You Make the Call: Readers’ Response
d through
the Consult
in
in the
, but we also
red blood
Each month
up to the expert’s
refuses packed
expert’s response
answer matches
a patient who
and post the
anemia in
see how your
s how to treat
dilemma and
MD, discusse
Neil Zakai,
This month,
was admitted
ty hospital
to a communi there any
us iron. Are
ma:
intraveno
Her son suggested
stage IV uterine her epoetin alfa and
proved?
transfusions?
Clinical Dilem
Witness with
am giving
ation (FDA)–ap
is a Jehovah’s
red blood cell
low, and I
cancer who
who
in is
packed
Administr
who refuse
I have a patient abscess. Her hemoglob
Food and Drug
for patients
). Is it U.S.
of anemia
with a uterine
cell substitute
for treatment
in-based red
other options
(a human hemoglob
PolyHeme
inion
Expert Op
nt of Medicine
Departme
gy Division,
MD
Hematology/Oncolo
Neil A. Zakai,
of Medicine,
y Medicine
Associate Professor of Pathology & Laborator
of Vermont
Associate Professor Medicine, University
of
Larner College
Vermont
Burlington,
s to
religious objection
patients with in need of a transfu-
Managing
blood products . Non-blood
blood and
challenge
sion is a clinical agents are currently
oxygen–carrying but can be ob-
roved
not FDA-app extended-access
an
tained using
called
sometimes
program,
use.”
“compassionate
to
designed
These are
agents until
be bridging
be
blood can
allogeneic
as for trauma
given (such
in war zones);
patients or
as a complete
using them
ent agent
blood replacem
well-
has not been of case
studied outside
request for
reports. The
t
is somewha
PolyHeme
as this product
surprising
in
hemoglob
is made from
allogeneic
from expired
so
cell units and may
red blood
ee,” but it
is not “blood-fr some Jehovah’s
e for
be acceptabl
sound: en-
Witnesses.
strategy is
Overall, your is iron replete and giving
patient
iesis-stimulating B12 and
suring the
her
iron and erythropo
l
making sure
parentera
as well as
also suggest
if needed
agents. I would normal and replete
process as
are
from her disease
folate levels
bleeding (both draws).
ng
minimizi
situa-
blood
iatrogenic
in an acute
alternative
well as from
transfu-
try a blood
these for routine
You could
not rely on
would
I
tion, but
sion needs.
REFERENCE
Apte SS. Blood
substitutes -
the polyheme
trials. Mcgill
J Med. 2008;11:59-65.
Colleague
Consult a
ASH
for ASH
Through
• Anemias
oietic cell
• Hematop
transplantation
inopathies
• Hemoglob
osis
is/thromb
• Hemostas
• Thromboc
es”) will
s (“colleagu
Assigned volunteer within two business
inquiries
respond to
phone).
by email or
days (either
clinical dilemma?
Have a puzzling
and read more s at
volunteer
Submit a question,
a Colleague
x
about Consult
nicians/Consult.asp
hematology.org/Cli
QR code.
or scan the
pa-
What induction ia chromosome–negat
cardiomyo
with Philadelph tic leukemia and ischemic of 35 percent?
acute lymphocy
r ejection fraction at
left ventricula
Email us
thy with a
you respond?
●
How would
matology.org
lnews@he
ashclinica
to a
a request related here,
listed
*If you have
c disorder not
ation to
hematologi
your recommend it can be
.org so
please email
hematology
ashconsult@ addition in the future.
for
considered
: ASH does
d
not recommen ,
tests, physicians
any specific
and
or endorse
, or opinions,
or
products, procedures
tion, warranty,
representa
any
disclaims any
Reliance on
to the same.
is solely
guaranty as
in this article
n provided
informatio
risk.
at your own
DISCLAIMER
November
48
ASH Clinical
For the full description of the clinical
dilemma, and to see how the expert
responded, turn to page 48.
ytopenias
I have taken care of many Jehovah’s Witness
patients. They can tolerate a very low
hemoglobin concentration. I would treat the
patient like any other patient at this stage.
I would continue the IV iron and the epoetin
alfa.
I have a patient who is a Jehovah’s Witness
with stage IV uterine cancer who was admit-
ted to a community hospital with a uterine
abscess. Her hemoglobin is low, and I am
giving her epoetin alfa and intravenous iron.
