ASH News Daily 2016 - Issue 1 - A-10


ASH News Daily

Page A-10

Saturday, December 3, 2016

®

IRON AND HEME

Ironman, Hemojevulin, and TMPRSS6:
How to Avoid a Civil War Among the Avengers of Iron
By Leslie Skeith, MD
"...with great power there must also
come - great responsibility!"

I

ron is an essential metal responsible for multiple cell functions
in the body, including transport
of oxygen by red blood cells. However, if there is an imbalance with too
much free iron, reactive oxygen species lead to cellular damage and organ dysfunction. In a new era of su-

adverse reaction was 38% in the GAZYVA treated
arm and 32% in the rituximab treated arm, with the
incidence of serious adverse events being 1% and
< 1%, respectively (Table 4). Cases of late-onset
neutropenia (occurring 28 days after completion of
treatment or later) were 16% in the GAZYVA treated
arm and 12% in the rituximab treated arm.
Non-Hodgkin Lymphoma
The incidence of neutropenia was higher in the
GAZYVA plus bendamustine arm (38%) compared
to the arm treated with bendamustine alone (32%).
Cases of prolonged neutropenia (3%) and late onset
neutropenia (7%) were also reported in the GAZYVA
plus bendamustine arm.
Infection:
Chronic Lymphocytic Leukemia
The incidence of infections was similar between
GAZYVA and rituximab treated arms. Thirty-eight
percent of patients in the GAZYVA treated arm and
37% in the rituximab treated arm experienced an
infection, with Grade 3-4 rates being 11% and 13%,
respectively. Fatal events were reported in 1% of
patients in both arms.
Non-Hodgkin Lymphoma
The incidence of infection was 66% in the
GAZYVA plus bendamustine arm and 56% in the
bendamustine arm, with Grade 3-4 events reported
in 16% and 14%, respectively. Fatal events were
reported in 3% of patients in the GAZYVA plus
bendamustine arm and 4% in the bendamustine arm.
Thrombocytopenia:
Chronic Lymphocytic Leukemia
The overall incidence of thrombocytopenia reported
as an adverse reaction was higher in the GAZYVA
treated arm (14%) compared to the rituximab treated
arm (7%), with the incidence of Grade 3-4 events
being 10% and 3%, respectively (Table 4). The
difference in incidences between the treatment arms
is driven by events occurring during the first cycle.
The incidence of thrombocytopenia (all grades) in the
first cycle were 11% in the GAZYVA and 3% in the
rituximab treated arms, with Grade 3-4 rates being
8% and 2%, respectively. Four percent of patients
in the GAZYVA treated arm experienced acute
thrombocytopenia (occurring within 24 hours after
the GAZYVA infusion).
The overall incidence of hemorrhagic events and
the number of fatal hemorrhagic events were similar
between the treatment arms, with 3 in the rituximab
and 4 in the GAZYVA treated arms. However, all fatal
hemorrhagic events in patients treated with GAZYVA
occurred in Cycle 1.
Non-Hodgkin Lymphoma
The incidence of thrombocytopenia was lower in the
GAZYVA plus bendamustine arm (15%) compared to
the arm treated with bendamustine alone (24%).
The incidence of hemorrhagic events in GAZYVA
plus bendamustine treated patients compared to
bendamustine alone was 11% and 10%, respectively.
Grade 3-4 hemorrhagic events were similar in
both treatment arms (5% in the GAZYVA plus
bendamustine arm and 3% in the bendamustine arm).
Tumor Lysis Syndrome: The incidence of Grade 3
or 4 tumor lysis syndrome in patients with CLL was
2% in the GAZYVA treated arm, and in patients with
iNHL was 0.5% in the GAZYVA plus bendamustine
treated arm.
Musculoskeletal Disorders:
Chronic Lymphocytic Leukemia
Adverse events related to musculoskeletal disorders
(all events from the System Organ Class), including
pain, have been reported in the GAZYVA treated arm
with higher incidence than in the rituximab treated
arm (18% vs. 15%).
Non-Hodgkin Lymphoma
Adverse events related to musculoskeletal disorders
(all events from the System Organ Class), including
pain, have been reported in the GAZYVA plus
bendamustine treated arm with higher incidence than
in the bendamustine alone arm (41% vs. 29%).
Liver Enzyme Elevations: Hepatic enzyme elevations
have occurred in CLL patients who received
GAZYVA in clinical trials and had normal baseline
hepatic enzyme levels (AST, ALT, and ALP). The
events occurred most frequently within 24-48 hours
of the first infusion. In some patients, elevations
in liver enzymes were observed concurrently with
infusion reactions or tumor lysis syndrome. In the
pivotal CLL study, there was no clinically meaningful
difference in overall hepatotoxicity adverse events
between all arms (4% of patients in the GAZYVA
treated arm). Medications commonly used to
prevent infusion reactions (e.g., acetaminophen)
may also be implicated in these events. Monitor liver
function tests during treatment, especially during
the first cycle. Consider treatment interruption or
discontinuation for hepatotoxicity.

