• Prescribing Information
  • Patient Site
  • Efficacy

    CR/CRi

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

    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.2
    1-sided P value using chi-square test.​​​​​​​
    • In the remission analysis of 218 randomized patients, 73% (n=64/88) treated with BESPONSA responded in Cycle 1 and 24% (n=21/88) responded in Cycle 2. All responses occurred within 3 cycles2,3

    Median DoR was longer with BESPONSA than with SC2

    • 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; DoR=duration of remission; EMD=extramedullary disease; SC=standard chemotherapy.

    MRD negativity

    The rate of MRD negativity* was higher for those receiving BESPONSA vs SC2

    MRD negativity was a secondary endpoint analyzed among responding patients in the first 218 patients randomized.1

    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 SC2
    • 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 SC2
    • 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 and is analyzed among responding patients in the full ITT population (N=326).3

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

    Subgroups

    CR/CRi rates were evaluated across a range of patients1,2

    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.

    Exploratory subgroup analyses

    CR/CRi and MRD-negative CR/CRi rates in patient subgroups1-3

    These subgroup analyses were exploratory and not powered to detect statistical significance. Subgroup data for CR/CRi rates are presented in the full forest plot. Small patient numbers and lack of multiplicity adjustments can be a limitation of these analyses. No conclusion about efficacy by subgroup can be drawn from these data. 

    Additionally, MRD-negative CR/CRi rates are presented for the selected subgroups below. MRD negativity rates are derived from a central laboratory subgroup analysis in patients achieving a CR/CRi per EAC from the ITT218 population.

    • Patients were stratified at randomization based on duration of first remission (<12 months vs ≥12 months), salvage status (first or second), and patient age at randomization (<55 years or ≥55 years)
    First 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.
    First remission <12 months 95% CI for CR/CRi: BESPONSA, 66.0-86.5; SC, 14.6-35.5. First remission ≥12 months 95% CI for CR/CRi: BESPONSA, 71.9-95.6; SC, 24.0-56.6.
    §<50% BMB 95% CI for CR/CRi: BESPONSA, 69.3-96.2; SC, 23.5-61.1. ≥50% BMB 95% CI for CR/CRi: BESPONSA, 67.0-86.6; SC, 15.3-35.4.
    ​​​​​​​ 
    BMB=bone marrow blast; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; EAC=Endpoint Adjudication Committee; HSCT=hematopoietic stem cell transplant; ITT=intent to treat; MRD=minimal residual disease; Ph+=Philadelphia chromosome–positive; SC=standard chemotherapy.

    HSCT

    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

    Consider involving the transplant team early in treatment planning, particularly when assessing a patient receiving BESPONSA for HSCT eligibility. 

    Consider involving the transplant team early in treatment planning, particularly when assessing a patient receiving BESPONSA for HSCT eligibility. 

     CI=confidence interval; HSCT=hematopoietic stem cell transplant; SC=standard chemotherapy.

    OS

    BESPONSA demonstrated a median OS of 7.7 months vs 6.2 months with SC and a 25% relative reduction in the risk of death1,2 

    The analysis of OS did not meet a prespecified boundary for statistical significance of P=0.0104.

    1-sided P value using log-rank test.

    Clinical variables predictive of OS in the INO-VATE ALL study5

    A 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

    Treatment arm

    Clinical factors

    BESPONSA
    (n=123)

    • Achieving CR/CRi
    • Achieving MRD negativity
    • Duration of remission (as a continuous variable)
    • Follow-up HSCT
    • Baseline platelet count ≥100 x 10 /L
    • Baseline hemoglobin ≥10 g/dL

    SC arm
    (n=80)

    • Prior HSCT
    • Follow-up HSCT
    • Baseline platelet count ≥100 x 10 /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
    1. 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.
    2. BESPONSA Prescribing Information. New York, NY: Pfizer Inc.
    3. Data on file. Pfizer Inc., New York, NY. 
    4. Jabbour E, Gökbuget N, Advani A, et al. Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leuk Res. 2020;88:1-9.
    5. 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

    INDICATION

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

    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.

    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.