63rd Annual Meeting of the Society of
Thrombosis and Haemostasis Research
Highlights of ASH®
in the Mediterranean
March 15 – 16, 2019
Athens, Greece
February 27 – March 2, 2019
Berlin, Germany
The 63rd congress will bridge preclinical and clinical
research and patient care in the field of hemostasis and
thrombosis, with the theme of “science meets clinical
practice.”
Highlights of ASH® in Latin America
April 5 – 6, 2019
Lima, Peru
Athens, Greece
rates in Stage 1. In addition to the adverse reactions
observed in Stage 2, in Stage 1 back pain (5% vs.
2%), anemia (12% vs. 10%) and cough (10% vs.
7%) were observed at a higher incidence in the
obinutuzumab treated patients. The incidence of
Grade 3 to 4 back pain (< 1% vs. 0%), cough (0%
vs. < 1%) and anemia (5% vs. 4%) was similar in
both treatment arms. With regard to laboratory
abnormalities, in Stage 1 hyperkalemia (33% vs. 18%),
creatinine increased (30% vs. 20%) and alkaline
phosphatase increased (18% vs. 11%) were
observed at a higher incidence in patients treated
with obinutuzumab with similar incidences of Grade
3 to 4 abnormalities between the two arms.
Patients received three 1000 mg doses of GAZYVA
on the first cycle and a single dose of 1000 mg once
every 28 days for 5 additional cycles in combination
with chlorambucil (6 cycles of 28 days each in total).
In the last 140 patients enrolled, the first dose of
GAZYVA was split between day 1 (100 mg) and day 2
(900 mg) [see Dosage and Administration (2.1)]. In
total, 81% of patients received all 6 cycles (of 28
days each) of GAZYVA-based therapy.
The most common adverse reactions (incidence ≥ 10%)
observed in patients with CLL in the GAZYVA
containing arm were infusion reactions, neutropenia,
thrombocytopenia, anemia, pyrexia, cough, nausea,
and diarrhea.
The most common Grade 3 to 4 adverse reactions
(incidence ≥ 10%) observed in patients with CLL
in the GAZYVA containing arm were neutropenia,
infusion reactions, and thrombocytopenia.
small lymphocytic lymphoma and marginal zone
lymphoma (a disease for which GAZYVA is not
indicated), who did not respond to or progressed
within 6 months of treatment with rituximab product
or a rituximab product-containing regimen. In
the population of patients with FL, the profile of
adverse reactions was consistent with the overall
NHL population. Patients were treated with either
GAZYVA in combination with bendamustine,
followed by GAZYVA monotherapy in patients that
have not progressed, or with bendamustine alone.
Patients randomized to the GAZYVA +
bendamustine arm received three weekly 1000 mg
doses of GAZYVA in the first cycle and a single
dose of 1000 mg once every 28 days for 5
additional cycles in combination with bendamustine
90 mg/m 2 on Days 1 and 2 in all 6 cycles. Patient
randomized to the bendamustine alone arm received
120 mg/m 2 on Days 1 and 2. This regimen continued
for 6 cycles of 28 days in duration. For patients
who did not progress on GAZYVA in combination
with bendamustine, a single dose of 1000 mg
GAZYVA monotherapy was given every two months
until progression or for a maximum of two years.
During combination therapy with GAZYVA and
bendamustine, 79% of patients received all 6
treatment cycles of GAZYVA and 76% received all
6 treatment cycles of bendamustine compared to
67% of patients in the bendamustine alone arm.
The most common adverse reactions (incidence ≥ 10%)
observed in GADOLIN in the GAZYVA containing
arm were infusion reactions, neutropenia, nausea,
fatigue, cough, diarrhea, constipation, pyrexia,
thrombocytopenia, vomiting, upper respiratory tract
infection, decreased appetite, arthralgia, sinusitis,
anemia, asthenia and urinary tract infection.
The most common Grade 3 to 4 adverse reactions
(incidence ≥ 10%) observed in GADOLIN in
the GAZYVA containing arm were neutropenia,
thrombocytopenia and infusion reactions.
