You Make the Call: Readers’ Response
TRAINING
submitted
in
response
b,
up to the experts’
Each month
post the expert’s your answer matches
R-CHOP (rituxima
program and
ic toxicity following
and see how
s neurolog
clinical dilemma
, MD, discusse
Carol Portlock
This month,
ne).
and predniso
vincristine,
do a bone
cin,
e, doxorubi
cyclophosphamid
but she had
marrow biopsy,
has
However, she
ma:
response.
events
B-cell lymphom R-CHOP with a great does not remember
of
diffuse large
Clinical Dilem
and
has stage III
had two courses
care for herself
a. I did not
She has
ld woman
longer
brain MRI.
She can no
A 73-year-o
be safe to use?
and normal
memory loss. what regimen would
a normal LP
short-term
If so,
pronounced
chemo brain?
developed
hour. Is this
from the previous
MD
Carol S. Portlock, a Service
Lymphom
Attending
of Medicine
Cancer Center
Department
Sloan Kettering
Memorial
NY
New York,
of exclusion.
is a diagnosis
“Chemo brain” provided in the clinical
on
implies that
The informati
though limited,
preexisting
description,
had no relevant ce and
the patient
of significan
be iden-
medical history
etiology could loss
that no clear
onset of memory
tified for the
and brain MRI).
(negative LP
regi-
a standard
R-CHOP is
such
with
associated
to
men rarely
toxicity. Etiologies e mul-
devastating
be progressiv
consider w ould phalopathy, which
tifocal leukoence rare complication
as a
is recognized
some other
therapy, or
or cyto-
of rituximab
(HIV
disease
viral/infectious might emerge during
that
megalovirus) present with dementia.
can
l and vincristine
n,
therapy and
steroid withdrawa
hypotensio
In older patients,
fatigue, orthostatic invoking tran-
cause excess
loss without
toxicity can
A simple
can cause memory
cular accident. isone
etc., which
attack or cerebrovas
l is to add hydrocort
sient ischemic
steroid withdrawa mg in the morning and
tox-
way to handle
cycles (20
vincristine
ce between
way to address warranted.
maintenan
and a simple
e if
10 mg at night), dosing low or discontinu complication
the
well-recognized
icity is to keep
disease is a
rare cause of
cular
Another
Cardiovas
in older patients. is hyponatremia
of R-CHOP
or confusion
of inap-
memory problems phamide/syndrome
,
cyclophos
or, more commonly
from either
c hormone
of steroid use. to define
propriate antidiureti
mia in the setting
necessity
from hyperglyce etiology, it is a medical
ly. Based on
according
it
Whatever the
g
to treat
possible, and is hard to justify continuin
Two
it
the cause, if
n provided,
and improved. a
is identified
the informatio
to result in
an etiology
insufficient
R-CHOP until
are most likely
in this devastat-
cycles of R-CHOP but continuing therapy
toxicity.
neurologic
curative outcome, only precipitate more
may
ing scenario
addition
with rituximab
J Chemother.
events risk associated
REFERENCES
a meta-analysis.
and fatal adverse
chemotherapy:
Y, Liu H. Severe
• Hua Q1, Zhu
lymphoma (B-NHL)
to B-cell non-Hodgkin’s
a review of potential
in the elderly:
2015;27:365-70.
B-cell lymphoma
B. Diffuse large
in the
• Sarkozy C, Coiffier
Cancer Res. 2013;19:1660-9.
outcome of patients CHOP
difficulties. Clin
E, et al. Long-term
to standard
C, Van Den Neste comparing rituximab-CHOP
de l’Adulte.
study
des Lymphomes
• Coiffier B, Thieblemont
Groupe d’Etudes
the first randomized
a study by the
LNH-98.5 trial,
in DLBCL patients:
chemotherapy
.
Blood. 2010;116:2040-5
Colleague
Consult a
ASH
for ASH
Through
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
inion
Expert Op
Clinical Dilemma:
We asked, and you answered! Here are a few
responses from this month’s “You Make the
Call.”
