ASH News Daily 2017 - Issue 1 - B-24

Page B-24

ASH News Daily

Saturday, December 9, 2017

ASH Grassroots Network Lunch

hanks to ASH's advocacy efforts
and the ASH Grassroots Network,
issues important to the future of
hematology have been brought to the attention of the U.S. Congress and federal
agencies. The ASH Grassroots Lunch provides a forum for interested members to
learn how they can participate in ASH's
advocacy efforts, communicate with
Congress and the White House, become
effective advocates for hematology, and
discuss the Society's legislative and regulatory priorities, including funding for
the National Institutes of Health (NIH).
Alan Wurtzel, a special advisor at

NBCUniversal and former President
of Research and Media Development
at NBCUniversal, will be the featured
speaker at this year's lunch. Mr. Wurtzel
will discuss issues impacting the changing political and media landscapes in
Washington and share his perspectives
on how the media - as well as hematology advocates - have a responsibility to
use truth to impact public opinion and
policy.
The lunch takes place today, Saturday
December 9, from 11:15 a.m. to 12:15 p.m.,
at the Omni Hotel at CNN Center, International Ballroom, North Tower, M2.

Alan Wurtzel (Photo by: Evans Vestal Ward/NBCUniversal)

MYLOTARGTM (gemtuzumab ozogamicin) for injection, for intravenous use
Initial U.S. Approval: 2000
Brief Summary of Prescribing Information
WARNING: HEPATOTOXICITY
Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as
sinusoidal obstruction syndrome (SOS), has been reported in association with the use of MYLOTARG
as a single agent, and as part of a combination chemotherapy regimen. Monitor frequently for
signs and symptoms of VOD after treatment with MYLOTARG.

Use in AML with Adverse-Risk Cytogenetics: In subgroup analyses in ALFA-0701, the addition of MYLOTARG
to standard combination chemotherapy did not improve event-free survival in the subgroup of patients having
adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63, 1.95). For patients being treated with MYLOTARG in combination
with daunorubicin and cytarabine for newly-diagnosed de novo AML, when cytogenetics testing results become
available consider whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks
for the individual patient.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, MYLOTARG can cause
embryo-fetal harm when administered to a pregnant woman. In animal studies, gemtuzumab ozogamicin caused
embryo-fetal toxicity, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum
recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive
potential to use effective contraception during treatment with MYLOTARG and for at least 6 months after the final
dose of MYLOTARG. Advise males with female partners of reproductive potential to use effective contraception during
treatment with MYLOTARG and for at least 3 months after the last dose of MYLOTARG. Apprise pregnant women of the
potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy
is suspected during treatment with MYLOTARG.
ADVERSE REACTIONS
The following serious adverse reactions associated with MYLOTARG are discussed in detail in other sections of the
prescribing information: hepatotoxicity, including VOD; infusion related reactions; and hemorrhage.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice.
Combination Therapy in Newly-Diagnosed De Novo CD33-positive AML:
The safety evaluation of MYLOTARG (3 mg/m2 Day 1, 4 and 7 in combination with daunorubicin and cytarabine
[DA]) in adults is based on data from ALFA-0701 for 131 patients treated with MYLOTARG plus DA and in 137
patients treated with DA alone. In this study, 123 patients received all 3 fractionated doses of MYLOTARG and
7 patients missed at least 1 dose, with a mean total dose administered during induction of 14.51 mg (range:
4.6-18.0). MYLOTARG was received by 91 (70%) patients in the MYLOTARG arm during Consolidation 1 and 64
(49%) patients in the MYLOTARG arm during Consolidation 2. Safety data consisting of selected TEAEs considered
most important for understanding the safety profile of MYLOTARG as well as all adverse events (AEs) that led
to the permanent discontinuation of treatment were retrospectively collected. The selected TEAEs consisted of
all grades hemorrhages, all grades VOD, and severe infections. Discontinuation due to any adverse reaction
occurred in 31% of patients in the MYLOTARG arm versus 7% in the DA arm. The most frequent (greater than or
equal to 1%) adverse reactions for patients treated with MYLOTARG that led to permanent discontinuation were
thrombocytopenia (15%), VOD (3%), and septic shock (2%). Fatal adverse reactions occurred in 8 patients (6%) in
the MYLOTARG arm versus 3 patients (2%) in the DA arm. In the MYLOTARG arm, 3 patients died of VOD, 4 patients
died of hemorrhage-related events (CNS hemorrhage, hemorrhagic shock), and 1 patient died of suspected
cardiac cause. In the DA arm, 3 patients died of sepsis.
Selected Grade 3 and Higher Adverse Reactions in Patients with Newly-Diagnosed De Novo AML in ALFA-0701
MYLOTARG + Daunorubicin + Cytarabine
(n, %)

