ABSTRACT
Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease that is often associated with several chromosomal and molecular abnormalities. Patients who have the Philadelphia (Ph) chromosome and associated BCR-ABL1 oncogene have a particularly poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only known curative treatment for Ph+ ALL and facilitating allo-HSCT in eligible patients is a key treatment goal. However, many patients relapse after allo-HSCT, particularly those with measurable residual disease prior to transplantation, and a significant percentage of patients are ineligible for allo-HSCT, particularly older patients. Hence, many patients require additional/alternative therapies to prolong survival. Studies are ongoing to determine the most effective first-line drug regimens for patients who subsequently undergo allo-HSCT and ineligible patients. Tyrosine kinase inhibitors targeted to Bcr-Abl are important novel therapies for Ph+ ALL. Although imatinib administered in combination with chemotherapy is established as the current first-line strategy, relapse is common, even among allo-HSCT recipients. Emerging data indicate that more potent multi-targeted kinase inhibitors (including dasatinib, nilotinib, and bosutinib) have promising efficacy in the first- or second-line setting. Here, the evidence base for existing drug treatments for Ph+ ALL is discussed and emerging therapeutic strategies are explored.
Subject(s)
Philadelphia Chromosome , Piperazines/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides , Child , Combined Modality Therapy , Dasatinib , Fusion Proteins, bcr-abl/genetics , Hematopoietic Stem Cell Transplantation , Humans , Imatinib Mesylate , Neoplasm, Residual/drug therapy , Neoplasm, Residual/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Thiazoles/therapeutic use , Transplantation Conditioning , Treatment OutcomeABSTRACT
Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).