Eradicating residual chronic myeloid leukaemia: basic research lost in translation

Chronic myeloid leukaemia is the poster child for reducing scientific progress to clinical practice. A series of fundamental discoveries, each building on the foundation of previous work, culminated in the approval of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukaemia therapy. In 2020, the survival of patients with chronic myeloid leukaemia in high-income countries is close to that of age-matched control populations. Unfortunately, the chance of enjoying life without taking TKIs, also known as treatment-free remission, is only 30–35%, and has not substantially increased over the past decade (appendix). 1 Saussele S Richter J Guilhot J et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018; 19: 747-757 Summary Full Text Full Text PDF PubMed Scopus (346) Google Scholar The prospect that two-thirds of patients with chronic myeloid leukaemia will have to continue taking TKIs indefinitely is disconcerting. Some clinically significant adverse effects, such as cardiovascular toxicity, were fully recognised only after regulatory approval, and we do not know the full scope of long-term toxicity, particularly for newer and more potent second and third generation TKIs. Off-target effects are often considered first in this context. However, one should not forget that ABL1 and ABL2 themselves are ancient kinases (that emerged in early vertebrates—bony fish), and simultaneous germline deletion of both genes is embryonically lethal. 2 Koleske AJ Gifford AM Scott ML et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron. 1998; 21: 1259-1272 Summary Full Text Full Text PDF PubMed Scopus (337) Google Scholar In addition, financial toxicity is a major personal and societal side effect of tyrosine kinase therapy for patients with chronic myeloid leukaemia. With this background, it is crucial to convert the deep responses that many patients achieve into functional cures, defined as non-recurrence of active chronic myeloid leukaemia after stopping TKIs.