Do we need more drugs for chronic myeloid leukemia?

Holyoake, T. L. and Helgason, G. V. (2015) Do we need more drugs for chronic myeloid leukemia? Immunological Reviews, 263(1), pp. 106-123. (doi: 10.1111/imr.12234) (PMID:25510274)

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Abstract

The introduction of protein tyrosine kinase inhibitors (TKIs) in 1998 transformed the management of chronic myeloid leukemia (CML), leading to significantly reduced mortality and improved 5 year survival rates. However, the CML community is faced with several clinical issues that need to be addressed. Ten to 15% of CML patients are diagnosed in advanced phase, and small numbers of chronic phase (CP) cases experience disease progression each year during treatment. For these patients, TKIs induce only transient responses and alternative treatment strategies are urgently required. Depending on choice of first line TKI, approximately 30% of CML CP cases show suboptimal responses, due to a combination of poor compliance, drug intolerance, and drug resistance, with approximately 50% of TKI-resistance caused by kinase domain mutations and the remainder due to unknown mechanisms. Finally, the chance of successful treatment discontinuation is on the order of only 10–20% related to disease persistence. Disease persistence is a poorly understood phenomenon; all CML patients have functional Philadelphia positive (Ph+) stem and progenitor cells in their bone marrows and continue to express BCR-ABL1 by DNA PCR, even when in very deep remission and following treatment discontinuation. What controls the maintenance of these persisting cells, whether it is necessary to fully eradicate the malignant clone to achieve cure, and how that might be approached therapeutically are open questions.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Helgason, Dr Vignir and Holyoake, Professor Tessa
Authors: Holyoake, T. L., and Helgason, G. V.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Immunological Reviews
Publisher:John Wiley and Sons Ltd.
ISSN:0105-2896
ISSN (Online):1600-065X

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
439231Is Bcr-Able expression relevant for the survival of cancer stem cells in chronic myeloid leukaemiaTessa HolyoakeMedical Research Council (MRC)G0600782RI CANCER SCIENCES
503111A randomised Phase II trial of Imatinib (IM) versus hydroxychloroquine (HCQ) with IM for patients with chronic myeloid leukaemia (CML) in cytogenic response (CyR)- CHOICESTessa HolyoakeMedical Research Council (MRC)G0900882RI CANCER SCIENCES
503112A randomised Phase II trial of Imatinib (IM) versus hydroxychloroquine (HCQ) with IM for patients with chronic myeloid leukaemia (CML) in cytogenic response (CyR)- CHOICESTessa HolyoakeMedical Research Council (MRC)G0900882RI CANCER SCIENCES
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
498552Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES