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Reprise: gemtuzumab ozogamicin for older patients with acute myeloid leukemia.

The article by Burnett et al published with this editorial again focuses our attention on the use of gemtuzumab ozogamicin (GO), a humanized anti-CD33 antibody linked to a calicheamicin derivative, as a component of therapy for older adults who have been diagnosed with acute myeloid leukemia (AML). The authors report that in a prospective randomized trial, a single dose of GO at the beginning of induction chemotherapy was associated with clinically meaningful and statistically significant improvement in the cumulative incidence of relapse, relapse-free survival, and overall survival. This study sends a strong message about choice of end points and study design in trials of new agents in AML, and adds positive evidence to the mixed collection of clinical results for this intriguing drug. GO was granted accelerated approval by the US Food and Drug Administration in 2000 for use in patients with AML who were 60 years of age or older and had experienced relapse of their disease. The drug was voluntarily withdrawn from the US market in 2010, when the Data Safety and Monitoring Committee overseeing the conduct of the postmarketing confirmatory phase III trial recommended, based on results of a planned interim analysis, that GO randomizations be terminated for lack of efficacy in the presence of enhanced toxicity. That study, conducted by the Southwest Oncology Group (SWOG) as S0106, has been reported to date only in abstract form. There were no differences in rates of complete remission on induction, or in the disease-free survival of patients participating in the postconsolidation randomization. In addition, the rate of fatal adverse events during induction was statistically significantly higher for patients receiving GO in the randomized comparison, even though the rate among patients randomly assigned to GO was similar to the rates observed in previous AML studies conducted by SWOG. AML 16, the trial reported here, was not designed to test a simple question about the inclusion of GO in the induction regimen. There were two randomizations at study entry, to receive GO or not, and to undergo induction chemotherapy with daunorubicin/clofarabine (DC), the experimental arm, or daunorubicin/ara-C (DA), the standard therapy used as a control. This 2 2 design is an efficient choice if the outcome in one randomization is unlikely to be modulated by treatment assignment in the other. Should there be an interaction between the randomizations, one may be left with four smaller arms that lack the desired statistical power for comparison. A further complication in AML 16 is that the induction chemotherapy randomization closed before the end of the trial, and subsequent patients participating in the GO randomization were directly assigned to DA. Additional postinduction randomizations included whether or not the patient would receive a single cycle of consolidation (limited to patients who achieved a complete remission [CR] or partial remission with one induction cycle and were in CR after cycle two). All patients were eligible to be randomly assigned to maintenance with azacitadine or not. The complexity of the design is not unusual in studies of AML. What is unusual, however, is the fact that only the results of the GO randomization are reported here. Burnett et al note that the randomized chemotherapy interventions do not yet have mature data, and will be reportedelsewhere.Anadditionalchallenge is thefact thatonlyasubsetof the patients participating in the GO randomization participated in other randomized components of the trial. It will not be enough to report the results of the other randomizations to fully understand the data. What is needed to present these results fully is an analysis which addresses treatment options, whether by randomization or direct assignment, for all patients participating in the GO randomization. We await that future analysis to understand the data more fully so that we can assess just how a single dose of GO has led to a reduced rate of relapse among those who achieved CR and an improved rate of overall survival. Historically, clinical trials in AML have looked to the induction CR rate as an early indicator of whether the use of a new agent as part of the induction regimen can improve outcome. The experience with GO is that the impact of the drug is simply not seen in a comparison of rates of induction CR. In addition, the lack of improvement in induction CR rate contributed to the early closure of S0106. AML 16 persisted, although achievement of CR was a stated end point for the induction questions. Indeed, induction CR rates did not differ between patients who received a single dose of GO and those who did not. The study recently reported by Castaigne et al is a cleanly designed comparison of adding fractionated doses of GO, or not, to a standard induction and consolidation regimen. This trial, conducted by the Acute Leukemia French Association (ALFA-0701), also finds no difference in rates of induction CR, but identifies GO as significantly associated with improved event-free survival and overall survival (both end points defined for all randomized patients), as well as relapse-free survival (an end point restricted to patients achieving CR). Of particular importance is the fact that AML 16 and ALFA-0701 were both restricted to older patients with de novo AML. Median age on the Burnett et al study reported here was 67 years. Identifying novel therapies for older AML patients has been a major challenge. It appears that GO is promising as a component of the treatment JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 32 NOVEMBER 1