Introduction:

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Cooperative group trials and targeted therapies have significantly improved survival rates in pediatric B-ALL; however, 10-20% of patients still relapse, with 5-year overall survival post relapse around 50%. CD19-directed therapies including chimeric antigen receptor T-cell therapy (CART) and blinatumomab have rescued multiply relapsed B-ALL patients. Limitations of blinatumomab include continuous infusion for 28 days and unexpected hospital visits. As blinatumomab moves into frontline therapy it is noted that CD19 escape is prevalent. Inotuzumab Ozogamacin (InO) is an antibody-drug conjugate targeting CD22 on leukemic blasts given as a once-weekly infusion over three weeks. Phase 3 trials of InO in adults with B-ALL showed improved remission rates compared to standard chemotherapy and led to FDA approval of InO for adults (2019) and children (2024). This study aimed to describe our single-center experience of InO in patients with relapsed/refractory B-ALL, many of whom were heavily pretreated.

Methods:

We identified all patients treated at Children's Healthcare of Atlanta from 1/1/2015-7/28/2025 with B-ALL who received at least one dose of InO after time of relapse/refractory status. Patient demographics, treatment pre- and post- InO, and vital status were abstracted from the electronic medical record and reported descriptively.

Results:

Twenty-two patients with relapsed/refractory B-ALL received InO. The mean age at diagnosis and initial InO infusion was 10.5 and 12.5 years, respectively (range: 11 months-17 years; 23 months-20 years). Two patients (9%) were ≥18 years of age at time of first InO infusion. At diagnosis, 8 (36.5%) patients had National Cancer Institute (NCI) Standard Risk B-ALL, 13 (59.1%) were NCI High Risk, and 1 (4.5%) had infant ALL. Overall, 17/22 (77.3%) achieved at least 1 complete remission (CR, range: 0-5) prior to InO therapy, while 5/22 (22.7%) were refractory (unable to achieve CR) to initial therapy. Nineteen patients (86.4%) received a full course of InO (0.8mg/m2 day 1, 0.5mg/m2 day 8 and 15), 2/22 (9.1%) had disease progression in peripheral blood after the second InO dose and stopped treatment, and 1/22 (4.5%) received lower doses of InO. CR with minimal residual disease (MRD) ≤0.01% by Multiparameter Flow Cytometry (MFC) was achieved after InO in 14/22 patients (63.6%); only those who received full dose InO achieved CR. Of the patients with MRD <0.01% after InO, 8/14 (57.1%) are still alive at a median time of 2.3 years. Definitive therapy included CART (n=2, 14.3%), bone marrow transplant (BMT; n=9, 64.3%), and CART followed by BMT (CART+BMT; n=3, 13.6%). Survivors after InO include patients receiving CART (2/2, 100%), BMT (5/9, 55.6%) and CART-BMT (1/3, 33%). All patients who died after BMT were in remission; causes of death were attributed to BMT toxicity with 1 patient having defibrotide-treated veno-occlusive disease (VOD). The CART-BMT patient died from progressive disease.

Of those patients not achieving remission post InO, 7/8 (87.5%) died, with 6/8 (75%) receiving no further cure-directed therapy following InO. Of the remaining 2 patients not in CR after InO, 1 is alive post-CART and the other underwent CART+BMT but died due to complications of BMT including defibrotide treated VOD (in remission at time of death).

Interestingly, t(1;19) was found in 5/22 (22.7%) patients, all of whom died, and accounted for the majority 4/6 (66.6%) of patients with progression after InO.

Conclusions:

This single institution study shows that full-dose InO leads to MRD negative CR in relapsed/refractory patients with B-ALL, serving as an effective bridge to subsequent therapy with CART, BMT, or CART+BMT. Over half of these patients are still alive, further demonstrating the use of InO as a bridge from disease to consolidative therapy. While VOD is a common concern after InO treatment, in our cohort only 2 patients had defibrotide-treated VOD, both following BMT. Further adverse event evaluation is ongoing. In our small cohort the t(1;19) translocation appears to be a negative prognostic indicator for response to InO; future studies should further investigate this association. Overall, these data show InO is a viable alternative to targeted salvage therapies and has the benefit of being able to treat CD22-positive, leukemia with decreased burden of delivery for patients and families during drug infusion.

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2025
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