Daunorubicin + Cytarabine
(n, %)

Induction
Infectiona
Hemorrhageb
Veno-occlusive liver diseasec

N = 131
61 (47%)
24 (18%)
3 (2%)

N = 137
53 (39%)
12 (9%)
0

Consolidation 1
Infectiona
Hemorrhageb
Veno-occlusive liver diseasec

N = 91
50 (55%)
5 (5%)
0

N = 103
43 (42%)
0
0

Consolidation 2
Infectiona
Hemorrhageb
Veno-occlusive liver diseasec

N = 64
32 (50%)
4 (6%)
0

N = 107
54 (50%)
0
0

Abbreviations: AML=acute myeloid leukemia; N=number of patients; PT=preferred term.
a
Infection is a grouped term consisting of multiple preferred terms.
b
Hemorrhage is a grouped term consisting of multiple preferred terms.
c
Veno-occlusive liver disease includes the following reported PTs: Veno-occlusive liver disease, veno-occlusive disease.

All patients in ALFA-0701 developed severe neutropenia, thrombocytopenia and anemia. The incidence of Grade
3-4 thrombocytopenia that was prolonged in the absence of active leukemia was higher in patients treated
with MYLOTARG.
Prolonged Cytopeniasa in ALFA-0701

MYLOTARG + Daunorubicin + Cytarabine
(n/N, %)

Daunorubicin + Cytarabine
(n/N, %)

Induction
Prolonged thrombocytopenia
Prolonged neutropenia

19/101 (19%)
3/106 (3%)

7/97 (7%)
0/101 (0%)

Consolidation 1
Prolonged thrombocytopenia
Prolonged neutropenia

21/87 (24%)
3/88 (3%)

6/91 (7%)
1/97 (1%)

Consolidation 2
Prolonged thrombocytopenia
Prolonged neutropenia

22/62 (35%)
1/62 (2%)

25/103 (24%)
2/105 (2%)

Platelets less than 50 Gi/L or neutrophils less than 0.5 Gi/L lasting past cycle Day 42 in the absence of active leukemia.

T:10"

