Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.

BACKGROUND Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

[1]  J. Melo,et al.  The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. , 1997, Blood.

[2]  N. Rosenberg,et al.  Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Rowley.  A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining , 1973, Nature.

[4]  B. Druker,et al.  Chronic myeloid leukemia: current treatment options. , 2001, Blood.

[5]  N. Lydon,et al.  Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. , 1997, Blood cells, molecules & diseases.

[6]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[7]  B. Druker,et al.  Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. , 2000, The Journal of clinical investigation.

[8]  B. Cheson,et al.  Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[10]  G. Jenster,et al.  Acute leukaemia in bcr/abl transgenic mice , 1990, Nature.

[11]  C. Sawyers,et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. , 2001, The New England journal of medicine.

[12]  Z. Estrov,et al.  Chronic Myelogenous Leukemia: Biology and Therapy , 1999, Annals of Internal Medicine.

[13]  G. Daley,et al.  Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. , 1990, Science.

[14]  P. Nowell,et al.  A minute chromosome in human chronic granulocytic leukemia , 1960 .

[15]  C Chastang,et al.  Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. , 1997, The New England journal of medicine.

[16]  M. Andreeff,et al.  Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. , 1995, Blood.

[17]  H. Kantarjian,et al.  Determinants of prognosis in late chronic-phase chronic myelogenous leukemia. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  M. Andreeff,et al.  Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  S. Woolf,et al.  An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. , 1999, Blood.

[20]  A. Rimm,et al.  ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKAEMIA , 1984, The Lancet.

[21]  C. Sawyers.  Chronic myeloid leukemia. , 1999, The New England journal of medicine.

[22]  J. Goldman,et al.  Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16‐year period , 1997, British journal of haematology.

[23]  Z. Estrov,et al.  Chronic Myelogenous Leukemia : A Concise Update , 2003 .

[24]  E. Buchdunger,et al.  In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. , 1999, Journal of the National Cancer Institute.

[25]  M. Baccarani,et al.  Staging and prognosis in chronic myelogenous leukemia. , 1988, Seminars in hematology.

[26]  A. Elefanty,et al.  bcr‐abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. , 1990, The EMBO journal.