Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia

Brian Druker, Moshe Talpaz, Debra J. Resta, Bin Peng, Elisabeth Buchdunger, John M. Ford, Nicholas B. Lydon, Hagop Kantarjian, Renaud Capdeville, Sayuri Ohno-Jones, Charles L. Sawyers

Research output: Contribution to journalArticle

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Abstract

Background: BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. Methods: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results: Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions. Conclusions: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

Original languageEnglish (US)
Pages (from-to)1031-1037
Number of pages7
JournalNew England Journal of Medicine
Volume344
Issue number14
DOIs
StatePublished - Apr 5 2001

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Safety
Interferon-alpha
Cytogenetics
Leukemia, Myeloid, Chronic Phase
Philadelphia Chromosome
Maximum Tolerated Dose
Myalgia
Therapeutics
Metaphase
Nausea
Diarrhea
Edema
Phosphotransferases
Imatinib Mesylate
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. / Druker, Brian; Talpaz, Moshe; Resta, Debra J.; Peng, Bin; Buchdunger, Elisabeth; Ford, John M.; Lydon, Nicholas B.; Kantarjian, Hagop; Capdeville, Renaud; Ohno-Jones, Sayuri; Sawyers, Charles L.

In: New England Journal of Medicine, Vol. 344, No. 14, 05.04.2001, p. 1031-1037.

Research output: Contribution to journalArticle

Druker, B, Talpaz, M, Resta, DJ, Peng, B, Buchdunger, E, Ford, JM, Lydon, NB, Kantarjian, H, Capdeville, R, Ohno-Jones, S & Sawyers, CL 2001, 'Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia', New England Journal of Medicine, vol. 344, no. 14, pp. 1031-1037. https://doi.org/10.1056/NEJM200104053441401
Druker, Brian ; Talpaz, Moshe ; Resta, Debra J. ; Peng, Bin ; Buchdunger, Elisabeth ; Ford, John M. ; Lydon, Nicholas B. ; Kantarjian, Hagop ; Capdeville, Renaud ; Ohno-Jones, Sayuri ; Sawyers, Charles L. / Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. In: New England Journal of Medicine. 2001 ; Vol. 344, No. 14. pp. 1031-1037.
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AU - Buchdunger, Elisabeth

AU - Ford, John M.

AU - Lydon, Nicholas B.

AU - Kantarjian, Hagop

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AU - Sawyers, Charles L.

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N2 - Background: BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. Methods: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results: Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions. Conclusions: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

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