Inotuzumab ozogamicin (Besponsa; Pfizer Inc) has received FDA approval for treating pediatric patients aged 1 year and older with relapsed or refractory (R/R) CD22-positive B-cell acute lymphoblastic leukemia (ALL). This approval marks a significant advancement in the treatment landscape for this challenging patient population, offering a targeted therapy with promising clinical outcomes. The approval was granted on March 6, 2024.
Clinical Efficacy and Safety
The FDA's decision was based on the results of the phase 3 INO-VATE ALL study (NCT01564784), a multicenter, single-arm, open-label trial involving 53 pediatric patients aged 1 year and older. The study evaluated the efficacy of inotuzumab ozogamicin, with initial doses of 1.4 mg/m2/cycle in 12 patients and 1.8 mg/m2/cycle in 41 patients. Patients received premedication with an antipyretic, methylprednisolone, and an antihistamine.
The primary efficacy outcome measures included complete remission (CR), duration of CR, and the proportion of patients with minimal residual disease (MRD)-negative CR. Complete remission was defined as less than 5% blasts in the bone marrow, absence of peripheral blood leukemia blasts, full recovery of peripheral blood counts, and resolution of any extramedullary disease. MRD was defined as leukemic cells consisting of less than 1 × 10-4 (< 0.01%) of bone marrow nucleated cells.
The results showed that 42% of all patients (95% CI: 28.1%-55.9%) achieved CR, with a median duration of CR of 8.2 months (95% CI: 2.6 months-not evaluable). The undetectable MRD rate in patients with CR was 95.5% (95% CI: 77.2%-99.9%) based on flow cytometry and 86.4% (95% CI: 65.1%-97.1%) based on real-time quantitative reverse transcriptase PCR.
Common adverse events (AEs; ≥ 20%) included thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache. The recommended dose for inotuzumab ozogamicin is 1.8 mg/m2 per cycle, administered in divided doses on days 1, 8, and 15.
Additional Studies and Findings
The phase 2 ITCC-059 study (NCT02981628) further investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin in pediatric patients with multiple R/R ALL. This study established the RP2D at 1.8 mg/m2. Results indicated that 85% of patients with multiple R/R ALL reached CR after one course of single-agent inotuzumab ozogamicin at the RP2D, and 100% had MRD negativity.
Another phase 2 trial, COG AALL1621, also demonstrated promising results with inotuzumab ozogamicin monotherapy in the pediatric population, showing a CR rate of 58.3% after cycle 1. However, this study also reported sinusoidal obstruction syndrome (SOS) in some patients following hematopoietic stem cell transplant (HSCT).
Mechanism of Action
Inotuzumab ozogamicin is a CD22-directed monoclonal antibody-drug conjugate (ADC). It binds to CD22-expressing tumor cells, leading to internalization and release of N-acetyl-gamma-calicheamicin dimethylhydrazide, a cytotoxic agent that induces DNA double-strand breaks, cell cycle arrest, and apoptotic death.
Considerations and Warnings
Inotuzumab ozogamicin carries a warning for hepatotoxicity, including veno-occlusive disease, and an increased risk of post-HSCT non-relapse mortality. Patients must be premedicated with a corticosteroid, antipyretic, and antihistamine prior to each infusion. Cytoreduction is recommended for patients with circulating lymphoblasts exceeding 10,000/mm3 before the first dose.
Current Treatment Landscape
While inotuzumab ozogamicin is a valuable addition to the treatment arsenal for R/R B-cell ALL, other immunotherapy options exist, including blinatumomab and CAR T-cell therapies like tisagenlecleucel. The choice of therapy depends on individual patient characteristics and disease status.
Ongoing clinical trials, such as the phase 2 Study of Pedi-cRIB (NCT05645718), are exploring the combination of inotuzumab ozogamicin with chemotherapy regimens to further improve outcomes in pediatric patients with R/R ALL.
Conclusion
The approval of inotuzumab ozogamicin represents a significant step forward in the treatment of pediatric R/R B-cell ALL, providing a targeted and effective option for patients facing this challenging disease. Continued research and clinical trials will further refine its use and optimize outcomes for affected children.
