Current treatment options for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
The clinical management of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been challenging primarily due to the aggressive nature of the disease and limited effective treatment options. The outcome for patients who receive conventional chemotherapy alone is poor, with remission duration of around 12 months and disease-free survival (DFS) rates of not more than 10%. Allogeneic stem cell transplantation (alloSCT) has been the only known curative treatment option, but is limited by the availability of a matched donor and the risk of treatment-related mortality. Given the role of BCR-ABL in the leukemogenesis of Ph+ ALL, current treatments have focused on inhibition of this oncogenic tyrosine kinase. Early studies demonstrate that the use of the BCR-ABL tyrosine kinase inhibitor (TKI), imatinib, before alloSCT results in improved response rates and DFS when combined with standard chemotherapy regimens. Remission duration also is improved when combination chemotherapy and imatinib are administered intensively, even in the absence of allogeneic stem cell transplant. However, resistant disease remains an important problem, and the mechanisms underlying resistance in Ph+ ALL are multifactorial. Novel TKIs are currently under development and are effective in some patients with imatinib-resistant disease. The dual BCR-ABL/SRC family kinase inhibitor, dasatinib, has shown promising activity in the treatment of Ph+ ALL after imatinib failure and has recently been approved in this indication. Other TKI-based therapies are also showing potential in imatinib-resistant disease. This article reviews current and emerging treatments in Ph+ ALL.
Stock
Wendy
W
Department of Medicine, Section of Hematology and Oncology, University of Chicago and University of Chicago Cancer Research Center, Chicago, IL 60637-1463, USA. wstock@medicine.bsd.uchicago.edu
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib