Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis

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This meta-analysis aimed to explore TFR in chronic myeloid leukemia chronic phase (CML-CP) patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation. METHODS: We performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Revman5.4 software. RESULTS: A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 60% [95CI:0.56-0.63] at 12 months and 55% [95CI:0.52-0.59] at 24 months, and a cumulative total of 2 CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (12months: P<0.001,24months: P=0.006), and molecular response depth MR5.0 (12months:P=0.005,24months: P=0.02). CONCLUSION: Our study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 61% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334) Treatment-free remission Tyrosine kinase inhibitors Chronic myeloid leukemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Chronic myeloid leukemia (CML) is the result of the transformation of primitive hematopoietic cells by the breakpoint cluster region protein (BCR)/Abbelsen murine leukemia virus oncogene homologue (ABL) oncogene. [ 1 ] Since the appearance of the first-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), imatinib, and later second- and third-generation TKIs, the prognosis of patients with CML has significantly improved, with the majority of patients achieving a stable deep molecular response (DMR) [ 2 – 4 ] . Currently, first-line TKIs for the treatment of CML include imatinib, nilotinib, dasatinib, radotinib, and bosutinib et al. [ 5 ] . There are still some patients who are resistant to TKIs, mainly due to mutations in the structural domain of BCR-ABL kinase. Third-generation TKIs, such as ponatinib and asciminib, are used as second-line TKI therapy for patients previously resistant or intolerant to TKIs. [ 6 , 7 ] . However, patients on long-term medication face complex chronic adverse effects and carry a heavy financial burden [ 3 , 8 , 9 ] . The STIM trial [ 10 ] demonstrated for the first time that TKI discontinuation was achievable in a subset of patients achieving CMR, and treatment-free remission (TFR) became a new long-term goal for patients with CML-CP. Aaron N Winn's Decision Analytic Modeling study showed that attempts to discontinue TKI therapy could save more than $ 54 billion over the next 30 years [ 11 ] . Nevertheless, many questions remain unanswered, such as, which patients are the best group to try TFR, and which factors predict loss of major molecular response after discontinuation, the European leukemia expert consensus suggests a DMR of at least 2–3 years [ 5 ] , the Los Angeles CML expert consensus suggests at least 2 years to achieve a DMR [ 12 ] , and the Canadian trial suggests that the length of the DMR before discontinuation should be prolonged to more than 6 years [ 13 ] . Since the first clinical trial of imatinib discontinuation, most of the multiple clinical trials in the last decade have demonstrated the feasibility and safety of discontinuation, a 2019 meta-analysis demonstrated the safety of restarting treatment with TKIs again after failed attempts at TFR [ 14 ] , and a 2019 meta-analysis examined molecular relapse rates after discontinuation of TKIs, but included limited databases and trials [ 15 ] . There is still a lack of comprehensive and systematic analytic studies, and research on the long-term discontinuation of TKIs in CML patients in the post-TKI era still needs to be updated and improved. Therefore, this systematic review will study the treatment-free remission after discontinuation of TKIs in patients with CML-CP through meta-analysis, explore the possible influencing factors of treatment-free remission as well as the safety, and further discuss the optimal patient population in which TFR can be attempted to provide evidence-based medical support for clinical guidelines. Methods This systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [ 16 ] and has been registered with PROSPERO (ID: CRD42023471334) 2.1 Search strategy A systematic literature search was conducted utilizing five databases, PubMed, Embase, Web of Science, Cochrane Library, and CNKI. The time was limited from the time of library construction to September 2023, and the language was limited to English and Chinese. Literature was screened using endnote with the search formula: (Chronic myeloid leukemia AND CML) AND (imatinib OR nilotinib OR dasatinib OR bosutinib OR radotinib OR flumatinib OR tyrosine kinase inhibitor OR TKI) AND (stop OR withdrawal OR discontinue OR discontinuation OR treatment-free remission OR treatment-free remission). (Detailed search formula in Supplement 1) 2.2 Selection criteria Inclusion criteria: (1) adult patients with a diagnosis of CML-CP stage were included; (2) patients were treated with TKIs; (3) discontinuation after achieving a deep molecular response (DMR); (4) prospective RCTs, non-RCTs; and (5) molecular relapse was defined as the loss of the major molecular response (MMR) or the loss of MR4.0; Exclusion criteria: (1) Reviews or meta-analyses; (2) Case reports, Replies, or comments; (3) Lack of required TFR rate; (4) Pediatric patients; (5) Retrospective trials; (6) Basic trials. We extracted outcomes from the most complete and recent articles if the data from the same trial were published more than once. Two researchers (Tang and Zhang) independently screened the abstracts as well as the titles, and then read the full text of the relevant studies. Any disagreements were resolved by consensus or by a third reviewer (Zheng). 2.3 Outcome indicators: Primary outcome: Number of patients in treatment-free remission (TFR) and treatment-free remission rate at 12, 24 months after discontinuation; Secondary outcome: cumulative adverse reaction rate after patient discontinuation, number of people experiencing CML progression, and CML-related deaths. 2.4 Data Extraction : Two investigators (Tang AND Zhang) independently extracted the first author, time of publication, type of study, sample size, participant characteristics (including age, gender, Sokal score, and type of TKI used for treatment), duration of TKI treatment before discontinuation, duration of DMR before discontinuation, depth of molecular response (MR) before discontinuation of TKI, 12 months and 24 months the number of patients in treatment-free remission. Data collection was performed using Excel, with one researcher extracting data from the included studies and another researcher confirming the accuracy of the data. Any disagreements were resolved by consensus. 2.5 Risk of bias (quality) assessment Two reviewers (Zheng AND Tang) independently assessed the risk of bias of the included studies. Included non-randomized clinical studies were assessed using a scale (MINORS) [ 17 ] . Any disagreement will be resolved by mutual discussion as well as expert review. Sensitivity analyses were performed to assess the robustness of the results based on bias. Publication bias was assessed by funnel plots of standard error effect sizes. 2.6. Statistical analysis This analysis was a single-group rate meta-analysis, calculated using the inverse variance (IV) method, which does not require the use of proportionality transformations such as log, logit, or double inverse chord, as there were no TFR proportions close to the 0/1 extremes for each study. We obtained the required data from the original article or from the relevant Kaplan-Meier curves provided in the original article and calculated the ratio of patients in TFR for each study and the 95% confidence intervals (CI) from the extracted data in conjunction with Engauge Digitizer 4.1 and an excel file [ 18 ] provided by Tierney et al. The appropriateness of summarizing the results of individual studies was assessed using the I2 statistic, which determines statistical heterogeneity. The I2 value reflects the total variability of the various studies as indexed by the study population, treatment regimen, or discontinuation, rather than chance or random error. I2 < 30% was defined as mild heterogeneity, 30% < I2 50% was defined as high heterogeneity. A fixed-effects model will be used for calculations when I2 < 50%; a random-effects model will be used for calculations of combined effect values (overall mean TFR rate) and 95% confidence intervals (CI) when I2 ≥ 50%. Subgroup analyses will be used to examine sources of heterogeneity and to determine whether the overall effect of the included