Inotuzumab ozogamicin in paediatric very high risk first B-cell acute lymphoblastic leukaemia relapse (ITCC-059): a multicentre, single-arm, phase 2 trial

Background Children with very high-risk first relapse of B-cell acute lymphoblastic leukaemia have very poor outcomes with conventional chemotherapy. Inotuzumab ozogamicin has shown high antitumoral activity in second or higher relapsed or refractory B-cell acute lymphoblastic leukaemia. We aimed to evaluate the preliminary activity of inotuzumab ozogamicin single-agent in children with very high risk first B-cell acute lymphoblastic leukaemia relapse. Methods ITCC-059 was a multicentre, international, single-arm, phase 1–2 trial, designed to identify the recommended dose of inotuzumab ozogamicin (as monotherapy or with chemotherapy) for paediatric patients with relapsed or refractory CD22-positive acute lymphoblastic leukaemia, as previously reported, and to evaluate its activity and safety. An amendment to the original trial (April 26, 2021) introduced a third cohort, which enrolled patients at 20 hospitals across 12 countries, to evaluate the activity and safety of inotuzumab ozogamicin in children older than 1 year and younger than 18 years with CD22-positive very high risk first B-cell acute lymphoblastic leukaemia relapse and with a performance level of Karnofsky greater than 60% (for patients older than 16 years) or Lansky greater than 60% (for patients aged 16 years or younger). Very high risk relapse was defined as isolated bone marrow or combined relapse occurring less than 18 months after initial diagnosis or with cytogenetic or molecular high-risk characteristics ( KTM2A::AFF1, TCF3::PBX1, TCF3::HLF , hypodiploidy, TP53 ^mut/del). Patients were treated with intravenous inotuzumab ozogamicin at 1·8 mg/m² in cycle 1 (0·8 mg/m² on day 1, 0·5 mg/m² on day 8, and 0·5 mg/m² on day 15). Subsequent inotuzumab ozogamicin cycles were given to responding patients at a dose of 1·5 mg/m² per cycle (0·5 mg/m² on day 1, 0·5 mg/m² on day 8, and 0·5 mg/m² on day 15). A maximum of 6 cycles of inotuzumab ozogamicin were allowed. The primary endpoint for the phase 2 study for cohort 3 was the overall response rate, defined as the combined rate of patients with complete remission, complete remission with insufficient platelet recovery, and complete remission without recovery of counts as best response. Due to slow recruitment, the statistical design was amended to reduce the sample size. Recruitment continued until the amendment was approved by the competent authority (Feb 11, 2025), therefore response analysis for the primary endpoint was conducted only for the initial population that satisfied the amended minimum sample size. Safety outcomes were analysed in all patients who received at least one dose of the study drug and completed a baseline assessment and at least one post-baseline disease assessment. This trial is registered with the European Clinical Trials Information System, 2023-504694-20-00, and EudraCT, 2016-000227-71. Enrolment for cohort 3 of the study is complete, but follow-up is ongoing. Findings Between April 26, 2021, and Feb 11, 2025, 45 patients were screened for inclusion. Eight patients were excluded and 37 patients were enrolled and received treatment. Median age was 11 years (IQR 4–15); 22 (59%) of 37 patients were male and 15 (41%) were female. Among the first 31 enrolled patients (minimal amended sample size), 22 responded after treatment with inotuzumab ozogamicin (overall response rate 71%, 80% CI 58–82). All patients had at least one grade 3–4 haematologic laboratory test abnormality, with neutropenia (35 [95%] of 37 patients) and thrombocytopenia (31 patients [84%]), being the most common. The most common non-haematological grade 3–4 adverse events were febrile neutropenia (11 [30%] of 37 patients), infections (eight patients [22%], including one case of grade 5 lung infection), aspartate aminotransferase elevation (12 patients [32%]), and alanine aminotransferase elevation (ten patients [27%]). Serious adverse events occurred in 17 patients (46%). No treatment-related deaths occurred. Sinusoidal-obstructive-syndrome cases occurred in four (17%) of 23 transplanted patients, all of which resolved after intervention with defibrotide. Interpretation Inotuzumab ozogamicin showed high activity as reinduction treatment in paediatric very high risk first B-cell acute lymphoblastic leukaemia relapse and a favourable toxicity profile with no treatment-related deaths. Funding Pfizer.