Pulling Back the Curtain: Alexis Thompson, MD, MPH
“Practicing hematology allows us
to have ... meaningful relationships
with patients, making a difference
in their lives while also moving the
field forward.”
BESPONSA (inotuzumab ozogamicin) for injection, for
intravenous use
Initial U.S. Approval: 2017
Brief Summary of Prescribing Information
WARNING: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD)
(ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME and INCREASED RISK
OF POST-HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY
HEPATOTOXICITY, INCLUDING VOD
• Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or
refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was
greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning
regimens containing 2 alkylating agents and last total bilirubin level ≥ upper limit of normal
(ULN) before HSCT were significantly associated with an increased risk of VOD.
• Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver
disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA
treatment cycles.
• Elevation of liver tests may require dosing interruption, dose reduction, or permanent
discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD
occurs, treat according to standard medical practice.
INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITY
• There was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA,
resulting in a higher Day 100 post-HSCT mortality rate.
1. INDICATIONS AND USAGE
BESPONSA is indicated for the treatment of adults with relapsed or refractory B-cell precursor ALL.
5. WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity, Including Hepatic VOD (also known as Sinusoidal Obstruction Syndrome [SOS])
In the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal
hepatic VOD was observed in 23/164 patients (14%) in the BESPONSA arm during or following
treatment or following a HSCT after completion of treatment. VOD was reported up to 56 days after
the last dose during treatment or during follow-up without an intervening HSCT. The median time
from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days). In the BESPONSA arm,
among the 79 patients who proceeded to a subsequent HSCT, VOD was reported in 18/79 patients
(23%), and among all 164 patients treated, VOD was reported in 5/164 patients (3%) during study
therapy or in follow-up without an intervening HSCT. The risk of VOD was greater in patients who
underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2
alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total
bilirubin level ≥ ULN before HSCT are significantly associated with an increased risk of VOD. Other
risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior
HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles.
Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g.,
cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening
of liver disease, including developing VOD, following treatment with BESPONSA. Monitor closely for
signs and symptoms of VOD; these may include elevations in total bilirubin, hepatomegaly (which
may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to
HSCT, the recommended duration of treatment with BESPONSA is 2 cycles; a third cycle may be
considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles. For
patients who proceed to HSCT, monitor liver tests closely during the first month post-HSCT, then
less frequently thereafter, according to standard medical practice. In the INO-VATE ALL trial,
increases in liver tests were reported. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests
occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively. In all patients, monitor liver
tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose
of BESPONSA. Elevations of liver tests may require dosing interruption, dose reduction, or
permanent discontinuation of BESPONSA. 5.2 Increased Risk of Post-Transplant Non-Relapse
Mortality In the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed
in patients receiving BESPONSA compared to the Investigator’s choice of chemotherapy arm
(standard chemotherapy [SC]), resulting in a higher Day 100 post-HSCT mortality rate. Overall,
79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the SC arm had a
follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the
BESPONSA arm compared to the SC arm, respectively. In the BESPONSA arm, the most common
causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events
that occurred post-HSCT were fatal. In the BESPONSA arm, among patients with ongoing VOD at
time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to
MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection). Monitor closely
for toxicities post-HSCT, including signs and symptoms of infection and VOD. 5.3 Myelosuppression
In the INO-VATE ALL trial, myelosuppression was observed in patients receiving BESPONSA.
Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients
(49%), respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23/164 patients
(14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia were
reported in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia,
which may be life-threatening, was reported in 43/164 patients (26%). For patients who were in
CR or CRi at the end of treatment, the recovery of platelets counts to > 50,000/mm 3 was later than
45 days after the last dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients
(2%) who received SC. Complications associated with myelosuppression (including infections
and bleeding/hemorrhagic events) were observed in patients receiving BESPONSA. Infections,
including serious infections, some of which were life-threatening or fatal, were reported in
79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic
shock, and pseudomonal sepsis, were reported in 8/164 patients (5%). Bacterial, viral, and
therapy: We are at a point now where we
can take the beta-globin gene itself and
modify it to treat these conditions. It’s
rewarding to have been a part of that,
working alongside an extraordinary
group of people who have contributed
to these advances. In science, it is never
just one person, but a collective. The
hematology community has been a major
contributor to advancing gene therapy,
both in developing new techniques and
fungal infections were reported. Hemorrhagic events were reported in 54/164 patients (33%).
