Effect of Renal and/or Hepatic Impairment on the Pharmacokinetics and Safety of Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: Inotuzumab ozogamicin (InO) is an antibody drug conjugate targeting CD22 antigen linked to N-acetyl-g-calicheamicin dimethyl hydrazide, a potent cytotoxic antibiotic that induces double strand DNA breaks. The pharmacokinetics of InO has been characterized in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The primary objective of this analysis was to assess the pharmacokinetics and safety of InO in patients with renal and/or hepatic impairment.

Methods: The effects of renal and hepatic impairment on the pharmacokinetics of InO clearance (CL) were evaluated in adult patients with relapsed or refractory ALL (n=234) following administration of 1.2-1.8 mg/m² fractionated over 2 or 3 doses given weekly. For assessment of renal function, patients were stratified into 5 subgroups using baseline creatinine clearance (BCrCL): normal (≥90 mL/min), mild (60-89 mL/min), moderate (30-59 mL/min), severe (15-29 mL/min), and end-stage renal disease (<15 mL/min).

For assessment of hepatic impairment, patients were stratified into 5 subgoups per criteria from the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG), which categorizes impairment based on baseline total bilirubin (TB) and aspartate aminotransferase (AST): normal (TB and AST ≤ upper limit of normal [ULN]), mild B1 (TB ≤ ULN and AST > ULN), mild B2 (TB >1-1.5 x ULN, any AST), moderate (TB >1.5-3 x ULN, any AST), and severe (TB >3 x ULN, any AST).

Data from adult patients with relapsed or refractory ALL (n=161) who received InO at a starting fractionated dose of 1.8 mg/m² were used to evaluate the safety of InO in patients with some degree of renal and/or hepatic dysfunction. For each of the renal function and NCI ODWG hepatic impairment subgroups, the percentage of patients exhibiting Grade ≥3 for any adverse events and Grade ≥3 hepatoxicity adverse event, respectively, was reported. Severity of hepatoxicity was determined through standardized search criteria with Standard Medical Dictionary for Regulatory Activities queries (cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, noninfectious; and liver-related investigations, signs, and symptoms) and preferred terms (veno-occlusive liver disease or veno-occlusive disease; hepatic vein occlusion or thrombosis; portal vein thrombosis; Budd-Chiari syndrome; chronic graft versus host disease in liver; and acute graft versus host disease in liver).

Results: For renal impairment, the median InO CL was 0.0394, 0.0403, 0.0308, and 0.0273 L/h, respectively, in individuals with normal (n=184), mild (n=32), moderate (n=17), and severe renal impairment (n=1). There were no patients with end-stage renal disease. Grade ≥3 adverse events were reported in 91.7% of patients with normal, 81.8% with mild, 100% with moderate, and 0% with severe or end-stage renal disease renal impairment.

For hepatic impairment, the median InO clearance was 0.0363, 0.0520, 0.0382, and 0.0238 L/h, respectively, in individuals with normal (n=167), mild B1 (n=58), mild B2 (n=8), and moderate hepatic impairment (n=1). There were no patients with severe hepatic impairment. Hepatotoxicity Grade ≥3 adverse events were reported in 23.6% of patients with normal, 6.8% with mild B1, and 3.1% with mild B2 hepatic function; no such events occurred in patients with moderate or severe hepatic impairment.

Conclusions: InO pharmacokinetics were not affected by renal or hepatic impairment status, and safety was similar regardless of renal and/or hepatic function. Therefore, no starting-dose adjustment is required for patients with relapsed or refractory ALL with pre-existing mild to severe renal dysfunction or mild hepatic impairment.