Approval summary: Gemtuzumab ozogamicin in relapsed acute myeloid leukemia

Purpose: Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic a ntibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute my eloid leukemia (AML). In this study, me review the preclinical and clinical profiles of this immunoconjugate and the regulatory review that led to mar keting approval by the United States Food and Drug Administration. Experimental Design: From the literature and manufacturer's data, we review the activity, tolerability, and pharmacokinetics of gemtuzumab ozogamicin in preclinical and Phase I studies and ifs activity, efficacy, and side eff ects in three Phase 2 trials of 142 patients with relapsed AML. Results: In Phase I studies, the major toxicity was myelosuppression, espec ially neutropenia and thrombocytopenia, resulting from the expression of CD 33 on myeloid progenitor cells. The Phase 2 dose was 9 mg/m(2) infused i.v. over 4 h, repeated on day 14. A minority of patients experienced acute inf usion-related symptoms, usually transient and occasionally requiring hospit alization. The complete response (CR) rate with full recovery of hematopoie sis was 16%. A subset of patients [CRs with incomplete platelet recovery (C Rps)] mas identified with blast clearance and neutrophil recovery but incom plete platelet recovery. The duration of responses of CRps appeared to be s imilar to those of the CRs, although the numbers were small. The question o f the equivalence of these response groups was a central issue in the revie w of this new drug application (NDA). After considerable discussion, the On cology Drugs Advisory Committee recommended allowing inclusion of CRps resu lting in an overall response rate in the Phase 2 studies of 30%. In the sub group of patients over 60 years of age, the overall response rate was 26%. Response duration was difficult to establish because of the high prevalence of postremission therapies. Tolerability and ease of administration may be improved compared with conventional chemotherapy, except for hepatotoxicit y, with 31% of patients exhibiting abnormal liver enzymes. One patient died of liver failure in the Phase 2 trials. Conclusions: Marketing approval of gemtuzumab ozogamicin was granted on May 17, 2000 by the United States Food and Drug Administration under the Accel erated Approval regulations. Gemtuzumab ozogamicin is indicated for the tre atment of patients with CD33 positive AML in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemot herapy. The approved dose was 9 mg/m(2) i.v. over 4 h and repeated in 14 da ys. Completion of the ongoing studies of gemtuzumab ozogamicin in relapsed AML and initiation of randomized clinical trials comparing the effects of g emtuzunab ozogamicin in combination with conventional induction chemotherap y to conventional chemotherapy alone on survival are mandated to confirm cl inical benefit under the accelerated approval Subpart H regulations. Postma rketing reports of fatal anaphylaxis, adult respiratory distress syndrome ( ARDS), and hepatotoxicity, especially venoocclusive disease (VOD) in patien ts treated with gemtuzumab ozogamicin, with and without associated hematopo ietic stem cell transplantation (HSCT), have required labeling revisions an d the initiation of a registration surveillance program. Tumor lysis and AR DS have been reported in patients with leukocytes above 30,000/ml treated w ith gemtuzumab ozogamicin; therefore, the reduction of leukocyte counts to below 30,000/ml is recommended prior to treatment. Patients should be caref ully monitored for acute hypersensitivity, hypoxia, and delayed hepatotoxic ity following treatment with gemtuzumab ozogamicin.