conference reporter

63rd ASH Annual Meeting and Exposition

Molecular Status for the Discontinuation of Tyrosine Kinase Inhibitor Therapy

by Jorge E. Cortes, MD

Overview

As seen at the 63rd ASH Annual Meeting and Exposition, treatment-free remission (TFR) is an important goal in chronic myeloid leukemia (CML). Factors that predict the successful discontinuation of tyrosine kinase inhibitor (TKI) therapy in CML continue to be studied.

Following these proceedings, featured expert Jorge E. Cortes, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Cortes are presented here. 

Jorge E. Cortes, MD

Director, Georgia Cancer Center
Professor of Medicine
Augusta University
Augusta, GA

“Treatment discontinuation has become a reality and is an important goal for many patients with CML. It can be accomplished in the clinic, but it is very important that it is done in a way that optimizes outcomes."


Jorge E. Cortes, MD

Treatment discontinuation has become an increasingly important goal for many patients with CML. Eligible individuals first need to achieve a sustained deep molecular response (DMR); however, the optimal parameters for the depth and duration of the molecular response are still being studied. Trials conducted before it was known that TKI discontinuation was possible used very stringent criteria for depth of response that are not used clinically, such as MR5 (≤0.001% BCR-ABL1 on the international reporting scale [IS]). Today, MR4 (≤0.01% BCR-ABL1 IS) and MR4.5 (≤0.0032% BCR-ABL1 IS) are used, and various durations of DMR prior to TKI discontinuation are being evaluated.

At ASH 2021, Mahon et al reported the final analysis from the prospective EURO-SKI trial, now at full enrollment and after 3 years of follow-up (abstract 633). This trial evaluated molecular recurrence-free survival after stopping TKI therapy in a large Pan-European cohort of patients with CML. Eligible individuals had received any TKI for at least 3 years without treatment failure and achieved an MR4 that was sustained for at least 1 year. In a previously reported interim analysis, the molecular relapse-free survival for these patients was 61% at 6 months and 50% at 24 months, where molecular relapse-free survival was defined by loss of major molecular response (MMR; >0.1%). Here, in the final analysis, the median TKI treatment duration was 7.5 years, and the median duration of MR4 before TKI cessation was 4.7 years. At 36 months, 46% of patients were in MMR, the molecular recurrence-free survival rate was 48%, and the molecular recurrence- and treatment-free survival rate was 46%. Researchers reported that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence (ie, between 6 and 36 months [57 patients]), TKI treatment duration before discontinuation was the only relevant variable in a preliminary univariate logistic analysis.

As noted, the EURO-SKI trial used an MR4 for at least 1 year as part of the eligibility criteria; however, there is ongoing debate regarding the criteria for discontinuation that should be used clinically, since deeper, more sustained responses (eg, MR4.5 sustained for at least 2 years) may be preferable. Contemporary guidelines suggest the use of MR4, while I tend to favor the MR4.5 for at least 2 years for most patients. If you make the criteria less stringent, this will allow more patients to pursue the goal of TFR, but the goal is undermined if this results in more relapses. So, I think that we need to use the more stringent criteria, but we also need to see how we can get more patients to meet those stringent criteria. 

The risk of relapse is highest between 6 months and 2 years after treatment discontinuation. Although the risk decreases after 6 months, and then again after 2 years, it still remains. For each additional year of response duration, the probability of relapse is likely reduced by a few percentage points, which might not seem like much, but the benefit is cumulative. If you accumulate 5 or 6 years of durational remission, you could decrease your risk by 15% to 20%, which is a significant reduction.

Regarding the choice of TKI and the goal of discontinuation, the probability of achieving DMR with imatinib is a bit lower than with the second-generation TKIs, but one can still start with imatinib and achieve TFR. Other strategies include starting with a more potent TKI or starting with imatinib and then switching to a different TKI in those who have not achieved DMR. The latter approach has been studied with nilotinib, but the optimal duration of nilotinib consolidation to increase the chances of achieving successful TFR continues to be characterized. At ASH 2021, Rea and colleagues presented data on the ENESTPath study, reporting findings suggesting that there is no significant incremental benefit of TFR success from an additional year of nilotinib consolidation for those who sustained DMR for 2 years on nilotinib after switching from first-line imatinib (abstract 635).

Although we are mostly focused on the molecular criteria for discontinuation, I would add that the patient must be motivated to do this. Some patients know that they would become very anxious about relapsing after discontinuation, and, for them, suffering from these anxieties is not worth it, as the medications are quite safe. Additionally, patients and clinicians must be mindful of the monitoring intensity that is required, and they must be willing to adhere to a strict monitoring schedule. If you detect a relapse early, it is usually not clinically relevant. The TKI is restarted in this case, the patient responds again, and they are fine. But when discontinuation occurs without monitoring, the disease can progress to become a more difficult situation that you may not be able to control.

Treatment discontinuation has become a reality and is an important goal for many patients with CML. It can be accomplished in the clinic, but it is very important that it is done in a way that optimizes outcomes. This includes eligible patients meeting the required molecular response, at the very least MR4, although I would emphasize that deeper and longer responses are associated with better outcomes. 

References

Atallah E, Schiffer CA. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom? Haematologica. 2020;105(12):2738-2745. doi:10.3324/haematol.2019.242891

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, 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(20):2333-2340. doi:10.1200/JCO.2015.64.8899

Etienne G, Nicolini NE, Dulucq S, et al. Achieving a complete molecular remission under imatinib therapy is associated with a better outcome in chronic phase chronic myeloid leukaemia patients on imatinib frontline therapy. Blood. 2012;120(21):3754. doi:https://doi.org/10.1182/blood.V120.21.3754.3754

Mahon F-X, Richter J, Hochhaus A, et al. FINAL analysis of a Pan European STOP tyrosine kinase inhibitor trial in chronic myeloid leukemia: the EURO-SKI study [abstract 633]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Mughal TI, Psaila B, DeAngelo DJ, Saglio G, Van Etten RA, Radich JP. Interrogating the molecular genetics of chronic myeloproliferative malignancies for personalized management in 2021. Haematologica. 2021;106(7):1787-1793. doi:10.3324/haematol.2020.267252

Rea D, Kyrcz-Krzemien S, Sportoletti P, et al. Treatment-free remission (TFR) after two different durations of nilotinib consolidation in patients with chronic myeloid leukemia (CML) previously treated with imatinib: ENESTPath study results [abstract 635]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Saussele S, Richter J, Guilhot J, et al; EURO-SKI Investigators. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747-757. doi:10.1016/S1470-2045(18)30192-X


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