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FDA Approves
Emapalumab for
Previously Treated HLH
The U.S. Food and Drug Administration
(FDA) approved emapalumab, an anti-
interferon gamma monoclonal antibody,
for the treatment of adults and children
with primary hemophagocytic lympho-
histiocytosis (HLH) that was refractory or
relapsed or progressed following conven-
tional HLH therapy.
The approval, which also included
patients who could not tolerate conven-
tional therapy, was based on results from
a multicenter, open-label, single-arm trial,
which included 27 pediatric patients who
received emapalumab at a starting dose of
1 mg/kg every three days. All participants
received dexamethasone as background
HLH treatment, at doses ranging between
5 to 10 mg/m 2 per day. Before administra-
tion of emapalumab, patients also received
prophylaxis for herpes zoster, Pneumocystis
jirovecii, and fungal infections.
At the end of the treatment period, the
overall response rate (defined as a complete
response [CR] or partial response [PR] or
improvement in HLH), was 63 percent.
Responses included seven CRs and eight
PRs, and two patients who experienced an
improvement in HLH (defined as ≥3 HLH
abnormalities improved by ≥50% from
baseline).
The most common adverse events
(AEs; occurring in ≥20% of patients) were
infections, hypertension, infusion-related
reactions, and pyrexia.
Emapalumab also received priority-
review, breakthrough-therapy designation,
and orphan-product designation.
Source: FDA news release, November 20, 2018.
Venetoclax Approved
for Frontline AML
The BCL2 inhibitor venetoclax, in com-
bination with azacitidine or decitabine or
low-dose cytarabine, was approved by the
FDA for the treatment of patients with
newly diagnosed acute myeloid leukemia
(AML) who are aged 75 years or older or
who have comorbidities that preclude use
of intensive induction chemotherapy.
The approval is based on results from
two phase II trials: the M14-358 and M14-
397 studies.
The M14-358 study evaluated vene-
toclax in combination with azacitidine
(n=67) or decitabine (n=13) in patients
with newly diagnosed AML. Twenty-five
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patients who received venetoclax in com-
bination with azacitidine achieved a CR,
with a median duration of remission of 5.5
months (range = 0.4-30 months). Seven
of the patients who received venetoclax in
combination with decitabine achieved a
CR, with a median duration of remission of
4.7 months (range = 1.0-18 months).
The M14-387 study evaluated venetoclax
in combination with low-dose cytarabine in
patients with newly diagnosed AML (n=61),
including patients with previous exposure to
a hypomethylating agent for an antecedent
hematologic disorder. When combined
with low-dose cytarabine, treatment with
venetoclax induced CR in 13 patients,
with a median observed remission
duration of six months (range = 0.03-25
months).
The most common AEs (occurring in
≥30% of patients) associated with venetoclax
were nausea, diarrhea, thrombocytopenia,
constipation, neutropenia, febrile neutro-
penia, fatigue, vomiting, peripheral edema,
pneumonia, dyspnea, hemorrhage, anemia,
rash, abdominal pain, sepsis, back pain,
myalgia, dizziness, cough, oropharyngeal
pain, pyrexia, and hypotension.
Source: FDA news release, November 23, 2018.
Glasdegib Receives
Approval for Older
Patients With AML
The FDA approved glasdegib, in combina-
tion with low-dose cytarabine, for patients
with newly diagnosed AML who are aged
75 years or older or who have comorbidities
that preclude the use of intensive induction
chemotherapy.
The agency’s decision was based on
results from the multicenter, open-label
BRIGHT AML 1003 study, which included
115 patients with AML who met the follow-
ing criteria: 75 years or older, severe cardiac
disease, Eastern Cooperative Oncology
Group performance status score ≤2, or base-
line serum creatinine >1.3 mg/dL.
Patients were randomized 2:1 to receive
glasdegib 100 mg/day with low-dose cyta-
rabine (20 mg subcutaneously twice daily
on days 1 to 10 of a 28-day cycle; n=77) or
low-dose cytarabine alone (n=38).
With a median follow-up of 20
months, median overall survival was 8.3
months (range = 4.4-12.2 months) for the
glasdegib arm and 4.3 months (range =
1.9-5.7 months) for the cytarabine-alone
arm (hazard ratio = 0.46; 95% CI 0.30-
0.71; p=0.0002).
