SEARCH:   Advanced

Blood, 1 October 2004, Vol. 104, No. 7, pp. 2204-2205. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cortes, J. Articles by Kantarjian, H. Search for Related Content PubMed PubMed Citation Articles by Cortes, J. Articles by Kantarjian, H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE To the editor: Discontinuation of imatinib therapy after achieving a molecular response Imatinib has become standard therapy for patients with chronic myelogenous leukemia (CML). A complete cytogenetic response can be achieved in 75% to 90% of patients treated in early chronic phase,1,2 and a fraction of patients have undetectable levels of BCR-ABL by polymerase chain reaction (PCR).1,3,4An important unanswered question for patients who achieve a complete molecular response is whether imatinib therapy may be discontinued safely. We herein report on 3 patients who achieved a molecular response (ie, undetectable levels of BCR-ABL) and relapsed shortly after discontinuation of therapy. The first patient (Figure 1A) is a 34-year-old woman who was treated with interferon- (IFN) when first diagnosed with CML. After loss of major cytogenetic response, she started imatinib (400 mg) orally daily. She rapidly achieved a complete cytogenetic response, and after 9 months of therapy she had undetectable levels of BCR-ABL. After 21 months she had identical results, and 9 months later she decided to stop therapy (12 months' total duration of undetectable BCR-ABL), as she wanted to become pregnant. Three months after discontinuation of therapy she had 5% metaphases positive for the Philadelphia chromosome (Ph), and therapy was immediately restarted. Three months after restarting therapy, all 100% metaphases were diploid, and BCR-ABL was again undetectable. View larger version (16K): [in this window] [in a new window]   Figure 1.. Cytogenetic and molecular analysis during and after therapy with imatinib. Patients 1 (A), 2 (B), and 3 (C).   The second patient (Figure 1B) is a 70-year-old man who started therapy with imatinib (800 mg) daily for newly diagnosed CML in chronic phase. He achieved a complete cytogenetic remission 3 months after therapy was started. After 6 months he had undetectable levels of BCR-ABL. Subsequent evaluations at 9 and 12 months from the start of therapy showed low levels of BCR-ABL/ABL (0.01 and 0.0009, respectively), but they were again undetectable at the 18-month evaluation. The patient decided to discontinue therapy because of grade 2 tearing of his eyes. Six months later, the patient had recurrence of chronic-phase disease with 100% Ph-positive metaphases. Imatinib therapy was restarted, and 6 months later the patient again achieved a complete cytogenetic remission, with a 2-log reduction in BCR-ABL transcripts. The third patient (Figure 1C) is a 40-year-old woman who had failed prior IFN therapy and had progressed to the accelerated phase. Imatinib therapy was initiated at 600 mg daily, and she achieved a major cytogenetic response (Ph 10%) after 3 months. This improved to a complete cytogenetic response 3 months later with low levels of BCR-ABL/ABL (0.37 to 0.39). After 24 months of therapy, BCR-ABL became undetectable and remained undetectable for 18 months. The patient decided to discontinue therapy, as she desired to become pregnant. Seven months after discontinuation of therapy she had 6% Ph-positive metaphases by fluorescence in situ hybridization (FISH) (100% diploid by cytogenetic analysis), and the BCR-ABL/ABL ratio had increased to 8.31%. At the time of this letter's composition, the patient had not elected to restart imatinib therapy. These 3 patients illustrate the need for continued therapy with imatinib after achieving molecular remission. Despite undetectable BCR-ABL levels on imatinib that were sustained for up to 21 months, relapses rapidly occurred in all 3 patients. In all 3 patients the relapse was both molecular and cytogenetic, but no changes in peripheral blood counts occurred. The rapid recurrence of disease despite having been undetectable