ON
and EDUCATI
e
Consult a Colleagu month’s
through ASH’s
to next
responses
your
question
do. Send in
e the Call we’ll pick a challenging clinical
what you would
You Mak
want to know in the next print issue.
the Call,”
“You Make
, but we also
A 73-year-old woman has stage III diffuse large
B-cell lymphoma. I did not do a bone marrow bi-
opsy, but she had a normal LP and normal brain
MRI. She has had two courses of R-CHOP with
a great response. However, she has developed
pronounced short-term memory loss. She can
no longer care for herself and does not remem-
ber events from the previous hour. Is this chemo
brain? If so, what regimen would be safe to use?
• Anemias
oietic cell
• Hematop
transplantation
inopathies
• Hemoglob
osis
is/thromb
• Hemostas
To see how the expert responded, turn to
page 69.
as
• Lymphom
disorders
roliferative
• Lymphop
s
• Leukemia
Waldenström
myeloma &
• Multiple
macroglobulinemia
liferative disorders
• Myelopro
s
plastic syndrome
• Myelodys
ytopenias
• 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
a:
’s Clinical Dilemm with
Next Month
ld who presented hia
fit 92-year-o with Philadelp
d
An otherwise
was diagnose acute lymphocytic
pancytopenia
B-cell
anthracycline-
me negative
chromoso
about using
I am
I am worried
of his age.
leukemia.
rapy because
e (low-
based chemothe
e plus prednison consider
you
g vincristin
considerin
However, would ab ozogamicin or
intensity therapy). (i.e., inotuzum
therapies
setting?
alternative
in the upfront
us at
blinatumomab) you respond? Email
●
How would
matology.org.
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*If you have
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ation to
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your recommend it can be
.org so
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ASH Clinical
News
69
News.org
ASHClinical
Summary of Clinical Trial Experience in
Diffuse Large B-Cell Lymphoma (DLBCL)
The data in Table 2 were obtained in the MabEASE
study, a comparative, randomized, parallel-group,
multicenter study to investigate the efficacy
of RITUXAN HYCELA (1,400 mg rituximab and
23,400 Units hyaluronidase human; n=369) versus
375 mg/m 2 a rituximab product by intravenous
infusion (n=203) both in combination with CHOP
(R-CHOP) in previously untreated patients with
CD20-positive DLBCL.
Eighty two percent of patients receiving RITUXAN
HYCELA or rituximab completed all 8 cycles of
study treatment. In both RITUXAN HYCELA and
rituximab treatment groups, patients experienced
4.9 months median duration of rituximab exposure
in each arm.
The demographic characteristics were balanced
between the two treatment groups. Most patients
were Caucasian (79%) and more than half (54%)
were male. The study population had a median
age of 64 years (61% of patients aged ≥ 60 years)
with median BSA of 1.83 m 2 (1.83 and 1.84 m 2
for RITUXAN HYCELA and rituximab groups,
respectively).
The incidences of adverse reactions of any grade
(RITUXAN HYCELA [94%] vs. rituximab [92%])
(Table 2), Grade 3–4 adverse reactions (RITUXAN
HYCELA [63%] vs. rituximab [57%]), and serious
adverse reactions (RITUXAN HYCELA [42% ]
vs. rituximab [37%]) were generally comparable
between the two treatment groups. The common
adverse reactions (occurring in ≥ 20% of patients
in any treatment group) were neutropenia, alopecia,
nausea, and anemia.
A total of 91 patients (16%) died, including 58/369
patients (16%) in RITUXAN HYCELA and 33/203
patients (16%) in rituximab. Of these patients, 44
patients (29 patients RITUXAN HYCELA [8%] vs.
15 patients rituximab [7%]) died due to adverse
reactions and 35 patients (22 patients RITUXAN
HYCELA [6%] vs. 13 patients rituximab [6%]) died
due to disease progression. Pneumonia (4 patients
RITUXAN HYCELA vs. 1 patient rituximab), septic
shock (2 patients RITUXAN HYCELA vs. 3 patients
rituximab), and cardiac arrest (1 patient RITUXAN
HYCELA vs. 3 patients rituximab) were the most
common adverse reactions leading to death.
The incidence of administration-related reactions
was balanced between the RITUXAN HYCELA
and rituximab groups (28% vs. 29%). Grade 1–2
ARRs constituted 97% of the overall ARRs for the
RITUXAN HYCELA arm and 80% for the rituximab
arm. Of the reported ARRs, local cutaneous
reactions with RITUXAN HYCELA were reported in
17 patients. These events resolved within a median
of 2 days from the onset (range 1 to 32 days).
Majority of these reactions were Grade 1 and 2
and were observed in 16 patients (4%).
