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We are witnessing an unprecedented paradigm shift in the treatment of acute myeloid leukemia (AML). For nearly 4 decades-since the introduction of cytarabine- and anthracycline-based induction chemotherapy in the 1970s-treatment options for patients with AML have remained limited, and outcomes remain poor for the majority of patients, particularly the elderly. Over the past 10 to 15 years, we have better elucidated the genetic and molecular basis of AML, which has led to our current understanding of disease heterogeneity. We now appreciate that numerous distinct disease subtypes exist, each with their own disease characteristics and risk profile. In keeping with this improved understanding, we have seen the introduction of numerous new agents that are mechanistically targeted against a specific mutation, a deranged cellular pathway, and/or a specific AML disease subset. Within the last 3 years alone, the US Food and Drug Administration has approved 8 new targeted agents for the treatment of AML. With their introduction comes a new sense of optimism, along with questions about how to best use these agents. In this article, we discuss the recently approved agents in AML, the rationale behind their development and the trials that served as the basis for their approval, and the implications of their introduction into the treatment armamentarium.

Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) commonly receive intensive chemotherapy to achieve disease remission. In the United States and many other countries, it is standard practice that these patients remain hospitalized "preemptively" until blood count recovery, owing to the risk for overwhelming infections and bleeding during pancytopenia. This care policy requires hospitalization for an average of 3 to 4 weeks after completion of chemotherapy. However, highly effective oral prophylactic antimicrobials are now available, and transfusion support of outpatients has become routine in recent years. As a result, the care of patients with hematologic malignancies treated with intensive modalities is increasingly shifting from inpatient to outpatient settings. Benefits of this shift could include the reduced need for medical resources (eg, transfusions or intravenous antimicrobial therapy), improved quality of life (QOL), decreased rates of nosocomial infections, and lower costs. Increasing evidence indicates that select AML patients undergoing intensive remission induction or salvage chemotherapy can be discharged early after completion of chemotherapy and followed closely in a well-equipped outpatient facility in a safe and costeffective manner. Further demonstration that the current approach of preemptive hospitalization is medically unjustified, economically more burdensome, and adversely affects health-related QOL would very likely change the management of these patients throughout this country and elsewhere, resulting in the establishment of a new standard practice that improves cancer care.

This paper addresses several scientific and ethical issues that arise in the design and conduct of phase II clinical trials of experimental therapies. Although we discuss chemotherapy trials in acute leukemia, the issues pertain to a much larger class of early-phase clinical trials. Our focus is on the manner in which numerical values of standard and targeted response rates of a statistical design are specified, the number of interim tests that are applied, and the effects of these design features on early stopping probabilities and the treatments that patients actually receive. These points are illustrated by numerical comparisons of alternative designs for a particular phase II trial of a new drug for relapsed or refractory acute myelogenous leukemia. We show that statistical designs that target inappropriately low response rates or that apply early stopping rules too infrequently are at odds with good statistical and medical practice and that such designs often provide less benefit to the patients in the trial than would be obtained by simply treating all patients with standard therapy. The general conclusions are that statistical designs have both scientific and ethical implications, and that science, statistics, and ethics cannot be treated as separate issues.

Gemtuzumab ozogamicin was recently approved in the United States for the treatment of older patients with CD33-positive acute myeloid leukemia (AML) in first relapse. However, the lack of randomized clinical trials makes it so difficult to determine which patients are best suited for this compared with other treatment regimens. Results for 128 patients given gemtuzumab ozogamicin in phase II trials were compared with those for 128 patients given high-dose cytarabine (HDAC) combination therapy in different trials Multivariate logistic regression was used to analyze age, duration of first complete remission (CR1), and cytogenetics for potential differences between the groups. rare of overall remission )combined complete remission [CR] plus CR with incomplete platelet recovery [CRp]) following treatment with gemtuzumab ozogamicin or HDAC therapy were 38% and 41%, respectively. Gemtuzumab ozogamicin treatment was associated with a higher overall remission rate compared with HDAC treatment if CR1 duration was 3-10.5 months. In contrast, HDAC treatment was associated with a higher overall remission rate than gemtuzumab ozogamicin treatment if CR1 duration was >19 months. If CR1 duration was between 10.5 and 19 months, the differences in treatment responses were not statistically significant. Thee results reflect the much stronger treatment than with gemtuzumab ozogamicin treatment. Early death (occurring within the first 6 weeks of therapy) was less likely in patients <45 years of age after ADAC and was less likely in patients >75 years of age after gemtuzumab ozogamicin treatment. These data support the recommended use of gemtuzumab ozogamicin as monotherapy in older patients with AML in first relapse, but caution against this use in patients, particularly younger ones, with a long duration of CR1.