Are there any other options for treatment of
anemia for patients who refuse packed red
blood cell transfusions?
is a service
Consult a Colleague facilitate the exchange
helps
members that between hematologists
on
can seek
of informati
ASH members
and their peers. clinical cases from qualified
on
consultation
:
11 categories
experts in
as
• Lymphom
disorders
roliferative
• Lymphop
s
• Leukemia
Waldenström
myeloma &
• Multiple
ulinemia
macroglob
s
liferative neoplasm
• Myelopro
s
plastic syndrome
• Myelodys
a:
’s Clinical Dilemm for a patient
B-cell
Next Month regimen would you choose
ive precursor
Clinical Dilemma:
We asked, and you answered! Here are a few
responses from this month’s “You Make the
Call.”
e program
a Colleagu
month’s clinical
to next
question submitte in your response
e the Call we pick a challenging clinical
do. Send
You Mak
what you would print issue.
the Call,”
want to know
next
“You Make
cells.
Steven Sandler, MD
Advocate Illinois Masonic Medical Center
Skokie, IL
2018
News
product, 76% and 73%, respectively, completed
the full course. Dose modification due to adverse
reactions occurred in 74% of the GAZYVA arm
and 63% of the rituximab product arm throughout
study treatment, and discontinuation of any study
drug due to adverse reactions occurred in 18% and
15%, respectively.
Throughout treatment and follow-up, the most
common adverse reactions (incidence ≥ 20%)
observed at least 2% more in the GAZYVA arm
included infusion related reactions, neutropenia,
upper respiratory tract infection, cough,
constipation and diarrhea (Table 8). Neutropenia,
infusion related reactions, febrile neutropenia and
thrombocytopenia were the most common Grade 3
to 5 adverse reactions (incidence ≥ 5%) observed
more frequently in the GAZYVA arm.
ophthalmic herpes simplex, ophthalmic herpes zoster,
oral herpes, varicella, varicella zoster virus infection.
Pneumonia includes pneumonia bacterial,
pneumonia haemophilus, pneumonia
pneumococcal, pneumonia fungal, pneumocystis
jirovecii infection, pneumocystis jirovecii
pneumonia, atypical pneumonia, lung infection,
pneumonia, pneumonia aspiration, lung infiltration.
Cough includes cough, productive cough, upper-
airway cough syndrome.
Diarrhea includes diarrhea, defecation urgency,
frequent bowel movement, gastroenteritis,
gastroenteritis viral.
Headache includes cluster headache, headache,
sinus headache, tension headache, migraine.
Insomnia includes initial insomnia, insomnia, sleep
disorder.
Pruritus includes pruritus and pruritus generalized.
During the monotherapy period, the common
adverse reactions (incidence ≥ 10%) observed at
least 2% more with GAZYVA were upper respiratory
tract infection (40%), cough (23%), musculoskeletal
pain (20%), neutropenia (19%) and herpesvirus
infection (13%).
Table 9 summarizes treatment-emergent laboratory
abnormalities during treatment and follow-up.
The Grade 3 to 4 abnormalities reported at least
2% more in the GAZYVA arm were lymphopenia,
leukopenia, neutropenia, thrombocytopenia and
hyperuricemia. Patients in the GAZYVA arm, as
compared to the rituximab product arm, had higher
incidences of Grade 4 neutropenia (38% vs. 30%,
respectively), Grade 4 lymphopenia (33% vs. 22%),
and Grade 4 leukopenia (17% vs. 12%).
Table 8 Common Adverse Reactions (≥ 10%
Incidence and ≥ 2% Greater in the GAZYVA
Arm) in Patients with Previously Untreated NHL
(GALLIUM)
Body System
Adverse
Reactions a, b
GAZYVA +
chemotherapy
followed
by GAZYVA
monotherapy
n = 691 Rituximab
product +
chemotherapy
followed by
rituximab product
monotherapy
n = 694
All Grades Grades
%
3 to 5 % All Grades Grades
%
3 to 5 %
Injury, Poisoning and Procedural Complications
Infusion Related
72
12
60
8
Reaction c
Blood and Lymphatic System Disorders
53
49
47
41
Neutropenia d
Thrombocytopenia d 14
7
8
3
Table 9 Common New or Worsening Laboratory
Abnormalities (≥ 10% Incidence and ≥ 2%
Greater in the GAZYVA Arm) in Patients with
Previously Untreated NHL (GALLIUM)
Infections and Infestations
Upper Respiratory
Tract Infection
Herpesvirus
Infection 50 18 3 14 1
Pneumonia 14 7 12 6
3
43
1
Laboratory
Abnormalities a
Respiratory, Thoracic and Mediastinal Disorders
Cough
35
< 1
28
< 1
Gastrointestinal Disorders
Constipation
32
< 1
29
< 1
Diarrhea
30
3
26
16
0
14
< 1
13 0 10 < 1
Pruritus 11 < 1 9 0
Includes adverse reactions reported throughout study treatment and
follow-up.
