Inotuzumab (InO) is an anti-CD22 immunoconjugate for patients with relapsed or refractory CD22 positive B-cell acute lymphoblastic leukemia (B-ALL). Liver toxicity is a recognized side effect of InO, including sinusoidal obstruction syndrome (SOS), but is not fully understood. This study describes a new aspect of InO-induced hepatotoxicity by outlining six patients who developed abnormal liver function tests (LFTs) and thrombocytopenia, with liver biopsies showing sinusoidal congestion without evidence of SOS. Liver biopsies were obtained from all six patients and LFTs were monitored before initiating InO treatment, during treatment, and after discontinuing treatment. All six patients experienced abnormal LFTs at a median of 15 days after the last dose of InO and improvement in LFTs at a median of 17 days after discontinuing InO. Initial baseline AST, ALT, ALP, and total bilirubin values prior to InO therapy ranged from 10-45 U/L, 10-45 U/L, 60-207 U/L, and 0.2-0.9 mg/dL respectively and increased up to 2 to 4 times the upper limit of normal after completing varying cycles of InO with hepatotoxicity grades ranging from 1-2. LFTs returned to 1 to 1.5 times the upper limit of normal after discontinuing InO. The patients' liver biopsies all demonstrated different levels of hepatic sinusoidal congestion (HSC) without evidence of SOS. This study provides new evidence describing HSC, where we hypothesize that InO induced hepatotoxicity are due to calicheamicin. We propose a new clinical entity called "calicheamicin syndrome" with its quadriad components: History of using InO or GO, elevated LFTs, thrombocytopenia, and abnormal liver imaging.