perheroes such as hemojevulin (HJV)
and TMPRSS6, hematologists need a
rulebook of engagement to avoid civil war among the iron superheroes.
Before attending the scientific session or oral sessions on regulation of
iron metabolism, understand who's
who in the superhero world of iron.
Here is a breakdown of this complex
and ever-changing landscape.
Hepcidin
*	 A

circulating

25-amino

Gastro-Intestinal Perforation: Cases of gastrointestinal perforation have been reported in patients
receiving GAZYVA, mainly in NHL.
6.2 Immunogenicity
Serum samples from patients with previously
untreated CLL were tested during and after treatment
for antibodies to GAZYVA. Of the GAZYVA treated
patients with CLL, 7% (18/271) tested positive for
anti-GAZYVA antibodies at one or more time points.
In the pivotal iNHL trial, two out of 194 (1%) patients
in the GAZYVA plus bendamustine arm tested
positive for anti-GAZYVA antibodies at baseline and
experienced infusion reactions. No patients with
iNHL developed anti-GAZYVA antibodies during or
following GAZYVA treatment. Neutralizing activity of
anti-GAZYVA antibodies has not been assessed.
Immunogenicity data are highly dependent on
the sensitivity and specificity of the test methods
used. Additionally, the observed incidence of a
positive result in a test method may be influenced
by several factors, including sample handling, timing
of sample collection, drug interference, concomitant
medication, and the underlying disease. Therefore,
comparison of the incidence of antibodies to
GAZYVA with the incidence of antibodies to other
products may be misleading. Clinical significance of
anti-GAZYVA antibodies is not known.
6.3 Additional Clinical Trial Experience
Worsening of Pre-existing Cardiac Conditions: Fatal
cardiac events have been reported in patients treated
with GAZYVA.
7 DRUG INTERACTIONS
No formal drug interaction studies have been
conducted with GAZYVA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
GAZYVA is likely to cause fetal B-cell depletion
based on findings from animal studies and the drug's
mechanism of action [see Clinical Pharmacology
(12.1)]. There are no data with GAZYVA use in
pregnant women to inform a drug-associated risk.
Monoclonal antibodies are transferred across the
placenta. In animal reproduction studies, weekly
intravenous administration of obinutuzumab to
pregnant cynomolgus monkeys from day 20 of
pregnancy until parturition which includes the period
of organogenesis at doses with exposures up to
2.4 times the exposure at the clinical dose of 1000
mg monthly produced opportunistic infections and
immune complex mediated hypersensitivity reactions.
No embryo-toxic or teratogenic effects were
observed in the monkeys [see Data]. Consider the
potential risk to the fetus when prescribing GAZYVA
to a pregnant woman.
The background risk of major birth defects and
miscarriage for the indicated population is unknown;
however, the estimated background risk in the U.S.
general population of major birth defects is 2% to
4% and of miscarriage is 15% to 20% of clinically
recognized pregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
GAZYVA is likely to cause fetal B-cell depletion
[see Data]. Avoid administering live vaccines to
neonates and infants exposed to GAZYVA in utero
until B-cell recovery occurs [see Warnings and
Precautions (5.8)] and Clinical Pharmacology (12.2)].
Data
Animal Data
In a pre- and post-natal development study, pregnant
cynomolgus monkeys received weekly intravenous
doses of 25 or 50 mg/kg obinutuzumab from day
20 of pregnancy until parturition, which includes the
period of organogenesis. The high dose results in
an exposure (AUC) that is 2.4 times the exposure in
patients with CLL at the recommended label dose.
There were no embryo-toxic or teratogenic effects in
animals. Secondary opportunistic infections, immune
complex mediated hypersensitivity reactions, or a
combination of both were observed in exposed
dams. When first measured on day 28 postpartum,
obinutuzumab was detected in offspring at levels in
the range of maternal serum levels on the same day,
and B-cells were completely depleted. The B-cell
counts returned to normal levels, and immunologic
function was restored within 6 months after birth.
Obinutuzumab was measured in the milk of lactating
cynomolgus monkeys on day 28 postpartum
after weekly intravenous administration from day
20 of pregnancy until parturition. Concentrations
in milk were approximately 0.04% and 0.13% of
concentrations in maternal serum in the 25 and
50 mg/kg groups, respectively.