Table 4 Summary of Adverse Reactions
Reported in ≥ 5% of Patients with CLL and at
Least 2% Greater in the GAZYVA Treated Arm
(Stage 2)
GAZYVA +
Chlorambucil
n = 336 Rituximab
product +
Chlorambucil
n = 321
All Grades Grades
%
3 to 4 % All Grades Grades
%
3 to 4 %
Body System
Adverse
Reactions
Table 6 Summary of Adverse Reactions
Reported in ≥ 5% of Patients with Relapsed or
Refractory NHL and at Least 2% Greater in
the GAZYVA plus Bendamustine Followed by
GAZYVA Monotherapy Treated Arm (GADOLIN)
Injury, Poisoning and Procedural Complications
Infusion Related
66
20
38
4
Reaction
a
Blood and Lymphatic System Disorders
Neutropenia
38
33
32
28
Thrombocytopenia 14
10
7
3
Leukopenia
6
4
2
< 1
General Disorders and Administration Site Conditions
Pyrexia
9
< 1
7
< 1
Gastrointestinal Disorders
Diarrhea
10
2
8
< 1
Constipation
8
0
5
0
Infections and Infestations
Nasopharyngitis
6
< 1
3
0
Urinary Tract
5
1
2
< 1
Infection
a
Body System
Adverse
Reactions
Pyrexia
Asthenia
Table 5 Post-Baseline Laboratory
Abnormalities by CTCAE Grade in ≥ 5% of
Patients with CLL and at Least 2% Greater in
the GAZYVA Treated Arm (Stage 2)
GAZYVA +
Chlorambucil
n = 336 Rituximab
product +
Chlorambucil
n = 321
All Grades Grades
%
3 to 4 % All Grades Grades
%
3 to 4 %
Hematology
Neutropenia
Lymphopenia
Leukopenia
Thrombocytopenia
Anemia
Chemistry
Hypocalcemia
Hypokalemia
Hyponatremia
AST/SGOT
increased
ALT/SGPT
increased
Hypoalbuminemia
76
80
84
48
39 46
39
35
13
10 69
50
62
40
37 41
16
16
8
10
37
14
26
27 3
1
7
2 32
10
18
21 <1
<1
2
<1
28 2 21 1
23 <1 16 <1
Summary of Clinical Trial Experience in
Non-Hodgkin Lymphoma
GADOLIN
The GADOLIN study evaluated safety in 392 patients
with relapsed or refractory NHL, including FL (81%),
Bendamustine
n = 198
All Grades Grades
%
3 to 4 % All Grades Grades
%
3 to 4 %
Injury, Poisoning and Procedural Complications
69
11
63
6
Infusion Related
Reaction a
Blood and Lymphatic System Disorders
Neutropenia
35
33
28
26
Gastrointestinal Disorders
Constipation
19
0
16
0
Dyspepsia
5
0
3
0
General Disorders and Administration Site Conditions
Adverse reactions reported under “Blood and lymphatic system
disorders” reflect those reported by investigator as clinically significant.
Laboratory
Abnormalities
GAZYVA +
Bendamustine
followed
by GAZYVA
monotherapy
n = 194
18
11
1
1
14
8
0
0
Infections and Infestations
Upper
13
2
8
1
Respiratory
Tract Infection
Sinusitis
12
1
5
0
Urinary Tract
10
3
6
0
Infection
Nasopharyngitis
9
0
4
0
Musculoskeletal and Connective Tissue Disorders
Arthralgia
12
0
5
0
Pain in Extremity
9
1
4
0
Respiratory, Thoracic and Mediastinal Disorders
Cough
26
0
17
0
Nasal
7
0
2
0
Congestion
Skin and Subcutaneous Tissue Disorders
Pruritus
9
0
6
0
a
Defined as any related adverse reaction that occurred during or within
24 hours of infusion.
During the monotherapy period with GAZYVA, the
most common adverse reactions (incidence ≥ 5%)
in GADOLIN were cough (15%), upper respiratory
tract infections (12%), neutropenia (11%), sinusitis
(10%), diarrhea (8%), infusion related reactions
(8%), nausea (8%), fatigue (8%), bronchitis (7%),
arthralgia (7%), pyrexia (6%), nasopharyngitis
(6%), and urinary tract infection (6%). Grade 3 to 4
adverse reactions during the monotherapy period
included neutropenia (10%) and, at 1% each,
anemia, febrile neutropenia, thrombocytopenia,
sepsis, upper respiratory tract infection, and urinary
tract infection.
