Developing Drugs for Leukemias

Abstract

At present, available therapies are only partially effective in patients with leukemia and the vast majority of patients cannot be cured with current treatment strategies. Hence, there is an obvious need to develop more specific and effective drugs for the treatment of these diseases. In the last twenty years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the molecular abnormalities in acute and chronic leukemia. These achievements have provided new opportunities for the development of innovative drugs, and leukemia mortality rates have begun to decline. Molecular-targeted drugs were first introduced for the treatment of hematological malignancies. Imatinib was the first small moleculetargeted drug successfully used for the treatment of chronic myeloid leukemia (CML), and rituximab was the first tumor-specific antibody to be introduced for the treatment of CD20-positive lymphomas and chronic lymphocytic leukemia (CLL). The introduction of imatinib and rituximab has changed the mortality rates associated with CML and B-cell lymphoid malignancies. In CML the availability of tyrosine kinase inhibitors (TKIs) changed the management and prognosis of this disease [1]. However, about 20% of CML patients do not achieve optimal response on imatinib treatment and they need alternative drugs. The availability of second generation TKIs, such as dasatinib and nilotinib, has provided new therapeutic hope for patients with imatinib resistance [2]. In addition, new molecules with different modes of action have demonstrated activity in patients with highly-resistant mutants such as MK0457 and danusertib, which exhibit inhibitory activity against Aurora kinases [3]. Current therapies are frequently inappropriate and unsuccessful for acute myeloid leukemia (AML), especially for older patients. For these patients, there is an obvious need to develop better strategies and new, more specific and active drugs. The search for new drugs in AML has led to the development of many new antileukemic agents potentially active in this form of leukemia [4]. Novel agents potentially useful in the treatment of patients with AML include monoclonal antibodies, molecular target drugs, newer nucleoside analogs and other drugs. These new agents seem unlikely to be curative when administered as monotherapy. They will rather have to be used in combination with other new agents or with more standard therapy. Nucleoside analogs are clinically important antileukemic drugs which compete with physiologic nucleosides and consequently, interact with a large number of intracellular targets. Recently, three novel nucleoside analogs, clofarabine, troxacitabine and sapacitabine, have been introduced into clinical trials in AML and shown promise. However, phase II and III randomized trials are necessary to verify whether these drugs confer an advantage in the treatment of this disease.