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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
There is some debate as to the effect of any of the currently licensed TKIs in affecting the progenitor/stem cells in CML. Studies have assessed alternative strategies in targeting pathways that regulate the survival and maintenance of CML stem cells.84 Candidate pathways that appear to be activated by BCR-ABL1 include the JAK-STAT, mTOR, PI3K/AKT, and autophagy signaling pathways and the mechanisms by which CML stem cells interact with their microenvironment. Results from clinical trials assessing the role of the allosteric inhibitor asciminib have been impressive, and the drug is now in a Phase III study, being compared with bosutinib in patients who have failed at least two TKIs.85 Another drug of interest is radotinib, a second-generation TKI with a chemical structure similar to that of nilotinib. The drug is currently only available in South Korea, where it is licensed for both first and subsequent lines of therapy. Other interesting investigational drugs include pioglitazone, a diabetes drug, which was noted to accord MR4,5 in about half of the newly diagnosed patients studied in a small Phase II trial. This drug, however, is associated with an increased risk of bladder cancer. Immunotherapy has, of course, been used successfully in patients with CML, not only in the allo-SCT setting but also with interferons, in particular pegylated interferon-α; anecdotal success has also been reported with vaccines developed against BCR-ABL1 and other CML-specific peptides. Studies suggest that CML stem cells evade immune surveillance exerted by the innate immune system, which can be modulated by JAK2 inhibitors and IFN-α.86 Research has also shown that coordinated inhibition of nuclear export and BCR-ABL1 selectively targets CML stem cells.87
Chronic Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
There is some debate as to the effect of any of the currently licensed TKIs in affecting the progenitor/stem cells in CML. There is some support for this from the observation of the second slower slope of the BCR-ABL1 transcript decline and the observation that ~40% of patients in the STIM trial have maintained TFR. Studies have assessed alternative strategies in targeting pathways that regulate the survival and maintenance of CML stem cells. Candidate pathways that appear to be activated by BCR-ABL1 include the JAK-STAT, mTOR, PI3K/AKT and autophagy signalling pathways, and the mechanisms by which CML stem cells interact with their microenvironment, for example, through an increased expression of interleukin-1 receptors, and several studies are now ongoing (Figure 6.10). Results from clinical trials assessing the role of the allosteric inhibitor, asciminib (ABL001; previously known as GNF-5), have been impressive and the drug is now in a phase III study being compared to bosutinib in patients who have failed at least two TKIs. Another drug of interest is radotinib, a second-generation TKI, with a chemical structure similar to that of nilotinib. The drug is currently only available in South Korea, where it is licensed for both first and subsequent lines of therapy. Other interesting investigational drugs include pioglitazone, a diabetes drug, which was noted to accord MR4.5 in about half of the newly diagnosed patients studied in a small phase II trial, randomizing patients to either standard-dose imatinib alone or imatinib with pioglitzone. This drug however is associated with an increased risk of bladder cancer. Immunotherapy has of course been used successfully in patients with CML, not only in the allo-SCT setting, but also with interferons, in particular pegylated interferonα-2a; anecdotal success has also been reported with vaccines developed against BCR-ABL1 and other CML-specific peptides. Studies suggest how CML stem cells evade immune surveillance exerted by the innate immune system that can be modulated by JAK2 inhibitors and interferon γ.
An evaluation of asciminib for patients with chronic myeloid leukemia previously treated with ≥2 tyrosine kinase inhibitors
Published in Expert Review of Hematology, 2022
Valentin García-Gutiérrez, Juan Carlos Hernandez-Boluda
Radotinib is TKI approved in Korea for the front-line treatment of CML. In a Phase III trial, radotinib showed superiority over imatinib in terms of MMR (primary end point of the study) and CCyR rates [18]. In addition, radotinib was shown to be effective and well tolerated in patients with CP CML who did not respond to BCR::ABL1 inhibitors. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 65% of the patients, including 47% patients with complete cytogenetic response by 12 months. In this study, 95% of the patients received radotinib after imatinib failure, while only 5% of the patients were previously exposed to imatinib and dasatinib or nilotinib [19].
Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy
Published in Expert Review of Hematology, 2018
Fulvio Massaro, Gioia Colafigli, Matteo Molica, Massimo Breccia
Radotinib is an oral BCR/ABL1 inhibitor that presents a structural analogy to nilotinib, actually approved in South Korea for both newly diagnosed CML patients and those resistant or intolerant to at least one TKI. Radotinib inhibits wild-type BCR/ABL1 kinase with an IC50 (half maximal inhibitory concentration) of 34 nm. Several other kinases are inactivated by the drug, but at higher concentrations: PDGFRα (IC50 = 75.5 nm), PDGFRβ (IC50 = 130 nm), c-KIT (1324 nm), and SRC (>2000 nm) [9]. Radotinib showed activity against the most common BCR/ABL1 mutations, except T315I. In vitro, radotinib showed high inhibitory capacity against CML cell lines, demonstrating higher efficacy than imatinib [10]. No dose-limiting toxicities were reported in a phase I study for a daily dose up to 1000 mg [11]. A phase II trial was conducted, in order to demonstrate safety and efficacy of radotinib in CP-CML patients resistant or intolerant to first-line TKI treatment. The study enrolled 77 patients, receiving a starting dose of 400 mg twice daily (bid). After 12 months of treatment, 65% of patients achieved a MCyR and 47% a CCyR. Most common grade 3–4 hematologic adverse events (AEs) were thrombocytopenia (24.7% of patients) and anemia (5.2%). Grade 3–4 non-hematologic adverse events were represented by fatigue (3.9%), asthenia (3.9%), nausea (2.6%), myalgia (1.3%), rash (1.3%), and pruritus (1.3). ALT and AST elevation, of all grades, were the most common events reported, with a rate of 85.7 and 72.7%, respectively (grade 3–4: 11.7 and 10.4%). Other common grade 3–4 biochemical alterations were hyperbilirubinemia (23.4%) and hyperglycemia (19.5%). A dose reduction had to be performed in 68.8% of cases, while 42.9% permanently stopped the drug: reasons for discontinuation were laboratory tests abnormality (45.5%), disease progression (24.2%), non-hematologic AEs (9%), death (6.1%), and other reasons (15.2%) [12].