trials varies with the type of trial and clinical characteristics such as year of publication, depth of molecular response before discontinuation, and molecular relapse criteria. type of TKI, prior interferon therapy, age, gender, sokal score, the median duration of DMR, and median duration of TKI therapy. The above processing was performed using Revman5.4. Results 3.1 Study identification Our initial search yielded 6938 studies, 4369 were excluded due to duplication, and after initial screening of titles and abstracts, 2026 were further excluded due to incompatibility with the topic and other language. The remaining 533 articles were further screened, and 514 were excluded because of (1) Reviews or meta-analyses; (2) Case reports, Replies, or comments; (3) Lack of required TFR rate; (4) Pediatric patients; (5) Retrospective trials; (6) Basic trials. The concrete selection procedure is depicted in Fig. 1 . Only one discontinuation-related RCT has been published since the establishment of the library, but it was excluded due to non-compliance with the discontinuation criteria [ 19 ] , Sung-Eun Lee’s trial in 2013 had a 100% TFR in transplanted patients and did not analyze the transplantation group separately [ 20 ] , and the D-FREE trial was aborted after a one-year TFR of 16.7%, probably due to the insufficient duration of TKI treatment and insufficient duration of the DMR [ 21 ] . They were excluded to minimize the impact on data synthesis. The HOVON and the NILST trial defined molecular relapse criteria as a single loss of MR 4.5 [ 19 , 22 ] , and the STIM molecular relapse criterion of a single loss of MR 5.0 were excluded [ 10 ] . 3.2 Study characteristics A total of 19 trials [ 23 – 41 ] involving 2336 patients were included in this meta-analysis. Eight trials have investigated the probability of TFR after imatinib treatment [ 23 , 25 , 32 , 36 , 39 – 41 ] , four trials have investigated the probability of TFR after dasatinib treatment [ 24 , 28 – 30 ] , three trials have investigated the probability of TFR after nilotinib treatment [ 26 , 34 , 37 ] , and the remaining four trials have investigated the probability of TFR after treatment with different TKIs [ 27 , 31 , 33 , 38 ] . There were no clinical trials related to the discontinuation of flumatinib, third-generation TKIs, etc., and only the LAST, GIMEMA CML0307 trial had 7 patients on bosutinib [ 26 , 27 ] . The discontinuation criteria for all trials was maintaining a stable DMR. All included trials defined molecular relapse as loss of MMR/loss of MR4.0 and as a trigger for restarting the TKI. Additional detailed characteristics of the included trials are shown in Tables 1 and 2. Major molecular response (MMR) was defined as BCR-ABL/ABLIS ≤ 0.1% by QPCR. MR4 was defined as BCR-ABL/ABLIS ≤ 0.01% (internal reference ABL copy number ≥ 10 4 ); MR4.5 was defined as BCR-ABL/ABLIS ≤ 0.003 2% (internal reference ABL copy number ≥ 3.2×10 4 ); MR5 was defined as BCR-ABL/ABLIS ≤ 0.001% (internal reference ABL copy number ≥ 10 5 ) and/or BCR-ABL was not detected (i.e., UMRD/CMR). DMR was defined as obtaining the efficacy of MR4 and above. TFR was defined as the period when TKI therapy was stopped and no molecular relapse occurred. [ 5 ] 3.3 Risk of bias (quality) assessment To assess the quality of non-comparative single-arm clinical trials, we used the MINORS Methodological items. Specifics regarding the quality evaluation are included in Table 3. Figure 2 was used to assess publication bias through funnel plots of standard error effect sizes. 3.4Treatment-free Remission Rate and Safety Using random-effects modeling combined, the overall mean TFR rate at 12 months was 60% (95CI: 0.56–0.63; I2 = 61%) and the overall mean TFR rate at 24 months was 55% (95CI: 0.52–0.59; I2 = 60%) with a high heterogeneity, as shown in Fig. 3 . Of the 19 trials included in this review, 2 cases of disease progression were cumulatively reported after discontinuation in the A-STIM trial [ 40 ] , GIMEMA CML 0307 trial and only 1 case of CML-related death was cumulatively reported after discontinuation in the GIMEMA CML 0307 trial [ 26 ] . The cumulative incidence of adverse reactions during the TFR are detailed in Table 2. Adverse reactions were mainly withdrawal syndromes with clinical manifestations of skeletal connective tissue pain. We do not synthesize the data here because most recent trials have not documented adverse reactions. 3.5 Subgroup Analyses 3.5.1 Previous interferon therapy As shown in Fig. 4 , the median proportion of patients previously treated with interferon across trials was 12%. The overall mean 12-month TFR rates for trials with a proportion of previously IFN-treated patients ≤ 12% [ 24 , 28 , 29 , 33 , 36 , 37 ] and for trials with a proportion > 12% [ 31 , 32 , 35 , 38 – 41 ] were 54% (95CI: 0.51–0.58) and 65% (95CI: 0.61–0.69), respectively; at 24 months the overall mean TFR rates were 51% (95CI: 0.48–0.55) and 60% (95CI. 0.55–0.65), with high heterogeneity (12m, P = 0.0002; 24m, P = 0.0006). These data suggested that better TFR was associated with prior interferon therapy. 3.5.2 Depth of Molecular Response Before Entering the TFR Phase As shown in Fig. 5 , the overall mean 12-month TFR rates for reaching molecular reaction depth MR4.5 [ 24 , 31 , 34 , 35 , 37 , 38 ] and reaching MR5.0 [ 31 , 35 , 36 , 39 – 41 ] in each trial were 55% (95CI: 0.51–0.58) and 66% (95CI: 0.61–0.69), respectively; the overall mean 24-month TFR rates were 51% (95CI: 0.48–0.55) and 61% (95CI: 0.55–0.65), with high heterogeneity (12m, P = 0.005; 24m, P = 0.02). Where STAT2 and STIM213 counted the number of patients who achieved MR5 and MR4.5, respectively, in subgroups we analyzed them separately. These data revealed that better TFR was associated with the depth of molecular response. 3.5.3. Other factors No significant differences were found in the 12-month TFR or the 24-month TFR when subgroup analyses were conducted on other factors, such as the year of trial publication, molecular relapse criteria, and patient characteristics (age, sex, Sokal score, TKI type, median duration of DMR, and median duration of TKI therapy). Our findings indicated that these other factors were not associated with TFR rates. The above results are shown in Table 4. Discussion Our study showed a 12-month overall mean TFR rate of 60% [95CI:0.56–0.63] and a 24-month overall mean TFR rate of 55% [95CI:0.52–0.59], indicating that more than half of the CML-CP patients were able to maintain TFR two years after TKI discontinuation. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (12months: P < 0.001,24months: P = 0.006), and molecular response depth MR5.0 (12months:P = 0.005,24months: P = 0.02), which is in line with the findings of previous trials [ 23 , 33 , 35 ] , although this analysis exists heterogeneity. According to the previous study [ 15 ] , the duration of DMR and TKI therapy before discontinuation were found to be associated with TFR. However, our analysis was not, and the possible explanation is the effect of heterogeneity in the inclusion of trials with other factors, further research may significantly impact the estimated effect sizes and potentially alter them. Although subgroup analyses of several trials have shown that TFR rates are not associated with the duration of TKI treatment and DMR duration before TKI discontinuation [ 28 , 29 , 31 , 38 , 39 ] . Adverse effects in patients maintained on TFR were mainly characterized by skeletal muscle myalgia, i.e., withdrawal syndrome. Although the EURO-SKI and ENESTop study reported rates of 31% and 74%, the rates of grade 3 to 4 adverse reactions were only 1% and 13%, respectively [ 33 , 34 ] . The D-STOP trial, on the other hand, reported an incidence of only 5.6% [ 28 ] . In addition, progression or CML-related deaths occurred after discontinuation in only 2 cases. The above demonstrates the feasibility and safety of TKI discontinuation. The following limitations are worth considering in this meta-analysis. Firstly, there was a high degree of heterogeneity in the clinical trials we included. This arose from differences in trial design, including criteria for the discontinuation population, the definition of molecular relapse, and different molecular monitoring methods such as Droplet digital PCR (dd-PCR) and RQ-PCR. Dd-PCR demonstrated more accurate molecular relapse monitoring than RQ-PCR [ 42 , 43 ] . Since there is no RCT for clinical trials related to drug discontinuation, it also affects the