by PCR suggests that the tempo of CML may be more rapid than previously thought. Also, the 2 patients who restarted therapy responded rapidly, suggesting no acquired resistance to imatinib, but rather representing the need for continued therapy. There is one other patient reported who experienced a rapid relapse after discontinuation of therapy despite a molecular response that had been sustained for 8 months.5 Thus, it cannot be recommended at the present time to discontinue therapy for patients who achieve a molecular remission with imatinib. Jorge Cortes, Susan O'Brien, and Hagop Kantarjian Correspondence: Jorge Cortes, Department of Leukemia, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org. References Kantarjian H, Talpaz M, O'Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103: 2873-2878.[Abstract/Free Full Text] O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348: 994-1004.[Abstract/Free Full Text] Hughes T, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349: 1423-1432.[Abstract/Free Full Text] Rosti G, Martinelli G, Bassi S, et al. Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood. 2004;103: 2284-2290.[Abstract/Free Full Text] Mauro MJ, Druker BJ, Maziarz RT. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res. 2004;28: 71-73.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia Hagop Kantarjian, Moshe Talpaz, Susan O'Brien, Guillermo Garcia-Manero, Srdan Verstovsek, Francis Giles, Mary Beth Rios, Jianqin Shan, Laurie Letvak, Deborah Thomas, Stefan Faderl, Alessandra Ferrajoli, and Jorge Cortes Blood 2004 103: 2873-2878. [Abstract] [Full Text] [PDF] This article has been cited by other articles: B. Chapuy, M. Panse, U. Radunski, R. Koch, D. Wenzel, N. Inagaki, D. Haase, L. Truemper, and G. G. Wulf ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug Haematologica, November 1, 2009; 94(11): 1528 - 1536. [Abstract] [Full Text] [PDF] E. Mattarucchi, O. Spinelli, A. Rambaldi, F. Pasquali, F. Lo Curto, L. Campiotti, and G. Porta Molecular Monitoring of Residual Disease in Chronic Myeloid Leukemia by Genomic DNA Compared with Conventional mRNA Analysis J. Mol. Diagn., September 1, 2009; 11(5): 482 - 487. [Abstract] [Full Text] [PDF] A. Hayat, S. R. McCann, S. Langabeer, S. Irvine, M. F. McMullin, and E. Conneally Effective use of imatinib-mesylate in the treatment of relapsed chronic myeloid leukemia after allogeneic transplantation Haematologica, February 1, 2009; 94(2): 296 - 298. [Full Text] [PDF] N. N. Bewry, R. R. Nair, M. F. Emmons, D. Boulware, J. Pinilla-Ibarz, and L. A. Hazlehurst Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance Mol. Cancer Ther., October 1, 2008; 7(10): 3169 - 3175. [Abstract] [Full Text] [PDF] R. A. Larson, B. J. Druker, F. Guilhot, S. G. O'Brien, G. J. Riviere, T. Krahnke, I. Gathmann, Y. Wang, and for the IRIS (International Randomized Interferon Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study Blood, April 15, 2008; 111(8): 4022 - 4028. [Abstract] [Full Text] [PDF] H. Konig, T. L. Holyoake, and R. Bhatia Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606 Blood, February 15, 2008; 111(4): 2329 - 2338. [Abstract] [Full Text] [PDF] A. D. Klion, J. Robyn, I. Maric, W. Fu, L. Schmid, S. Lemery, P. Noel, M. A. Law, M. Hartsell, C. Talar-Williams, et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing Blood, November 15, 2007; 110(10): 3552 - 3556. [Abstract] [Full Text] [PDF] M. Yan, J.-K. Luo, K. J. Ritchie, I. Sakai, K. Takeuchi, R. Ren, and D.