ASH Clinical News May 2015 | Page 52

Literature Scan

“ esearch will need to determine
R
if even more sensitive methods
of MRD measurement can
improve our precision in
predicting outcome.”

• Standard-risk patients with MRD levels
≥1 percent: 65.1 percent

—CHING-HON PUI, MD

Table 5 Post-Baseline Laboratory Abnormalities by
CTCAE Grade in ≥ 5% of Patients and at Least 2%
Greater in the GAZYVA Treated Arm (Stage 1)
GAZYVA
+ Chlorambucil
n = 241

Investigations

Chlorambucil
n = 116

All
Grades
All
Grades
Grades % 3–4 % Grades % 3–4 %
Hematology
Neutropenia

78

48

53

27

Lymphopenia

80

40

9

3

Leukopenia

84

37

12

<1

Chemistry
Hypocalcemia

38

3

33

2

Hyperkalemia

33

5

18

3

Hyponatremia

30

8

12

3

AST
(SGOT increased)

29

1

16

0

Creatinine
increased

30

<1

20

2

ALT
(SGPT increased)

27

2

16

0

Hypoalbuminemia

23

<1

15

<1

Alkaline phosphatase 18
increased

0

11

0

Hypokalemia

1

5

<1

15

Table 6 Post-Baseline Laboratory Abnormalities by
CTCAE Grade in ≥ 5% of Patients and at Least 2%
Greater in the GAZYVA Treated Arm (Stage 2)
Investigations

GAZYVA
+ Chlorambucil
n = 336

Rituximab
+ Chlorambucil
n = 321

All
Grades
All
Grades
Grades % 3–4 % Grades % 3–4 %
Hema tology
Neutropenia

76

46

69

41

Lymphopenia

80

39

50

16

Leukopenia

16

84

35

62

Thrombocytopenia 48

13

40

8

Anemia

39

10

37

10

Chemistry
Hypocalcemia

37

3

32

<1

Hyperkalemia

14

1

10

<1

Hyponatremia

26

7

18

2

AST
27
(SGOT increased)

2

21

<1

ALT
28
(SGPT increased)

2

21

1

Hypoalbuminemia 23

<1

16

<1

Infusion Reactions: The incidence of infusion reactions
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 on the trial,
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)].
Neutropenia: The incidence of neutropenia reported as an
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.

(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.
Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor
lysis syndrome was 2% in the GAZYVA treated arm versus
0% in the rituximab treated arm.
Musculoskeletal Disorders: 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%).
Liver Enzyme Elevations: Hepatic enzyme elevations have
occurred in 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 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.
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, 7% (18/271)
tested positive for anti-GAZYVA antibodies at one or more
time points. 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
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of
GAZYVA in pregnant women. Women of childbearing
potential should use effective contraception while receiving
GAZYVA and for 12 months following treatment. GAZYVA
should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. Mothers who
have been exposed to GAZYVA during pregnancy should
discuss the safety and timing of live virus vaccinations for
their infants with their child’s healthcare providers.
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. There were no teratogenic effects in
animals. The high dose results in an exposure (AUC)
that is 2.4 times the exposure in patients with CLL at the
recommended label dose. When first measured on day
28 postpartum, obinutuzumab was detected in offspring,
and B cells were completely depleted. The B-cell counts
returned to normal levels, and immunologic function was
restored within 6 months after birth.

Infection: The incidence of infections was similar between
GAZYVA and rituximab treated arms. Th irty-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.

8.3 Nursing Mothers
It is not known whether obinutuzumab is excreted in
human milk. However, obinutuzumab is excreted in the
milk of lactating cynomolgus monkeys and human IgG
is known to be excreted in human milk. Because many
drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants
from obinutuzumab, a decision should be made whether
to discontinue nursing or discontinue the drug, taking into
account the importance of the drug to the mother.

Thrombocytopenia: The overall incidence of thrombocytopenia
reported as an adverse reaction was higher in the GAZYVA
treated arm (14%) compared to the rituximab treated arm

Similarly, the investigators found that those
low-risk patients who initially had a day
19 MRD level of ≥1 percent but were able
to convert to an MRD-negative status by
day 46 had a better event-free survival rate
after 10 years than those from the same risk
group who still had detectable MRD on day
46 (88.9% vs. 59.2%, respectively).

8.5 Geriatric Use
Of 336 previously untreated CLL patients who received
GAZYVA in combination with chlorambucil, 273 patients
(81%) were ≥ 65 years of age and 156 patients (46%) were
≥ 75 years of age. The median age was 74 years. Of the 156
patients ≥ 75 years of age, 72 (46%) experienced serious
adverse events and 11 (7%) experienced adverse events
leading to death. For 180 patients < 75 years of age, 59
(33%) experienced a serious adverse event and 4 (2%) an
adverse event leading to death. No significant differences
in efficacy were observed between patients ≥ 75 years of
age and those < 75 years of age [see Clinical Studies (14.1)].
8.6 Renal Impairment
Based on population pharmacokinetic analysis, a baseline
creatinine clearance (CrCl) ≥ 30 mL/min does not affect
the pharmacokinetics of GAZYVA. GAZYVA has not been
studied in patients with a baseline CrCl < 30 mL/min [see
Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
GAZYVA has not been studied in patients with hepatic
impairment.
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)].

Dr. Pui believes that the results from this
study also show that measuring MRD levels
just twice during remission induction –
rather than multiple times during the more
than two years of treatment – was sufficient
to guide treatment for most pediatric ALL
patients. These findings could also potentially save money and protect patients from
risks associated with MRD testing.
The team of investigators from St.
Jude Children’s Research Hospital plan to
examine the ability of MRD measurements to reduce treatment for patients
with an extremely low risk of relapse
to improve quality of life and reduce
treatment-related morbidity. “By contrast, for patients with MRD levels ≥1
percent on day 19, we will test more
intensive or novel therapy during and
after remission induction to attempt
to improve cure rate,” he added.
Dr. Pui acknowledges, however,
that MRD is not a perfect predictor
of relapse risk: “For example, relapse
occurred in 26 of 430 patients with
undetectable MRD at the end of
continuation treatment.” By contrast,
relapse occurred in only two of the 11
patients who had decreasing MRD
levels between the end of induction
and week 7 of maintenance therapy
who were treated with chemotherapy
alone. “Research will need to determine if even more sensitive methods of
MRD measurement can improve our
precision in predicting outcome,” Dr.
Pui noted. ●
Reference
Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential
minimal residual disease measurements in the context of riskbased therapy in childhood acute lymphoblastic leukaemia: a
prospective study. Lancet Oncol. 2015;16:465-74.

• 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)].

GAZYVA® [obinutuzumab]

Initial US Approval: 2013

Manufactured by:
Genentech, Inc.

Code Revision Date:
December 2014

A Member of the Roche Group
South San Francisco, CA
94080-4990

GAZYVA is a
registered trademark
of Genentech, Inc.

U.S. License No: 1048

GAZ/011615/0009 1/15
© 2015 Genentech, Inc.

High-Cost
Surveillance
Imaging
Falls Short
on Survival
Benefit in
DLBCL

8.4 Pediatric Use
The safety and effectiveness of GAZYVA in pediatric
patients has not been established.

Surveillance imaging to monitor
patients with diffuse large B-cell lymphoma (DLBCL) in first remission
ma y be common practice, but a new
cost-effectiveness analysis has found

May 2015