Background: Individuals with Down syndrome (DS) have a 20-fold increased risk of B-cell acute lymphoblastic leukemia (B-ALL), and experience more frequent relapse and toxicities during ALL therapy, including infection-related mortality. Inotuzumab ozogamicin (InO) is a monoclonal anti-CD22 antibody conjugated to calicheamicin that has demonstrated efficacy and tolerability in adult and pediatric B-ALL, but has not been well studied to date in patients with DS. Here, we report a retrospective study of children, adolescents and young adults (AYA) with DS and B-ALL treated with InO, to provide real-world safety and efficacy data in this vulnerable population.

Methods: Data were submitted for subjects receiving InO at 13 institutions between 2016-2024. Data were abstracted from the medical record and compiled on a standardized case report form for a retrospective cohort of patients with DS who received InO at any time during ALL therapy. Bone marrow (BM) response was reported as M1, M2, or M3 based on morphology with <5%, 5-25%, or <25% blasts; and M1 was further reported as minimal residual disease positive (M1/MRD+) or negative (M1/MRD-) based on > or <0.01% blasts by flow cytometry, respectively.

Results: The cohort consisted of 23 individuals with DS and B-ALL, with a median age of 8.5 years at diagnosis (range 2.8-35.8). Patients were 56% male, 30.4% non-Hispanic White, 65.2% Hispanic, and 4.3% non-Hispanic other. Three patients received InO in first remission, and 20 following first or greater relapse. The number of InO cycles received was one (n=12), two (n=5), three (n=1), or four (n=5). Among 22 patients with BM evaluations performed following their first cycle of InO, 8 converted from M2/M3 to M1/MRD-; 5 converted from M2/M3 to M1/MRD+; and 7 maintained M1 status pre- and post-InO. Only 2 of 22 patients were not M1 post-InO: one converted from M3 to M2, and one remained M3 pre- and post-InO. Six of 11 patients had BMs after InO cycle 2: one converted from M2 to M1/MRD+, one from M1/MRD+ to M1/MRD-; 3 were M1/MRD- pre- and post-InO, and one was M1/MRD+ pre- and post-InO. Two patients demonstrated progressive disease in cycles 3 and 4, two were M1/MRD-, and the remainder did not have BMs following these cycles. Overall, InO was fairly well tolerated. Adverse events reported for the 23 patients included transaminitis (grade 3 in 8 and grade 4 in 2); hyperbilirubinemia (grade 3 in 2 and grade 4 in 2); bleeding or hemorrhage (grade 3 in 3); and infections (grade 3 in 4 and one grade 5 lung infection with an unidentified organism during InO cycle 4). There was one additional fatal event, a cardiac arrest near the end of InO cycle 2. No sinusoidal obstruction syndrome was reported during InO, and only one case occurred subsequently during hematopoietic stem cell transplant (HSCT) and resolved with supportive care. Following InO, 14 patients (60.9%) went on to receive HSCT (n=7), chimeric antigen receptor (CAR) T cells (n=4), or both (n=3). Median follow-up time from start of first InO cycle for the full cohort was 339 days (range 39-1183). Ten patients (43.5%) were alive and in remission at last follow-up, at a median of 344 days (range 141-903). Of these 10 patients with sustained remission, post-InO therapy included HSCT (n=3), CAR T cells (n=1), both (n=1), or other therapies (n=5).

Conclusions: In this retrospective real-world cohort, InO demonstrated efficacy and a tolerability profile that may be acceptable compared to intensive salvage chemotherapy in children and AYA with DS and relapsed ALL, with 10 of 23 (43.5%) maintaining subsequent durable remissions. Further studies are warranted to investigate the role of InO in improving outcomes in this high-risk patient population.

Disclosures

Li:Novartis Pharmaceuticals Canada: Membership on an entity's Board of Directors or advisory committees. Guest:Amgen: Current Employment; Jazz Pharmaceuticals: Speakers Bureau; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Leger:Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Miller:AbbVie, Gilead Sciences, Thermo Fisher Scientific, and United Health Group: Current equity holder in publicly-traded company. Quigg:Alexion AstraZeneca Rare Disease: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Rheingold:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Brien:Jazz Pharmaceuticals: Consultancy; AbbVie, Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

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