acid hormone that originates in
the liver
*	 A leader in iron superheroes
who can make system-level changes
but is highly dependent on the environment for its superpower
Superpower: A negative regulator of iron; hepcidin downregulates
iron absorption in intestinal cells and
macrophages by degrading the iron
exporter ferroportin (FPN)
Activates superpower: Inflammatory cytokines, increased iron stores

8.2 Lactation
Risk Summary
There is no information regarding the presence
of GAZYVA in human milk, the effects on the
breastfed infant, or the effects on milk production.
However, low levels of obinutuzumab were present
in the milk of lactating cynomolgus monkeys [see
Use in Specific Populations (8.1)]. Human IgG is
known to be present in human milk. Published data
suggest that antibodies in breast milk do not enter
the neonatal and infant circulations in substantial
amounts. The developmental and health benefits of
breastfeeding should be considered along with the
mother's clinical need for GAZYVA and any potential
adverse effects on the breastfed infant from GAZYVA
or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of GAZYVA in
pediatric patients have not been established.
8.5 Geriatric Use
Chronic Lymphocytic Leukemia
Of 336 patients with previously untreated CLL who
received GAZYVA in combination with chlorambucil,
81% were 65 years and older, while 46% were
75 and older. Of the patients 75 years and older,
46% experienced serious adverse events and 7%
experienced adverse events leading to death. Of
the patients younger than 75, 33% experienced a
serious adverse event and 2% an adverse event
leading to death. No significant differences in efficacy
were observed between younger and older patients
[see Clinical Studies (14.1)].
Non-Hodgkin Lymphoma
Of 194 patients with iNHL treated with GAZYVA
plus bendamustine, 44% were 65 and over, while
14% were 75 and over. In patients 65 and over, 52%
of patients experienced serious adverse events
and 26% experienced adverse events leading to
treatment withdrawal while in patients under 65,
28% and 12% experienced serious adverse events
and adverse events leading to treatment withdrawal,
respectively. No clinically meaningful differences in
efficacy were observed between these patients and
younger patients.
10 OVERDOSAGE
There has been no experience with overdose in
human clinical trials. Doses ranging from 50 mg up
to and including 2000 mg per infusion have been
administered in clinical trials. For patients who
experience overdose, treatment should consist of
immediate interruption or reduction of GAZYVA and
supportive therapy.
17 PATIENT COUNSELING INFORMATION
Advise patients to seek immediate medical attention
for any of the following:
* Signs and symptoms of infusion reactions
including dizziness, nausea, chills, fever,
vomiting, diarrhea, breathing problems, or
chest pain [see Warnings and Precautions
(5.3) and Adverse Reactions (6.1)].
* Symptoms of tumor lysis syndrome such as
nausea, vomiting, diarrhea, and lethargy [see
Warnings and Precautions (5.4) and Adverse
Reactions (6.1)].
* Signs of infections including fever and cough
[see Warnings and Precautions (5.5) and Adverse
Reactions (6.1)].
* Symptoms of hepatitis including worsening
fatigue or yellow discoloration of skin or eyes
[see Warnings and Precautions (5.1)].
* New or changes in neurological symptoms
such as confusion, dizziness or loss of balance,
difficulty talking or walking, or vision problems
[see Warnings and Precautions (5.2)].
Advise patients of the need for:
* Periodic monitoring of blood counts [see
Warnings and Precautions (5.6 and 5.7) and
Adverse Reactions (6.1)].
* Avoid vaccinations with live viral vaccines [see
Warnings and Precautions (5.8)].
* Patients with a history of hepatitis B infection
(based on the blood test) should be monitored
and sometimes treated for their hepatitis [see
Warnings and Precautions (5.1)].
Advise pregnant women of potential fetal B-cell
depletion [see Use in Specific Populations (8.1)].

