Molecular Responses in Patientswith ChronicMyelogenous Leukemia in Chronic PhaseTreatedwith ImatinibMesylate
Purpose:To determine the clinical significance ofmolecular response and relapse amongpatients with chronic myelogenous leukemia (CML) treated with imatinib. Experimental Design:We analyzed the results of quantitative PCR in 280 patients with CML in chronic phasewho achieved complete cytogenetic remissionwith imatinib (117 after IFN-A failure and163 previously untreated). Median follow-upwas 31months (range, 3-52months). Results: Median BCR-ABL/ABL ratio before the start of therapy was 39.44 (range, 0.252170.53). A major molecular response (BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%), and transcripts becameundetectable (completemolecular response) in 95 (34%). Bymultivariate analysis, only treatment withhigh-dose imatinib (P =0.02)was associatedwith achievement of a major molecular response. Nine of 166 (5%) patients who achieved a major molecular response lost their cytogenetic remission, comparedwith 25of 68 (37%)among thosewhodidnot achieve this response (P <0.0001). Patients achievingamajormolecular response12months after the start of therapy had significantly better complete cytogenetic remission duration than others. A >1-log reduction in transcript levels after 3 months of therapy predicted for an improved probability of achieving amajormolecular response at 24months. Increasing levels of BCR-ABL transcriptspredicted for a loss of cytogenetic remissiononly amongpatientswho didnot achieve amajormolecular response. Conclusions: Achieving a major molecular response, particularly within the first year of therapy, is predictive of a durable cytogenetic remission andmay be the future goal of therapy in CML. Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a potent and selective tyrosine kinase inhibitor (1, 2). It was initially developed as an inhibitor of Bcr-Abl, the protein product of the Philadelphia chromosome (Ph) characteristic of chronic myelogenous leukemia (CML). The activity of imatinib in CML has made it the current standard therapy in this disease. Among patients who failed prior therapy with IFN-a, 45% to 60% of patients achieve a complete cytogenetic remission, and 80% of patients remain alive and free of progression after 4 years (3–5). A randomized trial in patients with previously untreated CML in early chronic phase showed the higher efficacy and better toxicity profile of imatinib compared with IFN-a (6). Over 75% of these patients achieved a complete cytogenetic remission with imatinib, >95% remained alive and free of progression at 18 months (6–8). Higher doses of imatinib improved the complete cytogenetic remission rates to 90% both in patients who failed prior IFN-a therapy (9) and in those previously untreated (10, 11). As the rates of complete cytogenetic remission improve, monitoring of minimal residual disease by PCR has become more important. Patients are currently routinely followed with quantitative PCR techniques (e.g., real-time PCR) to determine the levels of BCR-ABL transcripts during the course of therapy (12). The prognostic significance of levels of minimal residual disease determined by PCR have been established in CML after bone marrow transplantation and IFN-a therapy (13–15). The clinical significance of molecular response among patients treated with imatinib is being investigated. The International Randomized Study of Interferon and STI571 (IRIS) trial showed that a significantly higher proportion of patients who were in complete cytogenetic remission at 6 months had at least a 3-log reduction of BCR-ABL/BCR levels if treated with imatinib compared with those treated with IFN-a (42% versus 13%, P = 0.03; ref. 16). Patients with at least a 3-log reduction of BCR-ABL/BCR levels after 12 months of therapy had a significantly better probability of disease-free survival compared with those in complete cytogenetic remission but with a less than 3-log reduction of BCR-ABL/BCR (16). This data has www.aacrjournals.org Clin Cancer Res 2005;11(9) May1, 2005 3425 Authors’ Affiliations: Departments of Leukemia, Bioimmunotherapy, and Laboratory Medicine, the University of Texas M.D. Anderson Cancer Center, Houston,Texas Received10/20/04; revised1/26/05; accepted 2/1/05. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: J. Cortes is a Clinical Research Scholar for the Leukemia and Lymphoma Society. Requests for reprints: Jorge Cortes, Department of Leukemia, the University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030. Phone: 713-794-5783; Fax: 713-794-4297; E-mail: jcortes@mdanderson.org. F2005 American Association for Cancer Research. Cancer Therapy: Clinical Research. on June 9, 2017. © 2005 American Association for Cancer clincancerres.aacrjournals.org Downloaded from not been confirmed in independent series, and additional questions remain, including the factors predictive of a molecular response, the durability of response, and the significance of increasing transcript levels. We analyzed the results of molecular monitoring in patients with CML in chronic phase treated with imatinib at our institution to determine the frequency of molecular response to imatinib and the long-term prognostic implications of molecular responses.