ASH Clinical News ACN_4.14_Full Issue_web | Page 29

UP FRONT
in understanding hematologic disorders,
malignant and nonmalignant.
I believe that what underlies every inch
of progress in collaborative clinical trials
and clinical research skills has been a core
belief to develop hypothesis-driven stud-
ies that improve patient care. Of course,
now we can use molecular or genetic
tools to look at prognosis for a variety of
conditions. This means we can have con-
versations with patients’ families that are
evidence-based, and we can offer them
new therapies that address the specific
molecular mutations discovered in the lab.
There also have been monumental
changes in the ways we think about
caring for individuals with complex ill-
nesses. Practicing hematology allows us
to have remarkably intense and meaning-
ful relationships with patients, making a
difference in their lives while also moving
the field forward.
Adverse Reactions (All Grades [%], ≥Grade 3 [%]) With ≥10% Incidence a in Patients With
Relapsed or Refractory B-Cell Precursor ALL Who Received SC (N=143 n ) were infection b (76; 54),
thrombocytopenia c (61; 59), neutropenia d (45; 43), anemia e (59; 47), leukopenia f (43; 42), febrile
neutropenia (53; 53), lymphopenia g (27; 26), decreased appetite (13; 2), headache h (27; 1),
hemorrhage i (28; 5), nausea (46; 0), abdominal pain j (23; 1), diarrhea (38; 1), constipation (24;
0), vomiting (24; 0), stomatitis k (26; 3), hyperbilirubinemia (17; 6), fatigue l (25; 3), pyrexia (42;
6), chills (11; 0), transaminases increased m (13; 5), gamma-glutamyltransferase increased (8; 4), and
alkaline phosphatase increased (7; 0).
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days
after the last dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Severity grade of adverse reactions were according to NCI CTCAE version 3.0.
Abbreviations: N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.
a. Only adverse reactions with ≥10% incidence in the BESPONSA arm are included. b. Infection also includes any reported
preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. c. Thrombocytopenia also
includes platelet count decreased. d. Neutropenia also includes the following reported preferred terms: neutrophil count
decreased. e. Anemia also includes hemoglobin decreased. f. Leukopenia also includes monocytopenia and white blood cell
count decreased. g. Lymphopenia also includes B-lymphocyte count decreased and lymphocyte count decreased.
h. Headache also includes migraine and sinus headache. i. Hemorrhage also includes terms retrieved in the Standard MedDRA
Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following: Conjunctival hemorrhage,
Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding,
Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous,
Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric
hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural
hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal
hemorrhage, and Vaginal hemorrhage. j. Abdominal pain also includes abdominal pain lower, abdominal pain upper,
abdominal tenderness, esophageal pain, and hepatic pain. k. Stomatitis also includes aphthous ulcer, mucosal inflammation,
mouth ulceration, oral pain, and oropharyngeal pain. l. Fatigue also includes asthenia. m. Transaminases increased
also includes Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and
Hypertransaminasemia. n. 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
Additional adverse reactions (all grades) that were reported in less than 10% of patients treated
with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased
(5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following:
hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone
marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%),
and electrocardiogram QT prolonged (1%).
Lab abnormalities a (N; All Grades [%]; Grade 3/4 [%]) in patients with relapsed or refractory B-Cell
precursor ALL who received BESPONSA were platelet count decreased (161; 98; 76), hemoglobin
decreased (161; 94; 40), leukocytes decreased (161; 95; 82), neutrophil count decreased (160; 94; 86),
lymphocytes (absolute) decreased (160; 93; 71), GGT increased (148; 67; 18), AST increased (160; 71;
4), ALP increased (158; 57; 1), ALT increased (161; 49; 4), blood bilirubin increased (161; 36; 5), lipase
increased (139; 32; 13), hyperuricemia (158; 16; 3), amylase increased (143; 15; 2).