The most common AEs (occurring
in ≥20% of patients) included anemia,
fatigue, hemorrhage, febrile neutropenia,
musculoskeletal pain, nausea, edema,
thrombocytopenia, dyspnea, decreased
appetite, dysgeusia, mucositis, constipa-
tion, and rash.
risks of the following: fatal infusion reac-
tions, severe skin and mouth reactions,
hepatitis B virus reactivation, and progres-
sive multifocal leukoencephalopathy.
Source: FDA news release, November 28, 2018.
Source: FDA news release, November 23, 2018.
First Biosimilar for
Rituximab Gains
Approval
The FDA approved rituximab-abbs,
the first biosimilar of rituximab, for the
treatment of adult patients with CD20-
positive, B-cell non-Hodgkin lymphoma
(NHL). This marks the first biosimilar
approved for NHL and the 15th biosimilar
approved for use in the U.S.
“As part of the FDA’s Biosimilars Action
Plan, we’re advancing new policies to
make the development of biosimilars more
efficient and to enable more opportuni-
ties for biosimilar manufacturers to make
these products commercially successful
and competitive,” said FDA Commissioner
Scott Gottlieb, MD. “We’ll continue to
make sure biosimilar medications are
evaluated efficiently through a process that
makes certain that these new medicines
meet the FDA’s rigorous standards for
approval.”
The indication for rituximab-abbs
covers the indications of its reference
product, including: patients with previ-
ously untreated, CD20-positive follicular
lymphoma (in combination with first-line
chemotherapy); patients achieving a CR
or PR to a rituximab product in combina-
tion with chemotherapy, as single-agent
maintenance therapy; and patients with
non-progressing, low-grade, CD20-
positive, B-cell NHL (as a single agent
after first-line cyclophosphamide, vincris-
tine, prednisone chemotherapy).
The FDA’s approval of rituximab-abbs
was based on a review of the agent’s struc-
tural and functional characteristics, animal
study data, human pharmacokinetic data,
clinical immunogenicity data, and other
clinical data that demonstrated the agent
was biosimilar to rituximab.
Rituximab-abbs was approved as a bio-
similar – not an interchangeable – product.
The most common AEs associated with
rituximab-abbs included infusion reactions,
fever, lymphopenia, chills, infection, and
asthenia. The FDA’s approval letter advised
health-care providers to monitor patients
for tumor lysis syndrome, cardiac adverse
reactions, renal toxicity, and bowel obstruc-
tion and perforation.
Like its reference product, rituximab-
abbs carries a boxed warning for increased
FDA Approves
Gilteritinib for FLT3-
Mutated AML
The oral FLT3/AXL inhibitor gilteritinib
was approved by the FDA for the treat-
ment of adult patients with FLT3-mutated,
relapsed or refractory AML. The FDA also
expanded the indication for the LeukoStrat
CDx FLT3 Mutation Assay, a companion
diagnostic to detect the FLT3 mutation.
“[Mutations in the FLT3 gene] are as-
sociated with a particularly aggressive form
of the disease and a higher risk of relapse,”
said Richard Pazdur, MD, director of the
FDA’s Oncology Center of Excellence and
acting director of the Office of Hematology
and Oncology Products in the FDA’s
Center for Drug Evaluation and Research.
“[Gilteritinib] is the first drug to be ap-
proved that can be used alone in treating
patients with AML with a FLT3 mutation
who have relapsed or who don’t respond to
initial treatment.”
The agency’s decision was based on in-
terim results from the phase III ADMIRAL
trial of 138 patients with relapsed or refrac-
tory AML and a confirmed FLT3 mutation.
Participants were randomized 2:1 to receive
either gilteritinib 120 mg daily or salvage
chemotherapy. After a median follow-up of
4.6 months (range = 2.8-15.8 months), 29
gilteritinib-treated patients achieved CR or
CR with partial hematologic recovery, for
a CR rate of 21 percent. Of the 106 patients
who required red blood cell or platelet
transfusions at the start of treatment with
gilteritinib, 31 percent became transfusion-
free for at least 56 days.
The most common AEs included
myalgia/arthralgia, fatigue, and liver
transaminase elevation. The approval also
advises health-care providers to monitor
patients for posterior reversible encepha-
lopathy syndrome, prolonged QT interval,
and pancreatitis. Instances of differen-
tiation syndrome were rare, according to
the approval letter, but were observed in
gilteritinib-treated participants.
Gilteritinib was approved through
the FDA’s fast-track and priority-review
pathways, and it also received orphan-drug
designation. ●
Source: FDA news release, November 28, 2018.
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