The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

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August 17, 2017

On Aug. 17, 2017, the U.S. Food and Drug Administration approved inotuzumab ozogamicin (BESPONSA™, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The approval was based on data from INO-VATE ALL (NCT01564784), a randomized (1:1), open label, international, multicenter study in 326 patients with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. Patients were required to have ≥5% bone marrow blasts and to have received one or two previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome positive B cell precursor ALL were required to have disease that failed treatment with at least one tyrosine kinase inhibitor and standard chemotherapy.

Patients were randomized to receive inotuzumab ozogamicin (n=164) or investigator’s choice of chemotherapy (n=162). Of the initial 218 randomized patients, 35.8% of those who received inotuzumab ozogamicin experienced complete remission (CR) for a median 8.0 months and 89.7% of those patients achieved minimal residual disease (MRD)-negativity. Of the patients who received chemotherapy, 17.4% experienced CR for a median 4.9 months and 31.6% of those patients achieved minimal residual disease MRD-negativity.

The most common adverse reactions occurring in greater than 20% of patients 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%) adverse reactions reported as the reason for permanent discontinuation were infection, thrombocytopenia, hyperbilirubinemia, transaminases increased, and hemorrhage.

For the first cycle, the recommended dose of inotuzumab ozogamicin for all patients is 1.8 mg/m2 per cycle, administered as three divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2). The recommended dosing for subsequent cycles depends on response to treatment. Details are available in the full prescribing information:

FDA previously granted Orphan Drug and Breakthrough Therapy designations to inotuzumab ozogamicin for the treatment of ALL, as well as priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist’s Applications to Practice

Inotuzumab Ozogamicin for the Treatment of Adults with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia

Author:  Michelle A. Borg, PharmD
PGY-2 Hematology/Oncology Pharmacy Resident
National Institutes of Health Clinical Center
Bethesda, MD

What is the potential role for inotuzumab ozogamicin in the treatment of relapsed or refractory (RR) B-cell precursor acute lymphoblastic leukemia (ALL)?1-5

  • Inotuzumab ozogamicin received breakthrough-therapy designation for the treatment of ALL in October 2015.  On August 17, 2017, the U.S. Food and Drug Administration (FDA) approved inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor ALL.
    • FDA approval was based on data from INO-VATE ALL, a randomized  international multicenter open label phase-3 trial in adult patients with CD22-positive, Philadelphia chromosome (Ph)-positive or Ph-negative relapsed or refractory ALL who were scheduled to receive their first or second salvage treatment (N = 326).  Patients with Ph-negative ALL were required to have received one or two previous induction chemotherapy regimens, and patients with Ph-positive ALL had to be unresponsive to prior treatment with at least one second- or third-generation TKI and standard induction chemotherapy.  Patients were randomized to receive either inotuzumab ozogamicin or standard chemotherapy.  The control treatment included the investigator’s choice of one of three standard regimens:  FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine.
    • Of the initial 218 randomized patients included in the intention-to-treat analysis (n = 109 for each group), results from the 2 primary end points were as follows:
      • Complete remission (CR) rates were significantly higher with inotuzumab ozogamicin compared with standard therapy (80.7% vs. 29.4%, p < .001).
        • Significantly more patients proceeded to hematopoietic stem cell transplant (HSCT) directly after treatment in the inotuzumab ozogamicin group compared to the standard-therapy group (41% vs. 11%, p < .001) because of higher remission rates. 
      • Median overall survival was 7.7 months (95% confidence interval [CI] = 6.0–9.2) for inotuzumab ozogamicin and 6.7 months (95% CI = 4.9–8.3) for standard therapy (hazard ratio [HR] .77 (97.5% CI = .58–1.03, p = .04). 
  • Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) composed of a recombinant humanized antibody to CD22, a linker, and a semisynthetic derivative of calicheamicin. It is the first ADC commercially available for treatment of either Ph-positive or Ph-negative ALL.
  • Inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells and is internalized, subsequently releasing calicheamicin inside the cell. Calicheamicin induces double-strand DNA breaks, followed by cell cycle arrest and apoptosis.
  • Inotuzumab ozogamicin is currently recommended by the National Comprehensive Cancer Network as a treatment option for patients with relapsed or refractory Ph-negative B-cell ALL (category 1) and for patients with Ph-positive B-cell ALL refractory or intolerant to tyrosine kinase inhibitors (TKIs) (category 2A).

What role can the pharmacist play in the management of patients on inotuzumab ozogamicin?3

  • Because of the complexity of dosing based on patient response, pharmacists play a vital role in ensuring accurate dosing.
    • For cycle 1 in all patients, the cycle length is 21 days (can be extended to 28 days if patients achieve CR or CR with incomplete hematologic recovery [CRi] based on bone marrow biopsy, or in the presence of toxicity).  On day 1, patients receive .8 mg/m2, and on days 8 and 15 they receive .5 mg/m2.
    • For subsequent cycles in patients achieving CR or CRi, the cycle length is 28 days.  Patients receive .5 mg/m2 on days 1, 8, and 15.
    • For subsequent cycles in patients not achieving CR or CRi, the cycle length is 28 days.  Patients receive .8 mg/m2 on day 1 and .5 mg/m2 on days 8 and 15. 
  • The recommended duration of treatment with inotuzumab ozogamicin for patients proceeding to HSCT is two cycles.  However, a third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after two cycles.
    • For patients not proceeding to HSCT, a maximum of six cycles may be administered. 
  • A corticosteroid, antipyretic, and antihistamine should be administered prior to all infusions of inotuzumab ozogamicin because of the risk for infusion-related reactions, and patients should be observed during and for at least 1 hour after the end of infusion.    
    • If a reaction occurs, the infusion may be interrupted and the administration of steroids or antihistamines may be considered, depending on severity. 
  • If patients have circulating lymphoblasts, it is recommended to reduce the peripheral blast count to 10,000/mm3 or less by using a combination of hydroxyurea, steroids, and/or vincristine before the first dose of inotuzumab ozogamicin to reduce the risk for reactions.
  • Dosing modifications should be made for adverse events according to the prescribing information. 
    • Common adverse reactions include infection (48%), fatigue (35%), hemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), abdominal pain (23%), myelosuppression (more than 20%), and hepatotoxicity (14%). 
    • Boxed warnings include hepatotoxicity, specifically hepatic veno-occlusive disease (VOD) and sinusoidal obstruction syndrome (SOS), and increased risk of post-HSCT nonrelapse mortality.   
    • Warnings and precautions include myelosuppression, infusion-related reactions, QT interval prolongation, and embryo-fetal toxicity.
    • After the dose is reduced for inotuzumab ozogamicin–related toxicity, do not re-escalate.
  • Concomitant use of inotuzumab ozogamicin with drugs known to prolong the QT interval or induce Torsades de pointes may increase the risk of clinically significant QTc interval prolongation. 
    • Discontinue these drugs or use alternative concomitant drugs that do not prolong the QT/QTc interval while the patient is receiving inotuzumab ozogamicin whenever possible.
    • When it is not feasible to avoid concomitant use of these agents, obtain EKGs and electrolytes prior to the start of treatment and periodically throughout in order to assess changes from baseline and make appropriate intervention.
  • Inotuzumab ozogamicin is supplied as a single-dose vial containing an off-white or white lyophilized powder for reconstitution and dilution. Each vial contains .9 mg of inotuzumab ozogamicin.
    • Each vial should be reconstituted with 4 ml of sterile water for injection to obtain a final concentration of .25 mg/ml.
    • The maximum time from reconstitution through the end of administration should be 8 hours or less, with 4 hours or less between reconstitution and dilution.
    • The medication should be protected from light and should not be mixed or administered as an infusion with other medications.

Clinical Pearls1-3

  • The degree of CD22 expression (90% or greater or less than 90%) did not affect the comparative remission rates with inotuzumab ozogamicin versus standard therapy.
  • Inotuzumab ozogamicin afforded no significant benefit in CR rates compared with standard chemotherapy in patients who were Ph-positive or t(4;11)-positive (p = .08 and p = 1, respectively).
  • Although the authors of the pivotal trial suggest a longer OS with use of inotuzumab ozogamicin on the basis of a post hoc analysis, the objective was not met at the prespecified end point and cannot be fully assessed at this time.
  • The risk of VOD/SOS was increased in patients who had HSCT conditioning regimens with two alkylating agents and total bilirubin levels greater than or equal to the upper limit of normal (ULN) before HSCT.  Therefore, the choice of conditioning regimen should be considered in patients previously treated with inotuzumab ozogamicin.  Additionally, post-HSCT nonrelapse mortality was higher in the inotuzumab ozogamicin group than the standard therapy group. 
    • Upon approval of the agent, the FDA is requiring that inotuzumab ozogamicin undergo additional postmarketing studies to further evaluate the risks for developing VOD/SOS, transplant-related mortality (nonrelapse), and non-transplant-related mortality. 
  • Access and support information is available from a live representative at 877.744.5675.  Patient support includes reimbursement, benefit verification, patient assistance, and copay options.


  1. U.S. Food and Drug Administration. Inotuzumab ozogamicin BLA Approval.  August 17, 2017.  Accessed September 8, 2017.
  2. 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.
  3. Besponsa [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017.
  4. Inotuzumab ozogamicin (CMC-544). Pfizer Oncology: Fact Sheet. May 2012. Accessed August 30, 2017.
  5. Acute Lymphoblastic Leukemia. Version 2.2017. National Comprehensive Cancer Network. Accessed August 30, 2017.