ASH Clinical News ACN_5.6_Full_Issue_Digital | Page 9

You Make the Call: Readers’ Response
We asked, and you answered! Here are a few responses
from this month’s “You Make the Call.”
To see how the expert responded, turn to page 39.
Clinical Dilemma:
I have a patient with a strong family history of chronic lym-
phocytic leukemia (CLL) who was recently diagnosed with
CLL. Her mother and brother have CLL as well. What is the
status of familial CLL? Has a gene been identified yet?
The incidence of Grade 3 to 4 infections in the
GAZYVA and rituximab product treated arms was
lower in patients receiving GCSF prophylaxis (14%;
16%) compared with patients not receiving GCSF
prophylaxis (24%; 18%). The incidence of fatal
infections in patients receiving GCSF prophylaxis
in the GAZYVA and rituximab product treated arms
was 2% and 0%, respectively, and was 2% and
< 1% in patients not receiving GCSF prophylaxis.
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
product treated arm (7%), with the incidence
of Grade 3 to 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
was 11% in the GAZYVA and 3% in the rituximab
product treated arms, with Grade 3 to 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
product 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 in GADOLIN
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 to 4
hemorrhagic events were similar in both treatment
arms (5% in the GAZYVA plus bendamustine arm
and 3% in the bendamustine arm).
In GALLIUM, thrombocytopenia was reported as
an adverse reaction in 14% of the GAZYVA treated
arm and 8% of the rituximab product treated arm,
with the incidence of Grade 3 to 4 events being 7%
and 3% respectively. 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
9% in the GAZYVA and 3% in the rituximab product
treated arms, with Grade 3 to 4 rates being 5% and
1%, respectively. In GALLIUM, both treatment arms
had a 12% overall incidence of hemorrhagic events
and a < 1% incidence of fatal hemorrhagic events.
Tumor Lysis Syndrome: The incidence of Grade
3 or 4 tumor lysis syndrome in GAZYVA treated
patients was 2% in CLL11, 0.5% in GADOLIN and
0.9% in GALLIUM.
Musculoskeletal Disorders:
Chronic Lymphocytic Leukemia
Adverse reactions related to musculoskeletal
disorders (all events from the body system),
including pain, have been reported in the GAZYVA
treated arm with higher incidence than in the
rituximab product treated arm (18% vs. 15%).
Non-Hodgkin Lymphoma
In GADOLIN, adverse reactions related to
musculoskeletal disorders (all events from the body
system), including pain, have been reported in
the GAZYVA plus bendamustine treated arm with
higher incidence than in the bendamustine alone
arm (41% vs. 29%).
In GALLIUM, musculoskeletal disorders were
reported in 54% of patients in the GAZYVA treated
arm and 49% of patients in the rituximab product
treated arm.
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 CLL11 study,
there was no clinically meaningful difference in
overall hepatotoxicity adverse reactions 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.
Gastrointestinal Perforation: Cases of
gastrointestinal perforation have been reported in
patients receiving GAZYVA, mainly in NHL.
Worsening of Pre-existing Cardiac Conditions:
Fatal cardiac events have been reported in patients
treated with GAZYVA.
Familial CLL is a well-defined clinical entity. To a certain
degree, all of the common leukemias have some degree
of familial inheritance.
However, based on data in the Utah Cancer Registry,
the incidence approaches 6 to 8 percent. Of equal
importance is that monoclonal B-cell lymphocytosis
(MBL) can occur in unaffected first-degree relatives up to
13 to 17 percent of the time. See studies by the National
Cancer Institute, Mayo Clinic, and from Leeds, England.
It is my impression that the diagnosis of CLL in the
second generation occurs at an earlier age than in the
first generation. Some investigators say that this is
6.2 Immunogenicity
As with all therapeutic proteins, there is potential
for immunogenicity. 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 GAZYVA in the studies described
below with the incidence of antibodies in other
studies or to other products may be misleading.
Seven percent (18/271) of patients with CLL tested
positive for anti-GAZYVA antibodies at one or
more time points in CLL11. No patients developed
anti-GAZYVA antibodies during or following
GAZYVA treatment in GADOLIN, while 1 patient
(1/564, 0.2%) developed anti-GAZYVA antibodies
in GALLIUM. Neutralizing activity of anti-GAZYVA
antibodies has not been assessed.
6.3 Postmarketing Safety Information
The following adverse reactions have been
identified during post-approval use of GAZYVA.
• Immune/Autoimmune Events: Serum sickness
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.
