Reply to Comment on low-dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment-free remission in chronic myeloid leukemia patients: Results of a retrospective study.

Abstract

We appreciate the interest of Campiotti et al in our work.1 Reducing the risk and severity of adverse effects (AEs) of tyrosine kinase inhibitors (TKIs) while increasing the number of patients who can achieve treatment-free remission (TFR) represents current challenges in chronic myeloid leukemia (CML). As a result, the use of low-dose TKIs should be considered insofar as they do not appear to affect TFR. In this context, Campiotti et al have pointed out that monitoring the plasma TKI concentration would be relevant for the interpretation of drug toxicity and the success of maintenance treatment. We have reported a retrospective, multicenter study showing that patients treated with low-dose TKIs for toxicity reasons before they stop treatment could achieve TFR in a proportion comparable to that for patients receiving a standard TKI dose.1 In this study, we included patients with chronic-phase chronic myeloid leukemia (CP-CML), and TKI dose reductions (imatinib, n = 10; second-generation TKI, n = 16) were initiated mainly because of nonhematological toxicities (92%). It should be recalled that standard TKI doses (400 mg daily for imatinib, 100 mg daily for dasatinib, 600 mg daily for nilotinib, and 400 mg daily for bosutinib) are introduced as first-line treatment for CP-CML according to current European LeukemiaNet recommendations without consideration of patient heterogeneity (age, sex, weight, and body surface area).2 For imatinib, a lower dose (300 mg daily) may be considered if the standard dose is not tolerated and the response remains optimal. Note that a recent clinical trial has demonstrated that in cases of newly diagnosed CP-CML, 50 mg of dasatinib daily could be effective and better tolerated than the standard dose.3 Patients' responses to the same TKI dose can vary according to pharmacokinetic and pharmacodynamic characteristics related to drug absorption and metabolism. For example, imatinib influx and efflux pumps have been shown to influence the achievement of a deep molecular response (DMR) or subsequent TFR.4 Several strategies of dose optimization based on minimal plasma concentrations of TKIs have been tested in clinical trials and have maintained efficiency with an improved side-effect profile.5, 6 The concept of dose adjustment is currently being discussed among CML researchers as a means of optimally managing the disease.7 Consequently, we agree with Campiotti et al that the determination of the plasma TKI concentration could be a helpful approach to reconciling the goal of reducing AEs with the need to control the leukemic clone. In our study,1 TFR was not impaired by low-dose TKI regimens administered for 1 year or longer before TKI cessation. As noted by Campiotti et al, drug blood level testing would have allowed measurement of the exact concentration in the plasma versus the theoretical expected concentration considered to be optimal. This would help us to understand why some patients retain a sustained DMR despite the dose reduction. It should be recalled that 65.4% of our patients experienced a ≥50% TKI full-dose reduction. In this case, it is quite unlikely that the plasma concentration was in the therapeutic range. Aoyama et al8 recently observed in a K562 cell line model that the cytostatic effect (depending on intracellular accumulation) of imatinib, nilotinib, or dasatinib persists even after the disappearance of the drug in the plasma. The therapeutic effects of TKIs are primarily based on their intracellular activity, plasma concentrations being only an indirect but useful marker. The mechanisms of DMR persistence under low-dose TKIs and the implications of TKI de-escalation strategies for TFR outcomes remain unclear. The residual CML stem cell compartment and the immune system during TKI de-escalation and after withdrawal are currently being explored.9, 10 In this situation, we can hypothesize that low-dose TKIs may maintain their antitumor function and have a more pronounced immunological effect. At the clinical level, relevant data such as patient compliance, TKI dose, AEs, BCR-ABL1 kinetics, and the specific mutation profile aside from BCR-ABL1 should be considered as a whole to set up a precision-based therapeutic approach as proposed by Saglio et al.11 After unprecedented successes in CML treatment, it is time to switch to a more personalized therapeutic strategy to decrease AEs and costs without impairing the achievement of a DMR and a subsequent TFR. The English of this article was reviewed by Jeffrey Arsham, an American medical translator. No specific funding was disclosed. Emilie Cayssials reports belonging to scientific advisory boards for Incyte Biosciences and Novartis Pharma and receiving travel support from Pfizer and Bristol-Myers Squibb. The other authors made no disclosures.