Includes grouped preferred terms.
c
Except where noted, individual events that meet the definition of
“infusion related reaction” are excluded from Table 8 above, as they are
already included in the group term “Infusion Related Reaction”. The
most common individual terms within the group term “Infusion Related
Reaction” in decreasing order of frequency are nausea, chills, pyrexia
and vomiting.
d
Includes adverse reactions reported as infusion related reactions.
a
b
Infusion related reactions are defined as any
related adverse reaction that occurred during or
within 24 hours of infusion.
Neutropenia includes neutropenia,
agranulocytosis, febrile neutropenia,
granulocytopenia and neutrophil count decreased;
febrile neutropenia includes febrile neutropenia,
neutropenic infection, neutropenic sepsis, and
febrile bone marrow aplasia.
Thrombocytopenia includes thrombocytopenia
and platelet count decreased.
Upper respiratory tract infection includes upper
respiratory tract congestion, upper respiratory
tract inflammation, sinusitis bacterial, upper
respiratory tract infection bacterial, pharyngitis
streptococcal, sinusitis fungal, upper respiratory
fungal infection, acute sinusitis, chronic sinusitis,
laryngitis, nasopharyngitis, pharyngitis, rhinitis,
sinusitis, tonsillitis, upper respiratory tract infection,
rhinovirus infection, viral pharyngitis, viral rhinitis,
viral upper respiratory tract infection.
Herpesvirus infection includes genital herpes,
genital herpes zoster, herpes dermatitis, herpes
ophthalmic, herpes simplex, herpes simplex
pharyngitis, herpes virus infection, herpes zoster,
herpes zoster disseminated, herpes zoster infection
neurological, herpes zoster oticus, nasal herpes,
All Grades Grades
%
3 to 4 % All Grades Grades
%
3 to 4 %
ALT/SGPT
increased
AST/SGOT
increased
Hypophosphatemia
Hypoalbuminemia
Hypoproteinemia
Hypocalcemia
Hyperuricemia
Hyponatremia
Hyperkalemia
Hypernatremia
Psychiatric Disorders
Insomnia
15
< 1
12
< 1
Metabolism and Nutrition Disorders
Decreased
14
< 1
12
< 1
Appetite
Skin and Subcutaneous Tissue Disorders
Alopecia Rituximab
product +
chemotherapy
followed by
rituximab product
monotherapy
n = 694
Hematology
Lymphopenia
Leukopenia
Neutropenia
Thrombocytopenia
Chemistry
2
Nervous System Disorders
Headache
18
< 1
15
< 1
Musculoskeletal and Connective Tissue Disorders
Arthralgia
GAZYVA +
chemotherapy
followed
by GAZYVA
monotherapy
n = 691
a
97 83 95 67
92
84
68 49
59
11 89
76
50 39
50
4
50 3 43 2
44 1 41 1
36
33
32
32
28
26
23
16 5
1
0
1
28
4
1 33
25
30
26
22
20
17
13 5
1
0
1
22
3
1
0
< 1
Includes lab abnormalities, reported throughout treatment and follow-
up, that were new or worsening, or worsening from baseline unknown.
In the monotherapy phase, new-onset Grade 3 or 4
neutropenia was reported in 21% of patients in the
GAZYVA arm (Grade 4, 10%) and 17% of patients
in the rituximab product arm (Grade 4, 9%).
Infusion Reactions:
Chronic Lymphocytic Leukemia
The incidence of infusion reactions in the CLL11
study was 65% with the first infusion of GAZYVA.
The incidence of Grade 3 or 4 infusion reactions was
20% with 7% of patients discontinuing therapy. The
incidence of reactions with subsequent infusions
was 3% with the second 1000 mg and < 1%
thereafter. No Grade 3 or 4 infusion reactions were
reported beyond the first 1000 mg infused.
