Award Lecture: CML Research and Treatment in 2025

The discovery of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) from a highly fatal leukemia (median survival 3-6 years) to an indolent one with a 10-year relative survival rate of 90+%. Six BCR::ABL1 TKIs are approved for the treatment of CML, five of them, imatinib, dasatinib, bosutinib, nilotinib, and asciminib as frontline therapy, and all 5 plus ponatinib as later-line therapies. The goals of CML therapy are: 1) Normalize survival: this is achievable with any of the TKIs, provided the patients can afford the TKI, comply with the treatment, are monitored optimally, and can change therapy when resistance develops. 2) Improve the rate of durable (sustained) deep molecular response (DMR = BCR::ABL1 transcripts on the International Scale [IS] < 0.01%). This can translate into a treatment-free remission (TFR; equal to molecular cure) rate of 30-45% if the DMR is sustained for 2+ years, and of 80+% if the DMR is sustained for 5+ years. 3) Reduce the risk of early and late TKI-associated complications. 4) Make the TKIs available and affordable to 100 % of patients. Imatinib, the first generation TKI, fulfills all 4 treatment aims: it is associated with a 10-year relative survival rate of 92%; the 10-year resistance rate is 10%, and the 10-year rate of blastic phase is 5.6%; it produces potential TFR rates of 40+% if the treatment is given for 8-10+ years; its side-effects are well-known, mostly mild-moderate, and long-term toxicities are manageable; and it is cost-effective (annual price < $500). The second generation TKIs (dasatinib, bosutinib, nilotinib) are more potent and result in faster achievement of DMRs, but are not known yet to result in higher TFR rates. Dasatinib 50 mg daily is as effective as the approved dose of 100 mg daily, and is less toxic. This led to attempts to develop the newer generation TKIs, and all chronic targeted therapies at an Optimal Biologic Dose (OBD) rather than at a dose below the Maximum Tolerated Dose (MTD). The third generation TKIs are even more potent and also effective against the T315I mutation (resistant to imatinib and second-generation TKIs. These include currently ponatinib and asciminib. Ponatinib is very potent but also toxic. Doses of 15-30 mg daily may retain much of the efficacy and reduce toxicities compared with 45 mg daily. Asciminib Selectively Targets the Abl Myristoyl Pocket and is thus referred to as a STAMP inhibitor. Asciminib is approved for both frontline therapy (80mg daily) and in later line therapy ( 80 mg daily; 200 mg BID for T315I mutated CML). A frontline randomized trial of asciminib versus TKI of choice (1:1 randomization versus imatinib; and 1:1 randomization versus a second generation TKI) fulfilled the primary endpoint: higher 12-month major molecular response (MMR) rate compared with imatinib, or compared with TKI of choice. It was also associated with a lower incidence of side-effects and of treatment discontinuation. Novel TKIs under development include olverembarinib and ELNV001, which both inhibit the ABL1 kinase domain (like previous TKIs including ponatinib). Novel STAMP inhibitors under development include TGRX678 and TERN701. With the existing 6 TKIs in practice and 4 more under development, we hope all the 4 aims of CML therapy will be fulfilled even better, in particular improving the rate of TFR and reducing side-effects. This is the legacy of Dr Richard Silver, a role model for all CML experts whose careers were influenced by his original research and mentorship.