Literature Scan
median time to platelet engraftment was 20
days in the ATG group compared with 16.5
days in the no-ATG group (hazard ratio
[HR] = 0.84; 95% CI 0.55-1.27; p=0.827).
“This is the third of three randomized
trials of ATG in unrelated donor transplantation, all having had positive results
in favor of ATG and all showing minimal
likelihood of harm,” Dr. Walker told ASH
Clinical News. “The optimal dose of ATG
is unknown, but this may be critical, so
clinicians should employ doses used in successful randomized trials.”
No differences were seen between the
treatment groups in time to non-relapse
mortality, time to disease relapse, or OS.
“Patients who received ATG reported
significantly lower symptom burden attributable to chronic GVHD at 12 months
than patients who did not receive ATG, as
measured by the Lee scale [which measures
the effect of GVHD symptoms on patients’
functioning and well-being],” Dr. Walker
and co-authors wrote. Out of a possible 100
points (with higher scores reflecting higher
symptom burden), patients who received
ATG had Lee scale scores of 14.95, versus
20.93 in the no-ATG group (p=0.017).
At 12 months, 137 patients were alive
without relapse and were given seven
Lyophilized Powder for Solution for Intravenous Injection
ADVERSE REACTIONS
Brief Summary of Prescribing Information: Please see
package insert for full Prescribing Information.
Common adverse reactions observed in greater than 5% of
subjects in the clinical trial were development of inhibitors to
porcine factor VIII.
INDICATIONS AND USAGE
OBIZUR, Antihemophilic Factor (Recombinant), Porcine
Sequence, is a recombinant DNA derived, antihemophilic
factor indicated for the treatment of bleeding episodes in
adults with acquired hemophilia A.
Limitations of Use:
Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction (AR) rates observed in the clinical
trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates
observed in clinical practice.
CONTRAINDICATIONS
The safety and efficacy of OBIZUR was evaluated in a multicenter, prospective, open-label, clinical trial that investigated
adult patients with acquired hemophilia A. Twenty-nine adult
subjects were enrolled in the study, received at least one dose
of OBIZUR and were evaluable for safety. Of the 29 adult
subjects, 10 were between the ages of 40 and 65, and 19 were
65 years of age or older (18 Caucasian, 6 African-American,
and 5 Asian). Ten (34%) subjects were female.
OBIZUR is contraindicated in patients who have had lifethreatening hypersensitivity reactions to OBIZUR or its
components (including traces of hamster proteins).
The most frequently reported adverse reaction in patients
with acquired hemophilia A was the development of inhibitors
to porcine factor VIII.
WARNINGS AND PRECAUTIONS
Immunogenicity
• Safety and efficacy of OBIZUR has not been established in
patients with baseline anti-porcine factor VIII inhibitor titer
greater than 20 BU.
• OBIZUR is not indicated for the treatment of congenital
hemophilia A or von Willebrand disease.
Hypersensitivity Reactions
Hypersensitivity reactions can occur with OBIZUR. OBIZUR
contains trace amounts of hamster proteins. Early signs of
allergic reactions, which can progress to anaphylaxis, include
angioedema, chest-tightness, dyspnea, hypotension,
wheezing, urticaria, and pruritus. Immediately discontinue
administration and initiate appropriate treatment if allergic
or anaphylactic-type reactions occur.
Inhibitory Antibodies
Inhibitory antibodies to OBIZUR have occurred. Monitor
patients for the development of antibodies to OBIZUR by
appropriate assays. If the plasma factor VIII level fails to
increase as expected, or if bleeding is not controlled after
OBIZUR administration, suspect the presence of an antiporcine factor VIII antibody. If such inhibitory antibodies
to anti-porcine factor VIII are suspected and there is a
lack of clinical response, consider other therapeutic options.
Monitoring Laboratory Tests
• Perform one-stage clotting assay to confirm that adequate
factor VIII levels have been achieved and maintained.
– Monitor factor VIII activity 30 minutes and 3 hours after
initial dose.
– Monitor factor VIII activity 30 minutes after
subsequent doses.
• Monitor the development of inhibitory antibodies to
OBIZUR. Perform a Nijmegen Bethesda inhibitor assay if
expected plasma factor VIII activity levels are not attained
or if bleeding is not controlled with the expected dose of
OBIZUR. Use Bethesda Units (BU) to report inhibitor levels.
All subjects were monitored for development of inhibitory
antibodies to OBIZUR using the Nijmegen modification of the
Bethesda inhibitor assay. A subject was considered to have
developed an OBIZUR inhibitor if the titer was ≥0.6 Bethesda
Units (BU)/mL.
Of the 29 subjects treated with OBIZUR, 19 subjects were
negative for anti-porcine factor VIII antibodies at baseline.
Five of the 19 (26%) developed anti-porcine factor VIII
antibodies following exposure to OBIZUR. Of the 10 subjects
with detectable anti-porcine factor VIII antibodies at baseline,
2 (20%) experienced an increase in titer and eight (80%)
experienced a decreasing to a non-detectable titer.
All subjects were also monitored for development of binding
antibodies to baby hamster kidney (BHK) protein by a
validated sequential ELISA (enzyme-linked immunosorbent
assay). No patients developed de novo anti-BHK antibodies.
The detection of antibody formation is highly 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, comparison of the
incidence of antibodies to OBIZUR with the incidence of
antibodies to other products may be misleading.
questionnaires to evaluate each treatments’
effects on quality of life. Overall happiness
(measured by Atkinson Happiness Scale)
was significantly higher in the ATG group,
compared with the no-ATG group (with
scores of 7.40 vs. 6.16; p=0.027).
Serious adverse events did not differ
between the ATG and no ATG groups
(34% vs. 42%), though Epstein-Barr virus
reactivation was more common among
patients receiving ATG (20 patients with
one death [33%] vs. 2 patients with no
deaths [3%]). No deaths were attributed
directly to ATG, the researchers noted.
Limitations of the study included the
non-blinded design and short follow-up
period. “A longer follow-up might reveal
additional symptom burden because
organ damage and immunosuppressive
side effects are expected to accumulate
in patients affected by chronic GVHD,”
noted Dr. Walker and co-authors.
The researchers noted that future
clinical research should be conducted
to find answers to several questions.
“Although this study supports an important role for ATG in hematopoietic
cell transplantation, several questions
related to its use remain unanswered,”
they wrote. “First, the optimum timing
and dosing of ATG needs further investigation with respect to the potential
harms of Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, and disease relapse
after non-myeloablative and reduced
intensity conditioning.”
Also, although an increase in disease
relapse was not noted in this trial in
patients receiving non-myeloablative
conditioning, “a specifically designed
trial with adequate numbers of patients
is needed to resolve this controversial
question.”
“ATG should be added to myeloablative and non-myeloablative preparative regimens for hematopoietic cell
transplantation when using unrelated
donors,” concluded Dr. Walker and
colleagues. “The benefits of decreases
in steroid use are clinically significant. Epstein-Barr virus reactivation
is increased, but is manageable by
prospective monitoring and the use of
rituximab.” ●
REFERENCE
Walker I, Panzarella T, Couban S, et al. Pretreatment with antithymocyte globulin versus no anti-thymocyte globulin in patients
with haematological malignancies undergoing haemopoietic
cell transplantation from unrelated donors: a randomized,
controlled, open-label, phase 3, muticentre trial. Lancet Oncol.
2016;17:164-73.
Baxalta and Obizur are trademarks of Baxalta Incorporated.
Manufactured by:
Baxalta US Inc.
Westlake Village, CA 91362 USA
U.S. License No. 140
USBS/MG114/15-0031
March 2016