Abstract
Residual leukemia is demonstrable by reverse transcriptase-polymerase chain reaction in most patients with chronic myeloid leukemia who obtain a complete cytogenetic response (CCR) to imatinib. In patients who relapse during imatinib therapy, a high rate of mutations in the kinase domain of BCR-ABL have been identified, but the mechanisms underlying disease persistence in patients with a CCR are poorly characterized. To test whether kinase domain mutations are a common mechanism of disease persistence, we studied patients in stable CCR. Mutations were demonstrated in eight of 42 (19%) patients with successful amplification and sequencing of BCR-ABL. Mutation types were those commonly associated with acquired drug resistance. Four patients with mutations had a concomitant rise of BCR-ABL transcript levels, two of whom subsequently relapsed; the remaining four did not have an increase in transcript levels and follow-up samples, when amplifiable, were wild type. BCR-ABL-kinase domain mutations in patients with a stable CCR are infrequent, and their detection does not consistently predict relapse. Alternative mechanisms must be responsible for disease persistence in the majority of patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cortes J, O'Brien S, Kantarjian H . Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004; 104: 2204–2205.
Higashi T, Tsukada J, Kato C, Iwashige A, Mizobe T, Machida S et al. Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases. Am J Hematol 2004; 76: 275–278.
Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL et al. Dynamics of chronic myeloid leukaemia. Nature 2005; 435: 1267–1270.
Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005; 105: 2093–2098.
Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.
Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125.
Diamond J, Goldman JM, Melo JV . BCR-ABL, ABL-BCR, BCR, and ABL genes are all expressed in individual granulocyte-macrophage colony-forming unit colonies derived from blood of patients with chronic myeloid leukemia. Blood 1995; 85: 2171–2175.
Willis S, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D et al. High sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005; 106: 2128–2137.
Deininger MW, McGreevey L, Willis S, Bainbridge TM, Druker BJ, Heinrich MC . Detection of ABL kinase domain mutations with denaturing high-performance liquid chromatography. Leukemia 2004; 18: 864–871.
Press RD, Love Z, Tronnes AA, Yang R, Tran T, Mongoue-Tchokote S et al. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib-treated patients with CML. Blood 2006; 107: 4250–4256.
Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.
von Bubnoff N, Schneller F, Peschel C, Duyster J . BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 2002; 359: 487–491.
Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003; 102: 276–283.
Hughes TP, Deininger MW, Hochhaus A, Branford S, Radich JP, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors–review and recommendations for ‘harmonizing’ current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.
Azam M, Latek RR, Daley GQ . Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003; 112: 831–843.
Lange T, Bumm T, Mueller M, Otto S, Al-Ali HK, Grommisch L et al. Durability of molecular remission in chronic myeloid leukemia patients treated with imatinib vs allogeneic stem cell transplantation. Leukemia 2005; 19: 1262–1265.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F 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.
Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction. Blood 2006; 107: 4532–4539.
Acknowledgements
Supported in part by NHLBI Grant HL082978-01 (MWD), Doris Duke Charitable Foundation (BJD, MCH), VA Merit Review Grant (MCH) and the Leukemia and Lymphoma Society (BJD, MWD, MCH). MWD is a Junior Faculty Scholar of the American Society of Hematology.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
Supplementary information
Rights and permissions
About this article
Cite this article
Sherbenou, D., Wong, M., Humayun, A. et al. Mutations of the BCR-ABL-kinase domain occur in a minority of patients with stable complete cytogenetic response to imatinib. Leukemia 21, 489–493 (2007). https://doi.org/10.1038/sj.leu.2404554
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2404554
Keywords
This article is cited by
-
Chronic Myelogenous Leukemia: Monitoring Response to Therapy
Current Hematologic Malignancy Reports (2011)
-
Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib treatment
International Journal of Hematology (2010)
-
Chronic myelogenous leukemia stem cells: What’s new?
Current Hematologic Malignancy Reports (2009)
-
Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy
Leukemia (2008)
-
Resistance to imatinib in chronic myelogenous leukemia: Mechanisms and clinical implications
Current Hematologic Malignancy Reports (2008)