Of the first 53 patients receiving GAZYVA in CLL11,
47 (89%) experienced an infusion reaction. After
this experience, study protocol modifications
were made to require pre-medication with a
corticosteroid, antihistamine, and acetaminophen.
The first dose was also divided into two infusions
(100 mg on day 1 and 900 mg on day 2). For the
140 patients for whom these mitigation measures
were implemented, 74 patients (53%) experienced
a reaction with the first 1000 mg (64 patients on
day 1, 3 patients on day 2, and 7 patients on
both days) and < 3% thereafter [see Dosage and
Administration (2)].
Non-Hodgkin Lymphoma
Overall, 69% of patients in the GADOLIN study
experienced an infusion reaction (all grades)
during treatment with GAZYVA in combination
with bendamustine. The incidence of Grade 3 to 4
infusion reactions in GADOLIN was 11%. In Cycle 1,
the incidence of infusion reactions (all grades) was
55% in patients receiving GAZYVA in combination
with bendamustine with Grade 3 to 4 infusion
reactions reported in 9%. In patients receiving
GAZYVA in combination with bendamustine, the
incidence of infusion reactions was highest on Day
1 (38%), and gradually decreased on Days 2, 8 and
15 (25%, 7% and 4%, respectively).
During Cycle 2, the incidence of infusion reactions
was 24% in patients receiving GAZYVA in
combination with bendamustine and decreased
with subsequent cycles.
During GAZYVA monotherapy in GADOLIN, infusion
reactions (all grades) were observed in 8% of
patients. No Grade 3 to 4 infusion reactions were
reported during GAZYVA monotherapy.
Overall, 2% of patients in GADOLIN experienced
an infusion reaction leading to discontinuation of
GAZYVA.
In GALLIUM, 72% of patients in the GAZYVA
treated arm experienced an infusion reaction (all
grades). The incidence of Grade 3 to 4 infusion
reactions for these patients was 12%. In Cycle 1,
the incidence of infusion reactions (all grades) was
62% in the GAZYVA treated arm with Grade 3 to 4
infusion reactions reported in 10%. The incidence
of infusion reactions (all grades) was highest on Day
1 (60%), and decreased on Days 8 and 15 (9% and
6%, respectively).
During Cycle 2, the incidence of infusion reactions
(all grades) in the GAZYVA treated arm was 13%
and decreased with subsequent cycles.
During GAZYVA monotherapy treatment in
GALLIUM, infusion reactions (all grades) were
observed in 9% of patients.
Overall, 1% of patients in GALLIUM experienced
an infusion reaction leading to discontinuation of
GAZYVA.
Neutropenia:
Chronic Lymphocytic Leukemia
The incidence of neutropenia reported as an
adverse reaction in CLL11 was 38% in the GAZYVA
treated arm and 32% in the rituximab product
treated arm, with the incidence of serious adverse
reactions 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 product treated arm.
Non-Hodgkin Lymphoma
The incidence of neutropenia in GADOLIN 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.
The incidence of neutropenia was higher during
treatment with GAZYVA in combination with
bendamustine (31%) compared to the GAZYVA
monotherapy treatment phase (12%).
The incidence of neutropenia in GALLIUM was
higher in the GAZYVA treated arm (53%) compared
to the rituximab product treated arm (47%).
Cases of prolonged neutropenia (1%) and late
onset neutropenia (4%) were also reported in the
GAZYVA treated arm. The incidence of neutropenia
was higher during treatment with GAZYVA in
combination with chemotherapy (45%) compared
to the GAZYVA monotherapy treatment phase (20%).
Infection:
Chronic Lymphocytic Leukemia
The incidence of infections was similar between
GAZYVA and rituximab product treated arms.
Thirty-eight percent of patients in the GAZYVA
treated arm and 37% in the rituximab product
treated arm experienced an infection, with Grade 3
to 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 in GADOLIN was 66%
in the GAZYVA plus bendamustine arm and 56%
in the bendamustine arm, with Grade 3 to 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.
The incidence of infections in GALLIUM was
82% in the GAZYVA treated arm and 73% in the
rituximab product treated arm, with Grade 3 to 4
events reported in 21% and 17%, respectively. In
the GAZYVA arm, fatal infections occurred in 2% of
patients compared to <1% in the rituximab product
arm.