Lab abnormalities a (N; All Grades [%]; Grade 3/4 [%]) in patients with relapsed or refractory B-Cell
precursor ALL who received SC were platelet count decreased (142; 100; 99), hemoglobin decreased
(142; 100; 70), leukocytes decreased (142; 99; 98), neutrophil count decreased (130; 93; 88),
lymphocytes (absolute) decreased (127; 97; 91), GGT increased (111; 68; 17), AST increased (134; 38;
4), ALP increased (133; 52; 3), ALT increased (137; 46; 4), blood bilirubin increased (138; 35; 6), lipase
increased (90; 20; 2), hyperuricemia (122; 11; 0), amylase increased (102; 9; 1).
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase;
GGT=gamma-glutamyltransferase.
a. Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.
6.2 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 inotuzumab ozogamicin in the
studies described below with the incidence of antibodies in other studies or to other products
may be misleading. In clinical studies of BESPONSA in patients with relapsed or refractory ALL,
the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based
immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera
tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay
was performed to detect neutralizing antibodies. In clinical studies of BESPONSA in patients with
relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin
antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies.
In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-
inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.
7. DRUG INTERACTIONS
Drugs That Prolong the QT Interval Concomitant use of BESPONSA with drugs known to prolong
the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc
interval prolongation. Discontinue or use alternative concomitant drugs that do not prolong QT/
QTc interval while the patient is using BESPONSA. When it is not feasible to avoid concomitant use
of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to the start of treatment, after
initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during
treatment.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies,
BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. There are no
available data on BESPONSA use in pregnant women to inform a drug-associated risk of major
birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin
caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in
patients at the maximum recommended dose, based on AUC. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk
to a fetus.
What is the best part of your day,
and what is the worst?
Every day, I look forward to walking in
to the office and engaging with my team,
which includes physicians, nurses, clinical
researchers, and professionals. They all
come to work each day just as committed
to serving our patients and conducting
research that can make a difference in
our patients’ lives. The worst part of my
day is billing, which I think many readers
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of
medications. The estimated background risk of major birth defects and miscarriage for the
indicated population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and
15-20%, respectively. Data Animal Data In embryo-fetal development studies in rats, pregnant
animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m 2 during
the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal
growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification
were observed at ≥ 0.11 mg/m 2 (approximately 2 times the exposure in patients at the maximum
recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m 2
(approximately 0.4 times the exposure in patients at the maximum recommended dose, based
on AUC). In an embryo-fetal development study in rabbits, pregnant animals received daily
intravenous doses up to 0.15 mg/m 2 (approximately 3 times the exposure in patients at the
maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of
0.15 mg/m 2 , slight maternal toxicity was observed in the absence of any effects on embryo-fetal
development. 8.2 Lactation Risk Summary There are no data on the presence of inotuzumab
ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects
on milk production. Because of the potential for adverse reactions in breastfed infants, advise
women not to breastfeed during treatment with BESPONSA and for at least 2 months after the
last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on its
mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm
when administered to a pregnant woman. Verify the pregnancy status of females of reproductive
potential prior to initiating BESPONSA. Contraception Females Advise females of reproductive
potential to avoid becoming pregnant while receiving BESPONSA. Advise females of reproductive
potential to use effective contraception during treatment with BESPONSA and for at least 8 months
after the last dose. Males Advise males with female partners of reproductive potential to use
effective contraception during treatment with BESPONSA and for at least 5 months after the last
dose. Infertility Females Based on findings in animals, BESPONSA may impair fertility in females of
reproductive potential. Males Based on findings in animals, BESPONSA may impair fertility in males
of reproductive potential. 8.4 Pediatric Use Safety and effectiveness have not been established in
pediatric patients. 8.5 Geriatric Use In the INO-VATE ALL trial, 30/164 patients (18%) treated with
BESPONSA were ≥65 years of age. No differences in responses were identified between older and
younger patients. Based on a population pharmacokinetic analysis in 765 patients, no adjustment
to the starting dose is required based on age. 8.6 Hepatic Impairment Based on a population
pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic
impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0-1.5 x ULN and AST any
level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST ≤ ULN; n=611).
