A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease

Gallipoli, P.; Horne, G. A.; Stobo, J.; Kelly, C.; Mukhopadhyay, A.; Latif, A. L.; Dixon-Hughes, J.; McMahon, L.; Cony-Makhoul, P.; Byrne, J.; Smith, G.; Koschmieder, S.; Br�mmendorf, T.; Schafhausen, P.; Thomson, F.; Cong, W.; Clark, R. E.; Milojkovic, D.; Helgason, G. V.; Foroni, L.; Nicolini, F. E.; Holyoake, T. L.; Copland, M.

Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment ‘successes’ was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment ‘successes’, molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in ‘success’ rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the ‘success’ rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen seriousadverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

Citation

Gallipoli, P., Horne, G. A., Stobo, J., Kelly, C., Mukhopadhyay, A., Latif, A. L., …Copland, M. (2020). A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease. Leukemia, 34, 1775–1786. https://doi.org/10.1038/s41375-019-0700-9

• Journal Article Type: Article
• Acceptance Date: Nov 14, 2019
• Online Publication Date: Jan 10, 2020
• Publication Date: 2020-07
• Deposit Date: Nov 20, 2019
• Publicly Available Date: Jul 11, 2020
• Journal: Leukemia
• Print ISSN: 0887-6924
• Electronic ISSN: 1476-5551
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 34
• Pages: 1775–1786
• DOI: https://doi.org/10.1038/s41375-019-0700-9
• Keywords: Anesthesiology and Pain Medicine; Cancer Research; Hematology
• Public URL: https://nottingham-repository.worktribe.com/output/3342268