8.2 Lactation
Risk Summary
There is no information regarding the presence
of GAZYVA in human milk, the effects on the
breastfed child, 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 child circulations in substantial
amounts. The developmental and health benefits of
just due to early detection. However, I almost always
elicit a history of familial CLL from patients with CLL
in their 50s. Be aware that relatives with familial CLL
also can have other lymphoproliferative disorders such
as non-Hodgkin lymphoma or hairy cell leukemia. It is
not uncommon to find a child with acute lymphocytic
leukemia whose grandfather has CLL. There is an im-
portant Italian study of these patterns, and it has been
confirmed in other clinics.
What else do we know about familial CLL? Second
primary tumors definitely occur. The FISH cytogenetic le-
sions of hemizygous and homozygous del13q14 are found
more commonly in familial CLL. The
hemizygous del13q14 is found in MBL
and many of the oncogene mutations
breastfeeding should be considered along with the
mother’s clinical need for GAZYVA and any potential
found in CLL have been detected in
adverse effects on the breastfed child from GAZYVA
MBL.
or from the underlying maternal condition.
8.4 Pediatric Use
Through the combined works
The safety and effectiveness of GAZYVA in
of
many
groups, the number of
pediatric patients have not been established.
8.5 Geriatric Use
identified single nucleotide polymor-
Chronic Lymphocytic Leukemia
phisms associated with CLL contin-
Of 336 patients with previously untreated CLL who
received GAZYVA in combination with chlorambucil,
ues to increase. At last count, some
81% were 65 years and older, while 46% were 75
43 markers from genomewide asso-
and older. Of the patients 75 years and older, 46%
experienced serious adverse reactions and 7%
ciation studies have been reported,
experienced adverse reactions leading to death.
Of the patients younger than 75, 33% experienced
many of which have been confirmed.
a serious adverse reaction and 2% an adverse
reaction leading to death. No significant differences
MBL is still the easiest biomarker
in efficacy were observed between younger and
for early preclinical detection at
older patients [see Clinical Studies (14.1)].
Non-Hodgkin Lymphoma
approximately six years prior to the
Of 194 patients in GADOLIN with relapsed or
refractory NHL treated with GAZYVA plus
diagnosis of CLL. The prevalence of
bendamustine, 44% were 65 and over, while 14%
an abnormal free light chain ratio,
were 75 and over. In patients 65 and over, 52% of
patients experienced serious adverse reactions
M-protein, or hypogammaglobu-
and 26% experienced adverse reactions leading
to treatment withdrawal while in patients under
linemia can be detected as early as
65, 28% and 12% experienced serious adverse
reactions and adverse reactions leading to treatment
nine years prior to the diagnosis of
withdrawal, respectively. No clinically meaningful
CLL. MBL and serum abnormalities
differences in efficacy were observed between these
patients and younger patients in GADOLIN.
can be found in unaffected first-
Of the 691 patients in GALLIUM treated with
GAZYVA plus chemotherapy as first-line therapy,
degree relatives with familial CLL.
33% were 65 and over, while 7% were 75 and
over. Of patients 65 and over, 63% experienced
serious adverse reactions and 26% experienced
adverse reactions leading to treatment withdrawal,
while in patients under 65, 43% experienced
serious adverse reactions and 13% had an adverse
reaction leading to treatment withdrawal. No
clinically meaningful differences in efficacy were
observed between these patients and younger
patients in GALLIUM.
10 OVERDOSAGE
There has been no experience with overdose in
human 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 (5.5) and Adverse
Reactions (6.1)].
• Signs of infections including fever and cough
[see Warnings and Precautions (5.6) 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 (5.7 and 5.8) and
Adverse Reactions (6.1)].
• Avoid vaccinations with live viral vaccines [see
Warnings and Precautions (5.9)].
• 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)
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
South San Francisco, CA 94080-4990
U.S. License No. 1048
Initial US Approval: 2013
Code Revision Date: November 2017
GAZYVA is a registered trademark of Genentech, Inc.
GAZ/010816/0009(2) 11/17 © 2017 Genentech, Inc.
Gerald Marti, MD, PhD
Center for Devices and Radiological
Health, U.S. Food and Drug
Administration
Silver Spring, MD
Even though CLL is likely the most
inheritable leukemia, I believe the
work is still ongoing to find a gene to
explain it.
Monica Verma, MD
Hamilton Health Care System
Dalton, GA
There have been reports of inherited
CLL in the context of a POT1 germline
mutation. Historically, POT1 germline
mutations have been associated with
an increased risk of glioblastomas,
melanoma, and cardiac angiosarco-
mas. Families with POT1 germline
mutations and CLL tend to have CLL
only without a solid tumor family
history.
Brittany DeGreef, MS, CGC
Northwestern Medical Group
Chicago, IL
ASH Clinical News
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