**2. Gemtuzumab ozogamicin (GO)**

Gemtuzumab ozogamicin (Mylotarg) is a humanized anti-CD33 IgG4 monoclonal antibody conjugated to a cytotoxic agent N-acetyl gamma calicheamicin via an acid-labile hydrazone linker. After GO binds to CD33, calicheamicin is being released and generates single and double strand breaks with subsequent cellular death [123]. In a phase I dose escalation study of an anti-CD33 calicheamicin immunoconjugate 40 patients with relapsed or refractory CD33(+) AML were treated. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients and the MTD was determined to be 9mg/m2 [124]. After the encouraging results from three open label phase II studies, the FDA approved GO for the treatment of patients with CD33-positive AML in first relapse who were ≥ 60 years and not suitable for intensive chemotherapy. 142 patients with AML in first relapse were enrolled in the studies with median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m2 , at 2-week intervals for two doses. 30% of patients obtained complete morphological remission. High incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia, and elevated hepatic transaminase levels were registered [125]. In a post-approval phase III trial gemtuzumab ozogamicin was administred during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. 637 patients were randomly assigned to receive daunorubicin, cytarabine, and GO vs. standard induction therapy with daunorubicin and cytarabine alone. The CR rate was 69% for DA + GO and 70% for DA (P = 0.59). In this study, the addition of GO to induction or postconsolidation therapy failed to show improvement in CR rate, disease-free survival, or overall survival. Also addition of GO was associated with a higher early mortality during induction (5.5% vs. 1.4%). Major causes of death were fatal hemorrhage and infection. Based on these negative results GO was withdrawn from the market in 2010 [126]. In a subsequent trials different schedules of GO were investigated. Phase 3, open-label study enrolled 280 patients aged 50–70 years with previously untreated de novo AML. Patients were randomly assigned in a 1:1 ratio to standard treatment (control group) with or without five doses of intravenous gemtuzumab during induction and day 1 of each of the two consolidation chemotherapy courses. Although the CR rates were similar between the two arms, IC plus GO provided a significantly improved median event free survival (EFS) (19.6 vs. 11.9 months, p = 0.00018) and median OS (34 vs. 19.2 months, p = 0.046). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the GO group than in the control group, without an increase in the risk of death from toxicity [127]. A meta-analysis of five open label, phase 3 trials comprising 3325 AML patients found that the addition of gemtuzumab ozogamicin significantly reduced

the risk of relapse and improved overall survival at 5 years without increased toxicity for GO treatment [128]. Based on these results FDA approved GO for the treatment of adults with newly diagnosed CD33-positive AML on 1 September 2017, and also approved Mylotarg for the treatment of patients aged 2 years and older with relapsed or refractory CD33-positive AML.
