Therapeutic approaches and drug-resistance in chronic lymphocytic leukaemia

Narjis Fatima; Kyle R Crassini; Lauren Thurgood; Yandong Shen; Richard I Christopherson; Bryone Kuss; Stephen P Mulligan; Oliver Giles Best

doi:10.20517/cdr.2019.111

Therapeutic approaches and drug-resistance in chronic lymphocytic leukaemia

Cancer Drug Resist. 2020 May 11;3(3):532-549. doi: 10.20517/cdr.2019.111. eCollection 2020.

Authors

Narjis Fatima^{1

2}, Kyle R Crassini¹, Lauren Thurgood³, Yandong Shen^{1

2}, Richard I Christopherson², Bryone Kuss³, Stephen P Mulligan^{1

2}, Oliver Giles Best^{1

2

3}

Affiliations

¹ Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
² School of Life and Environmental Sciences, University of Sydney, Sydney NSW 2008, Australia.
³ College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA 5042, Australia.

Abstract

The treatment of chronic lymphocytic leukaemia has been revolutionised in recent years, first by the introduction of chemoimmunotherapy regimens and subsequently by the development of drugs, including ibrutinib, idelalisib and venetoclax, that target components of the B-cell receptor signalling pathway or B-cell lymphoma 2 family of proteins. Despite high initial response rates in patients treated with chemoimmunotherapy or targeted agents, a significant proportion of patients relapse with progressive and refractory disease. In a subset of these patients, drug resistance has been associated with specific genetic lesions or activation of alternate pro-survival pathways. However, the mechanisms that confer drug resistance in the remainder of the patients with refractory disease have yet to be fully elucidated. In this review, we discuss our current understanding of the mechanics of drug resistance in chronic lymphocytic leukaemia and describe how this knowledge may aid in rationalising future treatment strategies to prevent the development of refractory or aggressive transformation of the disease.

Keywords: Chronic lymphocytic leukaemia; drug resistance; targeted cancer therapy.

Publication types

Review