Table 2: Incidence of Adverse Reactions in
≥ 5% of Patients with Previously Untreated
DLBCL Receiving RITUXAN HYCELA or
Rituximab in Combination with CHOP
Body System/
Adverse
Reactions
RITUXAN HYCELA
+ CHOP
(n=369)
All AEs
%
Grade 3–4
%
Gastrointestinal Disorders
Nausea
22
< 1
Constipation
15
< 1
Diarrhea
14
1
Vomiting
11
< 1
Abdominal Pain 7
< 1
Stomatitis
6
< 1
Dyspepsia
5
0
General Disorders and
Administration Site Conditions
Fatigue
19
1
Pyrexia
13
< 1
Asthenia
11
< 1
Mucosal
Inflammation
8
< 1
Edema Peripheral 8
< 1
Infections
Pneumonia
7
3
Rituximab +
CHOP
(n=203)
All AEs
%
Grade 3–4
%
24
17
10
8
7
5
7 < 1
< 1
1
< 1
< 1
0
0
15
13
12 1
0
< 1
8
4 1
0
4 2
Blood and Lymphatic System Disorders
Neutropenia
31
25
29
19
Anemia
23
5
21
4
Febrile
Neutropenia
14
14
12
11
Leukopenia
7
3
7
3
Lymphopenia
5
1
6
3
Table 2: Incidence of Adverse Reactions in
≥ 5% of Patients with Previously Untreated
DLBCL Receiving RITUXAN HYCELA or
Rituximab in Combination with CHOP (cont’d)
Body System/
Adverse
Reactions
RITUXAN HYCELA
+ CHOP
(n=369)
All AEs
%
Investigations
Neutrophil Count
Decreased
14
White Blood Cell
Count Decreased 7
Weight Decreased 8
Lymphocyte Count
Decreased
5
Grade 3–4
%
Rituximab +
CHOP
(n=203)
All AEs
%
Grade 3–4
%
11 14 11
4
< 1 7
4 5
< 1
2 3 2
Metabolism and Nutrition Disorders
Decreased Appetite 8
< 1
9
Nervous System Disorders
Neuropathy
Peripheral
12
< 1
Paresthesia
9
< 1
Headache
6
0
12
6
7
< 1
0
0
0
Skin and Subcutaneous Tissue Disorders
Alopecia
24
0
24
0
Respiratory, Thoracic and
Mediastinal Disorders
Cough
11
< 1
Dyspnea
6
0 9
4 0
< 1
Psychiatric Disorders
Insomnia
7 6 < 1
< 1
Would rule out rituximab leukoencephalopathy
and continue treatment with the same schedule.
Summary of Clinical Trial Experience
in Chronic Lymphocytic Leukemia
The data in Table 3 were obtained in part 2 of
the SAWYER study, a two-part, comparative,
randomized, parallel-group, multicenter study
of RITUXAN HYCELA versus a rituximab product
by intravenous infusion both in combination
with fludarabine and cyclophosphamide (FC)
chemotherapy in patients with previously
untreated CLL.
The safety analysis population in part 2 of the
study included 85 patients receiving RITUXAN
HYCELA (1,600 mg rituximab/26,800 Units
hyaluronidase human) and 89 patients receiving
500 mg/m 2 rituximab. In both RITUXAN HYCELA
and rituximab groups, patients had similar median
duration of rituximab exposure (4.9 vs. 4.7 months).
The majority of patients received all 6 cycles of
study treatment (86% RITUXAN HYCELA vs. 81%
rituximab).
The patient population was predominantly Caucasian
(96%), male (65%), with a median age of 60 years
and median BSA of 1.9 m 2 (1.97 and 1.86 m 2 for
the RITUXAN HYCELA and intravenous rituximab
groups, respectively). Overall, the treatment groups
were balanced with respect to demographic
characteristics, with the exception of more males in
the RITUXAN HYCELA arm (71% RITUXAN HYCELA
vs. 60% rituximab). Baseline disease characteristics
were similar between the two groups. Over half
of the patients (62%) had Binet Stage B disease
and the majority had typical CLL characterizations
(93%), with median time from first CLL diagnosis to
randomization being 18.5 months.
