conference reporter

63rd ASH Annual Meeting and Exposition

Resistance and Persistence in Chronic Myeloid Leukemia

by Elias Jabbour, MD

Overview

Dose optimization may improve persistence with tyrosine kinase inhibitor (TKI) therapy in chronic-phase chronic myeloid leukemia (CP-CML). New data on TKI dose optimization were presented at the 63rd ASH Annual Meeting and Exposition

Following these proceedings, featured expert Elias Jabbour, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Jabbour’s clinical perspectives are presented here. 

Elias Jabbour, MD

Professor of Medicine, Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“Treatment adherence truly starts with the patient-provider relationship. We try to educate patients on the potential side effects that they may expect, and, by involving them, they become more active in their own care, which results in better outcomes.”

Elias Jabbour, MD

Although TKI therapy in patients with CP-CML generally results in good overall survival that approaches a normal life expectancy, outcomes vary by patient and by treatment setting. This variability is multifactorial, depending on both clinical and patient-related factors. Outcomes are best when milestones are met, responses are optimal, and patients are followed closely and treated in accordance with the guidelines. 

Patient adherence with TKI medication is essential in obtaining the best outcomes. If you are nonadherent, the likelihood of achieving a deep molecular response is reduced. Perhaps more importantly nowadays, a complete molecular remission that lasts for several years is needed before TKI discontinuation can be considered, and nonadherence also reduces that likelihood. Nonadherence is driven by unintentional and intentional factors. Unintentional nonadherence is the result of factors such as patients forgetting to take their medication, whereas tolerability issues are often to blame for intentional nonadherence and discontinuation. Treatment adherence truly starts with the patient-provider relationship. We try to educate patients on the potential side effects that they may expect, and, by involving them, they become more active in their own care, which results in better outcomes. 

Further, each TKI has different side effects and safety profiles, so the selection of the TKI should be individualized for each patient. Once the TKI is chosen, dose optimization is crucial because it can limit the chronic side effects that may hinder patient adherence. In that regard, alternative TKI dosing regimens in CML are actively being explored to maximize drug exposure while minimizing toxicities. 

We saw 2 such abstracts at ASH 2021 that explored the use of dasatinib at lower doses, including our report with a 50-mg-per-day dose in patients with newly diagnosed CP-CML (abstract 631) and the study by Kumagai et al with a 20-mg-per-day starting dose in elderly patients with newly diagnosed CP-CML (abstract 3601). In abstract 631, we reported data from The University of Texas MD Anderson Cancer Center comparing low-dose dasatinib (50 mg/day) with standard-dose dasatinib (100 mg/day) in those with newly diagnosed CP-CML. The analysis used propensity score matching to identify 77 patients in each cohort without significant baseline differences. We were concerned that the lower dose of dasatinib might reduce TKI efficacy, but outcomes with the 50-mg dose and the 100-mg dose appeared to be similar. This is intriguing and needs to be better understood, as it appeared that the low dose resulted in good drug exposure by reducing the interference from intolerance and nonadherence.

TKI resistance in CML was also of interest at ASH 2021, and we saw different presentations on the management of resistance, including updates on ponatinib. Ponatinib was approved by the US Food and Drug Administration based on the phase 2 PACE trial, where it showed great efficacy in a population that had failed multiple drugs, including patients with T315I mutation; however, the dose of 45 mg per day was associated with a higher rate of arterial occlusive events. Thus, we return to the pursuit of dose optimization here in the resistant setting. In my mind, ponatinib could be one of the best TKIs available if we learn how to handle the toxicities. 

In the primary analysis of the phase 2 OPTIC trial, which had 3 cohorts, the optimal benefit-to-risk profile for ponatinib was achieved by starting with a 45-mg-per-day dose, followed by a dose reduction to 15 mg per day upon achieving 1% or lower BCR-ABL1IS. Further, the 30-mg to 15-mg cohort and the 15-mg cohort were felt to potentially provide benefit, especially in patients without T315I mutation. 

Abstract 2550 from ASH 2021 provided an in-depth analysis of dosing dynamics between the PACE trial and the OPTIC trial; specifically, we compared the efficacy and safety outcomes of different dosing strategies from the 2 trials. We found that the response-based2, dose-reduction strategy in the OPTIC trial resulted in more rapid dose reductions, lower overall median relative dose intensity, fewer dose reductions related to adverse events, and longer median time on therapy compared with PACE, further demonstrating the benefit of the response-based dosing regimen used in the OPTIC trial.

We need more treatments for patients with resistant CML, and asciminib is the first TKI for CML that specifically targets the ABL myristoyl pocket (STAMP). The primary analysis of the randomized, phase 3, ASCEMBL trial showed that asciminib had superior efficacy and better safety and tolerability profiles compared with bosutinib in those with CP-CML who had undergone prior treatment with 2 or more ATP-binding TKIs. 

At ASH 2021, Mauro and colleagues presented updated efficacy and safety results from ASCEMBL (abstract 310). Patients with CP-CML who were treated with 2 or more prior TKIs were randomized 2:1 to asciminib 40 mg twice daily or to bosutinib 500 mg once daily. By week 48, the cumulative incidence of major molecular response was 33.2% with asciminib and 18.6% with bosutinib. The authors concluded that the positive benefit-risk profile of asciminib compared with bosutinib after a median follow-up of 19.2 months continues to support asciminib as a new therapy in a heavily pretreated patient population. While the study is positive, longer follow-up is needed to assess the safety of asciminib in T315I- and non–T315I-resistant disease. Furthermore, it would be interesting to compare asciminib with ponatinib, which is approved for patients with CML who are resistant to 2 or more TKIs and for patients with T315I mutation.

References

Branford S. Why is it critical to achieve a deep molecular response in chronic myeloid leukemia? Haematologica. 2020;105(12):2730-2737. doi:10.3324/haematol.2019.240739

Cortes JE, Apperley J, Lomaia E, et al. OPTIC primary analysis: a dose-optimization study of 3 starting doses of ponatinib (PON). J Clin Oncol. 2021;39(suppl 15):7000. doi:10.1200/JCO.2021.39.15_suppl.7000

Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404. doi:https://doi.org/10.1182/blood-2016-09-739086

Cortes J, Lang F. Third-line therapy for chronic myeloid leukemia: current status and future directions. J Hematol Oncol. 2021;14(1):44. doi:10.1186/s13045-021-01055-9

Jabbour EJ, Deininger MW, Abruzzese E, et al. Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials [abstract 2550]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol. 2018;93(3):442-459. doi:10.1002/ajh.25011

Kumagai T, Murai K, Ureshino H, et al. Very low-dose dasatinib is a safe and effective therapy for elderly patients with newly-diagnosed chronic-phase chronic myeloid leukemia: results from the DAVLEC study, a single-arm, multicenter, phase 2 trial [abstract 3601]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Mauro MJ, Minami Y, Rea D, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib in patients with chronic myeloid leukemia in chronic phase after ≥2 prior tyrosine kinase inhibitors: update after 48 weeks [abstract 310]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. doi:10.1182/blood.2020009984

Sasaki K, Jabbour EJ, Issa GC, et al. Low-dose dasatinib 50 mg/day versus standard-dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: a propensity score analysis [abstract 631]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. 

Tan BK, Bee PC, Chua SS, Chen L-C. Monitoring and improving adherence to tyrosine kinase inhibitors in patients with chronic myeloid leukemia: a systematic review. Patient Prefer Adherence. 2021;15:2563-2575. doi:10.2147/PPA.S269355


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