Treatment-free remission in chronic myeloid leukemia patients treated with low-dose TKIS: A feasible option also in the real-life setting?

Background: Long-term use of TKIs may expose patients (pts) to significant adverse events (AEs) that may affect quality of life. In recent years, treatment-free remission (TFR) has become a new therapeutic goal and is considered feasible also by international expert guidelines. Most clinical trials have indeed demonstrated that this approach is safe in CML pts who have gained a sustained DMR during treatment at a standard dose. In the real-life practice, TKI dose reductions are often required to reduce AEs but their impact on the possibility of attempting a TFR is still a matter of debate. Aims: To explore the attitude of Italian hematologists towards the prescription of TKIs at a reduced dose and its impact on TFR attempts in CML pts. Methods: In September 2020 a questionnaire was sent to the 54 centers participating in the Campus CML. This interactive network connects Italian Hematology specialists active in the field of CML with the aim of sharing experiences and updates for the diagnosis and treatment of this disease, the identification and prevention of specific toxicities of the drugs used and also on possible future therapeutic approaches. The online survey consisted of questions regarding the use of reduced doses of TKIs in the clinical practice and the physicians’ propensity to offer a TFR to these pts. Results: The survey was completed by 45 centers (83%). All declared to have CML pts in treatment with low-dose TKIs (total number = 1.579). More in detail, this occurred in 22.4% of pts treated with imatinib, 24.2% with nilotinib, 34.0% with dasatinib, 70.3% with bosutinib and 74.5% with ponatinib. Dose reduction was due to AEs in most cases (70%), while only in the remaining pts TKIs were de-escalated after achieving molecular milestone. Most involved hematologists believed that reduced doses of TKIs should not influence TFR attempts; indeed, this approach was offered to 117 pts. The TKI most frequently used at reduced doses prior to a TFR attempt was imatinib (60 pts), followed by nilotinib (32 pts), dasatinib (22 pts) and, to a lesser extent, by ponatinib (2 pts) and bosutinib (1 patient). Before attempting TFR, 77 pts had received only one TKI, while 33 and 7 pts were, respectively, treated in second or later lines of therapy, with a median TKI duration of 121.8 months (range 16-221.9). At the time of TFR, all pts had already achieved a DMR, with a median treatment duration of 72 months. After a median follow-up from TKI discontinuation of 25 months (range 1.6-128.7), 88 pts (75.2%) were still in TFR. The median time to molecular recurrence (≥MMR) in the entire cohort was 3.9 months (range 1.6-29.6), and a MMR or a DMR was rapidly achieved in all cases after resuming TKI therapy (median time 5.8 months, range 1–25.8). Summary/Conclusion: In this large series of real-life CML patient management in Italy, treatment with low-dose TKI represents an important reality and, as expected, bosutinib and ponatinib are the drugs more frequently used in this setting. While a third of Italian hematologists still has some uncertainties on the feasibility of attempting a TFR after using reduced doses of TKIs outside of clinical trials, TFR is most often considered a safe option also in the real-life practice in pts treated with TKIs at a reduced dose either because of AEs or due to an optimal response already achieved. Interestingly, only about 25% of our series experienced a molecular recurrence, less than reported in pts treated at a standard dose. Consequently, TFR was not impaired by low-dose TKI regimens. Updated results will be presented.