CLINICAL NEWS
All participants received the same dose of eltrombopag
(but had different treatment start days and durations of
treatment) plus standard immunosuppressive therapy
(horse antithymocyte globulin [ATG] and cyclosporine).
Seventy-nine percent of patients responded to treatment,
with a median response duration of 24.3 months (range =
23 months to not estimable). The complete response rate
was 44 percent, which compared favorably with historical
controls of ATG/cyclosporine alone (27%).
Given the risks of hepatotoxicity, the agent was ap-
proved with dose modification guidelines and recom-
mendations for close monitoring.
In her discussion of eltrombopag’s expanded indica-
tion, Cynthia Dunbar, MD, from the National Heart,
Lung, and Blood Institute, also cited the favorable com-
parison with historical control data, noting that only 12
percent of patients treated with standard therapies “had
anything resembling normalization of their blood counts.”
Dr. Dunbar agreed that hepatotoxicity, as well as the se-
rious skin reactions that occurred in eltrombopag-treated
patients, is a concern for clinical practice. By monitoring
patients closely – at least through ATG therapy and until
hospital discharge – and following criteria for stopping or
holding eltrombopag outlined in its prescribing informa-
tion, she said that clinicians can avoid prematurely stop-
ping the drug. “It’s very important, in terms of salvaging
stem cells in these patients, to give the drug as early as
possible at the maximal dose tolerated,” she said.
The rates of cytogenetic evolution to myelodysplastic
syndromes or acute myeloid leukemia were low (approxi-
mately 8%) in eltrombopag-treated patients and were
similar to those experienced by patients receiving ATG/
cyclosporine alone.
These data have been “encouraging so far,” Dr. Dunbar
said, but despite high hopes “that [eltrombopag] would
result in a lower rate of relapse … there doesn’t seem to
be a decreased rate of relapse from our historical cohorts.”
The relapse rates appeared to be quite high, regardless of
whether eltrombopag was stopped at six months or 24
months (32% and 14%, respectively).
Eltrombopag is a welcome new treatment option
for patients living with sAA, but Dr. Dunbar expressed
restraint about how extensively it will change practice.
“Adding eltrombopag to initial [horse ATG and cyclo-
phosphamide] is indicated because of the higher response
rate and the more rapid and higher counts [achieved]
with this therapy,” she said, but “at this point, I don’t think
it should change decisions regarding transplant.”
Emicizumab
In November 2017, the FDA approved the bispecific
monoclonal antibody emicizumab for routine prophy-
laxis to prevent or reduce the frequency of bleeding epi-
sodes in adult and pediatric patients with hemophilia A
and FVIII inhibitors based on results from the phase III
HAVEN 1 and 2 trials. With findings from the HAVEN 3
trial, the FDA expanded its indication in 2018 to include
patients without inhibitors.
Laurel Menapace, MD, from the FDA’s OHOP, shared
results from these pivotal trials, which randomized pa-
tients with hemophilia A to receive emicizumab prophy-
laxis or no prophylaxis, with an option to cross over after
24 weeks of treatment. Emicizumab prophylaxis signifi-
cantly lowered annual bleeding rates (from 38.2 without
prophylaxis to 1.3 to 1.5 with prophylaxis) and incidence
of treated bleeds (from 47.6 to 2.5 to 2.6, respectively).
There were no patient deaths on the study, and
few patients discontinued treatment due to AEs. “The
FDA and the pharmaceutical sponsor were concerned
particularly with de novo FVIII inhibitor development,
which was not observed on the study,” Dr. Menapace said,
discussing safety events of clinical importance. “Further-
more, there was no evidence of neutralizing anti-drug
antibodies that resulted in loss of efficacy in HAVEN 3.”
No events of thrombotic microangiography or throm-
bosis were observed in the trial, although Dr. Menapace
noted that the agent’s approval mandates continued post-
marketing surveillance.
Barbara Konkle, MD, from BloodWorks North-
west and the University of Washington, discussed the
role of emicizumab in the management of patients with
hemophilia A, citing the agent’s ease of administration.
“[Currently available replacement products] require
intravenous infusions every other day to at least twice
weekly, which is quite a burden to the patient and family,”
she explained. “There also are venous access challenges,
so subcutaneous administration has long been a hope for
this patient population.”