Table 7 Post-Baseline Laboratory Abnormalities
by CTCAE Grade in ≥ 5% of Patients with
Relapsed or Refractory NHL and at Least 2%
Greater in the GAZYVA plus Bendamustine
Followed by GAZYVA Monotherapy Treated
Arm a (GADOLIN)
Laboratory
Abnormalities
GAZYVA +
Bendamustine
followed
by GAZYVA
monotherapy
n = 194 Bendamustine
n = 198
All Grades Grades
%
3 to 4 % All Grades Grades
%
3 to 4 %
Hematology
Neutropenia
Leukopenia
Lymphopenia
Chemistry
Hypocalcemia
Hypophosphatemia
ALT/SGPT
increased
Elevated
creatinine
Creatinine
clearance
decreased
a
75 52 77 42
86
99 47
93 88
99 34
85
38 2 26 2
41
35 7
1 38
31 7
4
87 4 92 2
58 6 61 4
Two percent different in either the All Grades or Grade 3 to 4 Lab
Abnormalities.
In the monotherapy phase of treatment with
GAZYVA, the most frequently reported hematological
laboratory abnormalities (incidence ≥ 20%)
were lymphopenia (80%), leukopenia (63%),
low hemoglobin (50%), neutropenia (46%) and
thrombocytopenia (35%). The most frequently
reported hematological Grade 3 to 4 laboratory
abnormalities (incidence ≥ 1%) during the
monotherapy period were lymphopenia (52%),
neutropenia (27%), leukopenia (20%) and
thrombocytopenia (4%).
In the monotherapy phase of treatment with
GAZYVA, the most frequently reported chemistry
laboratory abnormalities (incidence ≥ 20%) were
elevated creatinine (69%), decreased creatinine
clearance (CrCl; 43%), hypophosphatemia (25%),
AST/SGOT increased (24%) and ALT/SGPT
increased (21%). The most frequently reported
chemistry Grade 3 to 4 laboratory abnormalities
(incidence ≥ 1%) during the monotherapy period
were hypophosphatemia (5%), hyponatremia (3%)
and decreased CrCl (1%).
GALLIUM
A randomized, open-label multicenter trial
(GALLIUM) evaluated the safety of GAZYVA as
compared to rituximab product in 1385 patients
with previously untreated follicular lymphoma
(86%) or marginal zone lymphoma (14%). Patients
received chemotherapy (bendamustine, CHOP, or
CVP) combined with either GAZYVA (691 patients)
or rituximab product (694 patients), followed in
responding patients by GAZYVA or rituximab
product monotherapy every two months until
disease progression or for a maximum of two years.
The study excluded patients having an absolute
neutrophil count (ANC) < 1500 / μL, platelets
< 75,000 / μL, CrCl < 40 mL/min and, unless
attributable to lymphoma, hepatic transaminases
> 2.5 x upper limit of normal.
The median age was 60 (range: 23-88), 47% were
male, 82% were white, and 97% had an ECOG
performance status of 0 or 1. The chemotherapy
was bendamustine in 59%, CHOP in 31% and
CVP in 10% of patients. Following combination
therapy, 624 patients (90%) in the GAZYVA arm
and 612 patients (88%) in the rituximab product
arm received monotherapy.
Serious adverse reactions occurred in 50% of
patients on the GAZYVA arm and 43% of patients
on the rituximab product arm. Fatal adverse
reactions were reported during treatment in 3% in
the GAZYVA arm and 2% in the rituximab product
arm, most often from infections in the GAZYVA
arm. During treatment and follow-up combined,
fatal adverse reactions were reported in 5% of the
GAZYVA arm and 4% of the rituximab product arm,
with infections and second malignancies being
leading causes. In the GAZYVA arm, fatal infections
occurred in 2% of patients compared to < 1% in
the rituximab product arm.
During combination therapy, 93% of patients
received all treatment cycles in the GAZYVA arm,
and 92% received all treatment cycles in the
rituximab product arm. Of the responding patients
who began monotherapy with GAZYVA or rituximab