Sinusoidal Obstruction Syndrome in Children with CD22+ B-Cell Precursors Acute Lymphoblastic Leukemia (BCP-ALL) Treated with Inotuzumab Ozogamicin in Trial ITCC-059: Risk Factors and Outcomes

Introduction: Inotuzumab Ozogamicin (InO) is an FDA-approved antibody-drug conjugate for the treatment of adults and children with relapsed/refractory BCP-ALL. One of the most relevant toxicities associated with InO is sinusoidal obstruction syndrome (SOS), especially following hematopoietic stem cell transplantation (HSCT). We report the SOS cases from the pediatric trial ITCC-059 (NCT02981628).

Methods: The trial included BCP-ALL patients, 1-18 year-old, with refractory or ≥ 2^nd relapse, or any post-HSCT relapse; and first relapse very high-risk patients (VHR) (stratum III). In phase IA, phase II and stratum III, patients received single agent InO; while in phase IB InO was combined with vincristine and dexamethasone. In phase II and stratum III, all patients received InO at 1.8 mg/m²/cycle (1.5 mg/m²/cycle once in remission); while in phase IA and IB the dose of InO ranged from 0.8 to 1.8 mg/m²/cycle. All patients received intrathecal therapy.

Results: As of June 27^th 2024, 108 patients had been treated (25 in phase IA, 28 in phase II, 30 in Phase IB, and 25 in stratum III), median age was 9.5 years (IQR 5.75,14), 70 (65%) were male, 51 (47%) with ≥ 2^nd relapse, 32 (30%) previously transplanted of which 5 had >1 HSCT.

Overall, 14 (13%) patients developed SOS, 2 during treatment, 10 after HSCT, and 2 after subsequent chemotherapy including high-dose methotrexate and cyclophosphamide. SOS was diagnosed per the Seattle criteria and was graded (Gr) per CTCAE (1 Gr 2, 9 Gr 3 and 4 Gr 4).

In patients undergoing HSCT as consolidation after InO, the incidence of SOS was 20% (10/51), median time from last InO dose to HSCT was 50 days (range: 20-182 days), the mean cumulative dose of InO in these patients was 2.3 mg/m², median age was 9 years (range: 1-17). Of 51 transplanted patients, 11 (22%) had received a previous transplant, 15 (29%) received two alkylating agents as conditioning regimen, 36 (70%) received total body irradiation (TBI); 17 (33%) received prophylactic treatment with defibrotide at investigator discretion. In addition, 8 patients underwent HSCT after subsequent treatment lines due to non-response or relapse, without occurrence of SOS.

The 1-year overall survival (OS ) rate of the entire population (N=108) was 54.9% (95%CI 45.9-65.7), and 69.3% (95%CI 57.4-83.6) for patients with subsequent transplant (N=51); for the 14 patients developing SOS, 1-year OS was 33.3% (95%CI 15.4-72.1) (median follow up time 33 months (range 0.23-42).

All SOS cases received treatment with defibrotide, except one patient in which SOS resolved with supportive management. Among patients who developed SOS, 5/14 (36%) died because of this complication. This included 4/51 (8%) transplanted patients deceased as a result of SOS and septic shock (n=1) or multi-organ failure (n=3, MOF). In the other 6 with post-SCT SOS SOS resolved completely. Both patients developing SOS during InO treatment fully recovered, while of the two cases occurring after further chemotherapy post study treatment, one resolved and one patient died due to MOF with progressive leukemia.

The following risk factors were analyzed in patients receiving consolidation with HSCT after InO (N=51) using univariate logistic regression: age, TBI, conditioning with two alkylating agents, cumulative dose of InO, time from last InO dose to HSCT, previous HSCT and prophylactic use of defibrotide. The only statistically significant risk factor was the time from last InO dose to HSCT (p<0.05). With one additional day from last InO dose to HSCT, the odds of developing SOS decreased by 4% (p=0.036). Median time from last InO dose and HSCT was 28 days (range 20-87 days) in patients who did develop SOS and 55 days (range 21-182 days) in patients who did not. 75% of patients who developed SOS had received HSCT within 38 days of their last InO dose.

Discussion and conclusion: SOS occurred in 13% of pediatric patients treated with InO, and in 20% of subsequent patients after a subsequent transplant. Patients receiving HSCT after InO had 1y-OS of 69.3%, which is encouraging in this population. The time between last InO and HSCT seems a significant risk factor for developing SOS, as in previous studies in adults treated with gemtuzumab ozogamicin. Taking into account also the longer median half-life of InO in pediatrics (T1/2 423 h,17.6 days; Trial NCT02981628), a minimum interval of 35 days after last InO dose and HSCT could be considered based on these data.