Therapeutic strategies are evolving for the treatment of patients with newly diagnosed acute myelogenous leukemia (AML), as well as for those with relapsed or refractory disease. Clinical and laboratory studies have demonstrated that AML is not a single disease, but a heterogeneous group of diseases with different clinical features and natural histories. There are variable responses to therapy depending on both the biologic characteristics of the disease and the clinical characteristics of the patient. Nevertheless, studies evaluating the outcomes of relatively large numbers of patients with newly diagnosed AML show that the majority still die of their disease.[1-3]
Older adults with AML fare particularly poorly.[1-3] However, patients with several subtypes identified by specific cytogenetic abnormalities, including inv(16) or t(16;16); t(8;21); or t(15;17), have a much more favorable outcome with contemporary strategies.[4-11] Although much progress has been made in the treatment of AML patients with favorable karyotypes, the lack of progress in both older adults and those with unfavorable karyotypes has been disappointing. These cohorts of patients represent the major challenge for the future.
Dr. Estey, in his concise and comprehensive article, has provided us with the armamentarium to meet these challenges. His most important message focuses on the identification of patients with less than favorable prognoses and the importance of their enrollment into clinical trials that rationally test novel antileukemic agents and therapeutic strategies. Many of these new agents are based on the discovery of new molecular and immunophenotypic targets. The number of new agents available to explore is impressive.
New Agents and New Targets for AML
The anti-CD33 calicheamicin immunoconjugate, gemtuzumab ozogamicin (Mylotarg), is the first of these new targeted agents approved by the US Food and Drug Administration for clinical use in AML. The overall remission rate is 30%, which includes complete remissions by standard definitions plus complete remissions by all criteria with the exception of incomplete platelet recovery. Although similar remission rates can be achieved in patients in first relapse using a variety of other chemotherapy regimens (including high-dose cytarabine(Drug information on cytarabine) [ara-C]), gemtuzumab ozogamicin represents novel technology: an antibody linked to a potent cytotoxic agent that can be administered on an outpatient basis. Furthermore, it appears that this agent is effective not only in patients with favorable prognostic karyotypes, but also in those with intermediate- or poor-prognosis cytogenetics.
A second new class of agents is the farnesyl transferase inhibitors, which have shown encouraging results in a preliminary trial. Dr. Estey raises the exciting possibility that the bcr-abl tyrosine kinase inhibitor imatinib(Drug information on imatinib) mesylate (STI571, Gleevec), which is so effective in patients with chronic myeloid leukemia, may also play a role in patients with AML because of its ability to inhibit the tyrosine kinase associated with c-kit.[17,18]
Overview of Prognostic Factors