INDICATIONS AND USAGE
Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML): MYLOTARG is indicated for the treatment of
newly-diagnosed CD33-positive acute myeloid leukemia in adults.
Relapsed or Refractory CD33-positive AML: MYLOTARG is indicated for the treatment of relapsed or refractory
CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older.
CONTRAINDICATIONS
History of hypersensitivity to the active substance in MYLOTARG or any of its components or to any of the
excipients. Reactions have included anaphylaxis.
WARNINGS AND PRECAUTIONS
Hepatotoxicity, Including Veno-occlusive Liver Disease (VOD): Hepatotoxicity, including life-threatening
and sometimes fatal hepatic VOD events, have been reported in patients receiving MYLOTARG as a single
agent or as part of a combination chemotherapy regimen. In ALFA-0701, VOD events were reported
in 6/131 (5%) patients during or following treatment with MYLOTARG, or following later hematopoietic
stem cell transplantation (HSCT). The median time from the MYLOTARG dose to onset of VOD was 9 days
(range: 2-298 days), with 5 events occurring within 28 days of any dose of MYLOTARG and 1 event occurring
greater than 28 days after the last dose of MYLOTARG. Three of the 6 VOD events were fatal. VOD was also
reported in 2 patients in the control arm of ALFA-0701 after receiving MYLOTARG as a therapy for relapsed
AML. In MyloFrance-1 (MYLOTARG 3 mg/m2 on Days 1, 4 and 7), VOD events were reported in none of the
57 patients during or following treatment, or following HSCT after completion of MYLOTARG treatment.
Based on an analysis across trials, the risk of VOD was higher in adult patients who received higher
doses of MYLOTARG as monotherapy, in patients with moderate or severe hepatic impairment prior to receiving
MYLOTARG, in patients treated with MYLOTARG after HSCT, and in patients who underwent HSCT after treatment
with MYLOTARG. Patients who had moderate/severe hepatic impairment prior to treatment with MYLOTARG were
8.7 times more likely to develop VOD compared to patients without moderate/severe hepatic impairment at
baseline. Patients treated with MYLOTARG for relapse after HSCT were 2.6 times more likely to develop VOD
compared to patients without prior HSCT. Patients who underwent HSCT following MYLOTARG treatment were 2.9
times more likely to develop VOD after HSCT compared to patients without HSCT following MYLOTARG treatment.
Although no relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy
doses, the ALFA-0701 study recommended an interval of 2 months between the last dose of MYLOTARG and
HSCT. In MyloFrance-1, no patients underwent HSCT within 3.5 months of MYLOTARG therapy. Assess ALT, AST,
total bilirubin, and alkaline phosphatase prior to each dose of MYLOTARG. After treatment with MYLOTARG,
monitor frequently for signs and symptoms of VOD; these may include elevations in ALT, AST, total bilirubin,
hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not
identify all patients at risk of VOD. For patients who develop abnormal liver tests, more frequent monitoring
of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to
HSCT, monitor liver tests frequently during the post-HSCT period, as appropriate. Manage signs or symptoms
of hepatic toxicity by dose interruption or discontinuation of MYLOTARG. In patients who experience VOD,
discontinue MYLOTARG and treat according to standard medical practice.
Infusion-Related Reactions (Including Anaphylaxis): Life-threatening or fatal infusion related-reactions can
occur during or within 24 hours following infusion of MYLOTARG. Signs and symptoms of infusion-related
reactions may include fever, chills, hypotension, tachycardia, hypoxia and respiratory failure. Premedicate prior
to MYLOTARG infusion. Monitor vital signs frequently during infusion. Interrupt infusion immediately for patients
who develop evidence of infusion reaction, especially dyspnea, bronchospasm, or hypotension. Monitor patients
during and for at least 1 hour after the end of the infusion or until signs and symptoms completely resolve.
Discontinue use of MYLOTARG in patients who develop signs or symptoms of anaphylaxis, including severe
respiratory symptoms or clinically significant hypotension.
Hemorrhage: MYLOTARG is myelosuppressive and can cause fatal or life-threatening hemorrhage due to
prolonged thrombocytopenia. In ALFA-0701, (MYLOTARG in combination with chemotherapy), all grades and
Grade 3-4 bleeding events were reported in 118/131 (90%) and 27/131 (21%) patients, respectively. Fatal bleeding
events (including cerebral hematoma, intracranial hematoma, and subdural hematoma) occurred in 4/131 (3%)
patients. Thrombocytopenia with platelet counts less than 50 Gi/L persisting more than 42 days occurred in 19
(19%) patients in the induction phase. The proportion of patients with persistent thrombocytopenia increased
with progressive treatment phases and was higher in patients treated with MYLOTARG plus chemotherapy
than with chemotherapy alone. In AML-19 (MYLOTARG monotherapy at 6 mg/m2 Day 1 and 3 mg/m2 Day 8),
all grades and Grade 3 or higher bleeding were reported in 28/111 (25%) and 14/111 (13%) patients, respectively.
Fatal bleeding occurred in 1/111 (1%). In MyloFrance-1 (MYLOTARG 3 mg/m2 as monotherapy), Grade 3 bleeding
was reported in 4/57 (7%) patients, but no patient experienced Grade 4 hemorrhage. Assess blood counts prior
to each dose of MYLOTARG and monitor blood counts frequently after treatment with MYLOTARG until resolution
of cytopenias. Monitor patients for signs and symptoms of bleeding during treatment with MYLOTARG. Manage
severe bleeding, hemorrhage or persistent thrombocytopenia using dose delay or permanent discontinuation
of MYLOTARG, and provide supportive care per standard practice.
QT Interval Prolongation: QT interval prolongation has been observed in patients treated with other drugs
containing calicheamicin. When administering MYLOTARG to patients who have a history of or predisposition
for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients
with electrolyte disturbances, obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment
and as needed during administration.

T:7"

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 1