On Location
American Society of Hematology’s
2018 ANNUAL MEETING & EXPOSITION
his month, we continue our coverage of the 2018 ASH Annual Meeting
& Exposition, which featured practice-changing research from across
the spectrum of hematologic malignancies and blood disorders.
In this special issue, ASH Clinical News is taking a look at efforts to
improve the prognosis, treatment, and outcomes for patients living
with blood disorders worldwide shared at the meeting, including newly approved
agents in nonmalignant hematology and refined treatment approaches in
malignant hematology.
Visit ashclinicalnews.org/on-location for our complete coverage of the
meeting.
ASH Clinical News also was on site to speak with presenters and moderators
about the groundbreaking research that was shared at the meeting. Check out
all of the interviews at ashclinicalnews.org/multimedia/meeting-coverage.
Attendees browse the poster hall at the 2018 ASH Annual Meeting.
New Drug Approvals in Nonmalignant Hematology
In 2018, the U.S. Food and Drug Administration (FDA) set
a record for the number of approvals for new therapies – or
new indications for previously approved therapies – for
people living with blood disorders: There were 38 approv-
als in hematology, including 12 new molecular entities.
With so many new agents reshaping the treatment
landscape, the American Society of Hematology (ASH)
and the FDA partnered to bring hematologists practical
information about using these agents during the “ASH-
FDA Symposium on New Drug Approvals” at the 2018
ASH Annual Meeting. Experts convened to offer clinical
and regulatory perspectives on the newly available thera-
pies in two sessions focusing on therapies for malignant
and nonmalignant hematology.
In his overview of the new hematologic approvals in
2018, Angelo de Claro, MD, from the FDA’s Office of He-
matology and Oncology Products (OHOP), highlighted
the large percentage of therapies approved for pediatric
patients. “Pediatric approvals constituted a quarter of the
FDA hematology approvals,” he said. “This represents
continued success of established frameworks to increase
pediatric drug development.”
Here, we report on the newly approved agents with
nonmalignant hematologic indications from 2018:
• emapalumab – approved November 20, 2018, for the
treatment of adult and pediatric patients with primary
hemophagocytic lymphohistiocytosis (pHLH) that
is refractory to, recurrent after, progressive after, or
intolerant to conventional therapy
• eltrombopag – approved November 16, 2018, for
the firstline treatment of adult and pediatric patients
with severe aplastic anemia (sAA)
• emicizumab – approved October 4, 2018, as prophylaxis
to prevent or reduce the frequency of bleeding episodes
in adult and pediatric patients with hemophilia A with or
without factor VIII (FVIII) inhibitors
The session featured clinicians with significant experience
with these agents discussing treatment challenges, including
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ASH Clinical News
identification of the appropriate population, dosing, and
adverse events (AEs).
Emapalumab
“HLH is a rare, life-threatening syndrome characterized
by hyperinflammation, and, if untreated, it is always fatal
in the first few months after diagnosis,” Dr. de Claro said
during his discussion of emapalumab’s approval. The only
cure for HLH is allogeneic hematopoietic cell transplanta-
tion (alloHCT), and, prior to the new agent’s approval, the
conventional approach was reducing hyperinflammation,
typically with dexamethasone and etoposide. This was ac-
companied by immunosuppression of variable severity.
In her review of the FDA’s decision to approve ema-
palumab, Margaret Merino, MD, highlighted the toxicity
of conventional therapy, noting that pre-transplant mor-
tality rates range from 20 to 29 percent – largely due to
progressive disease or therapy-related complications.
Based on data suggesting a pathogenic role for
interferon-gamma (IFN-γ), researchers hypothesized that
neutralizing the anti–IFN-γ antibody could be effective
in the treatment of pHLH, Franco Locatelli, MD, PhD,
from the Bambino Gesù Children’s Hospital IRCCS in
Rome, Italy, explained. Dr. Locatelli was a principal in-
vestigator of the phase II/III pivotal trial of emapalumab.
Emapalumab binds to IFN-γ, blocking signal transduc-
tion of the IFN-γ pathway.
The drug was shown to be effective in the NI-0501-04
and NI-0501-05 studies, in which 34 children with pHLH
received between four and eight weeks of treatment with
emapalumab 1 mg/kg per day, every three to four days.
Emapalumab could be increased up to 10 mg/kg per day,
based on clinical and laboratory responses. Patients received
concomitant dexamethasone at doses of 5 to 10 mg/m 2 .
The overall response rate (defined as normalization or
≥50% improvement from baseline of fever, splenomegaly,
cytopenias, hyperferritinemia, fibrinogen or D-dimer
levels, and central nervous system abnormalities) was 63
percent in patients with relapsed/refractory disease and
64.7 percent in the entire cohort.
Seven of these patients achieved a complete response,
Dr. Locatelli added, and 70 percent of patients were able
to receive an alloHCT. Responses appeared to be durable,
with a median duration of response (until alloHCT con-
ditioning) of 33 days in the relapsed/refractory group and
33.5 days in the entire population.
The safety profiles were considered acceptable, Dr. Merino
reported, and were “similar to rates experienced by patients
receiving conventional therapies.” These included hyperten-
sion, infusion-related reactions, infection, and fever.
“[Children with pHLH] often [present with] and [are]
fighting associated infections, and current firstline therapy
often is ineffective,” said Leslie S. Kean, MD, PhD, from
Boston Children’s Hospital, who discussed the practical
considerations for using emapalumab in the clinic.
Given what she called “the IFN-γ effect,” Dr. Kean
said that the high rate of infections (56%) was expected.
“IFN-γ has complex effects as an immune modulator and
blocking IFN-γ may have untoward negative effects,” she
explained. “Patients with HLH already have an underly-
ing [risk of infection], so it is difficult to understand
whether a drug increases the risk of infection in these
patients in the absence of a randomized trial.”
“Secondline approval is appropriate,” Dr. Kean
concluded, “given small trial size and open questions
concerning the real-world risks of infection, non-
engraftment, and paradoxical immune-activating effects.”
It is important to note, Dr. Locatelli said, that “treat-
ment with emapalumab allows us to transplant patients in
better condition because we can spare them the extra tox-
icity associated with steroids and etoposide.” The clinical
trials data of emapalumab also suggest that IFN-γ plays a
key role in mediating graft rejection, “so this drug could
be useful in preventing the occurrence of graft failure in
this condition,” he added.
Eltrombopag
The oral thrombopoietin receptor agonist eltrombopag
was initially approved in 2014 for patients with previously
treated sAA, and the most recent approval extends its use
to the frontline setting. Nicole Gormley, MD, from the
FDA’s OHOP, discussed the agency’s decision to expand
the indication, citing data from the pivotal phase I/II
trial, which enrolled 153 patients with sAA.
January 2019 Annual Meeting Edition