Nilotinib, imatinib, and telomere homeostasis disruption in chronic myeloid leukemia

Reply to nilotinib versus imatinib: Molecular mechanism(s) of its better efficacy


We demonstrated in a series of patients with late chronic phase (CP) chronic myeloid leukemia (CML) that nilotinib induces high levels of response with acceptable toxicities, and prolongs progression-free survival.1 Recently, Bakalova et al2 speculated on the role of telomerase activity (TA) in CML and its relationship with tyrosine kinase inhibitors (TKIs) such as imatinib and nilotinib. They hypothesize that differential effects of TKIs on TA play a role in the future use of TKIs in terms of choice and dose.

To date, this assumption seems speculative because any direct effect of TKIs on TA has never been demonstrated convincingly in vivo. Moreover, it remains controversial whether TA in CP CML is increased in breakpoint cluster region/-Abelson oncogene (BCR-ABL)-positive (BCR-ABL+) hematopoietic stem cells specifically at all, or simply reflects the increased cell cycle activity within the CD34-positive leukemic compartment typically assayed for TA.3 Furthermore, studies addressing effects of TKIs on BCR-ABL+ cells provided controversial results ranging from inhibition of TA to no effect whatsoever, and even to increased levels of TA observed under treatment.4 In addition, as the authors point out, the direct or indirect effects of TKIs on TA might also be dose dependent.2

Nevertheless, the association of telomerase up-regulation with CP CML progression to accelerated phase (AP) and/or blast crisis (BC) has been reported consistently.4 Furthermore, evidence has accumulated over the last 15 years regarding the correlation of dysfunctional telomeres with disease progression. Telomere length has been demonstrated to be significantly shortened both compared with age-adjusted controls as well as compared with BCR-ABL T cells derived from the same patients.5 Accelerated telomere shortening has been correlated with disease stage (ie, CP > AP/BC), Hasford risk score, response to treatment, and (in patients with CP CML) with the duration until disease progression to AP/BC.4, 5 Based on these results, telomere length, at least in the context of intact cell cycle checkpoints, could represent a valuable prognostic and/or predictive biomarker for disease progression, response to TKIs, and potentially for maintenance of response upon cessation of TKI treatment.6 These questions are being addressed prospectively as part of a scientific subproject performed in patients with CP CML who are undergoing nilotinib as front-line treatment (the ENEST1st study).

In conclusion, increasing evidence points to a strong direct or indirect interaction between BCR-ABL activity and telomere maintenance in CML, which is most likely mediated via effects on TA. Whether this phenomenon could be used clinically as a predictive biomarker, and even for selection of individual TKIs most suitable for individual patients, remains to be demonstrated.


Dr. Manley is an employee of Novartis Pharma AG. The other authors made no disclosure.

Franck E. Nicolini MD, PhD*, Paul W. Manley MD, PhD†, Tim H. Brümmendorf MD‡, * Hématologie Clinique 1G, Centre Hospitalier Lyon Sud, Pierre Bénite, France, † Novartis Pharma AG, Basel, Switzerland, ‡ Medizinischen Klinik IV, Hämatologie und Onkologie, Universitätsklinikum Aachen, Aachen, Germany.