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HomeAboutDosingEfficacyAdult: Relapsed or
Refractory Patients
With Ph- or Ph+ ALLPediatric: Relapsed or
Refractory CD22-
Positive Patients With
B-cell Precursor ALLSafetySafetyAdult SafetyPediatric SafetySavings & SupportSavings & SupportEventsMaterialsVideosPersonalized patient supportOrdering BESPONSANCCN Guidelines® Recommendations
Prescribing InformationIndicationPatient Site
Adult Safety Data

Safety Overview

Common (≥10%)
ARs

Lab
abnormalities

VOD & post-
HSCT NRM

Tab Number 5

BESPONSA has a BOXED WARNING for VOD and post-HSCT NRM1
  • Hepatotoxicity, including fatal and life-threatening VOD, occurred in patients who received BESPONSA
  • A higher post-HSCT NRM rate occurred in patients receiving BESPONSA
  • Additional warnings and precautions include myelosuppression, infusion-related reactions, QT interval prolongation, and embryo-fetal toxicity
The most common (≥2%) serious adverse reactions (ARs) were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue1
  • The most common (≥2%) ARs reported as the reason for permanent discontinuation of treatment were infection, thrombocytopenia, hyperbilirubinemia, transaminases increased, and hemorrhage
  • The most common (≥5%) ARs reported as the reason for dosing interruption were neutropenia, infection, thrombocytopenia, transaminases increased, and febrile neutropenia
  • The most common (≥1%) ARs reported as the reason for dose reduction were neutropenia, thrombocytopenia, and transaminases increased
ReferencesHSCT=hematopoietic stem cell transplant; NRM=non-relapse mortality; VOD=veno-occlusive disease.ReferenceBESPONSA Prescribing Information. New York, NY: Pfizer Inc.
Common (≥10%) adverse reactions (ARs)1*†‡
  • Safety was reported in a total of 307 patients, including 164 patients receiving BESPONSA and 143 patients receiving SC
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Body systemBESPONSA
(n=164)		SC
(n=143)§
Adverse reactionAll grades, %Grades ≥3, %All grades, %Grades ≥3, %
Infections
Infection48287654
Blood and lymphatic system disorders
Thrombocytopenia51426159
Neutropenia49484543
Anemia36245947
Leukopenia35334342
Febrile neutropenia26265353
Lymphopenia18162726
Metabolism and nutrition disorders
Decreased appetite121132
Nervous system disorders
Headache282271
Vascular disorders
Hemorrhage335285
Gastrointestinal disorders
Nausea312460
Abdominal pain233231
Diarrhea171381
Constipation160240
Vomiting151240
Stomatitis132263
Hepatobiliary disorders
Hyperbilirubinemia215176
General disorders and administration site conditions
Fatigue355253
Pyrexia323426
Chills110110
Investigations
Transaminases increased267135
GGT increased211084
ALP increased13270
ReferencesOnly ARs with ≥10% incidence in the BESPONSA arm are included.1ARs 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).1ARs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.119 patients randomized to the SC arm did not receive treatment.1ReferencesALP=alkaline phosphatase; GGT=gamma-glutamyltransferase; HSCT=hematopoietic stem cell transplant; SC=standard chemotherapy.ReferenceBESPONSA Prescribing Information. New York, NY: Pfizer Inc.
Laboratory abnormalities1
  • Common (≥10%) grade 3/4 laboratory abnormalities with BESPONSA were neutrophil count decreased, leukocytes decreased, platelet count decreased, lymphocytes (absolute) decreased, hemoglobin decreased, GGT increased, and lipase increased
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Laboratory abnormality*BESPONSASC
nAll grades, %Grades 3/4, %nAll grades, %Grades 3/4, %
Hematology
Platelet count decreased161987614210099
Hemoglobin decreased161944014210070
Leukocytes decreased16195821429998
Neutrophil count decreased16094861309388
Lymphocytes (absolute) decreased16093711279791
Chemistry
GGT increased14867181116817
AST increased160714134384
ALP increased158571133523
ALT increased161494137464
Blood bilirubin increased161365138356
Lipase increased139321390202
Hyperuricemia158163122110
Amylase increased14315210291
ReferencesLaboratory abnormalities were summarized up to the end of treatment +42 days but prior to the start of a new anticancer therapy as per the USPI.1ReferencesALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma-glutamyltransferase; SC=standard chemotherapy. ReferenceBESPONSA Prescribing Information. New York, NY: Pfizer Inc.
BESPONSA has a BOXED WARNING for VOD and post-HSCT NRM1
  • Hepatotoxicity, including fatal and life-threatening VOD, occurred in patients who received BESPONSA ​​​​​​​
  • A higher post-HSCT NRM rate occurred in patients receiving BESPONSA
Evaluate VOD risk factors when considering treatment with BESPONSARisk factors significantly associated with VOD1
  • Dual-alkylator conditioning regimens
  • Last total bilirubin prior to HSCT ≥ULN
Other risk factors significantly associated with VOD1
  • Prior HSCT
  • Increased age
  • Prior or ongoing liver disease
  • Later salvage lines
  • Greater number of cycles
Multivariate analysis of VOD risk factors in the INO-VATE ALL study2
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Variable tested*
Patients (n)
Odds ratio
(95% CI)
Alkylator conditioning (dual, single)11, 518.61
(1.52-48.86)
Last bilirubin prior to follow-up HSCT (≥ULN, <ULN)11, 5115.31
(1.95-120.21)
Last AST or ALT prior to follow-up HSCT (>1.5 × ULN, ≤1.5 × ULN)11, 510.027
(0.001-0.83)
History of liver disease or hepatitis (yes, no)15, 475.13
(0.91-29.06)
Prior HSCT (yes, no)10, 526.02
(1.17-31.00)
Last bilirubin prior to conditioning regimen (≥ULN, <ULN)12, 507.08
(1.56-32.06)
Age (≥55 years, <55 years)11, 514.08
(0.82-20.37)
ReferencesA multivariate analysis from the January 4, 2017, cutoff.3Monitoring and management for all patients1
  • 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
  • Monitor liver tests, including ALT, AST, total bilirubin, and ALP, prior to and following each dose of BESPONSA
  • Permanently discontinue treatment if VOD (any grade) occurs
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Treatment considerations for patients proceeding to HSCT
AVOID DUAL-ALKYLATING AGENTSAvoid the use of HSCT conditioning regimens containing dual-alkylating agents. Dual-alkylator conditioning regimens were significantly associated with an increased risk of VOD.
LIMIT NUMBER OF CYCLES
Limit treatment with BESPONSA to 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and MRD negativity after 2 cycles.
MONITOR TOTAL BILIRUBIN

