A real-world multi-institution experience of standard vs alternative dosing of inotuzumab ozogamicin for Relapsed/Refractory pediatric B-cell acute lymphoblastic leukemia

Abstract Background: Inotuzumab ozogamicin (InO) is an active agent in children and adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The FDA-approved dosing is 1.8 mg/m2/cycle fractionated into 3 doses, although real-world utilization of InO has included lower dosing, fewer doses, or longer intervals between doses, primarily to minimize acute toxicity, serve as a short bridge to definitive therapy such as chimeric antigen receptor T-cell therapy (CAR-T), and potentially decrease the risk of sinusoidal obstructive syndrome (SOS) after allogeneic hematopoietic stem cell transplant (HSCT). In this multi-institutional retrospective chart review, we report a real-world experience of InO use in children, adolescent and young adult (CAYA) patients with R/R B-ALL, with a focus on comparing outcomes between standard and alternative dosing. Methods: Data were collected from six institutions for patients who received at least one dose of InO for the treatment of R/R B-ALL from January 2016 to December 2023. Clinical data was collected via review of medical records and entered into a RedCap database. Results: The cohort included 75 patients with R/R B-ALL (median age 9 years, range 0-32 years). Ethnicity comprised 47% non-Hispanic white, 11% Asian/Pacific Islander, 6% non-Hispanic black, and 8% other. Most patients received InO for relapsed disease (85%, n=64; 26 for first relapse, 38 for second or greater relapse) while 15% (n=11) received InO for primary refractory disease. The majority of patients (57%; n=43) received FDA-approved dosing, while the remainder received lower doses (9%, n=7; median dose 1.5 mg/m2/cycle) or only 1-2 doses (33%, n=25). 2-year overall survival (OS) for the entire cohort was 77.9%. Patients tolerated InO well with the most common adverse event being febrile neutropenia in 24%. No patient experienced SOS during InO therapy; however, 9% (n=7) developed SOS post-InO, during the course of HSCT (grade ≥3, n=6). SOS occurred at a mean of 58 days after the last InO administration (range 33-108 days). Six of the 7 patients who experienced SOS had received standard InO dosing. In 74 patients for whom response to InO was known, 59% (n=44) achieved CR/CRi, with 88.6% of these patients achieving this after 1 cycle and 11.4% after 2 cycles. Of 43 patients who received standard dosing, 30 achieved CR/CRi (70%), with 87% of those being flow MRD-negative (0.01%). Of 32 patients who received alternative dosing, 14 achieved CR/CRi (44%), with 79% of those being flow MRD-negative. Following InO, 69% of patients were able to proceed to CAR-T (n=18), HSCT (n=27), or both (n=7), while in 29% (n=22), InO was given either as definitive treatment or to patients who were not able to proceed to cellular therapy or HSCT. 30/43 patients (70%) who received standard dosing and 22/32 (69%) who received alternative dosing of InO proceeded to HSCT and/or CAR-T. In univariate analysis, only post-InO HSCT and/or CAR-T was significantly associated with improved 2-year OS (bridging therapy=85.8% vs. definitive therapy=59.1%; p0.001), with no difference based on dosing approach or relapse number in which InO was used. There was no significant difference in cumulative incidence of relapse based on InO dosing approach, relapse number for which InO was used, ability to achieve CR with InO, or time from InO to HSCT or CAR-T. Conclusion: In this multi-institutional, retrospective review we report on a real-word experience of the use of InO in CAYA with R/R B-ALL. InO was most commonly used at FDA-approved dosing; however, we identified modified dosing strategies for a proportion of patients. Notably, there were no differences in the ability to achieve CR or proceed to HSCT/CAR-T following InO based on different dosing approaches. Consistent with previous reports, InO was generally well-tolerated, with SOS occurring exclusively in the post-InO HSCT setting in this cohort. Our experience suggests that InO is most beneficial when used as a bridge to CAR-T and/or HSCT for R/R B-ALL and is effective at enabling patients to proceed to these definitive therapies. Continued refinement of optimal dosing strategies should be pursued to maximize efficacy and minimize toxicity.