Chronic myelogenous leukemia

Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells

Abstract

Following the achievement of deep molecular response on tyrosine kinase inhibitors (TKIs), approximately half of patients with chronic myeloid leukemia (CML) can discontinue TKI and remain in treatment-free remission (TFR). The ALLG CML8 study enrolled 40 imatinib-treated patients with undetectable BCR-ABL1 mRNA (approximately MR4.5). Molecular relapse was defined as detectable BCR-ABL1 on two consecutive tests or any single value >0.1%. With a median follow-up of 8.6 years (range 5.7–11.2 years), 18 patients remain in continuous TFR (45.0%; 95% confidence interval 31.9−63.4%). The latest relapse detected was 27 months after stopping imatinib. No patient progressed to advanced phase. Twenty-two patients met criteria for imatinib re-treatment and all regained undetectable molecular response. Nine patients in long-term TFR were monitored by highly sensitive individualized BCR-ABL1 DNA PCR in a sufficient number of samples to enable more precise quantification of residual leukemia. BCR-ABL1 DNA decreased from a median of MR5.0 in the first year of TFR to MR6.1 in the sixth year of TFR. Our results support the long-term safety and remarkable stability of response after imatinib discontinuation in appropriately selected CML patients. Serial high sensitivity testing provides a new and unexpected finding of gradually reducing CML cells in patients in long-term TFR.

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Acknowledgements

The authors acknowledge the important contribution of the TWISTER study patients and coordinators, and the ALLG as the study sponsor. This research was funded by the Australian National Health & Medical Research Council (Project grant #1051965), the Royal Adelaide Hospital Health Services Charitable Gifts Board, and Novartis Pharmaceuticals.

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DMR designed and supervised the study, performed experiments, analysed data, and prepared the manuscript; ISP performed the experiments, analysed data, and prepared the manuscript; NS, JFS, AKM, RJF CKA, ASY, APG, and APS contributed essential clinical data and reviewed the manuscript; PD and VAS performed experiments and reviewed the manuscript; JB contributed RQ-PCR data and reviewed the manuscript; CHK and DTY analysed data, and reviewed the manuscript; DLW supervised research and reviewed the manuscript; SB contributed RQ-PCR data, supervised research, and reviewed the manuscript; TPH designed the study, supervised research, and reviewed the manuscript.

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Correspondence to David M. Ross.

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Conflict of interest

DMR has received research funding from Novartis and Celgene, and honoraria from Novartis and BMS. AKM received honoraria from Novartis, BMS, and Specialised Therapeutics. ASY has received research funding from Novartis, BMS and Celgene, and honoraria from Novartis and BMS. DTY and TPH have received research funding and honoraria from Novartis, BMS, and Ariad. APG is an advisory board member for Novartis, BMS, Roche, Takeda, and MSD. APS has received honoraria from Novartis, BMS, Celgene, Roche, Amgen, and Specialised Therapeutics. SB has received research funding from Novartis, Ariad and Otsuka, honoraria from Novartis, BMS, Otsuka, Qiagen and Ariad, and is an advisory board member for Novartis and Qiagen. The remaining authors declare that they have no conflict of interest.

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Ross, D.M., Pagani, I.S., Shanmuganathan, N. et al. Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells. Leukemia 32, 2572–2579 (2018). https://doi.org/10.1038/s41375-018-0264-0

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