ASH News Daily 2016 - Issue 3 - A-23

ASH News Daily

Monday, December 5, 2016

Page A-23
®

Hematopoiesis
«« From Page A-2

and contrasted it with the wild-type
form. Mutant alleles could not interact with other members of the SWI/
SNF complex, leading to loss of terminal myeloid differentiation and neutrophil granular defects. The group
performed comprehensive functional
genomics analyses, including RNA
sequencing and ATAC sequencing,
to confirm altered transcriptional
networks and altered chromatin
landscapes, respectively. Murine and
zebrafish models confirmed hematopoietic defects in these species as well,
pointing to SMARCD2 as an ancient

member in a critical and evolutionarily conserved transcriptional network
controlling neutrophil differentiation
and prevention of leukemogenesis.
Dr. Andrew Roberts echoed to us
the comments made by Dr. Zon in
the introduction and, in general, the
sentiment shared by many hematologists surrounding the symbolic
importance of this work. He said, "A
real strength of hematology at ASH is
its tradition of bringing together astute clinical observations and detailed
studies in the laboratory to explain
the observations, often using cuttingedge technology adopted from other
fields." Dr. Roberts acknowledged
that this is a paradigmatic example

Sickle Cell
LASERS PRINTED AT

ADCETRIS, Seattle Genetics are US registered trademarks of Seattle Genetics, Inc.
© 2016 Seattle Genetics, Inc., Bothell, WA 98021
All rights reserved. Printed in USA USP-BVP-2015-0127(2)

Dr. Blachly indicated no relevant conflicts of interest.

«« From Page A-8

in more than a decade to demonstrate
a significant reduction in sickle-cell
pain crisis. The study, a phase II multinational trial of Selexys Pharmaceutical drug SelG1 vs. hydroxyurea,
demonstrated a 45 percent reduction
in the annual rate of sickle cell pain
crisis in the high-dose arm among a
sample size of 198 patients with SCD.
"These are remarkably exciting times
in sickle cell disease," ASH Vice President Dr. Alexis Thompson asserted.
"We want to encourage more investigators and more companies to keep
the pipeline of new agents moving."
Erythrocyte adhesion has long
been a subject of study in sickle cell
disease, and at the center of that has
been P-selectin. Inflammatory states
such as SCD cause activation of endothelial cells, thereby initiating the
release of adhesion molecules including P-selectin. These proteins then
result in erythrocyte and leukocyte
adhesion, which potentiate vasoocclusion. As Dr. Ataga explained,
"SelG1 is a humanized monoclonal
antibody directed against P-selectin.
It works by blocking the interaction
of P-selectin to its receptor with consequent reduction in the adherence of
sickle red cells and leukocytes to the
endothelium. This study confirms the
role of P-selectin (and more broadly,
cellular adhesion) in the pathogenesis
of vaso-occlusion in SCD."
The excitement around this study
is not limited to its validation of scientific research into the pathophysiology of SCD, however. Its implications are much more far-reaching and
personal for patients and hematologists alike. "Sel-G1 potentially provides another therapy, in addition to
hydroxyurea, for patients with sickle
cell disease who experience frequent
pain episodes," Dr. Ataga remarked.
As this plenary elegantly revealed,
SCD has finally emerged from its
drug desert. And this is truly a cause
for celebration.

SGNAC18142 - Branded Journal Ads - ASH News Daily Sec A
Colors: 4c +
TRIM/LIVE - DO NOT PRINT
Bleed: NO BLEED Trim: 10"w x 14"h Live: 19"w x 13"h
Output @ 100X%
Giant Creative Strategy

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.

esis. Over and over we heard that
perhaps one of the most important
parts of this work is the proof that
collaborators from a large number of
institutions can come together synergistically to do great science. To go
from clinical observation to multiple
discoveries in the area of Mendelian diseases, chromatin landscapes,
transcriptional regulation, and normal hematopoiesis surely requires
diverse expertise. ASH is happy to
be able to report such successful collaborations, and as hematologists,
we should be proud of our field.

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.

of bed-to-bench translational research
- reporting a novel human disease
phenotype in several families, dissecting its genetic etiology, and shedding
light on pathogenic mechanisms. "It
is a quite complete, novel, and multidimensional story that unravels a biological role ... [for] SMARCD2 and
the role of chromatin remodeling for
hematopoiesis and differentiation of
neutrophil granulocytes," he said.
This abstract is exemplary for
many reasons. Certainly, we can all
appreciate its origin story as an observation in a single patient. Hard
work and a prepared mind helped
take it all the way to new fundamental knowledge in hematopoi-

Dr. Naik indicated no relevant conflicts of interest.
307987gi501_ASH_PI_Pg4

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

Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 3