The new kid on the block: will asciminib change frontline therapy of chronic myeloid leukemia patients?

Since almost 25 years, treatment of chronic myeloid leukemia (CML) relies essentially on the use of tyrosine-kinase inhibitors (TKIs) directed against the oncogenic BCR::ABL1 fusion protein, encoding for a constitutively activated tyrosine-kinase (1). Four TKIs are approved for patients with newly diagnosed CML: the first-generation imatinib and three second-generation (2G) TKIs, namely dasatinib, nilotinib and bosutinib. All these three 2G-TKIs have been compared to imatinib as first line agents in chronic phase of chronic myeloid leukemia (CP-CML); though granting faster and deeper attainment of molecular responses, both in terms of major molecular response [MMR, defined as BCR::ABL1 transcript level ≤0.1% on the international scale (IS)] and deep molecular response (DMR, BCR::ABL1 transcript level ≤0.01% on the IS), none of them proved to be superior to imatinib in terms of overall survival (OS) (2-4). This lack of advantage is due to both a greater toxicity of 2G-TKIs and to the efficacy of these drugs even when used in second-line after imatinib failure (5). Asciminib is a novel allosteric BCR::ABL1 inhibitor that, rather than being adenosine 5'-triphosphate (ATP) competitive as “classical” TKIs, specifically targets the ABL myristoyl pocket; asciminib has demonstrated to be safe and active in CP-CML patients failing two lines of TKI therapy (6-8).

A recent paper from Hochhaus and colleagues reports on the results from a phase III multicenter clinical trial, named ASC4FIRST, that compared asciminib and the other TKIs approved for first-line therapy in the setting of newly diagnosed CP-CML (9). A total of 205 patients were randomized to receive asciminib (n=201) or a pre-randomization investigator’s choice of imatinib (n=102) or a 2G-TKI [n=102 (nilotinib, n=49; dasatinib, n=42; bosutinib, n=11)]. The co-primary endpoints of the study were rates of MMR at week 48 with asciminib vs. all other TKIs, and with asciminib vs. imatinib, while MMR at week 48 with asciminib vs. 2G-TKIs was a secondary end point. The primary endpoints were both met, as MMR at week 48 in the asciminib cohort was 67.7% compared to 49.0% with other TKIs (P<0.001) and 69.3% compared to 40.2% with imatinib (P<0.001), while asciminib was not statistically superior to 2G-TKIs (66.0% vs. 57.8%). More, asciminib was superior to all comparators and imatinib in terms of early molecular response (EMR, defined as BCR::ABL1 ≤10% IS at 12 weeks) (89.6% vs. 70.1% and 88.1% vs. 59.8%, respectively) and of DMR at 48 weeks (38.8% vs. 20.6% and 42.6% vs. 14.7%, respectively), but, again, not to 2G-TKIs (91.0% vs. 80.4% for EMR and 35.0% vs. 26.5% for DMR). Median time to MMR was shorter with asciminib (24.3 weeks) than with imatinib (48.6 weeks), with 2G-TKIs (36.1 weeks) and with all other TKIs (36.4 weeks). Considering safety, grade ≥3 adverse events (AEs) occurred in 38.0%, 44.4% and 54.9% of patients receiving asciminib, imatinib and 2G-TKIs, respectively. Most common AEs were hematologic toxicities, i.e., thrombocytopenia (13.0%, 6.1% and 13.7%) and neutropenia (10.0%, 17.2% and 17.6%); cumulative rate of arterial occlusive events was 1.0% with asciminib, 0% with imatinib and 2.0% with 2G-TKIs (dasatinib 1% and nilotinib 1%). The percentage of treatment discontinuation due to AEs was 4.5% with asciminib, 11.1% with imatinib and 9.8% with 2G-TKIs. Progression to advanced phase CML occurred in 2 patients in the asciminib arm (1%), 3 patients in the imatinib arm (3%) and 1 patient in the 2G-TKIs arm (1%, nilotinib). Emerging BCR::ABL1 mutations were reported in 8 patients receiving asciminib (4%), mostly in the myristoyl pocket, in 2 patients treated with imatinib (2%) and in 2 patients treated with 2G-TKIs (2%).

