Targeted therapies in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Abstract

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ; Glivec, Novartis Pharma AG, Basel, Switzerland), a signal transduction inhibitor with preferential effects against the tyrosine kinase activity of the protein product of the ABL proto-oncogene, induced hematologic responses in >or=90% of patients with chronic-phase chronic myeloid leukemia (CML). In Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event, making it another hematologic malignancy targeted by this ABL-tyrosine kinase inhibitor. In an international multicenter phase II trial, imatinib-induced hematologic responses (typically brief) were achieved in 60% of patients with relapsed or refractory Ph(+) ALL. Subsequently, the German Multicenter Study Group for Adult ALL (GMALL) analyzed 59 patients treated in two successive nonrandomized phase II trials of imatinib in patients with relapsed or refractory Ph(+) ALL. Peripheral blood blasts cell clearance occurred within 8 to 14 days in most patients. However, in a significant proportion, blast counts subsequently increased 16 to 50 days after treatment onset. Imatinib mesylate was particularly effective in patients with relapse after stem cell transplantation (SCT); 75% of patients achieved complete leukemic response. Rapid development of resistance during treatment with imatinib mesylate remains a major problem. Further research efforts should explore the mechanisms of resistance to imatinib mesylate; effectiveness of other targeted therapies (eg, farnesyl transferase inhibitors [FTIs]); combination therapies; and inclusion of strategies for immune response modification (eg, donor lymphocyte infusions, interferon-alpha) for Ph/BCR-ABL-positive leukemias.

• Authors: Dieter Hoelzer, Nicola Gökbuget, Oliver G Ottmann
• Journal: Seminars in hematology (Semin Hematol) Vol. 39 Issue 4 Suppl 3 Pg. 32-7 (Oct 2002) ISSN: 0037-1963 [Print] United States
• PMID: 12447850 (Publication Type: Journal Article, Review)
• Copyright: Copyright 2002, Elsevier Science (USA). All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzamides
• MAS1 protein, human
• Piperazines
• Proto-Oncogene Mas
• Pyrimidines
• Imatinib Mesylate

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzamides
• Drug Resistance, Neoplasm
• Humans
• Imatinib Mesylate
• Neoplasm, Residual
• Piperazines (pharmacology, therapeutic use)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, therapy)
• Proto-Oncogene Mas
• Pyrimidines (pharmacology, therapeutic use)
• Treatment Outcome