GAZYVA® (obinutuzumab)

Initial US Approval: 2013

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
South San Francisco, CA
94080-4990

Code Revision Date:
February 2016

U.S. License No. 1048

GAZYVA is a registered
trademark of Genentech, Inc.
GAZ/010816/0009
02/16
© 2016 Genentech, Inc.

Weaknesses: Hypoxia, ineffective
erythropoiesis, anemia, testosterone
Bone Morphogenic Protein 6
(BMP6) and HJV
*	
BMP6 and HJV act in concert together as the henchmen of
hepcidin
*	 Their resources are supplied
by the sons of mothers of decapentaplegic (SMAD) organization
Superpower: Makes hepcidin
stronger; BMP6 binds to its receptor BMPR and co-receptor hemojuvelin to activate the SMAD signaling
cascade, leading to upregulation of
hepcidin and consequently, less iron
absorption
Activates superpower: Iron-replete state; HFE and TFR2 signaling
Weaknesses: TMPRSS6
Helpful members of BMP-SMAD:
SMAD4 is integral to the BMPSMAD organization in order to enhance hepcidin's superpower. The
JAK2/STAT3 pathway works with
the BMP-SMAD pathway in an unknown and mysterious way
Estranged members of BMPSMAD: Twisted gastrulation 1
(TWSG1) and Growth differentiation
15 (GDF15) are BMP family members that fight to suppress hepcidin
in conditions like thalassemia
TMPRSS6
*	 Matriptase-2, a membraneassociated serine protease-2, is encoded by TMPRSS6
Superpower: Cleaves the BMP coreceptor HJV; by switching off BMPSMAD signaling, this downregulates
hepcidin and allows for increased
iron absorption
Activates superpower: Iron deficiency, hypoxia
Weaknesses: Hepatocyte growth factor activator inhibitor type-2 (HAI-2)
HFE
*	
The oldest and most notorious iron superhero with known activity since the mid-19th century
*	 HFE encodes HLA Class
1-like membrane-associated proteins
and works in concert with transferrin receptor-1 (TFR1)
Superpower: Regulates iron absorption in intestinal cells and macrophages by a largely unknown
mechanism
Activates superpower: Unknown
Weaknesses: Unknown
JAK2/STAT3
*	 More famous for other starring roles in hematology, JAK2/
»» IRON Page A-23



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

Contents
ASH News Daily 2016 - Issue 1 - A-1
ASH News Daily 2016 - Issue 1 - A-2
ASH News Daily 2016 - Issue 1 - A-3
ASH News Daily 2016 - Issue 1 - A-4
ASH News Daily 2016 - Issue 1 - A-5
ASH News Daily 2016 - Issue 1 - A-6
ASH News Daily 2016 - Issue 1 - A-7
ASH News Daily 2016 - Issue 1 - A-8
ASH News Daily 2016 - Issue 1 - A-9
ASH News Daily 2016 - Issue 1 - A-10
ASH News Daily 2016 - Issue 1 - A-11
ASH News Daily 2016 - Issue 1 - A-12
ASH News Daily 2016 - Issue 1 - A-13
ASH News Daily 2016 - Issue 1 - A-14
ASH News Daily 2016 - Issue 1 - A-15
ASH News Daily 2016 - Issue 1 - A-16
ASH News Daily 2016 - Issue 1 - A-17
ASH News Daily 2016 - Issue 1 - A-18
ASH News Daily 2016 - Issue 1 - A-19
ASH News Daily 2016 - Issue 1 - A-20
ASH News Daily 2016 - Issue 1 - A-21
ASH News Daily 2016 - Issue 1 - A-22
ASH News Daily 2016 - Issue 1 - A-23
ASH News Daily 2016 - Issue 1 - A-24
ASH News Daily 2016 - Issue 1 - A-25
ASH News Daily 2016 - Issue 1 - A-26
ASH News Daily 2016 - Issue 1 - Contents
ASH News Daily 2016 - Issue 1 - B-2
ASH News Daily 2016 - Issue 1 - B-3
ASH News Daily 2016 - Issue 1 - B-4
ASH News Daily 2016 - Issue 1 - B-5
ASH News Daily 2016 - Issue 1 - B-6
ASH News Daily 2016 - Issue 1 - B-7
ASH News Daily 2016 - Issue 1 - B-8
ASH News Daily 2016 - Issue 1 - B-9
ASH News Daily 2016 - Issue 1 - B-10
ASH News Daily 2016 - Issue 1 - B-11
ASH News Daily 2016 - Issue 1 - B-12
ASH News Daily 2016 - Issue 1 - B-13
ASH News Daily 2016 - Issue 1 - B-14
ASH News Daily 2016 - Issue 1 - B-15
ASH News Daily 2016 - Issue 1 - B-16
ASH News Daily 2016 - Issue 1 - B-17
ASH News Daily 2016 - Issue 1 - B-18
ASH News Daily 2016 - Issue 1 - B-19
ASH News Daily 2016 - Issue 1 - B-20
ASH News Daily 2016 - Issue 1 - B-21
ASH News Daily 2016 - Issue 1 - B-22
ASH News Daily 2016 - Issue 1 - B-23
ASH News Daily 2016 - Issue 1 - B-24
ASH News Daily 2016 - Issue 1 - B-25
ASH News Daily 2016 - Issue 1 - B-26
ASH News Daily 2016 - Issue 1 - B-27
ASH News Daily 2016 - Issue 1 - B-28
ASH News Daily 2016 - Issue 1 - B-29
ASH News Daily 2016 - Issue 1 - B-30
ASH News Daily 2016 - Issue 1 - B-31
ASH News Daily 2016 - Issue 1 - B-32
ASH News Daily 2016 - Issue 1 - B-33
ASH News Daily 2016 - Issue 1 - B-34
ASH News Daily 2016 - Issue 1 - B-35
ASH News Daily 2016 - Issue 1 - B-36
ASH News Daily 2016 - Issue 1 - B-37
ASH News Daily 2016 - Issue 1 - B-38
ASH News Daily 2016 - Issue 1 - B-39
ASH News Daily 2016 - Issue 1 - B-40
ASH News Daily 2016 - Issue 1 - B-41
ASH News Daily 2016 - Issue 1 - B-42
ASH News Daily 2016 - Issue 1 - B-43
ASH News Daily 2016 - Issue 1 - B-44
ASH News Daily 2016 - Issue 1 - B-45
ASH News Daily 2016 - Issue 1 - B-46
ASH News Daily 2016 - Issue 1 - B-47
ASH News Daily 2016 - Issue 1 - B-48
ASH News Daily 2016 - Issue 1 - C-1
ASH News Daily 2016 - Issue 1 - C-2
ASH News Daily 2016 - Issue 1 - C-3
ASH News Daily 2016 - Issue 1 - C-4
ASH News Daily 2016 - Issue 1 - C-5
ASH News Daily 2016 - Issue 1 - C-6
ASH News Daily 2016 - Issue 1 - C-7
ASH News Daily 2016 - Issue 1 - C-8
ASH News Daily 2016 - Issue 1 - C-9
ASH News Daily 2016 - Issue 1 - C-10
ASH News Daily 2016 - Issue 1 - C-11
ASH News Daily 2016 - Issue 1 - C-12
ASH News Daily 2016 - Issue 1 - C-13
ASH News Daily 2016 - Issue 1 - C-14
ASH News Daily 2016 - Issue 1 - C-15
ASH News Daily 2016 - Issue 1 - C-16
ASH News Daily 2016 - Issue 1 - C-17
ASH News Daily 2016 - Issue 1 - C-18
ASH News Daily 2016 - Issue 1 - C-19
ASH News Daily 2016 - Issue 1 - C-20
ASH News Daily 2016 - Issue 1 - C-21
ASH News Daily 2016 - Issue 1 - C-22
ASH News Daily 2016 - Issue 1 - C-23
ASH News Daily 2016 - Issue 1 - C-24
ASH News Daily 2016 - Issue 1 - C-25
ASH News Daily 2016 - Issue 1 - C-26
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