On August 17, 2017, inotuzumab ozogamicin (Besponsa) was approved for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).^1,2 

Supporting Efficacy Data 

APPROVAL WAS BASED on complete remission rates in the open-label phase III INO-VATE ALL trial,2,3 in which 326 patients with Philadelphia chromosome (Ph)-negative or Ph-positive relapsed or refractory B-cell precursor ALL were randomized to receive inotuzumab ozogamicin (n = 164) or investigator’s choice of chemotherapy (n = 162), consisting of FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor), HIDAC (high-dose cytarabine), or MXN/AraC (mitoxantrone plus cytarabine). Efficacy results were analyzed in the first 218 randomized patients (109 in each treatment group). 

In the inotuzumab ozogamicin group, complete response was achieved in 35.8% of patients, with a median response of 8.0 months, with 89.7% of these patients having minimal residual disease–negative status. In the investigator’s choice group, complete response was achieved in 17.4%, with a median response of 4.9 months and 31.6% of these patients having minimal residual disease–negative status. Complete response with incomplete hematologic recovery was observed in 45.0% vs 11.9% of patients. Efficacy results in the entire population were consistent with those in the 218 patients. 

How It Works 

INOTUZUMAB OZOGAMICIN is a CD22-directed antibody-drug conjugate. Inotuzumab, which recognizes human CD22, is covalently bonded to the small-molecule cytotoxic agent (N-acetyl-gamma-calicheamicin) via a linker. 

Preclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to binding of the antibody-drug conjugate to CD22-expressing tumor cells, followed by internalization of the conjugate within the cells and intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of the cytotoxic agent induces double-strand DNA breaks, causing cell-cycle arrest and apoptotic cell death. 

How It Is Used 

PATIENTS SHOULD be premedicated before each dose of inotuzumab ozogamicin with a corticosteroid, antipyretic, and antihistamine and should be monitored during and for at least 1 hour after the end of administration for infusion-related reactions. For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count ≤ 10,000/mm3 is recommended prior to the first dose. 

For the first cycle, the recommended total dose for all patients is 1.8 mg/m2 per cycle given in 3 divided doses on day 1 (0.8 mg/ m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2). Cycle 1 is 3 weeks in duration, but it may be extended to 4 weeks if the patient achieves a complete response or complete response with incomplete hematologic recovery or to allow recovery from toxicity. 

For subsequent cycles, the recommended total dose in patients who achieve a complete response or a complete response with incomplete hematologic recovery is 1.5 mg/m2 per cycle given as 3 divided doses on day 1 (0.5 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2); subsequent cycles are 4 weeks in duration. In patients who do not achieve a complete response or a complete response with incomplete hematologic recovery, the recommended total dose is 1.8 mg/m2 per cycle given as 3 divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2); subsequent cycles are 4 weeks in duration. Patients who do not achieve a complete response or a complete response with incomplete hematologic recovery within 3 cycles should discontinue treatment. 

For patients proceeding to hematopoietic stem cell transplantation (HSCT), the recommended duration of treatment is 2 cycles. A third cycle may be considered for patients who do not achieve complete response or complete response with incomplete hematologic recovery and minimal residual disease negativity after 2 cycles. For patients not proceeding to HSCT, additional cycles up to a maximum of six may be administered. 

Product labeling provides specific dosage modification recommendations for hematologic toxicity based on absolute neutrophil count and platelet count and nonhematologic toxicities. 

Safety Profile 

SAFETY DATA are from 164 inotuzumab ozogamicin patients and 134 investigator’s choice patients in the phase III trial supporting efficacy. Among patients in the inotuzumab ozogamicin group, median age was 47 years (range = 18–78 years), 56% were male, 68% and 31% had received one and two prior treatments for acute lymphoblastic leukemia, 68% were white, 19% were Asian, and 2% were black. 

The most common adverse events of any grade in inotuzumab ozogamicin recipients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, and hemorrhage; febrile neutropenia occurred in 26% (all grade ≥ 3) vs 53% in the investigator’s choice group (all grade ≥ 3). In the inotuzumab ozogamicin group, the most common adverse events leading to treatment discontinuation were infection, thrombocytopenia, hyperbilirubinemia, increased transaminases, and hemorrhage. Veno-occlusive disease was reported in 14% of inotuzumab ozogamicin recipients during or following treatment or following HSCT after completion of treatment. 

Inotuzumab ozogamicin carries boxed warnings for hepatotoxicity and increased risk of post-HSCT nonrelapse mortality. A higher posttransplant nonrelapse mortality rate was observed in patients receiving the agent in the phase III trial. 

The drug also carries warnings/precautions for myelosuppression, infusion-related reactions, QT interval prolongation, and embryofetal toxicity. Women should be advised not to breastfeed. Patients should be monitored for complete blood counts, signs and symptoms of infection, bleeding/hemorrhage, and other effects of myelosuppression during treatment. ECGs and electrolytes should be obtained at baseline and monitored during treatment, with more frequent monitoring in patients receiving other medications known to prolong QT interval. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572133.htm. Accessed September 7, 2017. 

2. Besponsa (inotuzumab ozogamicin) for injection prescribing information, Wyeth Pharmaceuticals Inc, August 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf. Accessed September 7, 2017. 

3. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740-753, 2016.