ASH News Daily 2016 - Issue 1 - A-23

ASH News Daily

Saturday, December 3, 2016

Page A-23
®

Iron

STAT3 has recently announced its intent to become a major iron superhero
Superpower: Harnesses the power
of inflammation to strengthen hepcidin's power, leading to upregulation
of hepcidin and consequently, less
iron absorption
Activates superpower: Inflammatory cytokines, lipopolysaccharides,
support from the SMAD organization
Weaknesses: Unknown

pensable local managers of iron metabolism.
Superpower: Coordinates the expression of iron importers (TFR1 and
DMT1) and iron exporters (FPN) at
a cellular level; IRP1 also manages
the hypoxia mediator, HIF2-alpha,
and IRP2 manages ferritin; IRP1 and
IRP2 regulate their targets post-transcriptionally by binding to untranslated regions of mRNA-encoding
proteins
Activates superpower: Iron deficiency, hypoxia
Weaknesses: Iron, oxygen

duces iron from a ferric (Fe3+) to ferrous (Fe2+) state at the brush border
of intestinal cells
Divalent metal transporter 1
(DMT1): Imports iron into intestinal
cells
FPN: Exports iron out of cells
(intestinal cells, liver cells, macrophages, placenta)
Hephaestin: Oxides iron back to a
Fe3+ state
Transferrin: Delivers iron to the
cells via transferrin receptor 1 (TFR1)
Ferritin: Intracellular iron storage
molecule

IRP1 and IRP2
* The lesser-known but indis-

Supporting Roles*
* Ferrireductase

*Does not include iron metabolism of heme-complexes

«« From Page A-10

Re-

307987gi501_ASH_PI_Pg4

PACIFIC DIGITAL IMAGE * 333 Broadway, San Francisco CA 94133 * 415.274.7234 * www.pacdigital.com

LASERS PRINTED AT

ADCETRIS, Seattle Genetics are US registered trademarks of Seattle Genetics, Inc.
© 2016 Seattle Genetics, Inc., Bothell, WA 98021
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Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy.
Contraception
Females
Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least
6 months after the final dose of ADCETRIS. Advise females to immediately report pregnancy.
Males
ADCETRIS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities.
Males with female sexual partners of reproductive potential should use effective contraception during
ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Infertility
Males
Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS.
Pediatric Use
Safety and effectiveness of ADCETRIS have not been established in pediatric patients.
Geriatric Use
Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine
whether they respond differently from younger patients.
Renal Impairment
Avoid the use of ADCETRIS in patients with severe renal impairment (CLcr <30 mL/min).
The kidney is a route of excretion for monomethyl auristatin E (MMAE). The pharmacokinetics and safety of
brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients
with mild (CLcr >50-80 mL/min; n=4), moderate (CLcr 30-50 mL/min; n=3) and severe (CLcr <30 mL/min;
n=3) renal impairment. In patients with severe renal impairment, the rate of Grade 3 or worse adverse reactions
was 3/3 (100%) compared to 3/8 (38%) in patients with normal renal function. Additionally, the AUC of MMAE
(component of ADCETRIS) was approximately 2-fold higher in patients with severe renal impairment compared
to patients with normal renal function. Due to higher MMAE exposure, ≥Grade 3 adverse reactions may be
more frequent in patients with severe renal impairment compared to patients with normal renal function.
Hepatic Impairment
Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
The liver is a route of clearance for MMAE. The pharmacokinetics and safety of brentuximab vedotin and
MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh
A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment. In patients with
moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared
to 3/8 (38%) in patients with normal hepatic function. Additionally, the AUC of MMAE was approximately
2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function.
OVERDOSAGE
There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely
monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.
PATIENT COUNSELING INFORMATION
* Peripheral neuropathy
Advise patients that ADCETRIS can cause a peripheral neuropathy. They should be advised to report to
their health care provider any numbness or tingling of the hands or feet or any muscle weakness.
* Fever/Neutropenia
Advise patients to contact their health care provider if a fever of 100.5°F or greater or other evidence of
potential infection such as chills, cough, or pain on urination develops.
* Infusion reactions
Advise patients to contact their health care provider if they experience signs and symptoms of infusion
reactions including fever, chills, rash, or breathing problems within 24 hours of infusion.
* Hepatotoxicity
Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper
abdominal discomfort, dark urine, or jaundice.
* Progressive multifocal leukoencephalopathy
Instruct patients receiving ADCETRIS to immediately report if they have any of the following
neurological, cognitive, or behavioral signs and symptoms or if anyone close to them notices these
signs and symptoms:
* changes in mood or usual behavior
* confusion, thinking problems, loss of memory
* changes in vision, speech, or walking
* decreased strength or weakness on one side of the body
* Pulmonary Toxicity
Instruct patients to report symptoms that may indicate pulmonary toxicity, including cough or shortness
of breath.
* Pancreatitis
Advise patients to contact their health care provider if they develop severe abdominal pain.
* Gastrointestinal Complications
Advise patients to contact their health care provider if they develop severe abdominal pain, chills, fever,
nausea, vomiting, or diarrhea.
* Females and Males of Reproductive Potential
ADCETRIS can cause fetal harm. Advise women receiving ADCETRIS to avoid pregnancy during
ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Advise males with female sexual partners of reproductive potential to use effective contraception during
ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Advise patients to report pregnancy immediately.
* Lactation
Advise patients to avoid breastfeeding while receiving ADCETRIS.

