Introduction to a series of reflections on a quarter century of TKIs for CML

It has now been a quarter of a century since the introduction of STI571 (imatinib [Gleevec]) at the annual meeting of the American Society of Hematology. I began my talk by acknowledging the giants of hematology whose work made the development of imatinib possible, from the first description of chronic myeloid leukemia (CML) in 1849 to the discovery and validation of BCR::ABL1 as the driving oncogenic event in this malignancy. The data from this phase 1 study showed a 100% response rate at effective doses of imatinib. After this meeting, phase 2 studies were launched, and in June 2000, a large, randomized study comparing imatinib with interferon-alfa and low-dose cytarabine was opened through an international collaboration that brought together investigators from 16 countries. This issue of Blood, with contributions from several of these key investigators, highlights critical advances in CML over the past 25 years. The articles in this review series, edited by Associate Editor Jason Gotlib, are:

• François Guilhot and Rüdiger Hehlmann, “Long-term outcomes of tyrosine kinase inhibitors in chronic myeloid leukemia”

• Timothy P. Hughes, Agnes S. M. Yong, and David M. Ross, “The evolution of treatment-free remission”

• Nataly Cruz-Rodriguez and Michael W. Deininger, “Novel treatment strategies for chronic myeloid leukemia”

One of the key insights, as noted by Guilhot and Hehlmann, is that the survival of patients with CML now approaches that of the general population.¹ This is as opposed to a 3- to 5-year life expectancy in the preimatinib era, unless a patient was eligible for and underwent an allogeneic stem cell transplant. Their article reviews all the randomized trials with imatinib and second-generation Abelson tyrosine kinase inhibitors. They conclude that although responses with imatinib are slower than with second-generation drugs, the overall survival is similar, and that imatinib has the best long-term safety risk.

Hughes, Yong, and Ross cover one of the most interesting aspects of CML, which is that ≈10% to 25% of patients with CML are eligible to stop therapy, and of those eligible, up to 50% can successfully discontinue therapy.² They noted that from a patient perspective, the most frequently mentioned motivation for stopping therapy was to minimize adverse effects, and the main deterrent was fear of relapse. What is intriguing to me is why only a small proportion of patients achieve sufficiently deep molecular responses to be eligible to stop therapy and why 50% of these patients are destined to relapse. What is it that differs between these subsets of patients, and what is it about the residual leukemia cells that allows them to persist? These issues and several combination strategies are reviewed by Cruz-Rodriguez and Deininger.³ They conclude by reminding us that despite the unprecedented success of treatment for CML, the story is far from complete. They compel us to continue research into achieving a cure for patients with CML. I would argue that much as CML was a paradigm for targeting cancer therapies, this last chapter could be a paradigm for eliminating residual disease in numerous other cancers.

I concluded my plenary talk 25 years ago by thanking the American Society of Hematology for supporting groundbreaking research and training in the hematological diseases and for their emphasis on mentorship. Our work has benefitted hundreds of thousands of patients, and I remain steadfast in my hope that many more patients will benefit from the work we are doing.

Conflict-of-interest disclosure: B.J.D. has a financial interest in the following companies. Scientific Advisory Board (SAB): Adela Bio, Aileron Therapeutics (inactive), Therapy Architects/ALLCRON (inactive), Cepheid, Labcorp (inactive), Nemucore Medical Innovations, Novartis, and RUNX1 Research Program; SAB and stock: Aptose Biosciences, Blueprint Medicines, Enliven Therapeutics, Iterion Therapeutics, GRAIL, and Recludix Pharma; Board of Directors and stock: Amgen and Vincerx Pharma; Board of Directors: Burroughs Wellcome Fund; Joint Steering Committee: Beat AML LLS (uncompensated); Advisory Committee: Multicancer Early Detection Consortium (uncompensated) and Malta North American Business Council (uncompensated); Founder: VB Therapeutics; sponsored research agreement: AstraZeneca, DELiver Therapeutics, Immunoforge (inactive), Terns, Enliven Therapeutics (inactive), and Recludix Pharma (inactive); clinical trial funding: Novartis and AstraZeneca; royalties from patent 6958335 (Novartis exclusive license) and Oregon Health and Science University (OHSU) and Dana-Farber Cancer Institute (Merck exclusive license, CytoImage, Inc, exclusive license, DELiver Therapeutics nonexclusive license, and Sun Pharma Advanced Research Company nonexclusive license); and US patents 4326534, 6958335, 7416873, 7592142, 10473667, 10664967, and 11049247. This potential conflict of interest has been reviewed and managed by OHSU.