magnitude of heterogeneity. Despite differences in trial design, the trials we included were of high methodological quality. To explore heterogeneity, our analyses were validated by different subcomponents. Subsequently, we excluded retrospective clinical trials to avoid high heterogeneity and publication bias. A total of 30 retrospective studies were excluded in the rescreening, and we read these articles, which involved a large number of patients and had mostly high second-year TFR, such as the retrospective cohort study of M. Ansuinelli, with a second-year TFR of 74% [ 44 ] . Therefore, it would be of interest to analyze the discontinuation population of retrospective studies separately in the future. In addition, we have not yet analyzed distant relapse. In clinical trials with sufficiently long follow-up, the TFR rate in the fifth year was 44% for DASFREE, 49% for EURO-SKI in the third year, and 53.57% for ENESTfreedom in the fourth year, et al [ 24 , 45 , 46 ] . We note the presence of distant recurrence, but there is a temporary lack of sufficient trial sample sizes for analysis. Similarly, the limited number of prospective trials included in this meta-analysis resulted in a low number of trials in certain subgroups in the subgroup analysis. Self-renewing leukemic stem cells are associated with relapse, and some patients are still unable to achieve TFR due to the persistence of leukemic stem cells (LSCs) [ 47 ] . Paola Pacelli noted that despite fluctuating residual CD26 + LSCs, maintaining a stable TFR is still possible. [ 48 ] . Namely, factors other than the presence of LSCs play a positive role in disease recurrence. M Matsushita's trial found a relapse rate of 63.6% in cxorf48-specific ctl-negative patients and 0% in cxorf48-specific ctl-positive patients [ 49 ] . Yazad D Irani's results showed that TIM-3 was consistently up-regulated in CD4 + T-cells, CD8 + T-cells, and T-regs in relapsed patients, compared to patients with maintained TFR. regs cells were consistently upregulated [ 50 ] . In addition, Gene expression analyses of publicly available datasets revealed increased expression of TIM-3 on CML stem cells in comparison to normal hematopoietic stem cells. These results from recent studies of TKI discontinuation suggest that CXorf48 and TIM-3 may be promising therapeutic targets for durable treatment-free remission in immunotherapy for CML patients. Management of patients who discontinued TKIs should also focus on their psychological as well as other domains. Giora Sharf investigated that 56% of patients reported fear or anxiety during treatment discontinuation, and 60% reported withdrawal symptoms at the time of discontinuation [ 51 ] . Possible reasons for anxiety in patients who discontinue may be due to the uncertainty of relapse, adverse effects, and regular monitoring after discontinuation. The study [ 15 ] has shown that patients who failed TFR mostly resumed DMR after re-treatment with TKI. For molecular monitoring after TKIs discontinuation, the expert consensus of the European Leukemia Net proposes lifelong [ 52 ] . Our observation that TFR failure occurs mainly within one year, but a few patients still experience distant relapse, albeit slow onset [ 24 , 45 , 46 ] , suggests that there is an urgent need for a cost-effective and user-friendly method for monitoring molecular response after discontinuation, as well as for more accurate predictors. Dennis Dong Hwan Kim's results suggest that BCR-ABL1 transcriptional doubling time can be used as a predictor of TFR failure in CML-CP patients after imatinib discontinuation, potentially avoiding the need for frequent monthly monitoring of molecular assays [ 53 ] . The results of our analysis suggest a strategy that seems feasible to improve the success of TFR by attempting to rationalize the application of interferon before or after discontinuation of the drug for those who reach a molecular response depth of MR 5.0 or deeper. A Burchert's trial demonstrated that this strategy resulted in high TFR rates, with up to 84% of patients obtaining MR5 before discontinuation after a median follow-up of 7.9 years [ 54 ] . Interestingly, our analysis showed no significant effect of DMR duration and duration of TKI therapy before discontinuation of TKIs on TFR rates, but the D-FREE trial tells us that ignoring DMR duration is not desirable. One possible explanation is that the TFR rate depends mainly on the patient's sensitivity to the TKI rather than the duration of treatment, i.e., the depth of the molecular response obtained after treatment with a TKI, and the same factor is also responsible for the time required to reach that depth after TKIs treatment, which has not been recorded in the majority of the trials, and which would be a predictor worth investigating. This factor was reported in only two trials, the TWISTER trial showed an association with better TFR (P = 0.04), but the KID trial did not correlate with TFR rates (P = 0.152) [ 36 , 41 ] . In Naranie Shanmuganathan's study, time to BCR-ABL1 halving on TKI treatment was the strongest independent predictor of TFR maintenance [ 55 ] . Another strategy that seems feasible is dose-escalation discontinuation. A Iurlo's retrospective analysis in Italy found that low-dose TKIs do not seem to affect the likelihood of achieving DMR, but may even improve TFR rates, which were 74% in the second year [ 56 ] . The DESTINY trial demonstrated that discontinuation of TKIs after one year of dose halving resulted in a 72% progression-free survival rate in the second year [ 57 ] , but more trials are needed to validate whether attempted discontinuation after dose reduction promotes TFR. The number of RCTs and prospective clinical trials related to this area is limited, and more high-quality clinical trials are needed to further explore this. Meanwhile, trials of other second and third-generation TKIs are anticipated. The latest asciminib trial demonstrated superior efficacy and fewer adverse events [ 58 ] . We searched ClinicalTrials.gov and found that there are still multiple large trials with no results output, and we will update our opinion if we find an impact on predictors in the future. Conclusion Our study showed that CML-CP patients who reached DMR could achieve a TFR of 60% in the first year and 55% in the second year after TKIs discontinuation, while achieving a molecular response depth of MR5.0 or higher and prior interferon therapy were associated with higher TFR rates. Further validation of the above predictors is needed due to the heterogeneity of the included trials, while we hope that future trials focus on the time taken for patients to enter the DMR and the emergence of withdrawal syndromes. Declarations Declaration of Competing Interest Our authors claim no known personal relation or competing financial interests affecting this work. Data Availability Data can be obtained upon request. CRediT authorship contribution statement Zhenxiang Zheng and Zhao Yinconceived and designed the experiments.Hao Tang analyzed and interpreted the data. Xinxia Zhang performed the experiments. Yangmin Zhu and Liling Zheng drafted the article and all other authors revised the article. All authors approved the final version of the article. Funding This study was supported by the Key Program for the National Natural Science Foundation of China (No. 82304901 and 82202034). Guangzhou Science and Technology Plan Project (No. 2023A03J0262, 2024A03J0991, 2024A04J4325, 2024A03J0991 and 2024A04J4325), the Foundation of Guangdong Second Provincial General Hospital (No. YN2023-001 and TJGC-2023002), Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515110430), Scientific Research Project Program of Sichuan Medical Association (No.S20038), Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome. Acknowledgements The authors gratefully acknowledged the support of Science and Technology Planning Project of Guangdong Province (No.2023B1212060063 ). Consent for publication Not applicable. 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E.; Polydoros, F.; Apperley, J. F.; Milojkovic, D.; Rothwell, K.; Pocock, C.; Byrne, J.; de Lavallade, H.; Osborne, W.; Robinson, L.; O'Brien, S. G.; Read, L.; Foroni, L.; Copland, M., De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematology 2019, 6 (7), E375-E383. Réa, D.; Boquimpani, C.; Mauro, M. J.; Minami, Y.; Allepuz, A.; Maheshwari, V. K.; D'Alessio, D.; Wu, Y.; Lawrance, R.; Narbutas, S.; Sharf, G.; Hochhaus, A., Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial. Leukemia 2023, 37 (5), 1060–1067. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tabel1Basiccharacteristicsofincludedstudies.tif Table1：Basic characteristics of included studies NR: no report. MolRec： Molecular Relapse Criteria *: loss of MMR or Loss of MR4 twice consecutively **: loss of MMR or Loss of MR4.5 twice consecutively ***: loss of MMR or two consecutive positive screens Table2Basiccharacteristicsofincludedpatients.tif Table 2：Basic characteristics of included patients NR: no report. *: Non-IFN treatment group and previous IFN treatment group, respectively TABLE3Qualityassessmentofthenoncomparativesinglearmclinicaltrialsincludedinthemetaanalysis..tif TABLE 3 Quality assessment of the single-arm clinical trials included in the meta-analysis. Items Q1-Q8: Q1: A clearly stated aim; Q2: Inclusion of consecutive patients; Q3: Prospective collection of data; Q4: Endpoints appropriate to the aim of the study; Q5: Unbiased assessment of the study endpoint; Q6: Follow-up period appropriate to the aim of the study; Q7: Loss to follow up less than 5%; Q8: Prospective calculation of the study size. *The items are scored 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate). Tabel4.SubgroupanalysisofpredictorsofsuccessfulTFR..tif Table4. Subgroup analysis of predictors of successful TFR. MolRec： Molecular Relapse Criteria Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3998884","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276338800,"identity":"60e2dbca-7748-4737-a987-132f16851da7","order_by":0,"name":"Zhenxiang Zheng","email":"","orcid":"","institution":"Jinan university","correspondingAuthor":false,"prefix":"","firstName":"Zhenxiang","middleName":"","lastName":"Zheng","suffix":""},{"id":276338801,"identity":"299a8384-c475-4d32-9dfd-9ed7254be2eb","order_by":1,"name":"Hao Tang","email":"","orcid":"","institution":"Jinan university","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Tang","suffix":""},{"id":276338802,"identity":"14c9ed38-6bd6-4671-9ef4-f03cb715726d","order_by":2,"name":"Xinxia Zhang","email":"","orcid":"","institution":"Jinan university","correspondingAuthor":false,"prefix":"","firstName":"Xinxia","middleName":"","lastName":"Zhang","suffix":""},{"id":276338803,"identity":"dac6162a-79a2-4069-b53b-0ced4e9fb2d3","order_by":3,"name":"Liling Zheng","email":"","orcid":"","institution":"Jinan university","correspondingAuthor":false,"prefix":"","firstName":"Liling","middleName":"","lastName":"Zheng","suffix":""},{"id":276338804,"identity":"091d5f1c-4256-404f-bfc4-fde02f4fa381","order_by":4,"name":"Zhao Yin","email":"data:image/png;base64,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","orcid":"","institution":"Jinan university","correspondingAuthor":true,"prefix":"","firstName":"Zhao","middleName":"","lastName":"Yin","suffix":""},{"id":276338805,"identity":"32a5fa15-b45d-46f1-9ab9-27f6e356f705","order_by":5,"name":"Yangmin Zhu","email":"","orcid":"","institution":"Jinan university","correspondingAuthor":false,"prefix":"","firstName":"Yangmin","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2024-02-29 07:32:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3998884/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3998884/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52034248,"identity":"f1cac850-eb9a-4965-9005-7d0999f97835","added_by":"auto","created_at":"2024-03-05 16:46:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":245903,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of the single-arm meta-analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1Flowchartofthesinglearmmetaanalysis.png","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/27117144610c4f6fc26423be.png"},{"id":52032866,"identity":"fdc4663c-a3f2-46c8-bc6a-edba5471ba58","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":155752,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure2Funnelplot.png","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/8d982c9d32aad9fbbb8b085a.png"},{"id":52032867,"identity":"bc74da47-f594-4110-af38-a3cdd05c4af1","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":489385,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of the overall mean TFR rate at 12 and 24 months after TKI discontinuation. TFR, treatment-free remission, TKI, tyrosine kinase inhibitor, 95% CI, 95% confidence interval, IV, inverse variance\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/804082daf8aa379233cbfb54.png"},{"id":52034249,"identity":"f7c18966-09b6-4097-8a8b-6bfeabb5e303","added_by":"auto","created_at":"2024-03-05 16:46:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":490997,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup analysis for TFR rate according to previous interferon therapy before TKI discontinuation. TFR, treatment-free remission, TKI, tyrosine kinase inhibitor, 95% CI, 95% confidence interval, IV, inverse variance\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/2868a14b0b8d2d649c20b57b.png"},{"id":52032872,"identity":"988ebc9a-9af7-41c0-871c-144b5153c474","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":494620,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup analysis for TFR rate according to the depth of molecular response before TKI discontinuation. TFR, treatment-free remission, TKI, tyrosine kinase inhibitor, 95% CI, 95% confidence interval, IV, inverse variance\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/f94e4e8b798bdf658fcc8842.png"},{"id":52417567,"identity":"5d69e9ca-123e-4f4f-8846-619eb2f3bdc6","added_by":"auto","created_at":"2024-03-11 12:08:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2096868,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/adf1c5b7-a5f2-4cc4-9d31-7f0341e25f53.pdf"},{"id":52032871,"identity":"93193270-6c56-4e5b-948a-1627057900d9","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1300174,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable1：Basic characteristics of included studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNR: no report. MolRec： Molecular Relapse Criteria\u003c/p\u003e\n\u003cp\u003e*: loss of MMR or Loss of MR4 twice consecutively\u003c/p\u003e\n\u003cp\u003e**: loss of MMR or Loss of MR4.5 twice consecutively\u003c/p\u003e\n\u003cp\u003e***: loss of MMR or two consecutive positive screens\u003c/p\u003e","description":"","filename":"Tabel1Basiccharacteristicsofincludedstudies.tif","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/68743ea2d31cd523fc6c7908.tif"},{"id":52032868,"identity":"f39d4145-e169-4224-b00b-c095d0a35afe","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":595240,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2：Basic characteristics of included patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNR: no report. *: Non-IFN treatment group and previous IFN treatment group, respectively\u003c/p\u003e","description":"","filename":"Table2Basiccharacteristicsofincludedpatients.tif","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/d15ead6eddbb64af779fdbac.tif"},{"id":52032870,"identity":"758e2470-dbad-474d-8b0b-4d89c1077c12","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":615972,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTABLE 3 Quality assessment of the single-arm clinical trials included in the meta-analysis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eItems Q1-Q8: Q1: A clearly stated aim; Q2: Inclusion of consecutive patients; Q3: Prospective collection of data; Q4: Endpoints appropriate to the aim of the study; Q5: Unbiased assessment of the study endpoint; Q6: Follow-up period appropriate to the aim of the study; Q7: Loss to follow up less than 5%; Q8: Prospective calculation of the study size.\u003c/p\u003e\n\u003cp\u003e*The items are scored 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate).\u003c/p\u003e","description":"","filename":"TABLE3Qualityassessmentofthenoncomparativesinglearmclinicaltrialsincludedinthemetaanalysis..tif","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/5f60580defe43b42787da2aa.tif"},{"id":52032874,"identity":"b579f155-c5c2-4e61-b3fa-bff5eb35d2da","added_by":"auto","created_at":"2024-03-05 16:38:57","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":517492,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable4. Subgroup analysis of predictors of successful TFR.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMolRec： Molecular Relapse Criteria\u003c/p\u003e","description":"","filename":"Tabel4.SubgroupanalysisofpredictorsofsuccessfulTFR..tif","url":"https://assets-eu.researchsquare.com/files/rs-3998884/v1/b50a8f12b4dcb93b17ce299d.