Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia

Br J Haematol. 2009 Jun;145(5):581-97. doi: 10.1111/j.1365-2141.2009.07666.x. Epub 2009 Apr 15.

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.

Publication types

  • Review

MeSH terms

  • 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
  • Philadelphia Chromosome*
  • Piperazines / therapeutic use*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / surgery
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / therapeutic use*
  • Thiazoles / therapeutic use
  • Transplantation Conditioning
  • Treatment Outcome

Substances

  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Dasatinib