Application of Inotuzumab Ozogamicin in Children with B-ALL

Introduction Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, about 75% of which are B-cell acute lymphoblastic leukemia, and the 5-year overall survival rate has reached more than 90%. The rate of drug resistance and heterogeneity of relapsed/refractory ALL is high, which makes it difficult to improve the re-remission rate with chemotherapy. Immunotherapy opens a new chapter in the treatment of relapsed/refractory ALL. More than 90% of leukemia cells in B-ALL patients express CD22, while normal cells hardly express CD22, making CD22 a reasonable therapeutic target for B-ALL. Inotuzumab Ozogamicin (InO) is an antibody-drug conjugate (ADC) targeting CD22. After entering the body, InO can target and specifically bind to CD22 antigen on the surface of B cells, release calicheamicin in the cell, break the DNA of the target cells and lead to the cell apoptosis. Although the ADC was approved in China in 2022 for the treatment of adults with relapsed/refractory B-ALL, there is a lack of data on InO in studies of pediatric with B-ALL and currently limited to case reports. This study analyzed 27 cases of children with B-ALL treated with InO in our center to evaluate its efficacy and safety. Methods From December 2022 to now, our center has evaluated 27 cases of B-ALL, including newly diagnosed B-ALL that achieved morphological remission but minimal residual disease(MRD) positive after induction therapy, and relapsed/refractory B-ALL. One case was infantile B-ALL with high WBC count. The patients were pretreated for 5 days with VAD regimen: Vindesine 3mg/m2,d1; Cytarabine 100mg/m2,d1-5; Dexamethasone 6mg/m2,d1-5 (dexamethasone can be replaced with methylprednisolone if the patient was intolerant). InO was administrated with 0.8mg/m2, 0.5mg/m2, and 0.5mg/m2 on D6, D13, and D20, 21 days for 1 cycle. Patients received the above regimen until relapse, disease progression, or intolerant toxicity. Bone marrow and minimal residual disease status were evaluated 3 weeks after the last dose of InO. Adverse complications such as CRS and VOD were monitored, and the effective rate of treatment (CR, PR, PD) was evaluated. All parents needed to sign an informed consent form. Results From December 2022 to July 2024, 27 patients were treated with InO. There were 12 cases with high risk (44.4%), including 8 newly diagnosed cases, 9 cases with medium risk (33.3%) and 6 cases with low risk (22.2%). The median age was 5.5 years. Genetic test results showed 2 TP53 positive, 1 MLL-AF4 positive, 6 TEL-AML positive, 2 FLT3 gene mutation, 2 E2A-PBX1 positive, 1 SSBP2-CSF1R positive, 2 IKZF1 positive and 2 CRLF2 positive. Five patients were treated with InO during the induction therapy, and six were treated with InO following by the Blinatumomab consolidation therapy. Complete response was achieved in 100% of patients with MRD negative and all fusion genes turned negative. No CRS, VOD or death occurred. Conclusions The results showed that MRD turned negative after InO treatment in all 27 children, showing encouraging efficacy and safety. However, immunoglobulin decline was associated with the risk of infection and required gamma globulin support therapy. We suggest that InO shall be increasingly applied in children with B-ALL who were initially diagnosed as high risk and MRD-positive after induction therapy. Keywords acute lymphoblastic leukemia; Inotuzumab Ozogamicin; Targeted therapy