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

CR/CRi

MRD negativity

Subgroups

HSCT

OS

BESPONSA® (inotuzumab ozogamicin) induced significantly more CR/CRi* vs SC1

CR/CRi was a primary endpoint and was analyzed in the first 218 patients randomized (remission analysis population) per the statistical plan.1,2

CR, per Endpoint Adjudication Committee (EAC), was defined as <5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥100 x 109/L and absolute neutrophil counts [ANC] ≥1 x 109/L), and resolution of any EMD. CRi, per EAC, was defined as <5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets <100 x 109/L and/or ANC <1 x 109/L), and resolution of any EMD.11-sided P value using chi-square test.
  • In the remission analysis population of 109 patients randomized to receive BESPONSA, 73% (n=64/88) responded in Cycle 1 and 24% (n=21/88) responded in Cycle 2. All responses occurred within 3 cycles.1,3
Median DoR was longer with BESPONSA than with SC1
  • Median duration of CR was 8.0 months (n=39; 95% CI, 4.9-10.4) with BESPONSA vs 4.9 months (n=18; 95% CI, 2.9-7.2) with SC
  • Median duration of CRi was 4.6 months (n=45; 95% CI, 3.7-5.7) with BESPONSA vs 2.9 months (n=14; 95% CI, 0.6-5.7) with SC
DoR, based on a later cutoff date than CR/CRi, was defined for patients who achieved CR/CRi per investigator’s assessment as time since first response of CR/CRi per investigator’s assessment to the date of a progression-free survival (PFS) event or censoring date if no PFS event was documented.

CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; ITT=intent to treat; MRD=minimal residual disease; SC=standard chemotherapy.

The rate of MRD negativity* was higher for those receiving BESPONSA vs SC1

MRD negativity was a secondary endpoint analyzed among responding patients in the first 218 patients randomized.2

Patients were considered MRD-negative when leukemic cells comprised <1 x 10–4 of bone marrow nucleated cells, as measured by flow cytometry.
  • MRD-negative CR rate was 89.7% (n=35/39; 95% CI, 75.8-97.1) with BESPONSA vs 31.6% (n=6/19; 95% CI, 12.6-56.6) with SC1
  • MRD-negative CRi rate was 69.4% (n=34/49; 95% CI, 54.6-81.7) with BESPONSA vs 23.1% (n=3/13; 95% CI, 5.0-53.8) with SC1
  • In the final ITT analysis of 326 patients, 45.7% (n=42/92) of MRD-negative responses with BESPONSA occurred in Cycle 1, 41.3% (n=38/92) in Cycle 2, and 12.0% (n=11/92) in Cycle 34
The analysis of MRD negativity rate by cycle was not prespecified.3CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; ITT=intent to treat; MRD=minimal residual disease; SC=standard chemotherapy.
Exploratory subgroup analyses​​​​​​​

These subgroup analyses were exploratory and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be a limitation of these analyses. No conclusion about efficacy in subgroups can be drawn from these data.

Efficacy across a range of subgroups: CR/CRi forest plot1,2 Efficacy by disease burden1,2,5

In a post hoc analysis of the phase 3 INO-VATE trial (N=326), the efficacy of BESPONSA vs SC was examined among patients with bone marrow blasts (BMB; ie, disease burden) at the following cutoffs: low (<50%; n=53 vs 48), moderate (50%-90%; n=79 vs 83), or high (>90%; n=30 vs 30). The primary endpoint of CR/CRi was analyzed in the first 218 patients randomized in the intent-to-treat population; this subgroup analysis was based on the full 326-patient population. Findings reported here, including differences among subgroups in the BESPONSA and SC treatment groups, should be interpreted with caution, given the post hoc nature of these analyses and the modest sample sizes evaluated. Exclusion criteria from the INO-VATE ALL trial (eg, patients with peripheral blasts ≥10,000/µL) affected the enrolled patient population and may impact the generalizability of these results.

Regardless of disease burden, patients treated with BESPONSA achieved a CR/CRi rate of at least 70%5 
Efficacy by age (≥55 years and <55 years)1-3,4

In a post hoc analysis of the phase 3 INO-VATE ALL trial (N=326), the efficacy of BESPONSA vs SC was examined among adult patients (≥18 years; median age 47). Patients were stratified based on patient age at randomization (≥55 years or <55 years). CR/CRi was a primary endpoint analyzed in the first 218 patients randomized in the intent-to-treat population. This subgroup analysis was based on the full 326-patient population.1,4

BESPONSA-treated patients aged ≥55 and <55 achieved CR/CRi rates ≥70%4Header References≥55 years old 95% CI for CR/CRi: BESPONSA, 57-81; SC, 24-49. <55 years old 95% CI for CR/CRi: BESPONSA, 66-83;SC, 20-38.4According to the investigator’s assessment of CR/CRi.4
Efficacy by salvage setting1-3

In a post hoc analysis of the phase 3 INO-VATE ALL trial (N=326), the efficacy of BESPONSA vs SC was examined among adult patients (≥18 years; median age 47). Patients were stratified based on salvage setting at randomization (first or second). CR/CRi was a primary endpoint analyzed in the first 218 patients randomized in the intent-to-treat population.1-3

ReferencesFirst salvage 95% CI for CR/CRi: BESPONSA, 77.9-94.2; SC, 18.8-40.6. Second salvage 95% CI for CR/CRi: BESPONSA,  49.0-81.4; SC, 16.3-48.1.2
Efficacy by duration of first remission1-3

