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HomeAboutDosingEfficacy & SafetyEfficacy & Safety Clinical TrialEfficacySafetySavings & SupportSavings & SupportEventsMaterialsVideosPersonalized patient supportOrdering BESPONSANCCN Guidelines® Recommendations
Prescribing InformationIndicationPatient Site
Safety

Safety Overview

Common (≥10%) ARs

Lab abnormalities

Tab Number 4

VOD & post-HSCT NRM

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 system BESPONSA
(n=164)
SC
(n=143)§
Adverse reaction All grades, % Grades ≥3, % All grades, % Grades ≥3, %
Infections
Infection 48 28 76 54
Blood and lymphatic system disorders
Thrombocytopenia 51 42 61 59
Neutropenia 49 48 45 43
Anemia 36 24 59 47
Leukopenia 35 33 43 42
Febrile neutropenia 26 26 53 53
Lymphopenia 18 16 27 26
Metabolism and nutrition disorders
Decreased appetite 12 1 13 2
Nervous system disorders
Headache 28 2 27 1
Vascular disorders
Hemorrhage 33 5 28 5
Gastrointestinal disorders
Nausea 31 2 46 0
Abdominal pain 23 3 23 1
Diarrhea 17 1 38 1
Constipation 16 0 24 0
Vomiting 15 1 24 0
Stomatitis 13 2 26 3
Hepatobiliary disorders
Hyperbilirubinemia 21 5 17 6
General disorders and administration site conditions
Fatigue 35 5 25 3
Pyrexia 32 3 42 6
Chills 11 0 11 0
Investigations
Transaminases increased 26 7 13 5
GGT increased 21 10 8 4
ALP increased 13 2 7 0
ReferencesOnly ARs with ≥10% incidence in the BESPONSA arm are included.ARs 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).ARs were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 3.0.19 patients randomized to the SC arm did not receive treatment.ALP=alkaline phosphatase; GGT=gamma-glutamyltransferase; HSCT=hematopoietic stem cell transplant; NRM=non-relapse mortality; SC=standard chemotherapy; VOD=veno-occlusive disease.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* BESPONSA SC
n All grades, % Grades 3/4, % n All grades, % Grades 3/4, %
Hematology
Platelet count decreased 161 98 76 142 100 99
Hemoglobin decreased 161 94 40 142 100 70
Leukocytes decreased 161 95 82 142 99 98
Neutrophil count decreased 160 94 86 130 93 88
Lymphocytes (absolute) decreased 160 93 71 127 97 91
Chemistry
GGT increased 160 67 18 111 68 17
AST increased 160 71 4 134 38 4
ALP increased 158 57 1 133 52 3
ALT increased 161 49 4 137 46 4
Blood bilirubin increased 161 36 5 138 35 6
Lipase increased 139 32 13 90 20 2
Hyperuricemia 158 16 3 122 11 0
Amylase increased 143 15 2 109 9 1
ReferencesLaboratory abnormalities were summarized up to the end of treatment +42 days but prior to the start of a new anti-cancer therapy as per the USPI.ALP=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 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, 51 8.61
(1.52-48.86)
Last bilirubin prior to follow-up HSCT (≥ULN, <ULN) 11, 51 15.31
(1.95-120.21)
Last AST or ALT prior to follow-up HSCT 
(>1.5 × ULN, ≤1.5 × ULN)
11, 51 0.027
(0.001-0.83)
History of liver disease or hepatitis (yes, no) 15, 47 5.13
(0.91-29.06)
Prior HSCT (yes, no) 10, 52 6.02
(1.17-31.00)
Last bilirubin prior to conditioning regimen (≥ULN, <ULN) 12, 50 7.08
(1.56-32.06)
Age (≥55 years, <55 years) 11, 51 4.08
(0.82-20.37)
ReferencesA multivariate analysis from the January 4, 2017, cutoff.Monitoring 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 AGENTS Avoid 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 incidence United States Rest of world
Incidence of VOD in all patients 6.7% (n=5/75) 20.2% (n=18/89)
Incidence of VOD in post-HSCT patients 8.6% (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 
ReferencesALT=alanine aminotransferase; AST=aspartate aminotransferase; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; HR=hazard ratio; 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. 
Efficacy & Safety

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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 non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate

Hepatotoxicity, Including Hepatic VOD: 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.

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%) patients, respectively.

Increased Risk of Post-HSCT Non-Relapse Mortality (NRM): 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. 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. Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Febrile neutropenia was reported in 43/164 patients (26%).

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 patients (2%). Premedicate with a corticosteroid, antipyretic, and 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 of ≥60 msec from baseline were measured in 4/162 patients (3%). 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 with 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 observed with BESPONSA were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia. The most common (≥2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.

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

INDICATION BESPONSA® (inotuzumab ozogamicin) is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Please see full Prescribing Information, including BOXED WARNING.