Retrospective analysis of inotuzumab-associated hepatotoxicity in adult patients with B-cell acute lymphoblastic leukemia: Expanding the Spectrum of calicheamicin syndrome

Background Inotuzumab ozogamicin (InO), a CD22-directed antibody–drug conjugate, is effective in relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), but hepatotoxicity remains a recognized adverse effect, most commonly sinusoidal obstruction syndrome (SOS). We previously described a distinct hepatotoxic pattern characterized by recent InO exposure, elevated liver function tests (LFTs), thrombocytopenia, and abnormal hepatic imaging, with biopsy demonstrating hepatic sinusoidal congestion (HSC) without venular occlusion. We termed this entity Calicheamicin Syndrome. This study expands upon that work through a retrospective cohort analysis. Methods Adult patients with R/R B-ALL treated with InO between 2018 and 2024 were retrospectively reviewed. Hepatotoxicity was defined as AST, ALT, ALP, or total bilirubin ≥2× the upper limit of normal within 30 days of InO administration. Patients were stratified by liver biopsy status, laboratory trends, clinical features, and imaging findings. Results Among 21 patients treated with InO, all developed LFT abnormalities, with peak values occurring a median of 16 days after the final dose. Six patients (28.6%) underwent liver biopsy, all demonstrating HSC without features of SOS. Biopsied patients experienced significantly deeper thrombocytopenia (median platelet nadir 26 × 10 9 /l vs. 80 × 10 9 /l; p = 0.03), while ALP elevations were similar between groups. Median time to hepatotoxicity improvement after InO discontinuation was 18 days, and no patients progressed to SOS. Conclusion Calicheamicin Syndrome represents a reproducible and reversible hepatotoxic entity distinct from SOS, characterized by InO exposure, transaminitis, thrombocytopenia, abnormal hepatic imaging, and HSC on pathology. Early recognition may facilitate monitoring and prevent progression to severe hepatic injury.