However, Dr. Konkle warned that “emicizumab will
not prevent all bleeding, so we have to have a plan for
[patients who experience] breakthrough bleeding, who
are undergoing surgery, or who have major bleeding.” She
continued, “Patients still need to have a bypassing [agent
available] and education about using [the factor] at home,
as well as close contact with providers.”
She also outlined another practical concern: Emici-
zumab can interfere with aPTT- and PTT-based assays and
results may not reflect the efficacy of the drug. “The fear
is that a patient will go to a hospital not familiar with this
drug, tell the provider he is on this great new drug, and his
PTT will be normal. He’d be taken for major surgery with-
out having a backup factor in case of bleeding,” she said.
While applauding the approval of an agent with a lower
treatment burden, Dr. Konkle also expressed concerns that
the less frequent dosing may inadvertently lead to lapses in
follow-up. “When we have a highly effective therapy that
doesn’t require administration very frequently and is not
very difficult to administer, our patients and their families
may not want to visit us very frequently,” she said. “But
because we have a number of issues with this new therapy
that we need to get more information on, I think it is espe-
cially critical that these patients be followed in specialized
hemophilia treatment centers where [specialized monitor-
ing and follow-up] can be performed.”
For Older Patients With CLL, Ibrutinib-Based Treatment Beats
Standard Chemoimmunotherapy
Results from a randomized phase III study indicate that
the Bruton tyrosine kinase (BTK) inhibitor ibrutinib
with or without rituximab was superior to standard-of-
care, upfront chemoimmunotherapy for older patients
with chronic lymphocytic leukemia (CLL). Lead
author Jennifer A. Woyach, MD, from the Ohio State
University Comprehensive Cancer Center, presented
the findings of the Alliance North American Intergroup
Study A041202 as a plenary abstract at the 2018 ASH
Annual Meeting, and published simultaneously in the
New England Journal of Medicine.
The study is the first head-to-head comparison of
ibrutinib with bendamustine plus rituximab (BR), Dr.
Woyach said, “which is probably our most aggressive
and most effective therapy in older [patients with] CLL.”
Previously, ibrutinib was compared with chlorambucil,
an earlier standard of care that is no longer routinely
used in practice.
“This really changes the conversation we have with
patients,” Dr. Woyach told ASH Clinical News. “Before,
we could say, ‘ibrutinib is showing very impressive
results, but we really don’t know how it compares with
ASHClinicalNews.org
our standard chemoimmunotherapy.’ The results of this
study allow us to say, ‘[ibrutinib] is better.’”
The study evaluated ibrutinib (with or without
rituximab) and BR in 547 patients with treatment-naïve,
intermediate- or high-risk CLL. Participants’ median
age was 71 years (range = 65-89 years), and most (54%)
had high-risk disease (defined as Ri stage III/IV).
Twenty-five percent of patients had high-risk cytogenet-
ics (del17p or del11q).
Participants were stratified according to disease stage
(high or intermediate) and cytogenetics, then random-
ized to one of three treatment arms:
• arm A: BR administered in six 28-day cycles
(n=183)
• arm B: ibrutinib administered orally (n=182)
• arm C: ibrutinib plus rituximab on days 1, 8, 15,
and 22 of course 2 and on day 1 of courses 3-6
(n=182)
Patients were treated until disease progression or unac-
ceptable toxicity; at the point of disease progression in
arm A, patients could cross over to arm B.
Of the 547 patients who underwent randomization,
524 patients (96%) could be assessed for the primary
progression free-survival (PFS) analysis (arm A = 176;
arm B = 178; arm C = 170).
After a median follow-up of 38 months (range not
provided), the median PFS was 41 months in arm A
but was not reached in either ibrutinib-containing arm.
Rates of two-year PFS also were higher in the ibrutinib-
containing arms: 74 percent in arm A, 87 percent in arm
B, and 88 percent in arm C. This translated to a lower
risk of disease progression or death in both ibrutinib-
containing arms (hazard ratio = 0.39 for arm A vs. arm
B and 0.38 for arm A vs. arm C; p<0.001 for both).
Dr. Woyach noted that, at the time of presentation,
there were no significant differences in overall survival
(OS) among the treatment arms (p=0.87) and that me-
dian OS was not reached for any arm, “likely due to the
relatively short follow-up and crossover design” of the
study, she noted.
ASH Clinical News
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