So, the question is: will asciminib significantly change our frontline therapy for CP-CML patients soon? At present, and probably also in the foreseeable future, choice of first line TKI is based on a combined evaluation of CML and patients features, the former being essentially linked to disease risk score and the latter on age and comorbidities/concomitant medications; moreover, the decision often depend on patient’s expectations, treating physician’s experience and, in many countries, on economic considerations. All the recommendations published from the European LeukemiaNet (ELN) panel, including the last one dated 2020 (1), do not suggest a specific TKI for newly diagnosed CML patients, neither do the National Comprehensive Cancer Network (NCCN) guidelines (10). In 2019, a group of Italian CML experts, led by late professor Baccarani, made some proposals to design treatment strategies to bring patients in a condition of treatment-free remission (TFR), a goal that has progressively emerged as OS survival of CML nearly equalized that of the healthy controls (11). The Italian experts reached a consensus on the assessment of disease risk using the ELTS (EUTOS Long Term Survival) scoring system, on the choice of a 2G-TKI in all young patients (age ≤40 years) and in intermediate- and high-risk patients aged 41–65 years, and of imatinib in low-risk patients aged 66–80 years and in all very elderly patients (age >80 years). No agreement was found for low-risk 41–65 years and for intermediate- and high-risk 66–80 years patients. A recent real-life study involving almost 2,000 Italian CP-CML patients showed that 55.4% of them received imatinib and 44.6% received a 2G-TKI as frontline therapy. According to what proposed few years before, 2G-TKIs have been chosen for most patients <45 years and for those without comorbidities, while imatinib was used in over 70–75% of patients aged >65 years, in those with comorbidities such as arterial hypertension, diabetes, previous neoplasms or cardiovascular events, and/or taking 3 or more concomitant medications at the time of CML diagnosis (12).

If, simplifying, imatinib is preferred in elderly and low risk patients and 2G-TKIs in younger and high-risk patients, how could asciminib change the prescription patterns? Asciminib is clearly superior to imatinib in terms of efficacy, and its safety profile seems promising, though long-term data are, obviously, scarce. Nonetheless, more than two decades of imatinib use have reassured physicians that no serious adverse events are expected (even if chronic, low-grade toxicities may have an impact on quality of life) (13), and the need for a fast DMR, the prerequisite for TFR attempt, could be less stringent in the elderly population. More, preliminary data from an international trial comparing nilotinib vs. imatinib with early switch to nilotinib (SUSTRENIM) showed that a significant percentage of patients receiving imatinib, around 30%, were eligible to TFR, a figure like the nilotinib arm; low-risk CML and, less strongly, younger age were associated with increased stable DMR in the imatinib cohort (14).

Compared to 2G-TKIs, at present asciminib does not seem to provide a significant clinical advantage in attaining deeper or faster molecular responses, though the ASC4FIRST trial report a trend toward higher rates of EMR and DMR with asciminib, and a median time to MMR one-third shorter (24 vs. 36 weeks). In line with this, the latest update of the trial presented at 2024 ASH annual meeting reported higher rates of MMR and MR4 at 96 weeks with asciminib compared with 2G-TKIs (72.0% vs. 56.9% and 45.0% vs. 31.4%, respectively) (15). Again, the match will be possibly played on safety, as it is well known that both dasatinib and nilotinib are associated with heinous side effects in the mid-long term, namely pleural effusions and pulmonary artery hypertension for dasatinib and peripheral artery obstructive disease for nilotinib, while bosutinib was associated with different toxicities including gastrointestinal, renal and, also, cardiovascular AEs (16).

For all CML patients, prevention of disease progression is desirable. However, recent data does not confirm a protective role of frontline 2G-TKIs over imatinib (17), and data from ASC4FIRST suggest that risk of progression under asciminib is rather the same than comparators.

Our opinion is that data from the ASC4FIRST trial represent valuable proof of concept that asciminib in first line could provide high rates of DMR, maybe even higher than 2G-TKIs. A recent paper from the Australian group on 101 newly diagnosed CML patients receiving asciminib 40 mg twice a day (BID), with the possibility to double the dose in case of suboptimal response or to add a “conventional” TKI in case of failure reported response rates even superior to the ASC4FIRST trial, with EMR 93%, MMR at 12 months 79% and DMR at 24 months 53% (18). Even in this study there was one progression to lymphoid blast crisis with multiple BCR::ABL1 mutations, and three more patients lost response to asciminib due to emerging mutations, both in the myristoyl site and the canonical T315I.

We feel that the drug could have an important role also in second line, either after failure of imatinib or a 2G-TKIs; in the latter case, it is well known that switch to an alternative 2G-TKI is rarely effective and the only reliable option is, at present, represented by ponatinib (19). Clinical trials of asciminib after 1 TKI are warranted. Last, the novel mechanism of action of the specifically targeting the ABL myristoyl pocket (STAMP) inhibitor opens the door to possible combination with the conventional ATP competitors, for instance in the setting of patients with suboptimal response to imatinib or 2G-TKIs; this could grant the achievement of DMR and TFR to a higher percentage of CML patients, as it has recently emerged that treatment discontinuation is feasible even after “failure” of one or two lines of therapy, providing that a stable DMR has been achieved (20).

