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ABSTRACT: Imatinib is a selective inhibitor of the BCR/ABL tyrosine kinase. The remarkable initial results of the first phase I clinical trial published in 1999 prompted the rapid initiation of large phase II trials. They also generated intense media coverage and significant interest from patients and clinicians and demand for access to imatinib before marketing approval. In response, a worldwide expanded access program (EAP) for imatinib was implemented in May 2000.
In total, 7380 patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia failing prior therapies were enrolled in 106 centers in 34 countries.
Time to progression and overall survival, as well as the safety profile, were similar to those observed in published phase II studies. At the end of the program, patients benefiting from treatment were continued on imatinib therapy by transferring to national health care systems or patient assistance programs.
The imatinib EAP successfully provided therapy to patients with CML before marketing approval. The program provides an efficient framework for the development of global EAPs for innovative investigational anticancer agents in patients without a satisfactory therapeutic alternative.
Annals of Oncology 08/2008; 19(7):1320-6. · 6.43 Impact Factor
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B J Druker,
M Talpaz,
D J Resta,
B Peng,
E Buchdunger, J M Ford,
N B Lydon,
H Kantarjian,
R Capdeville,
S Ohno-Jones,
C L Sawyers
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ABSTRACT: 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.
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.
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.
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.
New England Journal of Medicine 05/2001; 344(14):1031-7. · 53.30 Impact Factor
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ABSTRACT: BCR-ABL, a constitutively activated tyrosine kinase, is the product of the Philadelphia chromosome. This enzyme is present in virtually all cases of chronic myeloid leukemia (CML) throughout the course of the disease, and in 20 percent of cases of acute lymphoblastic leukemia (ALL). On the basis of the substantial activity of the inhibitor in patients in the chronic phase, we evaluated STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase, in patients who had CML in blast crisis and in patients with ALL who had the Ph chromosome.
In this dose-escalating pilot study, 58 patients were treated with STI571; 38 patients had a myeloid blast crisis and 20 had ALL or a lymphoid blast crisis. Treatment was given orally at daily doses ranging from 300 to 1000 mg.
Responses occurred in 21 of 38 patients (55 percent) with a myeloid-blast-crisis phenotype; 4 of these 21 patients had a complete hematologic response. Of 20 patients with a lymphoid blast crisis or ALL, 14 (70 percent) had a response, including 4 who had complete responses. Seven patients with a myeloid blast crisis continue to receive treatment and remain in remission from 101 to 349 days after starting the treatment. All but one patient with a lymphoid blast crisis or ALL has relapsed. The most frequent adverse effects were nausea, vomiting, edema, thrombocytopenia, and neutropenia.
The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.
New England Journal of Medicine 05/2001; 344(14):1038-42. · 53.30 Impact Factor
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ABSTRACT: The treatment recommendations for chronic myelogenous leukemia (CML) are evolving rapidly. In the past year, pegylated interferon and STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, have become commercially available and non-myeloablative stem cell transplants continue to be refined. Clinicians and patients face a bewildering array of treatment options for CML. In this article Dr. Sawyer reviews the clinical results with STI571 and ongoing investigations into mechanisms of resistance to STI571. Given the newness of STI571, a practical overview on the administration of STI571 is presented by Drs. Druker and Ford, focusing on aspects such as optimal dose, management of common side effects, and potential drug interactions. The most recent data on interferon-based regimens are reviewed by Dr. Baccarani in the third section. In the last section Dr. Goldman presents recent results of allogeneic stem cell transplants, including the reduced intensity conditioning regimens. Lastly, the proposed place of each of these treatments in the management of CML patients is addressed to assist in deciding amongst treatment options for CML patients.
Hematology 02/2001; · 1.49 Impact Factor
