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Cancer Therapy: Clinical

Molecular Responses in Patients with Chronic Myelogenous Leukemia in Chronic PhaseTreated with Imatinib Mesylate

Jorge Cortes,1,2 MosheTalpaz,2 Susan O’Brien,1Dan Jones,3 Rajyalakshmi Luthra,3 Jenny Shan,1Francis Giles,1,2 Stefan Faderl,1 Srdan Verstovsek,1 Guillermo Garcia-Manero,1 Mary B. Rios,1 and Hagop Kantarjian1


Purpose:To determine the clinical significance of molecular response and relapse among patients with chronic myelogenous leukemia (CML) treated with imatinib. Experimental Design:We analyzed the results of quantitative PCR in 280 patients with CML in chronic phase who achieved complete cytogenetic remission with imatinib (117 after IFN-A failure and163 previously untreated). Median follow-up was 31months (range, 3-52 months). Results: Median BCR-ABL/ABL ratio before the start of therapy was 39.44 (range, 0.252- 170.53). A major molecular response (BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%), and transcripts became undetectable (complete molecular response) in 95 (34%). By multivariate analysis, only treatment with high-dose imatinib (P = 0.02) was associated with achievement of a major molecular response. Nine of 166 (5%) patients who achieved a major molecular response lost their cytogenetic remission, compared with 25 of 68 (37%) among those who did not achieve this response (P <0.0001). Patients achieving a major molecular response12 months 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 a major molecular response at 24 months. Increasing levels of BCR-ABL transcripts pre- dicted for a loss of cytogenetic remission only among patients who did not achieve a major molec- ular response. Conclusions: Achieving a major molecular response, particularly within the first year of therapy, is predictive of a durable cytogenetic remission and may 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

Authors’ Affiliations: Departments of 1Leukemia, 2Bioimmunotherapy, and

3Laboratory Medicine, the University of Texas M.D. Anderson Cancer Center, Houston,Texas Received 10/20/04; revised 1/26/05; 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 with 18 U.S.C. Section 1734 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.

F 2005 American Association for Cancer Research.

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 com- pared with those in complete cytogenetic remission but with a less than 3-log reduction of BCR-ABL/BCR (16). This data has



Clin Cancer Res 2005;11(9) May 1, 2005

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