Drug therapy for acute myeloid leukemia

Abstract

Although improvement in outcomes has IntroductionAcute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells and impaired production of normal hematopoiesis leading to neutropenia, anemia, and thrombocytopenia. 1 If untreated, patients die of infection or bleeding usually in a matter of weeks. Some older adults may have a slower progressive clinical course. An estimated 10 600 new cases occurred in the United States in 2002 and 7400 patients died of the disease. 2 The overall incidence is 3.4 cases per 100 000 population; 1.2 cases per 100 000 population at age 30 and more than 20 cases per 100 000 population at age 80 years. 2 The median age is 20 years and has been increasing over the past decade.Historically, the diagnosis and response to therapy were established from morphology and cytochemistry. Although morphology remains the initial diagnostic tool for any patient with acute leukemia, the past decade has witnessed increased reliance on cell-surface antigen expression by immunophenotyping, usually carried out by flow cytometry, as well as cytogenetic and molecular markers.During the past 4 decades, many studies have investigated a wide variety of cytotoxic antileukemic agents. Most recently, insights into the molecular pathogenesis of AML have led to the development of the more specific targeted therapy. This review focuses on current and evolving drug therapy in the treatment of adults with AML. Current treatment resultsApproximately 50% to 75% of adults with AML achieve complete remission (CR) with the deoxycytidine analog cytarabine and an anthracycline antibiotic, such as daunorubicin or idarubicin, or the anthracenedione mitoxantrone, which inhibit the enzyme topoisomerase IIa. However, only 20% to 30% of patients enjoy long-term disease-free survival (DFS). The majority of patients die of their disease, primarily because of persistent or relapsed AML. In an Eastern Cooperative Oncology Group (ECOG) analysis of the outcome of approximately 3000 patients with previously untreated AML entered on 5 successive clinical trials with cytarabine and daunorubicin for induction and with increasingly more intensive postremission therapy, 62% achieved CR, but 76% relapsed or died. 3,4 The 5-year overall survival (OS) rate among 2000 patients younger than 55 years has improved from 11% in the 1970s to 37% in the 1990s. (Figure 1A-C). In contrast, among 1000 patients age 55 years and older, progress over the past 3 decades has been very modest. 5 Prognostic factorsThe outcome for adults with AML depends on a variety of factors, including age of the patient, intensity of postremission therapy, and biologic characteristics of the disease, the most important of which are the cytogenetics at presentation. 4,[6][7][8] (Figure 2). Other factors include the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance, 9 and mutations in or overex...

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

“…It has been claimed that IDA, which is more potent in vitro, is more efficient than DNR in terms of increasing the complete remission rate, prolonging remission duration, and improving survival in AML [2,3]. However, the therapeutic superiority of IDA has not yet been established [4].…”

Autologous stem cell transplantation for elderly patients with acute myeloid leukaemia conditioned with continuous infusion idarubicin and busulphan

“…However, the traditional chemotherapy regimens used to treat adults with AML have not changed significantly over the last two decades [4,5]. While complete remission (CR) rates may have improved, probably due to more appropriate supportive care, this has not converted into a significant survival advantage for patients aged over 60 years, in whom the role of post CR therapy remains undefined [6][7][8][9][10].…”

Granzyme B-H22(scFv), a human immunotoxin targeting CD64 in acute myeloid leukemia of monocytic subtypes

“…After remission, a second therapeutic phase is applied to remove residual cells that are likely to account for a relapse. Current approved postremission therapeutic strategies include intensive consolidation chemotherapy, high-dose chemotherapy with or without radiation therapy, low-dose maintenance therapy, and autologous or allogenic hematopoietic stem cell transplantation (3,4). For both induction and postremission therapy, the risks and benefits of the therapeutic approach have to be evaluated and stratified according to the patient's age and general condition, disease progression, cytogenetic aberrations of leukemic cells, and expression of proteins that confer multidrug resistance or that are pivotal to the regulation of cell proliferation and survival (3,4).…”