Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia

Abstract

Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML. Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality. Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.

Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

“…However, in a report of 23 consecutive patients given GO for AML who relapsed following HSCT, liver injury consistent with VOD/SOS occurred in almost half (n = 11); histology studies suggested that GO toxicity resulted from its targeting of CD33 + cells in hepatic sinusoids [52]. In 2010, GO was withdrawn from the market owing to an association of GO plus intensive chemotherapy with increased early deaths in patients with AML, as well as phase III clinical trial evidence showing no evidence of overall survival benefits [56,57]; it was reapproved for AML in 2017 based on efficacy and safety data for GO administered with a fractionated dosing schedule [58,59].…”

Nanocarriers as Magic Bullets in the Treatment of Leukemia

“…Free calicheamicin exerts its effect into the nucleus, where it binds DNA and induces double strand breaks, leading to cell cycle arrest and apoptosis. In principle, stem cells and non-hematopoietic cells should not be affected by this agent due to lack of CD33 expression [164]. The clinical trial aims at evaluating if giving CPX-351 and gemtuzumab ozogamicin may work better in treating patients with AML, compared to giving only one of these therapies alone.…”

Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

“…withdrawn from the market in 2010, due to increased early deaths seen in newly diagnosed AML patients receiving this agent in combination with intensive chemotherapy. However, in 2017, new data based on a fractionated dosing schedule supported its re-approval for patients with newly diagnosed and R/R AML [12,14].…”

“…Factors that affect the mAb affinity for antigen and the ability to elicit immune effector functions (e.g. Gemtuzumab ozogamicin targets CD33, which is expressed on hematopoietic cells of the myeloid lineage and myeloblasts in >80% of patients with AML [12]. Brentuximab vedotin targets CD30, a member of the tumor necrosis factor receptor family, expressed on the Reed-Sternberg cells in Hodgkin lymphoma and ALCL cells.…”