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Chronic Myeloproliferative Neoplasias

Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR

Abstract

Around 40–50% of patients with chronic myeloid leukemia (CML) who achieve a stable complete molecular response (CMR; undetectable breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR–ABL1) mRNA) on imatinib can stop therapy and remain in CMR, at least for several years. This raises the possibility that imatinib therapy may not need to be continued indefinitely in some CML patients. Two possible explanations for this observation are (1) CML has been eradicated or (2) residual leukemic cells fail to proliferate despite the absence of ongoing kinase inhibition. We used a highly sensitive patient-specific nested quantitative PCR to look for evidence of genomic BCR–ABL1 DNA in patients who sustained CMR after stopping imatinib therapy. Seven of eight patients who sustained CMR off therapy had BCR–ABL1 DNA detected at least once after stopping imatinib, but none has relapsed (follow-up 12–41 months). BCR–ABL1 DNA levels increased in all of the 10 patients who lost CMR soon after imatinib cessation, whereas serial testing of patients in sustained CMR showed a stable level of BCR–ABL1 DNA. This more sensitive assay for BCR–ABL1 provides evidence that even patients who maintain a CMR after stopping imatinib may harbor residual leukemia. A search for intrinsic or extrinsic (for example, immunological) causes for this drug-free leukemic suppression is now indicated.

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Acknowledgements

Professor Nicholas Cross and Dr Joannah Score (Wessex Regional Genetics Laboratory, Salisbury, United Kingdom) developed the original long-range PCR method for the detection of BCR–ABL1 genomic breakpoints. Dr John Reynolds, Ms Rachel Koelmeyer and Dr Ruth Columbus (Australasian Leukaemia & Lymphoma Group Trial Centre) contributed to the design of the clinical trial. Emeritus Professor Alexander Morley (Flinders University) provided advice on laboratory studies. This study was supported by research funding from Novartis Oncology to the Australasian Leukaemia & Lymphoma Group (clinical trial), and to the Institute of Medical & Veterinary Science, SA Pathology (laboratory studies).

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Correspondence to D M Ross.

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DMR was a PhD Scholar of the Leukaemia Foundation of Australia. DMR, SB, JFS, APS, CA, AKM, APG and TPH have received honoraria from Novartis Oncology. CS is an employee of Novartis Oncology. PAB, CF, PD, RJF and JVM have no conflict of interest to declare.

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Supplementary Information accompanies the paper on the Leukemia website

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Ross, D., Branford, S., Seymour, J. et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 24, 1719–1724 (2010). https://doi.org/10.1038/leu.2010.185

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