In conclusion, our opinion is that asciminib is a valuable and innovative option in the panorama of CML therapy and might possibly further change the CML treatment scenario. Nonetheless, a wide use of asciminib in the front-line setting is, at present, unlikely, due to lack of long-term data on potential toxicities and patterns of resistance linked to novel emerging mutations, and the economic burden of such a strategy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-217/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-217/coif). M.T. reports payments or honoraria from Novartis, BMS, Incyte, GSK, Abbvie, and AOP; and serves on the Data Safety Monitoring Board or Advisory Board of Novartis and GSK. G.B. reports consulting fees from GSK; payments or honoraria from Novartis, BMS, Incyte, GSK, and AOP; and serves on the Data Safety Monitoring Board or Advisory Board of Novartis and GSK. M.B. serves on the advisory boards of Amgen, Pfizer, Novartis, Bristol Myers Squibb, Incyte, Ascentage Pharma, and GlaxoSmithKline. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020;34:966-84. [Crossref] [PubMed]
2. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol 2016;34:2333-40. [Crossref] [PubMed]
3. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia 2021;35:440-53. [Crossref] [PubMed]
4. Brümmendorf TH, Cortes JE, Milojkovic D, et al. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial. Leukemia 2022;36:1825-33. [Crossref] [PubMed]
5. Tiribelli M, Bonifacio M, Binotto G, et al. Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients. Oncotarget 2018;9:14219-27. [Crossref] [PubMed]
6. Hochhaus A, Réa D, Boquimpani C, et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia 2023;37:617-26. [Crossref] [PubMed]
7. Mauro MJ, Hughes TP, Kim DW, et al. Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results. Leukemia 2023;37:1048-59. [Crossref] [PubMed]
8. Garcia-Gutiérrez V, Luna A, Alonso-Dominguez JM, et al. Safety and efficacy of asciminib treatment in chronic myeloid leukemia patients in real-life clinical practice. Blood Cancer J 2021;11:16. [Crossref] [PubMed]
9. Hochhaus A, Wang J, Kim DW, et al. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med 2024;391:885-98. [Crossref] [PubMed]
10. Shah NP, Bhatia R, Altman JK, et al. Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024;22:43-69. [Crossref] [PubMed]
11. Baccarani M, Abruzzese E, Accurso V, et al. Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP. Blood Adv 2019;3:4280-90. [Crossref] [PubMed]
12. Tiribelli M, Latagliata R, Breccia M, et al. Determinants of frontline tyrosine kinase inhibitor choice for patients with chronic-phase chronic myeloid leukemia: A study from the Registro Italiano LMC and Campus CML. Cancer 2023;129:2637-44. [Crossref] [PubMed]
13. Efficace F, Vignetti M, Sparano F, et al. Optimizing health-related quality of life in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Expert Rev Hematol 2021;14:293-302. [Crossref] [PubMed]
14. Breccia M, Castagnetti F, Piciocchi A, et al. SUSTRENIM trial: sustained deep molecular response and TFR rate in the long-term follow-up. HemaSphere 2024;8:S171.
15. Cortes JE, Hochhaus A, Hughes TP, et al. Asciminib (ASC) Demonstrates Favorable Safety and Tolerability Compared with Each Investigator-Selected Tyrosine Kinase Inhibitor (IS TKI) in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in the Pivotal Phase 3 ASC4FIRST Trial. Blood 2024;144:475. [Crossref]
16. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 2018;103:1298-307. [Crossref] [PubMed]
17. Giai V, Stagno F, Rosso T, et al. The Use of 2nd Generation TKIs As First Line Therapy Does Not Prevent CML Related Deaths: Results of an Italian CML Campus Prospective Study in 1277 Patients Treated First Line with Imatinib or 2nd Generation TKIs. Blood 2023;142:3168. [Crossref]
18. Yeung DT, Shanmuganathan N, Reynolds J, et al. Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study. Blood 2024;144:1993-2001. [Crossref] [PubMed]
19. Kantarjian HM, Jabbour E, Deininger M, et al. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia. Am J Hematol 2022;97:1419-26. [Crossref] [PubMed]
20. Bonifacio M, Scaffidi L, Miggiano MC, et al. A successful treatment-free remission is achievable also by chronic myeloid leukemia patients lacking optimal requirements. Blood Cancer J 2024;14:53. [Crossref] [PubMed]