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic myeloid leukemia (CML) is the result of the transformation of primitive hematopoietic cells by the breakpoint cluster region protein (BCR)/Abbelsen murine leukemia virus oncogene homologue (ABL) oncogene. \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e Since the appearance of the first-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), imatinib, and later second- and third-generation TKIs, the prognosis of patients with CML has significantly improved, with the majority of patients achieving a stable deep molecular response (DMR) \u003csup\u003e[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Currently, first-line TKIs for the treatment of CML include imatinib, nilotinib, dasatinib, radotinib, and bosutinib et al. \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. There are still some patients who are resistant to TKIs, mainly due to mutations in the structural domain of BCR-ABL kinase. Third-generation TKIs, such as ponatinib and asciminib, are used as second-line TKI therapy for patients previously resistant or intolerant to TKIs. \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, patients on long-term medication face complex chronic adverse effects and carry a heavy financial burden \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. The STIM trial \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e demonstrated for the first time that TKI discontinuation was achievable in a subset of patients achieving CMR, and treatment-free remission (TFR) became a new long-term goal for patients with CML-CP. Aaron N Winn's Decision Analytic Modeling study showed that attempts to discontinue TKI therapy could save more than \u003cspan\u003e$\u003c/span\u003e54\u0026nbsp;billion over the next 30 years \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNevertheless, many questions remain unanswered, such as, which patients are the best group to try TFR, and which factors predict loss of major molecular response after discontinuation, the European leukemia expert consensus suggests a DMR of at least 2\u0026ndash;3 years \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, the Los Angeles CML expert consensus suggests at least 2 years to achieve a DMR\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, and the Canadian trial suggests that the length of the DMR before discontinuation should be prolonged to more than 6 years \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Since the first clinical trial of imatinib discontinuation, most of the multiple clinical trials in the last decade have demonstrated the feasibility and safety of discontinuation, a 2019 meta-analysis demonstrated the safety of restarting treatment with TKIs again after failed attempts at TFR \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, and a 2019 meta-analysis examined molecular relapse rates after discontinuation of TKIs, but included limited databases and trials \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. There is still a lack of comprehensive and systematic analytic studies, and research on the long-term discontinuation of TKIs in CML patients in the post-TKI era still needs to be updated and improved.\u003c/p\u003e \u003cp\u003eTherefore, this systematic review will study the treatment-free remission after discontinuation of TKIs in patients with CML-CP through meta-analysis, explore the possible influencing factors of treatment-free remission as well as the safety, and further discuss the optimal patient population in which TFR can be attempted to provide evidence-based medical support for clinical guidelines.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e and has been registered with PROSPERO (ID: CRD42023471334)\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search strategy\u003c/h2\u003e \u003cp\u003eA systematic literature search was conducted utilizing five databases, PubMed, Embase, Web of Science, Cochrane Library, and CNKI. The time was limited from the time of library construction to September 2023, and the language was limited to English and Chinese. Literature was screened using endnote with the search formula: (Chronic myeloid leukemia AND CML) AND (imatinib OR nilotinib OR dasatinib OR bosutinib OR radotinib OR flumatinib OR tyrosine kinase inhibitor OR TKI) AND (stop OR withdrawal OR discontinue OR discontinuation OR treatment-free remission OR treatment-free remission). (Detailed search formula in Supplement 1)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Selection criteria\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eInclusion criteria:\u003c/h2\u003e \u003cp\u003e(1) adult patients with a diagnosis of CML-CP stage were included; (2) patients were treated with TKIs; (3) discontinuation after achieving a deep molecular response (DMR); (4) prospective RCTs, non-RCTs; and (5) molecular relapse was defined as the loss of the major molecular response (MMR) or the loss of MR4.0;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eExclusion criteria:\u003c/h2\u003e \u003cp\u003e(1) Reviews or meta-analyses; (2) Case reports, Replies, or comments; (3) Lack of required TFR rate; (4) Pediatric patients; (5) Retrospective trials; (6) Basic trials.\u003c/p\u003e \u003cp\u003eWe extracted outcomes from the most complete and recent articles if the data from the same trial were published more than once. Two researchers (Tang and Zhang) independently screened the abstracts as well as the titles, and then read the full text of the relevant studies. Any disagreements were resolved by consensus or by a third reviewer (Zheng).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3 Outcome indicators:\u003c/h2\u003e \u003cp\u003ePrimary outcome: Number of patients in treatment-free remission (TFR) and treatment-free remission rate at 12, 24 months after discontinuation;\u003c/p\u003e \u003cp\u003eSecondary outcome: cumulative adverse reaction rate after patient discontinuation, number of people experiencing CML progression, and CML-related deaths.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e2.4 Data Extraction\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eTwo investigators (Tang AND Zhang) independently extracted the first author, time of publication, type of study, sample size, participant characteristics (including age, gender, Sokal score, and type of TKI used for treatment), duration of TKI treatment before discontinuation, duration of DMR before discontinuation, depth of molecular response (MR) before discontinuation of TKI, 12 months and 24 months the number of patients in treatment-free remission. Data collection was performed using Excel, with one researcher extracting data from the included studies and another researcher confirming the accuracy of the data. Any disagreements were resolved by consensus.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.5 Risk of bias (quality) assessment\u003c/h2\u003e \u003cp\u003eTwo reviewers (Zheng AND Tang) independently assessed the risk of bias of the included studies. Included non-randomized clinical studies were assessed using a scale (MINORS) \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Any disagreement will be resolved by mutual discussion as well as expert review. Sensitivity analyses were performed to assess the robustness of the results based on bias. Publication bias was assessed by funnel plots of standard error effect sizes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.6. Statistical analysis\u003c/h2\u003e \u003cp\u003eThis analysis was a single-group rate meta-analysis, calculated using the inverse variance (IV) method, which does not require the use of proportionality transformations such as log, logit, or double inverse chord, as there were no TFR proportions close to the 0/1 extremes for each study. We obtained the required data from the original article or from the relevant Kaplan-Meier curves provided in the original article and calculated the ratio of patients in TFR for each study and the 95% confidence intervals (CI) from the extracted data in conjunction with Engauge Digitizer 4.1 and an excel file \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e provided by Tierney et al.