Total bilirubin ≥ULN prior to HSCT was significantly associated with an increased risk of VOD.
  • During the first month post HSCT, monitor liver tests closely, then less frequently thereafter according to standard medical practice
Incidence of VOD in the INO-VATE ALL studyIn the INO-VATE ALL study, 23 out of 164 patients (14%) treated with BESPONSA experienced VOD1
  • 18 patients experienced VOD after proceeding to HSCT (of 79 patients who received HSCT)
    • Median time to onset of VOD post HSCT was 15 days (range, 3-57)
    • In total, 5 cases of VOD were fatal
  • 5 patients experienced VOD during treatment or in follow-up without HSCT
Regional VOD incidence by location of trial site in the INO-VATE ALL study2
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VOD incidenceUnited StatesRest of world
Incidence of VOD in all patients6.7% (n=5/75)20.2% (n=18/89)
Incidence of VOD in post-HSCT patients8.6% (n=3/35)34.1% (n=15/44)
  • Data suggest that the use of conditioning regimens containing 2 alkylating agents was more common outside the United States3
Post-HSCT NRMVOD and infections were the most common causes of post-HSCT NRM1
  • Overall, 48% of BESPONSA patients proceeded to HSCT vs 22% of SC patients
  • Post-HSCT NRM was higher with BESPONSA (39%; n=31/79) vs SC (23%; n=8/35), resulting in a higher Day 100 post-HSCT mortality rate
ReferencesALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; HSCT=hematopoietic stem cell transplant; MRD=minimal residual disease; NRM=non-relapse mortality; SC=standard chemotherapy; ULN=upper limit of normal; VOD=veno-occlusive disease.​​​​ReferencesBESPONSA Prescribing Information. New York, NY: Pfizer Inc.Data on file. Pfizer Inc., New York, NY.Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017;4(8):e387-e398.
Safety

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PP-MCL-USA-0367
INDICATIONBESPONSA® (inotuzumab ozogamicin) is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Important Safety 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 (NRM):

  • Hepatotoxicity, including fatal and life-threatening VOD, occurred in patients who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment. The use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin ≥ 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
  • There was a higher post-HSCT NRM rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate

Hepatotoxicity, Including Hepatic VOD: In adult patients in the INO-VATE ALL trial, hepatotoxicity, including fatal and life-threatening VOD, occurred in 23/164 patients (14%) during or following treatment with BESPONSA or following subsequent HSCT. VOD was reported up to 56 days after the last dose during treatment or follow-up without an intervening HSCT. The median time from HSCT to onset of VOD was 15 days.