-E. Zhang Ubp43 regulates BCR-ABL leukemogenesis via the type 1 interferon receptor signaling Blood, July 1, 2007; 110(1): 305 - 312. [Abstract] [Full Text] [PDF] C. Miething, R. Grundler, C. Mugler, S. Brero, J. Hoepfl, J. Geigl, M. R. Speicher, O. Ottmann, C. Peschel, and J. Duyster Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment PNAS, March 13, 2007; 104(11): 4594 - 4599. [Abstract] [Full Text] [PDF] Y. Wang, D. Cai, C. Brendel, C. Barett, P. Erben, P. W. Manley, A. Hochhaus, A. Neubauer, and A. Burchert Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation Blood, March 1, 2007; 109(5): 2147 - 2155. [Abstract] [Full Text] [PDF] L. Garderet, R. Santacruz, V. Barbu, J. van den Akker, B. Carbonne, and N.C. Gorin Two successful pregnancies in a chronic myeloid leukemia patient treated with imatinib Haematologica, January 1, 2007; 92(1): e9 - e10. [Abstract] [Full Text] [PDF] P. Rousselot, F. Huguet, D. Rea, L. Legros, J. M. Cayuela, O. Maarek, O. Blanchet, G. Marit, E. Gluckman, J. Reiffers, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years Blood, January 1, 2007; 109(1): 58 - 60. [Abstract] [Full Text] [PDF] B. J. Druker, F. Guilhot, S. G. O'Brien, I. Gathmann, H. Kantarjian, N. Gattermann, M. W.N. Deininger, R. T. Silver, J. M. Goldman, R. M. Stone, et al. Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia N. Engl. J. Med., December 7, 2006; 355(23): 2408 - 2417. [Abstract] [Full Text] [PDF] S. H. Kaufmann Imatinib spells BAD news for Bcr/abl-positive leukemias PNAS, October 3, 2006; 103(40): 14651 - 14652. [Full Text] [PDF] C. T. Jordan, M. L. Guzman, and M. Noble Cancer stem cells. N. Engl. J. Med., September 21, 2006; 355(12): 1253 - 1261. [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF] A. Quintas-Cardama and J. E. Cortes Chronic Myeloid Leukemia: Diagnosis and Treatment Mayo Clin. Proc., July 1, 2006; 81(7): 973 - 988. [Abstract] [Full Text] [PDF] M. Copland, A. Hamilton, L. J. Elrick, J. W. Baird, E. K. Allan, N. Jordanides, M. Barow, J. C. Mountford, and T. L. Holyoake Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction Blood, June 1, 2006; 107(11): 4532 - 4539. [Abstract] [Full Text] [PDF] Y. L. Wang, J. W. Lee, E. Cesarman, D. K. Jin, and B. Csernus Molecular Monitoring of Chronic Myelogenous Leukemia: Identification of the Most Suitable Internal Control Gene for Real-Time Quantification of BCR-ABL Transcripts J. Mol. Diagn., May 1, 2006; 8(2): 231 - 239. [Abstract] [Full Text] [PDF] P. Ault, H. Kantarjian, S. O'Brien, S. Faderl, M. Beran, M. B. Rios, C. Koller, F. Giles, M. Keating, M. Talpaz, et al. Pregnancy Among Patients With Chronic Myeloid Leukemia Treated With Imatinib J. Clin. Oncol., March 1, 2006; 24(7): 1204 - 1208. [Abstract] [Full Text] [PDF] M. J. Mauro and R. T. Maziarz Stem Cell Transplantation in Patients With Chronic Myelogenous Leukemia: When Should It Be Used? Mayo Clin. Proc., March 1, 2006; 81(3): 404 - 416. [Abstract] [Full Text] [PDF] J. P. Radich, H. Dai, M. Mao, V. Oehler, J. Schelter, B. Druker, C. Sawyers, N. Shah, W. Stock, C. L. Willman, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia PNAS, February 21, 2006; 103(8): 2794 - 2799. [Abstract] [Full Text] [PDF] F. Ravandi and Z. Estrov Eradication of Leukemia Stem Cells as a New Goal of Therapy in Leukemia Clin. Cancer Res., January 15, 2006; 12(2): 340 - 344. [Abstract] [Full Text] [PDF] H. G. Jorgensen, M. Copland, E. K. Allan, X. Jiang, A. Eaves, C. Eaves, and T. L. Holyoake Intermittent Exposure of Primitive Quiescent Chronic Myeloid Leukemia Cells to Granulocyte-Colony Stimulating Factor In vitro Promotes their Elimination by Imatinib Mesylate Clin. Cancer Res., January 15, 2006; 12(2): 626 - 633. [Abstract] [Full Text] [PDF] C. A. Huff, W. Matsui, B. D. Smith, and R. J. Jones The paradox of response and survival in cancer therapeutics Blood, January 15, 2006; 107(2): 431 - 434. [Abstract] [Full Text] [PDF] M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF] S. Basciani, M. Brama, S. Mariani, G. De Luca, M. Arizzi, L. Vesci, C. Pisano, S. Dolci, G. Spera, and L. Gnessi Imatinib Mesylate Inhibits Leydig Cell Tumor Growth: Evidence for In vitro and In vivo Activity Cancer Res., March 1, 2005; 65(5): 1897 - 1903. [Abstract] [Full Text] [PDF] M. W. N. Deininger and T. L. Holyoake Can we afford to let sleeping dogs lie? Blood, March 1, 2005; 105(5): 1840 - 1841. [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cortes, J. Articles by Kantarjian, H. Search for Related Content PubMed PubMed Citation Articles by Cortes, J. Articles by Kantarjian, H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020