\u003c/p\u003e \u003cp\u003eThe appropriateness of summarizing the results of individual studies was assessed using the I2 statistic, which determines statistical heterogeneity. The I2 value reflects the total variability of the various studies as indexed by the study population, treatment regimen, or discontinuation, rather than chance or random error. I2\u0026thinsp;\u0026lt;\u0026thinsp;30% was defined as mild heterogeneity, 30% \u0026lt; I2\u0026thinsp;\u0026lt;\u0026thinsp;50% was defined as moderate heterogeneity and \u0026gt;\u0026thinsp;50% was defined as high heterogeneity. A fixed-effects model will be used for calculations when I2\u0026thinsp;\u0026lt;\u0026thinsp;50%; a random-effects model will be used for calculations of combined effect values (overall mean TFR rate) and 95% confidence intervals (CI) when I2\u0026thinsp;\u0026ge;\u0026thinsp;50%.\u003c/p\u003e \u003cp\u003eSubgroup analyses will be used to examine sources of heterogeneity and to determine whether the overall effect of the included trials varies with the type of trial and clinical characteristics such as year of publication, depth of molecular response before discontinuation, and molecular relapse criteria. type of TKI, prior interferon therapy, age, gender, sokal score, the median duration of DMR, and median duration of TKI therapy.\u003c/p\u003e \u003cp\u003eThe above processing was performed using Revman5.4.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study identification\u003c/h2\u003e \u003cp\u003eOur initial search yielded 6938 studies, 4369 were excluded due to duplication, and after initial screening of titles and abstracts, 2026 were further excluded due to incompatibility with the topic and other language. The remaining 533 articles were further screened, and 514 were excluded because of (1) Reviews or meta-analyses; (2) Case reports, Replies, or comments; (3) Lack of required TFR rate; (4) Pediatric patients; (5) Retrospective trials; (6) Basic trials. The concrete selection procedure is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOnly one discontinuation-related RCT has been published since the establishment of the library, but it was excluded due to non-compliance with the discontinuation criteria \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, Sung-Eun Lee\u0026rsquo;s trial in 2013 had a 100% TFR in transplanted patients and did not analyze the transplantation group separately \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, and the D-FREE trial was aborted after a one-year TFR of 16.7%, probably due to the insufficient duration of TKI treatment and insufficient duration of the DMR \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. They were excluded to minimize the impact on data synthesis. The HOVON and the NILST trial defined molecular relapse criteria as a single loss of MR 4.5 \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, and the STIM molecular relapse criterion of a single loss of MR 5.0 were excluded \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study characteristics\u003c/h2\u003e \u003cp\u003eA total of 19 trials \u003csup\u003e[\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e involving 2336 patients were included in this meta-analysis. Eight trials have investigated the probability of TFR after imatinib treatment \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e, four trials have investigated the probability of TFR after dasatinib treatment \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e, three trials have investigated the probability of TFR after nilotinib treatment \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e, and the remaining four trials have investigated the probability of TFR after treatment with different TKIs \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. There were no clinical trials related to the discontinuation of flumatinib, third-generation TKIs, etc., and only the LAST, GIMEMA CML0307 trial had 7 patients on bosutinib \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe discontinuation criteria for all trials was maintaining a stable DMR. All included trials defined molecular relapse as loss of MMR/loss of MR4.0 and as a trigger for restarting the TKI. Additional detailed characteristics of the included trials are shown in Tables\u0026nbsp;1 and 2.\u003c/p\u003e \u003cp\u003eMajor molecular response (MMR) was defined as BCR-ABL/ABLIS\u0026thinsp;\u0026le;\u0026thinsp;0.1% by QPCR. MR4 was defined as BCR-ABL/ABLIS\u0026thinsp;\u0026le;\u0026thinsp;0.01% (internal reference ABL copy number\u0026thinsp;\u0026ge;\u0026thinsp;10\u003csup\u003e4\u003c/sup\u003e); MR4.5 was defined as BCR-ABL/ABLIS\u0026thinsp;\u0026le;\u0026thinsp;0.003 2% (internal reference ABL copy number\u0026thinsp;\u0026ge;\u0026thinsp;3.2\u0026times;10\u003csup\u003e4\u003c/sup\u003e); MR5 was defined as BCR-ABL/ABLIS\u0026thinsp;\u0026le;\u0026thinsp;0.001% (internal reference ABL copy number\u0026thinsp;\u0026ge;\u0026thinsp;10\u003csup\u003e5\u003c/sup\u003e) and/or BCR-ABL was not detected (i.e., UMRD/CMR). DMR was defined as obtaining the efficacy of MR4 and above. TFR was defined as the period when TKI therapy was stopped and no molecular relapse occurred. \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of bias (quality) assessment\u003c/h2\u003e \u003cp\u003eTo assess the quality of non-comparative single-arm clinical trials, we used the MINORS Methodological items. Specifics regarding the quality evaluation are included in Table\u0026nbsp;3. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e was used to assess publication bias through funnel plots of standard error effect sizes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4Treatment-free Remission Rate and Safety\u003c/h2\u003e \u003cp\u003eUsing random-effects modeling combined, the overall mean TFR rate at 12 months was 60% (95CI: 0.56\u0026ndash;0.63; I2\u0026thinsp;=\u0026thinsp;61%) and the overall mean TFR rate at 24 months was 55% (95CI: 0.52\u0026ndash;0.59; I2\u0026thinsp;=\u0026thinsp;60%) with a high heterogeneity, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOf the 19 trials included in this review, 2 cases of disease progression were cumulatively reported after discontinuation in the A-STIM trial\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e, GIMEMA CML 0307 trial and only 1 case of CML-related death was cumulatively reported after discontinuation in the GIMEMA CML 0307 trial \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe cumulative incidence of adverse reactions during the TFR are detailed in Table\u0026nbsp;2. Adverse reactions were mainly withdrawal syndromes with clinical manifestations of skeletal connective tissue pain. We do not synthesize the data here because most recent trials have not documented adverse reactions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Subgroup Analyses\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e\u003cb\u003e3.5.1 Previous interferon therapy\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the median proportion of patients previously treated with interferon across trials was 12%. The overall mean 12-month TFR rates for trials with a proportion of previously IFN-treated patients\u0026thinsp;\u0026le;\u0026thinsp;12% \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e and for trials with a proportion\u0026thinsp;\u0026gt;\u0026thinsp;12% \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e were 54% (95CI: 0.51\u0026ndash;0.58) and 65% (95CI: 0.61\u0026ndash;0.69), respectively; at 24 months the overall mean TFR rates were 51% (95CI: 0.48\u0026ndash;0.55) and 60% (95CI. 0.55\u0026ndash;0.65), with high heterogeneity (12m, P\u0026thinsp;=\u0026thinsp;0.0002; 24m, P\u0026thinsp;=\u0026thinsp;0.0006). These data suggested that better TFR was associated with prior interferon therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.5.2 Depth of Molecular Response Before Entering the TFR Phase\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the overall mean 12-month TFR rates for reaching molecular reaction depth MR4.5 \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e and reaching MR5.0 \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e in each trial were 55% (95CI: 0.51\u0026ndash;0.58) and 66% (95CI: 0.61\u0026ndash;0.69), respectively; the overall mean 24-month TFR rates were 51% (95CI: 0.48\u0026ndash;0.55) and 61% (95CI: 0.55\u0026ndash;0.65), with high heterogeneity (12m, P\u0026thinsp;=\u0026thinsp;0.005; 24m, P\u0026thinsp;=\u0026thinsp;0.02). Where STAT2 and STIM213 counted the number of patients who achieved MR5 and MR4.5, respectively, in subgroups we analyzed them separately. These data revealed that better TFR was associated with the depth of molecular response.