In patients with moderate (total bilirubin > 1.5-3 x ULN and AST any level; n=3) and severe hepatic
impairment (total bilirubin > 3 x ULN and AST any level; n=1), inotuzumab ozogamicin clearance
did not appear to be reduced. No adjustment to the starting dose is required when administering
BESPONSA to patients with total bilirubin ≤ 1.5 x ULN and AST/ALT ≤ 2.5 x ULN. There is limited
safety information available in patients with total bilirubin > 1.5 x ULN and/or AST/ALT > 2.5 x ULN
prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤ 1.5 x ULN and AST/ALT ≤ to 2.5
x ULN prior to each dose unless due to Gilbert’s syndrome or hemolysis. Permanently discontinue
treatment if total bilirubin does not recover to ≤ 1.5 x ULN or AST/ALT does not recover to ≤ 2.5 x ULN.
17. PATIENT COUNSELING INFORMATION
Hepatotoxicity, Including Hepatic VOD (also known as SOS) Inform patients that liver problems,
including severe, life-threatening, or fatal VOD, and increases in liver tests may develop during
BESPONSA treatment. Inform patients that they should seek immediate medical advice if they
experience symptoms of VOD, which may include elevated bilirubin, rapid weight gain, and
abdominal swelling that may be painful. Inform patients that they should carefully consider
the benefit/risk of BESPONSA treatment if they have a prior history of VOD or serious ongoing
liver disease. Increased Risk of Post-HSCT Non-Relapse Mortality Inform patients that there is
an increased risk of post-HSCT non-relapse mortality after receiving BESPONSA, that the most
common causes of post-HSCT non-relapse mortality included infection and VOD. Advise patients
to report signs and symptoms of infection. Myelosuppression Inform patients that decreased
blood counts, which may be life-threatening, may develop during BESPONSA treatment and that
complications associated with decreased blood counts may include infections, which may be life-
threatening or fatal, and bleeding/hemorrhage events. Inform patients that signs and symptoms
of infection, bleeding/hemorrhage, or other effects of decreased blood counts should be reported
during treatment with BESPONSA. Infusion Related Reactions Advise patients to contact their
health care provider if they experience symptoms such as fever, chills, rash, or breathing problems
during the infusion of BESPONSA. QT Interval Prolongation Inform patients of symptoms that may
be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope.
Advise patients to report these symptoms and the use of all medications to their healthcare
provider. Embryo-Fetal Toxicity Advise males and females of reproductive potential to use effective
contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose,
respectively. Advise females of reproductive potential to avoid becoming pregnant while receiving
BESPONSA. Advise women to contact their healthcare provider if they become pregnant, or if
pregnancy is suspected, during treatment with BESPONSA. Inform the patient of the potential risk
to the fetus. Lactation Advise women against breastfeeding while receiving BESPONSA and for 2
months after the last dose.
Dr. Thompson and 2017 ASH President
Kenneth Anderson, MD.
can identify with. It’s a tedious but
necessary task. Enough said.
What do you enjoy doing
outside of work?
I spend as much time as I can
with my husband Garry. We enjoy
traveling and visiting family and
friends. Our favorite place to travel
is Barcelona and the area of southern
Spain – we love the architecture
and love, love, love the food. We’re
finishing renovations to our brick
American Foursquare house that was
built in 1918, and sometimes it’s great
just to spend weekends at home with
Garry and our chocolate Labrador
Retriever, Coltrane, just working in
the garden or going to the beach.
This year, we’re growing a variety of
vegetables and flowers. Digging in the
dirt isn’t something everyone wants
to do, but it’s therapeutic for me. And
yes – Chicago has beaches! ●
This product’s label may have been updated. For current full prescribing information, please visit
www.BESPONSA.com.
This brief summary is based on BESPONSA™ (inotuzumab ozogamicin)
Prescribing Information LAB-0763-1.0
Revised August 2017.
© 2017 Pfizer Inc.
All rights reserved.
August 2017
ASH Clinical News
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