In a post hoc analysis of the phase 3 INO-VATE ALL trial (N=326), the efficacy of BESPONSA vs SC was examined among adult patients (≥18 years; median age 47). Patients were stratified based on duration of first remission at randomization (≥12 months vs <12 months). CR/CRi was a primary endpoint analyzed in the first 218 patients randomized in the intent-to-treat population.1-3

ReferencesFirst remission ≥12 months 95% CI for CR/CRi: BESPONSA, 71.9-95.6; SC, 24.0-56.6. First remission <12 months 95% CI  for CR/CRi: BESPONSA, 66.0-86.5; SC, 14.6-35.5.2
HospitalizationHospital days per patient month6

Analysis overview

  • The study objective was to analyze hospitalization frequency of R/R ALL patients who received BESPONSA vs SC, based on data collected in the phase 3 INO-VATE ALL trial. Hospital days per patient month were analyzed for different treatment cycles, subgroups, and main reasons for hospitalizations

Key limitations

  • The analysis only compared BESPONSA with SC, as in the INO-VATE ALL trial. Other treatments were not included in the comparison
  • The INO-VATE ALL trial may not reflect everyday clinical practice, as both treatment and follow-up observation of patients were highly influenced by the clinical study protocol
  • Hospitalizations were only documented during study treatment. These analyses do not capture the potential impact of BESPONSA-related VOD on hospitalization during the HSCT period

Methodology

  • Analyses were performed on individual patient-level data from the January 2017 data cut (n=307), which included all R/R ALL patients who were randomized to either BESPONSA or SC therapy and received at least one dose of study drug
  • Due to differences in treatment duration between the BESPONSA and SC arms, hospitalization burden was defined as hospital days per observed patient month during study treatment
  • Admission for treatment administration was neither recommended nor mandated, but was entirely based on physician judgment
  • Number of patients with at least one hospitalization and the total number of days a patient was hospitalized from randomization until end of study were calculated to compare the hospitalization burden between treatments

These analyses were exploratory, not prespecified, and not powered to detect statistical significance. Small patient numbers, specifically in later cycles of the control arm, can be limitations of these analyses. Patients in the BESPONSA arm received a median of 3 cycles of study therapy, compared with a median of 1 cycle for the SC arm; patients in the SC arm received up to 4 cycles.

Hospitalization days during study treatment (per patient month)6

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References
  • 17.1% (28/164) of patients treated with BESPONSA did not need hospitalization (vs 5.6% [8/143] of patients treated with SC)3,6
  • 7.61 mean hospitalization days per patient month with BESPONSA (vs 18.42 days per month for patients treated with SC)3,6
Scroll left to view table
Reason for hospitalization Number of patients Hospitalizations per
patient month
Scheduled ALL treatment or study related 45.7% (75/164) of patients in the BESPONSA arm 
vs 63.6% (91/143) of patients in the SC arm
4.11 DAYS
(vs 10.62 days with SC)
Treatment toxicities 28.7% (47/164) of patients in the BESPONSA arm 
vs 21.0% (30/143) of patients in the SC arm
1.44 DAYS
(vs 2.80 days with SC)
ALL=acute lymphoblastic leukemia; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; HSCT=hematopoietic stem cell transplant; MRD=minimal residual disease; OS=overall survival; Ph+=Philadelphia chromosome–positive; R/R=relapsed or refractory; SC=standard chemotherapy.
In the INO-VATE ALL study, HSCT rates more than doubled with BESPONSA vs SC1,3 This rate represents the percentage of patients who proceeded directly to HSCT without the use of additional or follow-up induction therapies.
  • The median time from the last dose of BESPONSA (inotuzumab ozogamicin) to HSCT was 4.9 weeks (n=71; range, 1-19 weeks)3
CI=confidence interval; HSCT=hematopoietic stem cell transplant; SC=standard chemotherapy.
BESPONSA demonstrated a median OS of 7.7 months vs 6.2 months with SC and a 25% relative reduction in the risk of death1

The analysis of OS did not meet a prespecified boundary for statistical significance of P=0.0104.3

References1-sided P value using log-rank test.Clinical variables predictive of OS in the INO-VATE ALL study7A multivariate analysis using stepwise Cox regression modeling identified the following clinical variables associated with improved OS for each arm. Only patients with measurements for relevant variables were included. Small patient numbers are a limitation of these analyses. 
Treatment arm Clinical factors
BESPONSA 
(n=123)
  • Achieving CR/CRi
     
  • Achieving MRD negativity
     
  • Duration of first remission (as a continuous variable)
     
  • Follow-up HSCT
     
  • Baseline platelet count ≥100 x 109/L
     
  • Baseline hemoglobin ≥10 g/dL
SC arm
(n=80)
  • Prior HSCT
     
  • Follow-up HSCT
     
  • Baseline platelet count ≥100 x 109/L
     
  • Aged ≥55 years
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; OS=overall survival; SC=standard chemotherapy.
References BESPONSA Prescribing Information. New York, NY: Pfizer Inc.Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.Data on file. Pfizer Inc., New York, NY.Jabbour EJ, DeAngelo DJ, Stelljes M, et al. Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Cancer. 2018;124(8):1722-1732.DeAngelo DJ, Advani AS, Marks DI, et al. Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: outcomes by disease burden. Blood Cancer J. 2020;10(8):81.Marks DI, van Oostrum I, Mueller S, et al. Burden of hospitalization in acute lymphoblastic leukemia patients treated with Inotuzumab Ozogamicin versus standard chemotherapy treatment. Cancer Med. 2019;8(13):5959-5968.Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474-2487. 
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.