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.5.3. Other factors\u003c/h2\u003e \u003cp\u003eNo significant differences were found in the 12-month TFR or the 24-month TFR when subgroup analyses were conducted on other factors, such as the year of trial publication, molecular relapse criteria, and patient characteristics (age, sex, Sokal score, TKI type, median duration of DMR, and median duration of TKI therapy). Our findings indicated that these other factors were not associated with TFR rates. The above results are shown in Table\u0026nbsp;4.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study showed a 12-month overall mean TFR rate of 60% [95CI:0.56\u0026ndash;0.63] and a 24-month overall mean TFR rate of 55% [95CI:0.52\u0026ndash;0.59], indicating that more than half of the CML-CP patients were able to maintain TFR two years after TKI discontinuation. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (12months: P\u0026thinsp;\u0026lt;\u0026thinsp;0.001,24months: P\u0026thinsp;=\u0026thinsp;0.006), and molecular response depth MR5.0 (12months:P\u0026thinsp;=\u0026thinsp;0.005,24months: P\u0026thinsp;=\u0026thinsp;0.02), which is in line with the findings of previous trials \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, although this analysis exists heterogeneity. According to the previous study \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, the duration of DMR and TKI therapy before discontinuation were found to be associated with TFR. However, our analysis was not, and the possible explanation is the effect of heterogeneity in the inclusion of trials with other factors, further research may significantly impact the estimated effect sizes and potentially alter them. Although subgroup analyses of several trials have shown that TFR rates are not associated with the duration of TKI treatment and DMR duration before TKI discontinuation \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAdverse effects in patients maintained on TFR were mainly characterized by skeletal muscle myalgia, i.e., withdrawal syndrome. Although the EURO-SKI and ENESTop study reported rates of 31% and 74%, the rates of grade 3 to 4 adverse reactions were only 1% and 13%, respectively \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. The D-STOP trial, on the other hand, reported an incidence of only 5.6% \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. In addition, progression or CML-related deaths occurred after discontinuation in only 2 cases. The above demonstrates the feasibility and safety of TKI discontinuation.\u003c/p\u003e \u003cp\u003eThe following limitations are worth considering in this meta-analysis.\u003c/p\u003e \u003cp\u003eFirstly, there was a high degree of heterogeneity in the clinical trials we included. This arose from differences in trial design, including criteria for the discontinuation population, the definition of molecular relapse, and different molecular monitoring methods such as Droplet digital PCR (dd-PCR) and RQ-PCR. Dd-PCR demonstrated more accurate molecular relapse monitoring than RQ-PCR \u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. Since there is no RCT for clinical trials related to drug discontinuation, it also affects the magnitude of heterogeneity. Despite differences in trial design, the trials we included were of high methodological quality. To explore heterogeneity, our analyses were validated by different subcomponents.\u003c/p\u003e \u003cp\u003eSubsequently, we excluded retrospective clinical trials to avoid high heterogeneity and publication bias. A total of 30 retrospective studies were excluded in the rescreening, and we read these articles, which involved a large number of patients and had mostly high second-year TFR, such as the retrospective cohort study of M. Ansuinelli, with a second-year TFR of 74% \u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. Therefore, it would be of interest to analyze the discontinuation population of retrospective studies separately in the future.\u003c/p\u003e \u003cp\u003eIn addition, we have not yet analyzed distant relapse. In clinical trials with sufficiently long follow-up, the TFR rate in the fifth year was 44% for DASFREE, 49% for EURO-SKI in the third year, and 53.57% for ENESTfreedom in the fourth year, et al \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e. We note the presence of distant recurrence, but there is a temporary lack of sufficient trial sample sizes for analysis. Similarly, the limited number of prospective trials included in this meta-analysis resulted in a low number of trials in certain subgroups in the subgroup analysis.\u003c/p\u003e \u003cp\u003eSelf-renewing leukemic stem cells are associated with relapse, and some patients are still unable to achieve TFR due to the persistence of leukemic stem cells (LSCs) \u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e. Paola Pacelli noted that despite fluctuating residual CD26\u0026thinsp;+\u0026thinsp;LSCs, maintaining a stable TFR is still possible. \u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. Namely, factors other than the presence of LSCs play a positive role in disease recurrence. M Matsushita's trial found a relapse rate of 63.6% in cxorf48-specific ctl-negative patients and 0% in cxorf48-specific ctl-positive patients \u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e. Yazad D Irani's results showed that TIM-3 was consistently up-regulated in CD4\u0026thinsp;+\u0026thinsp;T-cells, CD8\u0026thinsp;+\u0026thinsp;T-cells, and T-regs in relapsed patients, compared to patients with maintained TFR. regs cells were consistently upregulated \u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e. In addition, Gene expression analyses of publicly available datasets revealed increased expression of TIM-3 on CML stem cells in comparison to normal hematopoietic stem cells. These results from recent studies of TKI discontinuation suggest that CXorf48 and TIM-3 may be promising therapeutic targets for durable treatment-free remission in immunotherapy for CML patients.\u003c/p\u003e \u003cp\u003eManagement of patients who discontinued TKIs should also focus on their psychological as well as other domains. Giora Sharf investigated that 56% of patients reported fear or anxiety during treatment discontinuation, and 60% reported withdrawal symptoms at the time of discontinuation \u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e. Possible reasons for anxiety in patients who discontinue may be due to the uncertainty of relapse, adverse effects, and regular monitoring after discontinuation. The study \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e has shown that patients who failed TFR mostly resumed DMR after re-treatment with TKI. For molecular monitoring after TKIs discontinuation, the expert consensus of the European Leukemia Net proposes lifelong \u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e. Our observation that TFR failure occurs mainly within one year, but a few patients still experience distant relapse, albeit slow onset \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e, suggests that there is an urgent need for a cost-effective and user-friendly method for monitoring molecular response after discontinuation, as well as for more accurate predictors. Dennis Dong Hwan Kim's results suggest that BCR-ABL1 transcriptional doubling time can be used as a predictor of TFR failure in CML-CP patients after imatinib discontinuation, potentially avoiding the need for frequent monthly monitoring of molecular assays \u003csup\u003e[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe results of our analysis suggest a strategy that seems feasible to improve the success of TFR by attempting to rationalize the application of interferon before or after discontinuation of the drug for those who reach a molecular response depth of MR 5.0 or deeper. A Burchert's trial demonstrated that this strategy resulted in high TFR rates, with up to 84% of patients obtaining MR5 before discontinuation after a median follow-up of 7.9 years \u003csup\u003e[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eInterestingly, our analysis showed no significant effect of DMR duration and duration of TKI therapy before discontinuation of TKIs on TFR rates, but the D-FREE trial tells us that ignoring DMR duration is not desirable. One possible