Grade 3 or 4 hemorrhagic events were reported in 8/164 patients (5%). One Grade 5 (fatal)
hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 patients (1%). The
most common hemorrhagic event was epistaxis which was reported in 24/164 patients (15%).
Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and
symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during
treatment with BESPONSA. As appropriate, administer prophylactic anti-infectives and employ
surveillance testing during and after treatment with BESPONSA. Management of severe
infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe
neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or
permanent discontinuation of BESPONSA. 5.4 Infusion Related Reactions In the INO-VATE ALL
trial, infusion related reactions were observed in patients who received BESPONSA. Infusion related
reactions (all Grade 2) were reported in 4/164 patients (2%). Infusion related reactions generally
occurred in Cycle 1 shortly after the end of the BESPONSA infusion and resolved spontaneously or
with medical management. Premedicate with a corticosteroid, antipyretic, and antihistamine
prior to dosing. Monitor patients closely during and for at least 1 hour after the end of infusion
for the potential onset of infusion related reactions, including symptoms such as fever, chills,
rash, or breathing problems. Interrupt infusion and institute appropriate medical management
if an infusion related reaction occurs. Depending on the severity of the infusion related reaction,
consider discontinuation of the infusion or administration of steroids and antihistamines.
For severe or life-threatening infusion reactions, permanently discontinue BESPONSA.
5.5 QT Interval Prolongation In the INO-VATE ALL trial, increases in QT interval corrected for
heart rate using Fridericia’s formula (QTcF) of ≥ to 60 msec from baseline were measured in
4/162 patients (3%). No patients had QTcF values greater than 500 msec. Grade 2 QT
prolongation was reported in 2/164 patients (1%). No ≥ Grade 3 QT prolongation or events of
Torsade de Pointes were reported. Administer BESPONSA with caution in 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, after initiation of any
drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.
5.6 Embryo-Fetal Toxicity BESPONSA can cause embryo-fetal harm when administered to a
pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities,
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
BESPONSA and for at least 8 months after the final dose of BESPONSA. 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 of BESPONSA. 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 BESPONSA.
6. ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
Hepatotoxicity, including hepatic VOD. Increased risk of post-transplant non-relapse mortality.
Myelosuppression. Infusion related reactions. QT interval prolongation 6.1 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. The
adverse reactions described in this section reflect exposure to BESPONSA in 164 patients with
relapsed or refractory ALL who participated in a randomized clinical study of BESPONSA versus
SC (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone +
cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (INO-VATE ALL Trial [NCT01564784]).
Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18-78 years),
56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2
prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.
In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range:
0.1-26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who
received SC, the median duration of treatment was 0.9 weeks (range: 0.1-15.6 weeks),
with a median of 1 treatment cycle started in each patient. In patients who received BESPONSA,
the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection,
anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia,
transaminases increased, abdominal pain, gamma-glutamyltransferase increased,
and hyperbilirubinemia. In patients who received BESPONSA, the most common
(≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal
pain, pyrexia, VOD, and fatigue. In patients who received BESPONSA, the most common
(≥ 2%) adverse reactions reported as the reason for permanent discontinuation were
infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased
(2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the
reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia
(10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common
(≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%),
thrombocytopenia (1%), and transaminases increased (1%). VOD was reported in 23/164
patients (14%) who received BESPONSA during or following treatment or following a HSCT
after completion of treatment.
Adverse Reactions (All Grades [%]; ≥Grade 3 [%]) With ≥10% Incidence a in Patients With
Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA (N=164) were infection b
(48; 28), thrombocytopenia c (51; 42), neutropenia d (49; 48), anemia e (36; 24), leukopenia f (35; 33),
febrile neutropenia (26; 26), lymphopenia g (18; 16), decreased appetite (12; 1), headache h (28; 2),
hemorrhage i (33; 5), nausea (31; 2), abdominal pain j (23; 3), diarrhea (17; 1), constipation (16; 0),
vomiting (15; 1), stomatitis k (13; 2), hyperbilirubinemia (21; 5), fatigue l (35; 5), pyrexia (32; 3),
chills (11; 0), transaminases increased m (26; 7), gamma-glutamyltransferase increased (21; 10),
and alkaline phosphatase increased (13; 2).
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