Second attempt to discontinue TKI after molecular relapse in patients with chronic myeloid leukemia: A real-life Italian multicenter study.

A More Rapid Initial Decline of BCR::ABL1 Transcripts and Longer Treatment Duration with Improvement of Treatment-Free Remission Rate after Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Comparative Monitoring of Minimal Residual Disease (MRD) By RT-Quantitative (RT-qPCR) and Digital PCR (dPCR) in Ph+ Chronic Myeloid Leukemia (CML) Patients Treated with TKIs for Recognition of Stable Deep Molecular Response (DMR) and Identification of Best Candidates to TKIs Treatment Discontinuation

Objective To explore the clinical outcomes and their influencing factors of tyrosine kinase inhibitors (TKI) discontinuation in patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods From January 1999 to April 2018, a total of 16 patients with CML-CP who underwent routine outpatient follow-up in Department of Hematology, West China Hospital of Sichuan University, and discontinued TKI for more than 6 months were selected as subjects. Among them, there were 6 male patients and 10 females; the median age at diagnosis was 39.5 years (24.8-53.8 years). The median age at time of TKI discontinuation was 45.5 years old (30.3-69.0 years old). According to whether molecular recurrence occurred during the follow-up period after TKI discontinuation, the patients were divided into recurrent group (n=5) and non-recurrent group (n=11). The clinical data of patients with TKI before and after discontinuation were collected by retrospective method. The causes of TKI discontinuation, treatment-free remission (TFR) status after TKI discontinuation and its possible influencing factors were analyzed. In this study, composition ratio of gender, stage of CML, and TKI discontinuation causes were compared between the two groups using Fisher′s exact test. The Mann-Whitney U test was used to compare the non-normal distribution measurement data, such as duration of TKI treatment, time from TKI treatment to major molecular response (MMR)/deep molecular response (DMR), time of MMR/DMR maintenance. The TFR rate at 6 and 12 months after TKI discontinuation in patients was calculated by Kaplan-Meier method. The procedure followed in this study was in line with the revised Helsinki Declaration of the World Medical Association in 2013. Results ① Among all the 16 patients with CML-CP, causes of TKI discontinuation included TKI-related adverse reactions (n=5), patients′ expectancy (n=5), pregnancy/planned pregnancy (n=4), financial burden (n=1), and combined solid tumor (n=1). The median time of TKI treatment in 16 patients with CML-CP was 53.0 months (34.0-156.0 months). Among them, 15 patients achieved DMR before TKI discontinuation and 1 patient only obtained MMR. The median time to achieve DMR before TKI discontinuation was 39.0 months (10.0-144.0 months). ② The median follow-up time of 16 patients with CML-CP after TKI discontinuation was 17.0 months (7.0-75.0 months). At the end of follow-up, 11 patients had no molecular recurrence, and the median time of TFR was 12.0 months (2.0-75.0 months). TFR rates at 6 and 12 months after TKI discontinuation were 68.8% and 61.9%, respectively. Molecular recurrence occurred in 5 patients. The median recurrence time was 4.0 months (2.0-5.0 months) after TKI discontinuation, and the BCR-ABLIS level was 0.14%-0.88% at the time of recurrence. Among the 5 patients with molecular recurrence, 4 patients restarted TKI at 3, 4, 6 and 8 months after relapse, obtained MMR after 2, 3, 4, and 5 months of restarting TKI, obtained molecular response (MR)4.5 after 2, 3, 7 and 8 months of restarting TKI, respectively. ③ In this study, 5 patients with molecular recurrence occurred within 6 months after TKI discontinuation. The composition ratio of gender, stage of CML, causes of TKI discontinuation, previous treatment of interferon-α, TKI type, as well as duration of TKI treatment, time of initiation of TKI treatment to MMR/DMR, time of MMR/DMR maintenance, age at TKI discontinuation between two groups were compared. And the differences were not statistically significant (P>0.05). ④ Among 16 patients with CML-CP, 2 patients developed TKI withdrawal syndrome, which was characterized by systemic bone pain or myalgia. Conclusions Patients with CML-CP who receive long-term TKI and maintain continuous DMR, long-term TFR can be obtained in about 50% patients, but long-term MR should be monitored after TKI discontinuation. The above-mentioned influencing factors that may affect the clinical outcomes of TKI discontinuation were not statistically different between the recurrent group and the non-recurrent group, which may be related to small sample size of this study. Key words: Leukemia, myeloid; Leukemia, myeloid, chronic-phase; Leukemia, myelogenous, chronic, BCR-ABL positive; Prognosis; Tyrosine kinase inhibitor; Treatment discontinuation; Treatment free remission

Improvement of Treatment-Free Remission Rate Following Discontinuation of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Phase, Chronic Myeloid Leukemia

