetelstat is an oligonucleotide that specifically
targets the RNA template of human telomerase and is
a potent competitive inhibitor of telomerase enzymatic
activity,” Dr. Mascarenhas explained. Its clinical activity
and toxicity were established in an earlier pilot study of
patients with intermediate-2 (int-2) or high-risk MF –
nearly half of whom had been previously treated with a
JAK inhibitor.
Patients were eligible for the analysis if they had
int-2 or high-risk MF, active symptoms of MF, and
measurable splenomegaly at baseline (palpable spleen
≥5 cm below the left costal margin). A total of 107
patients were enrolled, stratified based on spleen size
(≥15 cm or <15 cm) and platelet counts (75-150x10 9 /L
or >150x10 9 /L), then randomized to receive intravenous
imetelstat at 9.4 mg/kg (n=59) or 4.7 mg/kg (n=48),
every three weeks.
Baseline characteristics were well balanced between
the two arms, Dr. Mascarenhas reported. In the entire
population, the median age was 68 years (range = 31-86
years), 62 percent had a spleen that was ≥15 cm below
the left costal margin, and 25 percent were red blood
cell transfusion–dependent. Also, 98 percent of patients
had at least one detectable mutation, and 74 percent had
three or more mutations. “The median time to discon-
tinuation of ruxolitinib was less than two months, and
the duration of JAK inhibitor therapy was approximately
two years,” he added, highlighting that this was a heavily
pretreated patient population.
The researchers assessed spleen response and symp-
tom response at week 24 (co-primary endpoints) and
continued to follow patients to evaluate overall survival
(OS).
At the planned interim analysis after 20 patients
in each arm had been treated for at least 12 weeks, the
lower-dose arm was closed because it didn’t meet its
prespecified endpoints, the authors noted. Twelve of the
48 patients randomized to the 4.7-mg/kg group were
able to escalate to the 9.4-mg/kg arm.
As of April 26, 2018 (data cutoff for the primary,
24-week analysis), patients had a median follow-up of
22.6 months (range = 0.2-27.4 months). The median
duration of imetelstat treatment was 6.2 months (range
= 0.0-27.2 months), although this was influenced by
the early closure of the low-dose arm, Dr. Mascarenhas
noted.
At week 24, six patients (10.2%) in the 9.4-mg/kg arm
met the primary endpoint of spleen response per MRI
(achieving ≥35% spleen volume reduction), while no
patients on the 4.7-mg/kg arm had a response. Nineteen
patients (32%) and three patients (6%), respectively,
reached the endpoint for symptom reduction (achieving a
≥50% reduction in Total Symptom Score).
Treatment with imetelstat also appeared to improve
bone marrow fibrosis: Among the 57 patients who had
bone marrow assessments available at baseline and
follow-up, 19 (33%) had at least one grade reduction in
fibrosis.
Fifty patients (47%) had agreed to ongoing follow-up
in the OS analysis, and, as of the October 22, 2018 data
cutoff, median follow-up was 27.4 months (range = 0.2-
33.0 months).
Median OS was 19.9 months (95% CI 17.1 months to
not estimable) in the 4.7-mg/kg group and 29.9 months
(95% CI 22.8 months to not estimable) in the 9.4-mg/kg
group (p value not reported). “If we accounted for cen-
soring at the time of dose escalation, subsequent JAK
inhibitor use, or subsequent stem cell transplantation –
which some patients were able to go on to – the survival
was still superior at the higher dose,” Dr. Mascarenhas
said.
The authors also looked specifically at patients with
triple-negative disease (JAK2 V617F, CALR, and MPL
mutations) to determine whether a certain molecular
profile could predict poor outcome. They found no
significant differences in survival in the low-dose arm
but observed a higher median OS for triple-negative pa-
tients in the higher-dose arm: not estimable versus 24.6
months (range = 20.7 months to not estimable; p values
not reported). “Patients [who] would likely do poorly –
those with triple negativity – didn’t have worse outcome
on this drug,” Dr. Mascarenhas noted.
Myelosuppression was the most common adverse
event (AE) reported in the study and was “to be ex-
pected based on earlier trials,” he added. Rates of grade
≥3 cytopenias in the 4.7-mg/kg and 9.7-mg/kg groups
were as follows:
• thrombocytopenia: 11 (23%) and 24 (41%)
• anemia: 15 (31%) and 23 (39%)
• neutropenia: 5 (10%) and 19 (32%)
• leukopenia: 3 (6%) and 8 (14%)
Most grade 3/4 cytopenias were reversible within four
weeks, Dr. Mascarenhas reported.
Grade ≥3 non-hematologic AEs included dyspnea,
asthenia, and fatigue, and seven patients experienced a
grade 3/4 liver function test (LFT) elevation. The FDA
previously placed imetelstat on a clinical hold over
concerns about LFT elevations in earlier studies, but an
independent committee reviewed the hepatic toxicities
and found that none of the abnormalities in this trial
were related to imetelstat treatment.
Overall, the safety profile was deemed manageable
for this high-risk, poor-prognosis population, and, to-
gether with the median OS data, the authors concluded
that imetelstat 9.4 mg/kg every three weeks warrants
further testing in clinical trials.
The study is limited by the small patient population
and lack of a comparator arm. Observations about the
response rates with certain molecular profiles also will
need to be confirmed and evaluated in larger studies,
Dr. Mascarenhas added.
The authors report relationships with Janssen, which
sponsored the trial.
REFERENCE
Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with
intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to Janus kinase
inhibitor therapy: results of a phase 2 randomized study of two dose levels. Abstract #685.
Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.
ASH Clinical News
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