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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.
Health care resource utilization in 3L + patients with chronic phase chronic myeloid leukemia receiving asciminib or bosutinib
Published in Journal of Medical Economics, 2023
Jorge E. Cortes, Delphine Rea, Michael J. Mauro, Diana Tran, Pearl Wang, Kejal Jadhav, Aurore Yocolly, Koji Sasaki
Asciminib is a first-in-class agent Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibiting BCR::ABL1 oncoprotein that received US Food and Drug Administration approval in October 20218, Pharmaceuticals and Medical Devices Agency (Japan) approval in March 20229, and European Medicines Agency approval in August 2022 for use as a 3 L + therapy among CML in chronic phase (CML-CP) patients10. Bosutinib and ponatinib were the available treatment options for 3 L + CML-CP patients when the ASCEMBL phase 3 randomized controlled trial was designed11. However, ponatinib had an ongoing trial (OPTIC) which was reassessing its optimal dosing12, and had reported safety concerns in patients with cardiovascular comorbidities which limited its clinical usage13,14. For these reasons, bosutinib was selected as the appropriate reference treatment to compare asciminib against in the ASCEMBL trial. Asciminib demonstrated higher efficacy and better safety and tolerability profile manifested by low discontinuation rate due to adverse events (AEs) compared to bosutinib among 3 L + CML-CP patients in the pivotal ASCEMBL trial14,15.
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
In view of all the above, our opinion is that in case of open resistance to 2GTKIs, ponatinib should still be considered the drug of choice if the patient’s cardiovascular risk profile is low. If cardiovascular risk factors are present, or there is history of intolerance or suboptimal response to previous TKIs, asciminib constitutes a good treatment option (Figure 4). The recommended asciminib dose is 40 mg BID, with the exception of patients harboring the T315I mutations, in which the recommended dose is 200 mg BID. All in all, there are still many aspects of asciminib use that need to be clarified, such as the more convenient starting dose in each clinical situation or its combination with other drugs. Early data from combination studies have not yet shown any clinical benefit in terms of efficacy over asciminib monotherapy. Ongoing studies will help clarify this and other aspects of asciminib use in CML, but, in any case, the incorporation of this drug into clinical practice will be an important step forward.
An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia
Published in Expert Review of Hematology, 2022
Jay Yang, Malini Surapaneni, Charles A. Schiffer
Ponatinib is now approved and used in the limited patient populations refractory to other TKIs, those with the T315I mutation, which is usually found in patients with advanced disease, and in patients with Ph+ ALL. It is often an effective bridge to allogeneic transplantation in the younger group of such patients. Until recently, it was the only oral TKI option for such individuals. The FDA recently granted approval to asciminib, an oral agent which binds to the myristoyl pocket site on the BCR-ABL1 protein, effectively inhibiting signaling [32]. Asciminib was compared with bosutinib in patients in chronic phase previously treated with ≥2 TKIs, producing a statistically significant higher response rate in the range seen in the ponatinib studies [33]. There were responses seen in patients with the T315I mutation with an overall favorable side effect profile. Although cardiovascular toxicities were seen, there was no clear signal suggesting an increase in AOEs. Obviously, one cannot reliably compare the separate studies and many questions remain. A randomized trial directly comparing ponatinib and asciminib in this patient population is an idealistic wish unlikely to be fulfilled. It is likely, however, that there will increased use of asciminib at least in the advanced chronic-phase patients.