Third-line therapy for chronic myeloid leukemia: current status and future directions

Abstract

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

“…New TKIs have been designed to overcome ABL1 gatekeeper mutations (mainly T315I) and at present are only preclinically validated inhibitors, such as Bafetinib, Rebastinib, Tozasertib, and Danusertib [ 248 ]. Other new molecules are already under clinical trials e.g., PF-114, HQP1351 (Olverembatinib), and K0706 (Vodobatinib), which function competitively as inhibitors of BCR-ABL1 TK at the ATP-binding site ( Table 2 ) [ 249 ]. These inhibitors have presented an increased potency against a wide range of BCR-ABL1 mutations [ 249 , 250 , 251 , 252 ] and may overcome some the limitations of approved TKIs.…”

Inhibition of Casein Kinase 2 induces cell death in chronic myelogenous leukemia cells resistant to tyrosine kinase inhibitors

“…Growth characteristics (Supplementary Figure S2) together with proliferation analyses (Figure 2, Table 2) demonstrate that all the resistant cells decreased their sensitivity to TKIs as compared to their sensitive counterparts. The observed cross-resistance (insensitivity of the cells to another TKI than that used for resistance acquisition) confirms that the resistance mechanisms developed under the selective pressure of one inhibitor often provide resistance to other TKIs as well 61 .…”

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

“…More importantly, 40%-60% of patients who attained deep and durable molecular responses successfully maintained remission after TKI discontinuation. 12 , 22 , 23 , 68 Numerous studies have identified correlations between TFR and the cellular immune system, including a higher number of NK cells and a lower Treg proportion, as previously mentioned, compared with patients who show disease relapse or transformation, suggesting that TFR is based on immune regulation and should be considered to identify promising immunotherapeutic targets, allowing more patients to achieve successful TKI cessation. 81 , 82 , 91 , 92 However, to further evaluate the impact of the immune system on TFR, additional immunological parameters must be studied, preferably quantified, to determine the optimal therapeutic endpoint for successful TFR.…”

“…The subsequent introduction of ponatinib, which is effective in patients with genetic abnormalities that make them resistant to TKIs, has further improved treatment outcomes, and the overall survival rate is up to 90%. 6−10 − 12 …”