70%

with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and
dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed
tomographic imaging of the chest. Most patients responded to corticosteroids. The concomitant use of
ADCETRIS with bleomycin is contraindicated.
Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS. In Study 3,
pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in
the placebo arm. A causal association with single-agent ADCETRIS has not been established.
Serious adverse reactions
In Study 3, serious adverse reactions, regardless of causality, were reported in 25% of ADCETRIStreated patients. The most common serious adverse reactions were pneumonia (4%), pyrexia (4%),
vomiting (3%), nausea (2%), hepatotoxicity (2%) and peripheral sensory neuropathy (2%).
Dose modifications
Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients in Study 3 were
neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and
peripheral motor neuropathy (6%).
Discontinuations
Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients in Study 3.
Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory
neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%),
paraesthesia (1%) and vomiting (1%).
Post Marketing Experience
The following adverse reactions have been identified during post-approval use of ADCETRIS. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: febrile neutropenia.
Gastrointestinal disorders:
* Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting
with severe abdominal pain.
* Gastrointestinal complications (including fatal outcomes).
Hepatobiliary disorders: hepatotoxicity.
Infections: PML, serious infections and opportunistic infections.
Metabolism and nutrition disorders: hyperglycemia.
Respiratory, thoracic and mediastinal disorders: noninfectious pulmonary toxicity including pneumonitis,
interstitial lung disease, and ARDS (some with fatal outcomes).
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes.
Immunogenicity
Patients with classical HL and sALCL in Studies 1 and 2 were tested for antibodies to brentuximab vedotin
every 3 weeks using a sensitive electrochemiluminescent immunoassay. Approximately 7% of patients in
these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 30%
developed transiently positive antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab
antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently
or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced
adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher
incidence of infusion related reactions was observed in patients who developed persistently positive antibodies.
A total of 58 patient samples that were either transiently or persistently positive for anti-brentuximab
vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent of these
patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect
of anti-brentuximab vedotin antibodies on safety and efficacy is not known.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and
specificity, assay methodology, sample handling, timing of sample collection, concomitant medications,
and underlying disease. For these reasons, comparison of incidence of antibodies to ADCETRIS with the
incidence of antibodies to other products may be misleading.
DRUG INTERACTIONS
In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.
In vitro data indicate that MMAE is also a substrate of the efflux transporter P-glycoprotein (P-gp).
Effect of Other Drugs on ADCETRIS
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS
with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%.
Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely
monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4
inducer, reduced exposure to MMAE by approximately 46%.
P-gp Inhibitors: Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE.
Patients who are receiving P-gp inhibitors concomitantly with ADCETRIS should be closely monitored
for adverse reactions.
Effect of ADCETRIS on Other Drugs
Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does
not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the
exposure to drugs that are metabolized by CYP3A4 enzymes.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug's mechanism
of action. In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during
organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal
toxicities including congenital malformations. Consider the benefits and risks of ADCETRIS and possible
risks to the fetus when prescribing ADCETRIS to a pregnant woman.
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.
Data
Animal Data
In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10
mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and
13). Drug- induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of
the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased
numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs).
Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same
exposure in patients with classical HL or sALCL who received the recommended dose of 1.8 mg/kg
every three weeks.
Lactation
There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the
breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions
in a breastfed infant from ADCETRIS, including cytopenias and neurologic or gastrointestinal toxicities,
advise patients that breastfeeding is not recommended during ADCETRIS treatment.

Dcytb:

Emerging Superheroes
Emerging superheroes (new molecules) of local iron regulation will
be discussed in the scientific session "From Iron Trafficking to Traffic Jam" at 7:30 a.m. and 2:00 p.m in
the Grand Hall A of the Manchester
Grand Hyatt. Dr. Francesca Carlomagno will introduce the molecule
NCOA4, a nuclear coactivator that
promotes local degradation and
management of ferritin through
coupling of DNA replication regulation. Dr. Samira Lakhal-Littleton
will challenge the superhero role of
Hepcidin; Is there more to Hepcidin
than systemic control of ferroportin?
Dr. Lakhal-Littleton will review the
role of the hepcidin-FPN axis for local iron homeostasis, using cardiomyocytes as a case study. Lastly, Dr.
Mitchell Knutson will review potential candidates for non-transferrinbound iron transport, with a focus
on cardiac iron transporters. Dr.
Knutson will also introduce the potential role that DMT1 plays in normal cardiac iron metabolism.
Just another day in the world of
iron superheroes.

Dr. Skeith indicated no relevant conflicts of interest.

MPNs

«« From Page A-16

and press release relaying top-line
results of the pivotal phase III trials
SIMPLIFY-1 and SIMPLIFY-2. The
Late-Breaking Abstract presentation
on the randomized phase III trial
with pacritinib (PERSIST-2, LBA
#5) is widely anticipated. Dr. Mascarenhas explained that ruxolitinib
has revolutionized the way we treat
myelofibrosis as it dramatically improves cytokine-driven symptoms,
provides relief from splenomegaly,
with a likely survival benefit in patients with advanced myelofibrosis.
"But unmet needs remain," he said,
"such as those vulnerable myelofibrosis patients with low platelets
who are not able to receive ruxolitinib, and those with significant
RBC transfusion support." Dr. Mesa
goes on to add, "This agent has been
on a clinical hold, so I think there
will be great attention paid to efficacy, the safety profile, and whether
safety from the study could lead to
the agent moving forward in clinical
development."
So, you don't know JAK about
MPNs? No worries, attend today's
education session, or catch it on
Monday at 7:00 a.m. in the Marriot
Marquis San Diego Marina, Marriot
Grand 8-9.
Dr. Pemmaraju has received honorarium/done consulting for Stemline,
Novartis, and Incyte; and has received
research support from Novartis and
Stemline.

Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 1