Toward effective targeted therapy for the treatment of adult acute lymphoblastic leukemia

Through the effectiveness of combination chemotherapy and allogeneic stem cell transplantation (ASCT), the cure of acute lymphoblastic leukemia (ALL) in children evolved from the 1970s from an anecdotal wonder to a quantifiable reality. Although giving less spectacular results than those seen in children, these therapeutic approaches have been applied to adults over the last two decades, leading to an improved response rate and survival [1]. Retrospective comparisons demonstrating that adolescents with ALL significantly benefit from pediatric rather than adult chemotherapy regimens yielded to the recent development of pediatric-inspired regimens for adult ALL involving greater dose densities of many chemotherapeutic agents, such as l-asparaginase, vincristine, corticosteroids and methotrexate [2]. However, additional gains are unlikely to be achieved by simply intensifying therapy further, due to the offset of unacceptable toxicities. Furthermore, new procedures for ASCT modestly improve the outcome of adult ALL, while introducing higher risks of acute and late complications. There was therefore a clear and compelling rationale for developing therapies that specifically target the molecular abnormalities that cause leukemia. Encouraging signs have recently emerged with the development of novel therapeutic agents, opening a new era of treatment in adult ALL. Several points of intervention have been identified that may respond to targeted drugs. Concomitantly, the biology of leukemia stem cell (eradication of which is considered as the relevant goal of leukemia therapy) was better understood. Several primary studies with targeted agents have demonstrated impressive clinical activity, even in heavily pretreated patients. Others have demonstrated synergistic effects with chemotherapy and the feasibility of such combinations in clinical trials. The era of targeted therapy for ALL started about 15 years ago with the development of the first inhibitor of tyrosine kinase (TKI), imatinib mesylate [3]. Imatinib mesylate and then the other inhibitors of the ABL tyrosine kinase activity of the fusion protein BCR-ABL have revolutionized the treatment of Philadelphia chromosome-positive (Ph) ALL [4,5]. TKIs are now integral components of therapy for Ph ALL. The current consensus is that they improve patient