Objective: To analyze the treatment-free remission (TFR) outcomes after discontinuation of tyrosine kinase inhibitor (TKI) in children with chronic myeloid leukemia (CML). Methods: In this retrospective cohort study, clinical data of 14 chronic phase CML children aged <18 years who had achieved stable deep molecular response (DMR) for ≥ 2 years after standardized treatment with TKI and had a strong desire to discontinue TKI at Henan Cancer Hospital from September 30, 2016 to January 30, 2022 were collected retrospectively. According to the different TFR outcomes after discontinuation of TKI, patients were divided into loss of major molecular response (MMR) group and without loss of MMR group, differences in clinical characteristics between the two groups of children were analyzed using Mann-Whitney U test and Fisher exact test. Results: Out of 14 children with TKI discontinuation, 7 were male and 7 were female. The age at diagnosis was 14.0 (4.8, 17.0) years, and the age at TKI discontinuation was 22.0 (12.5, 27.0) years. Among them, 8 children were treated with imatinib prior to TKI discontinuation and 6 children were treated with second-line substitution of the second-generation TKI nilotinib or dasatinib prior to TKI discontinuation. The follow-up time was 37.0 (27.8, 47.5) months, and 7 cases lost MMR at the time of discontinuation of 3.0 (2.0, 11.0) months. Eight children gained TFR at 6 months, 7 children gained TFR at 12 and 24 months. Amongst the 6 children who received second-generation TKI prior to TKI discontinuation, 2 children lost MMR at 3 and 11 months and 4 children gained TFR, among the 8 children who discontinued imatinib, 5 children lost MMR at the time 3.0 (2.0, 9.0) months and 3 children gained TFR. The age at diagnosis and TKI discontinuation, the time from TKI treatment to the acquisition of DMR, the duration of TKI treatment before TKI discontinuation, the duration of DMR before TKI discontinuation, and the number of children treated with second-generation TKI were not statistically different between the 7 children in the group that did not lose the MMR and the 7 children in the group that lost the MMR (all P>0.05). All the 7 children with confirmed loss of MMR immediately restarted TKI therapy, and all regained DMR after 2.0 (2.0, 11.0) months of therapy. None of the children had disease progression. After TKI discontinued, only 1 child had mild bone pain, which could be relieved by oral antipyretic analgesic drugs. Conclusions: Children with CML who have achieved a durable stable DMR for≥2 years on TKI therapy can discontinue the TKI and obtain TFR. Both the longer duration of TKI therapy, the longer duration of DMR and the use of second-generation TKI therapy before TKI discontinuation, may allow more children with CML who are expecting TKI discontinuation to have access to TFR.

Long-Term Follow-up of Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia: A Single-Center Experience

Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free Trial

“Duration of Deep Molecular Response” Has Most Impact on the Success of Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - Results from the EURO-SKI Trial

Prospective Monitoring of Peripheral Blood CD26+ Leukemia Stem Cells in Chronic Myeloid Leukemia Patients from Time of TKI Discontinuation

Optimal Duration of Imatinib Treatment / Deep Molecular Response for Treatment-Free Remission after Imatinib Discontinuation from a Canadian Tyrosine Kinase Inhibitor Discontinuation Trial

171 Background: Since the introduction of tyrosine kinase inhibitors (TKIs), the effectiveness of treating chronic phase chronic myeloid leukemia has seen remarkable improvement. A current challenge in TKI therapy is achieving treatment-free remission (TFR) safely. Numerous TKI-stop trials and translational studies have investigated factors influencing TFR, including TKI treatment duration, duration of deep molecular response (DMR), cellular immunity activation, and bcr::abl1 transcript type. However, identifying reliable markers for achieving TFR safely remains uncertain. In this multicenter study, we focused on examining the association between TFR and cytotoxic T-lymphocytes (CTLs). Methods: Between June 2020 and March 2022, a total of 45 patients were enrolled: 38 patients with DMR for at least 1 year on TKIs (on TKI group) and 7 patients with DMR for at least 1 year after discontinuing TKIs (off TKI group). The study included 30 males, with a median age of 59 years (range: 29–87). Median TKI treatment duration was 7.7 years (range: 1.5–18.3), and median TKI cessation duration in the off TKI group was 4.9 years (range: 1.7–7.1). Molecular response and cellular immunity were monitored over 12 months post-consent for patients in the off TKI group and after TKI discontinuation for patients in the on TKI group. Results: During the observation period, 25 patients (65.8%) in the on TKI group maintained DMR, while 13 patients (34.2%) lost DMR. Conversely, all patients in the off TKI group sustained DMR. The median TKI treatment duration in the group maintaining DMR (9.45 years, range: 3.3–18.3, N = 32) significantly exceeded that in the group losing DMR (4.9 years, range: 1.5–11.9, N = 13) (P = 0.0048). Patients taking TKIs for over 7 years with a higher percentage of total memory CTLs than total effector CTLs maintained DMR. Conversely, patients losing DMR despite over 10 years of TKI treatment had a higher percentage of total effector CTLs than total memory CTLs. Among the 32 patients maintaining DMR, 19 exhibited a higher percentage of total effector CTLs than total memory CTLs, with 15 (78.9%) maintaining MR5 throughout the study. Furthermore, of the six patients maintaining DMR with relatively short TKI administration (median 5.5 years, range: 3.3–6.4), three displayed a higher percentage of total memory CTLs than total effector CTLs. Among the remaining three patients, two showed strong CTL activation, with one patient having an effector CTL clone over 30% and the other having a memory CTL clone over 30%. Conclusions: This study indicates that a sufficiently prolonged TKI treatment duration (&gt;7 years) and maintaining deeper DMR (≥ MR4.5, preferably MR5) are conducive to safely achieving TFR. Furthermore, a high percentage of total memory CTLs and intense CTL activation may serve as meaningful markers for TFR.

Prognostic Model of Successful Tyrosine Kinase Inhibitors Discontinuation Based on the Russian RU-SKI Multicenter Prospective Study

Quality of Life in Chronic Myeloid Leukemia Patients with Deep Molecular Response Who Stopped Therapy By Tyrosine Kinase Inhibitors: Interim Results of Russian Prospective Multicenter Trial RU-SKI

High Level of Successful TKI Discontinuation in Chronic Myeloid Leukemia (CML) Patients: Preliminary Results of AST-Argentina Stop Trial

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia. a randomized national fi-LMC comparative trial of two therapeutic strategies.