The incidences of adverse reactions were balanced
between the two treatment groups (96% RITUXAN
HYCELA vs. 91% rituximab), and the common
adverse reactions (occurring in ≥ 20% of patients
in any arm) were infections, neutropenia, nausea,
thrombocytopenia, pyrexia, anemia, vomiting, and
injection site erythema. The incidences of Grade 3–4
adverse reactions were also balanced between the
two treatment groups (69% RITUXAN HYCELA vs.
71% rituximab). The incidence of serious adverse
reactions was 29% for RITUXAN HYCELA and
33% for rituximab. The incidence of administration-
related reactions was 44% for RITUXAN HYCELA
and 45% for rituximab). Of the reported ARRs, local
cutaneous reactions with RITUXAN HYCELA were
reported in 15 patients. These events resolved
within a median of 6 days from the onset (range 3 to
29 days). Majority of these reactions were Grade 1
and 2 and were observed in 14 patients (16%).
A total of 9 patients (5%) died, including 5 patients
in the RITUXAN HYCELA group and 4 patients
in the rituximab group. In the RITUXAN HYCELA
group, 1 patient died due to herpes zoster infection,
1 patient died as a result of progressive multifocal
leukoencephalopathy (PML) (considered by the
investigator as related to rituximab), and 3 patients
died due to disease progression. In the rituximab
group, 2 patients died due to diarrhea and listeriosis
and 2 patients died due to disease progression.
Table 3: Incidence of Adverse Reactions in
≥ 5% of Patients with Previously Untreated
CLL Receiving RITUXAN HYCELA or Rituximab
in Combination with FC
Bod y System/
Adverse
Reactions
RITUXAN HYCELA
+ FC
(n=85)
All AEs
%
Grade 3–4
%
Gastrointestinal Disorders
Nausea
38
1
Vomiting
21
2
Diarrhea
12
0
Abdominal Pain
9
0
Constipation
8
0
General Disorders and
Administration Site Conditions
Pyrexia
32
5
Injection Site
Erythema
26
2
Injection Site Pain 16
1
Chills
13
0
Fatigue
11
0
Asthenia
8
1
Infections
Upper Respiratory
Tract Infection
Respiratory Tract
Infection
Bronchitis
Urinary Tract
Infection
Pneumonia
Rituximab
+ FC
(n=89)
All AEs
% Grade 3–4
%
35
22
11
6
8 0
1
3
0
0
25 1
0
0
10
10
17 0
0
1
0
2
13 0 12 1
8
7 1
0 4
6 1
0
2
2 0
2 8
6 1
2
Blood and Lymphatic System Disorders
Neutropenia
65
56
58
Thrombocytopenia 24
6
26
Leukopenia
19
14
16
Anemia
13
5
24
Febrile Neutropenia 11
8
8 52
9
12
9
8
Musculoskeletal and
Connective Tissue Disorders
Arthralgia
9
0
Pain In Extremity
7
1
Bone Pain
6
0 1
2
2 0
0
0
Nervous System Disorders
Headache
7
0 9 0
Skin and Subcutaneous Tissue Disorders
Erythema
15
0
7
0
Rash
12
0
10
1
Pruritus
8
0
4
0
Respiratory, Thoracic and Mediastinal Disorders
Cough
13
0
11
0
Oropharyngeal Pain 6
0
3
0
Dyspnea
4
0
8
1
Psychiatric Disorders
Insomnia
1 0 7 0
Vascular Disorders
Hypotension
1
Hypertension
0 0
0 7
6 1
1
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 RITUXAN HYCELA and rituximab in
the studies described below with the incidence of
antibodies in other studies or to other products may
be misleading.
In the SABRINA study, where previously untreated
patients with follicular lymphoma were treated with
RITUXAN HYCELA or rituximab in combination with
CVP or CHOP, the incidence of treatment-induced/
enhanced anti-rituximab antibodies in the RITUXAN
HYCELA group was similar to that observed in the
rituximab group (2.0% RITUXAN HYCELA vs. 1.5%
rituximab). The incidence of treatment-induced/
enhanced anti-recombinant human hyaluronidase
antibodies was 13% in the RITUXAN HYCELA
group compared with 8% in the rituximab group,
and the overall proportion of patients found to have
anti-recombinant human hyaluronidase antibodies
Sebastián Isnardi, MD
Buenos Aires, Argentina
She has meningeal lymphoma with or without
brain involvement.
Evan D. Slater, MD
Ventura, CA