ineligible to receive nelarabine and were only randomized
between the methotrexate arms; these patients did not
receive cranial irradiation, the investigators noted. Also, 3.4
percent of patients were not randomized to methotrexate or
nelarabine based on induction failure.
After four years of follow-up, the DFS and OS rates
among T-ALL patients were:
• DFS: 84.1%
• OS: 90.2%
Treatment with nelarabine improved DFS: 88 percent versus
83 percent (p=0.045).
The authors also reported no significant differences
between rates of four-year DFS in the participants receiving
escalating-dose, regardless of nelarabine exposure:
• escalating-dose methotrexate with nelarabine
(n=147): 91%
However, in those randomized to high-dose methotrexate,
nelarabine was associated with a significantly higher four-
year DFS rate:
• high-dose methotrexate with nelarabine (n=176): 87%
• high-dose methotrexate without nelarabine (n=185):
78% (p=0.011)
• escalating-dose methotrexate without nelarabine
(n=151): 89% (p=0.28)
”
5”
Immunogenicity
All clinical trial subjects were monitored for neutralizing
antibodies (inhibitors) to Factor VIII by the modified Bethesda
assay using blood samples obtained prior to the first infusion
of KOVALTRY, at defined intervals during the studies and at the
completion visit.
Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a
total of 204 pediatric and adult patients diagnosed with severe
hemophilia A (Factor VIII <1%) with previous exposure to
Factor VIII concentrates ≥50 EDs, and no history of inhibitors.
In the completed studies, no PTP developed neutralizing
antibodies to Factor VIII. In an ongoing extension study, a
13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent
with an acute infection and positive IgG anticardiolipin
antibodies. The Factor VIII recovery was 2.2 IU/dL per IU/kg,
annualized bleeding rate (ABR) was zero, and no change in
therapy was required.
In an actively enrolling clinical trial in PUPs, 6 of 14 treated
subjects (42.9% with a 95% Confidence Interval of 17.7-71.1%)
developed an inhibitor. Of these, 3 subjects (21.4%) had high
titer inhibitors, and 3 subjects (21.4%) had transient low titer
inhibitors for which no change in therapy was required.
The detection of antibody formation is dependent on the
sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity
in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection,
concomitant medications, and underlying disease. For these
reasons, it may be misleading to compare the incidence of
antibodies to KOVALTRY with the incidence of antibodies to
other products.
REFERENCE
8.2 Lactation
Risk Summary
There is no information regarding the presence of KOVALTRY
in human milk, the effects on the breastfed infant, or the effects
on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s
clinical need for KOVALTRY and any potential adverse effects
on the breastfed infant from KOVALTRY or from the underlying
maternal condition.
(5.2)]. Advise patients to contact their physician or
treatment center for further treatment and/or assessment,
if they experience a lack of clinical response to Factor VIII
replacement therapy, as this may be a manifestation of
an inhibitor.
• Advise patients to discard all equipment, including any
unused product, in an appropriate container.
• Advise patients to consult with their healthcare provider
prior to travel. Advise patients to bring an adequate supply
of KOVALTRY while traveling based on their current regimen
of treatment.
Resources at Bayer available to the patient:
For Adverse Reaction Reporting, contact Bayer Medical
Communications 1-888-84-BAYER (1-888-842-2937)
To receive more product information, contact KOVALTRY
Customer Service 1-888-606-3780
Bayer Reimbursement HELPline 1-800-288-8374
For more information, visit www.KOVALTRY-us.com
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data with KOVALTRY use in pregnant women to
inform on drug-associated risk. Animal reproduction studies
have not been conducted using KOVALTRY. It is not known
whether KOVALTRY can cause fetal harm when administered to a
pregnant woman or can affect reproduction capacity. KOVALTRY
should be given to a pregnant woman only if clearly needed.
In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Combining nelarabine with BFM chem otherapy was not
associated with additional toxicity: In the nelarabine-
treated group, 50 patients experienced
a disease relapse, secondary myeloid
neoplasm, or death, compared with 57
patients in the non–nelarabine-treated
8.4 Pediatric Use
group. “Nelarabine is known to have
Safety and efficacy studies with KOVALTRY have been
some serious neurotoxic effects, but
performed in pediatric PTPs. Body weight adjusted clearance of
we found that incidences of neurotox-
Factor VIII in children ≤12 years of age is higher than in adults
icity were similar across all four treat-
and adolescents. Consider higher or more frequent dosing in
ment arms,” Dr. Dunsmore reported,
children to account for this difference in clearance [see Clinical
Pharmacology (12.3)].
adding that nelarabine was associated
with fewer CNS relapses (n=1 and
8.5 Geriatric Use
Clinical studies with KOVALTRY did not include patients aged 65
n=14, respectively).
and over to determine whether or not they respond differently
Incidence of grade 3/4 peripheral
from younger patients. However, clinical experience with other
neuropathy also were similar (6% and
Factor VIII products has not identified differences between the
9%, respectively).
elderly and younger patients. As with any patient receiving
Dr. Dunsmore noted that the trial
recombinant Factor VIII, dose selection for an elderly patient
was
limited by the small number of
should be individualized.
patients with T-LLy and added that
17 PATIENT COUNSELING INFORMATION
future trials will have to determine
• Advise the patient to read the FDA-approved patient labeling
whether nelarabine will have a sur-
(Patient Information and Instructions for Use).
vival advantage in a protocol without
• Hypersensitivity reactions are possible with KOVALTRY
cranial irradiation.
[see Warnings and Precautions (5.1)]. Warn patients of the
The corresponding authors report
early signs of hypersensitivity reactions (including tightness
financial
relationships with Novartis,
of the chest or throat, dizziness, mild hypotension and
which provided support for the study,
nausea during infusion) which can progress to anaphylaxis.
Advise patients to discontinue use of the product if these
along with the Cancer Therapy
symptoms occur and seek immediate emergency treatment
Evaluation Program of the National
with resuscitative measures such as the administration of
Cancer Institute/National Institutes of
epinephrine and oxygen.
Health, GlaxoSmithKline, Novartis,
• I nhibitor formation may occur at any time in the treatment of
and St. Baldrick’s Foundation. ●
a patient with hemophilia A [see Warnings and Precautions
Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: A
randomized trial testing nelarabine in newly diagnosed t-cell
malignancy. Abstract #10500. Presented at the 2018 ASCO
Annual Meeting, June 2, 2018; Chicago, IL.
Bayer HealthCare LLC
Whippany, NJ 07981 USA
U.S. License No. 8
6907500BS
Attendees browse the posters at the 2018 ASCO
Annual Meeting.
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ASH Clinical News
FS:6.75”
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