Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, with the greatest prevalence in children, but it also affects adults, and has an increasing incidence with age. Chromosomal abnormalities in ALL have been frequently described, the most common is the Philadelphia chromosome (Ph). The resulting fusion gene, BCR-ABL1, encodes for a chimerical oncoprotein (BCR-ABL) with constitutive tyrosine kinase activity, which leads to uncontrolled cell proliferation, reduced apoptosis, and impaired cell adhesion. Treating Philadelphia chromosome-positive (Ph+) ALL patients with conventional chemotherapy has not substantially improved their long-term outcomes. Recently, however, BCR-ABL-targeted strategies have been successfully adopted. Imatinib is an oral competitive inhibitor of ABL with demonstrated phase 2 efficacy in patients with treatment-naive and pretreated ALL. Despite its efficacy, imatinib may induce specific resistance in a large proportion of patients, mainly because of the occurrence of ABL1 mutations. Therefore, novel inhibitors have been developed. Dasatinib is a multitargeted kinase inhibitor of BCR-ABL, SRC, C-KIT, PDGFRs, and ephrin A receptor kinases. Unlike imatinib, it binds both the active and inactive BCR-ABL as well as the majority of ABL mutants. Dasatinib is approved for treatment of imatinib-pretreated Ph+ ALL, and chronic myeloid leukemia (CML) on the basis of phase 2 trials that demonstrated impressive efficacy and favorable tolerability profiles. Nilotinib is another BCR-ABL targeted agent that is similar in structure to imatinib but has significantly greater binding affinity. It also has demonstrated promising efficacy in Ph+ ALL but is still being evaluated in phase 2 trials. In this article, the authors reviewed current knowledge on novel tyrosine-kinase inhibitors in adult Ph+ ALL patients.
Piccaluga
Pier Paolo
PP
Institute of Hematology and Medical Oncology L and A Seràgnoli S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. pierpaolo.piccaluga@unibo.it
Paolini
Stefania
S
Martinelli
Giovanni
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D012008:Recurrence; D016019:Survival Analysis; D013844:Thiazoles / Q000627:therapeutic use; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib