FDA Approves BESPONSA (Inotuzumab Ozogamicin) for Adults with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

On August 17, 2017, the U.S. Food and Drug Administration (FDA) approved BESPONSA (inotuzumab ozogamicin) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Hepatotoxicity, including fatal and life-threatening veno-occlusive disease (VOD) occurred in patients with relapsed or refractory ALL who received BESPONSA. The risk of VOD was greater in patients who underwent hematopoietic stem cell transplant (HSCT) after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ 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 higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate.

Administer BESPONSA with caution in patients who have a history of or predisposition for QTc prolongation, who are taking drugs that prolong QT interval, and in patients with electrolyte disturbances.  

 Approved Recommended Dosage


  • Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions. For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm3 is recommended prior to the first dose.

Cycle 1:

  • The recommended total dose of BESPONSA for all patients is 1.8mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.8mg/m2), Day 8 (0.5mg/m2), and Day 15 (0.5mg/m2). Cycle 1 is 21 days in duration, but may be extended to 28 days (i.e., 7-day treatment-free interval starting on Day 21) if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity.

  • Subsequent Cycles:

  • In patients who achieve a CR or CRi, the recommended total dose of BESPONSA is 1.5mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.5mg/m2), Day 8 (0.5mg/m2), and Day 15 (0.5mg/m2). Subsequent cycles are 28 days in duration.
  • In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8mg/m2 per cycle given as 3 divided doses on Day 1 (0.8mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5mg/m2). Subsequent cycles are 28 days in duration. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
  • For patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease negativity after 2 cycles.
  • For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.

Dosage Modifications:

  • Clinical monitoring recommendations and dosage modifications for toxicities with BESPONSA, including hematological, hepatic and other non-hematological, and infusion-related reactions, are described in the full prescribing information linked below.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate. N-acetyl-gamma-calicheamicin is a cytotoxic agent that is covalently attached to the antibody via a linker. 
  • General PK: PK of inotuzumab ozogamicin was characterized by a 2‑compartment model with linear and time-dependent clearance components. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4 (steady-state). 
  • Distribution: N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. 
  • Elimination: The clearance of inotuzumab ozogamicin at steady state was 0.03 L/h. The terminal half-life was 12.3 days. 
  • Metabolism: N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. 
  • Cardiac Electrophysiology: In patients with relapsed or refractory ALL, QTcF ≥ 60 msec from baseline were observed in 3% of patients in the BESPONSA arm and 2% of patients in the Investigator’s choice of chemotherapy arm. The highest mean for QTcF was 15.3 msec and observed at the beginning of Cycle 4 in the BESPONSA arm.

Drug Interactions
Discontinue drugs known to prolong QTc or use alternative drugs that do not prolong QTc interval or induce Torsades de Pointes. Concomitant use with BESPONSA may increase the risk of QTc interval prolongation. When it is not feasible to avoid concomitant use of drugs known to prolong QTc, monitor as described in the full prescribing information linked below.

Use in Specific Populations
Body surface area was found to significantly affect inotuzumab ozogamicin disposition.

Age (18-92 years), sex, race, or renal impairment (15‑89 mL/min) do not have a clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin. The pharmacokinetics in patients with end stage renal disease with or without hemodialysis is unknown.

Hepatic impairment:
No adjustment to the BESPONSA starting dose is required in patients with total bilirubin ≤ 1.5 × ULN and AST/ALT ≤ 2.5 × ULN. There is limited safety information available in patients with total bilirubin > 1.5 × ULN and/or AST/ALT > 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤ 1.5 × ULN and AST/ALT ≤ 2.5 × ULN prior to each dose unless due to Gilbert’s syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to ≤ 1.5 × ULN or AST/ALT does not recover to ≤ 2.5 × ULN.

Efficacy and Safety
The efficacy and safety of BESPONSA were demonstrated in a randomized, open‑label, international, multicenter study in patients with relapsed or refractory ALL. Efficacy of BESPONSA was established on the basis of achieving CR, the duration of CR, and attainment of minimal residual disease negativity. Additional information regarding the efficacy trial can be found in the full prescribing information linked below. The most common (≥ 20%) adverse reactions are thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

Full prescribing information is available at https://go.usa.gov/xRvhC.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.