VOD occurred in 8/53 (15%) of pediatric patients treated with single agent BESPONSA. Among the 26 pediatric patients who underwent HSCT, VOD occurred in 5 (19%) patients.

Patients with prior VOD or serious ongoing liver disease are at an increased risk of worsening liver disease, including development of 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. For patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles. A third cycle may be considered for patients who do not achieve a CR or CRi and MRD-negativity after 2 cycles. Monitor liver tests closely during the first month post HSCT, then less frequently thereafter, according to standard medical practice.

Grade 3/4 increases in aspartate aminotransferase, alanine aminotransferase, and total bilirubin occurred in 7/160 (4%), 7/161 (4%), and 8/161 (5%) adult patients, respectively. In a study of pediatric patients, liver test abnormalities occurred, with Grade 3/4 increases in AST, ALT, and blood bilirubin in 11/53 (21%), 11/53 (21%), and 5/53 (9%) of pediatric patients, respectively.

Increased Risk of Post-HSCT Non-Relapse Mortality (NRM): In adult patients in the INO-VATE ALL trial, there was a higher post-HSCT NRM rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate. The rate of post-HSCT NRM was 31/79 (39%) with BESPONSA and 8/35 (23%) with investigator’s choice of chemotherapy. In the BESPONSA arm, the most common causes of post-HSCT NRM included VOD and infections. In a study of pediatric patients, 26/53 patients (49%) had a follow-up HSCT. The post-HSCT NRM rate was 7/26 (27%). Monitor closely for toxicities post HSCT, including signs and symptoms of infection and VOD.

Myelosuppression: Myelosuppression, and severe, life-threatening, and fatal complications of myelosuppression, including hemorrhagic events and infections, have occurred with BESPONSA. In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Febrile neutropenia was reported in 43/164 adult patients (26%).

In a study of pediatric patients, Grade 3 or 4 thrombocytopenia occurred in 24/53 (45%) patients and grade 3 or 4 neutropenia in 21/53 (40%) patients. Infections occurred in 23/53 (43%) patients, and hemorrhage occurred in 22/53 (42%) patients. The most common types of hemorrhage were hematoma in 8/53 (15%), mouth hemorrhage in 6/53 (11%), and epistaxis in 6/53 (11%) patients.

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, and provide appropriate management. As appropriate, administer prophylactic anti-infectives during and after treatment with BESPONSA. Dose interruption, dose reduction, or permanent discontinuation may be required.

Infusion-Related Reactions: Infusion-related reactions (all Grade 2) were reported in 4/164 adult patients (2%). In pediatric patients, infusion-related reactions occurred in 4/53 (8%) patients. Premedicate with a corticosteroid, an antipyretic, and an antihistamine prior to dosing. Monitor patients closely during and for at least 1 hour after the end of the infusion for the potential onset of infusion-related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt the infusion and institute appropriate medical management if an infusion-related reaction occurs. Depending on the severity, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue BESPONSA.

QT Interval Prolongation: Increases in QT interval corrected for heart rate using Fridericia’s formula (QTcF) of ≥60 msec from baseline occurred in 4/162 adult patients (3%). In a study of pediatric patients, increases in QTcF of >60 msec from baseline occurred in 7/49 (14%) patients, and 3/52 (6%) of patients had QTcF values >500 msec. Administer BESPONSA with caution in patients who have a history of or predisposition to QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients who have electrolyte disturbances. Obtain electrocardiograms and electrolytes prior to treatment and after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.

Embryo-Fetal Toxicity: BESPONSA can cause embryo-fetal harm. Apprise pregnant women of the potential risk to the fetus. 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 women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA.

Adverse Reactions: The most common (≥20%) adverse reactions in adult and pediatric patients, including laboratory abnormalities, are thrombocytopenia, pyrexia, neutropenia, infection, anemia, vomiting, leukopenia, hemorrhage, fatigue, nausea, febrile neutropenia, headache, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

Nursing Mothers: Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose.


Please see full Prescribing Information, including BOXED WARNING.

INDICATION BESPONSA® (inotuzumab ozogamicin) is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year of age and older.