explanation is that the TFR rate depends mainly on the patient's sensitivity to the TKI rather than the duration of treatment, i.e., the depth of the molecular response obtained after treatment with a TKI, and the same factor is also responsible for the time required to reach that depth after TKIs treatment, which has not been recorded in the majority of the trials, and which would be a predictor worth investigating. This factor was reported in only two trials, the TWISTER trial showed an association with better TFR (P\u0026thinsp;=\u0026thinsp;0.04), but the KID trial did not correlate with TFR rates (P\u0026thinsp;=\u0026thinsp;0.152) \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. In Naranie Shanmuganathan's study, time to BCR-ABL1 halving on TKI treatment was the strongest independent predictor of TFR maintenance \u003csup\u003e[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnother strategy that seems feasible is dose-escalation discontinuation. A Iurlo's retrospective analysis in Italy found that low-dose TKIs do not seem to affect the likelihood of achieving DMR, but may even improve TFR rates, which were 74% in the second year \u003csup\u003e[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/sup\u003e. The DESTINY trial demonstrated that discontinuation of TKIs after one year of dose halving resulted in a 72% progression-free survival rate in the second year \u003csup\u003e[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/sup\u003e, but more trials are needed to validate whether attempted discontinuation after dose reduction promotes TFR.\u003c/p\u003e \u003cp\u003eThe number of RCTs and prospective clinical trials related to this area is limited, and more high-quality clinical trials are needed to further explore this. Meanwhile, trials of other second and third-generation TKIs are anticipated. The latest asciminib trial demonstrated superior efficacy and fewer adverse events \u003csup\u003e[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/sup\u003e. We searched ClinicalTrials.gov and found that there are still multiple large trials with no results output, and we will update our opinion if we find an impact on predictors in the future.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study showed that CML-CP patients who reached DMR could achieve a TFR of 60% in the first year and 55% in the second year after TKIs discontinuation, while achieving a molecular response depth of MR5.0 or higher and prior interferon therapy were associated with higher TFR rates. Further validation of the above predictors is needed due to the heterogeneity of the included trials, while we hope that future trials focus on the time taken for patients to enter the DMR and the emergence of withdrawal syndromes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur authors claim no known personal relation or competing financial interests affecting this work. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData can be obtained upon request. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhenxiang Zheng and Zhao Yinconceived and designed the experiments.Hao Tang analyzed and interpreted the data. Xinxia Zhang performed the experiments. Yangmin Zhu and Liling Zheng drafted the article and all other authors revised the article. All authors approved the final version of the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Key Program for the National Natural Science Foundation of China (No. 82304901 and 82202034). Guangzhou Science and Technology Plan Project (No. 2023A03J0262, 2024A03J0991, 2024A04J4325, 2024A03J0991 and 2024A04J4325), the Foundation of Guangdong Second Provincial General Hospital (No. YN2023-001 and TJGC-2023002), \u0026nbsp;Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515110430), Scientific Research Project Program of Sichuan Medical Association (No.S20038), Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledged \u0026nbsp;the support of Science and Technology Planning Project of Guangdong Province (No.2023B1212060063 ).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYin, Z.; Huang, G.; Gu, C.; Liu, Y.; Yang, J.; Fei, J., Discovery of Berberine that Targetedly Induces Autophagic Degradation of both BCR-ABL and BCR-ABL T315I through Recruiting LRSAM1 for Overcoming Imatinib Resistance. 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L.; Turkina, A.; Zaritskey, A.; Hehlmann, R., European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020, \u003cem\u003e34\u003c/em\u003e (4), 966\u0026ndash;984.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, D. D. H.; Kim, T. S.; Atenafu, E. G.; Novitzky Basso, I.; Forrest, D.; Bence-Bruckler, I.; Savoie, L.; Busque, L.; Keating, M. M.; Delage, R.; Xenocostas, A.; Liew, E.; Paulson, K.; Stockley, T.; Laneuville, P.; Lipton, J. H.; Kamel-Reid, S.; Leber, B., BCR-ABL1 transcript doubling time as a predictor for treatment-free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase. Br J Haematol 2022, \u003cem\u003e196\u003c/em\u003e (1), 136\u0026ndash;145.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurchert, A.; Saussele, S.; Eigendorff, E.; M\u0026uuml;ller, M. C.; Sohlbach, K.; Inselmann, S.; Sch\u0026uuml;tz, C.; Metzelder, S. 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C.; Binotto, G.; Bonifacio, M.; Rege-Cambrin, G.; Tiribelli, M.; Lunghi, F.; Gozzini, A.; Pregno, P.; Abruzzese, E.; Capodanno, I.; Bucelli, C.; Pizzuti, M.; Artuso, S.; Iezza, M.; Scalzulli, E.; La Barba, G.; Maggi, A.; Russo, S.; Elena, C.; Scortechini, A. R.; Tafuri, A.; Latagliata, R.; Caocci, G.; Bocchia, M.; Galimberti, S.; Luciano, L.; Fava, C.; Fo\u0026agrave;, R.; Saglio, G.; Rosti, G.; Breccia, M., Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study. Front Pharmacol 2023, \u003cem\u003e14\u003c/em\u003e, 1154377.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClark, R. E.; Polydoros, F.; Apperley, J. F.; Milojkovic, D.; Rothwell, K.; Pocock, C.; Byrne, J.; de Lavallade, H.; Osborne, W.; Robinson, L.; O'Brien, S. G.; Read, L.; Foroni, L.; Copland, M., De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematology 2019, \u003cem\u003e6\u003c/em\u003e (7), E375-E383.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026eacute;a, D.; Boquimpani, C.; Mauro, M. J.; Minami, Y.; Allepuz, A.; Maheshwari, V. K.; D'Alessio, D.; Wu, Y.; Lawrance, R.; Narbutas, S.; Sharf, G.; Hochhaus, A., Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial. Leukemia 2023, \u003cem\u003e37\u003c/em\u003e (5), 1060\u0026ndash;1067.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Treatment-free remission, Tyrosine kinase inhibitors, Chronic myeloid leukemia","lastPublishedDoi":"10.21203/rs.3.rs-3998884/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3998884/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBACKGROUND: \u003c/strong\u003eTreatment-free remission (TFR) is a new long-term goal for the treatment of patients with chronic myeloid leukemia (CML), but the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in chronic myeloid leukemia chronic phase (CML-CP) patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMETHODS: \u003c/strong\u003eWe performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Revman5.4 software.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS:\u003c/strong\u003e A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 60% [95CI:0.56-0.63] at 12 months and 55% [95CI:0.52-0.59] at 24 months, and a cumulative total of 2 CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (12months: P\u0026lt;0.001,24months: P=0.006), and molecular response depth MR5.0 (12months:P=0.005,24months: P=0.02).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONCLUSION:\u003c/strong\u003e Our study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 61% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic Review Registration:\u003c/strong\u003ehttps://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334)\u003c/p\u003e","manuscriptTitle":"Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 16:38:52","doi":"10.21203/rs.3.rs-3998884/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6238410f-7f9c-4b77-b38a-8826e5b750f4","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-05T04:50:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 16:38:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3998884","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3998884","identity":"rs-3998884","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}