Tyrosine Kinase Inhibitor Discontinuation In Patients Research Articles

Economic Impact Analysis of Treatment-Free Remission in Chronic Myeloid Leukemia Patients with Sustained Deep Molecular Response in the AST-2018 Trial

Introduction: The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML), bringing the life expectancy of patients close to that of the general population. However, TKI treatment is associated with adverse events, some of them serious or affecting quality of life. In addition, drug costs have a high economic impact, especially in low-income countries. Treatment-free remission (TFR) is an emerging goal for CML patients and it has been associated with cost savings in different country analyses. Main Objective: Assess the economic impact of TKI discontinuation in patients included in the AST2018 Trial. Secondary objective: Estimate the long-term saving in patients included in the AST2018 Trial, considering Argentinian life expectancy. Methods: AST2018 is a multicentric, prospective trial that recruited aged >18 years CML chronic phase patients, with confirmed typical BCR-ABL1 transcripts b3a2 and/or b2a2, under TKI treatment for at least ≥ 4 years and sustained MR4.0 for ≥ 2 years. Molecular tests were centralized in 2 harmonized laboratories and performed monthly for the first 6 months, every 2 months until the 1st year, and every 3 months until month 24. TKI was restarted at confirmed loss of major molecular response (MMR). The economic impact was evaluated by an Excel-based budget impact model, in order to estimate the costs of the patients in first-line pharmacological treatment for CML. We considered the costs of TKI-treatment, PCRs performing and medical visits as money flow. We calculated the present value of savings, in US dollars, in patients who discontinued treatment during the trial. Results: Between February 2018 and March 2022, we evaluated 50 CML patients in the AST2018 trial, 46 were enrolled from 7 centers in Argentina, and were included in this economic analysis. The median patients’ age was 57.5 years (24-85). TKI treatment before discontinuation was Imatinib 34/46 (74%), Nilotinib 4/46 (9%) and Dasatinib 8/46 (17%). After 24 months since first patient was enrolled, 30/46 (65%) patients continued free from TKI, Imatinib 21/34, Nilotinib 2/4 and Dasatinib 7/8, with a median follow-up of 31.3 months (range 25.9 - 38.1). Treatment was restarted after losing MMR in 16/46 (35%) patients. We considered the costs of TKI treatment, PCR performing and physician visits, and we calculated the estimated cost saving per patient at 24 months on TFR: Imatinib US$ 78,433; Dasatinib US$ 102,817 and Nilotinib US $106,161. For the 30 patients who persisted in TFR for 24 months, total cost saving was US$ 2,579,137. For 17 patients who lost MMR, US$ 335,043 dollars were saved previously to TKI reinitiation. Adding up both amounts, the total economic saving in AST2018 was US$ 2,914,181. We performed an analysis of the potential cost savings of remaining in TFR beyond 24 months and according to life expectancy in Argentina (76 years), median age of patients in this trial and cost per patient/year on TKI treatment, the estimated cost saving per patient was US$ 714,512. Conclusions: This is the first economic analysis of the AST2018 trial on TKI discontinuation in CML patients with sustained deep molecular response in Argentina. Our analysis shows that, in spite of the PCR spending, there is a considerable saving in patients on TFR. A careful approach for patients participating in TFR trials or programs will decrease the risk of relapse and make TFR a reality in our region. Potential advantages of TFR will not only impact in patients’ quality of life but also show considerable reduction in the use of economic resources. In developing countries, where lack of molecular monitoring is still an issue outside academic centers, these savings could be redirected to this unmet need making TFR feasible and a goal for the patient and the healthcare system. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Free Remission after Combination Therapy with Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed after a Prior Attempt at TKI Discontinuation-H Jean Khoury Cure CML Consortium Study

Successful tyrosine kinase inhibitor (TKI) discontinuation is currently one of the main goals of CML therapy. Patients who are in sustained deep molecular remission can attempt TKI discontinuation; approximately 50% of such patients will achieve a successful treatment free remission (TFR) and the other 50% will have molecular recurrence , warranting reinitiation of TKI therapy. Molecular recurrence is defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) . With a goal to increase the ultimate fraction of successful TFR, inquiry has begun into the rate and optimal approach to TFR after a second attempt at TKI discontinuation in patients with molecular recurrence after their first attempt. Molecular recurrence, is suspected to be driven by CML progenitor element(s) capable of, permitted to, and/or signaled to proliferate; different approaches to eradicate such a compartment have been proposed. One such potential means may be through alternative and synergistic BCR::ABL1 inhibition with the allosteric inhibitor asciminib in combination with approved TKIs for CML. Asciminib is a potent BCR::ABL1 inhibitor with a novel, allosteric mode of action. The activity of asciminib is a result of its ability to bind a vacant pocket on the kinase domain that is normally occupied by the myristoylated N-terminus of ABL, a negative regulatory element lost upon the fusion of ABL to BCR. Asciminib has an excellent selectivity profile, is several-fold more potent than current approved TKIs such as nilotinib, and in vitro was active in the low nanomolar range against a spectrum of clinically observed ATP site mutations. Asciminib demonstrated efficacy in phase I studies in resistant/intolerant chronic and accelerated phase CML, including T315I mutation positive and ponatinib pretreated patients. In a phase III trial, asciminib was more active than bosutinib in a phase III trial in patients who had received 2 prior TKIs Our primary objective in this study is to determine the 1-year TFR rate after 12 months of combination therapy with imatinib plus asciminib, followed by treatment cessation, in subjects who have previously had molecular recurrence first TFR attempt. This is a single arm phase II study that will enroll a maximum of 51 patients (NCT04838041). All subjects will have a confirmed diagnosis of CML-CP. Each subject must have previously attempted to discontinue imatinib, and were restarted on imatinib at the time of molecular recurrence in order to be eligible for this trial. This trial will use asciminib 40 mg PO daily plus imatinib at a maximum dose of 400 mg PO once daily in the combination treatment phase of this trial. All eligible subjects will be treated with asciminib and imatinib on cycle 1 day 1 of the combination therapy phase. Patients will remain on imatinib for 12 cycles. RQ-PCR to measure BCR::ABL1 transcripts in the peripheral blood at screening and at specific time points during the first 12 cycles on trial (combination therapy phase). At the end of 12 cycles, asciminib and imatinib will be discontinued in any subject who has continued in stable deep remission and thus meets criteria for TFR. This study will assess a wide range of PROs before and after stopping imatinib. These will be done in conjunction with RQ-PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. The alternative hypothesis of relapse rate after second discontinuation of TKI combination treatment is 35% will be tested against a one-sided alternative of historical control of 55% relapse rate. Simon's two-stage admissible design will be used. The null hypothesis that the true TFR rate (no loss of MMR) is 45% will be tested against a one-sided alternative. In the first stage 29 patients will be accrued. If there are 15 patients or fewer who maintain TFR in these 29 patients, the study will be stopped. Otherwise, 18 additional patients will be accrued for a total of 47. The null hypothesis will be rejected if 27 or more patients maintain TFR in 47 patients. This design yields a type I error rate of 5% and power of 85% when the true TFR rate is 65%. To account for a potential dropout rate of 8% due to adverse events or loss of response, 51 patients will be enrolled to achieve the 47 patients needed.

A Retrospective Analysis of TKI Discontinuation in Patients with CML

To investigate the clinical characteristics of the patients with chronic myeloid leukemia (CML) discontinued tyrosine kinase inhibitors (TKI) therapy and the outcome of the patients. 35 cases of CML patients experienced initiative discontinuation of TKI therapy in our hospital from June 1st 2015 to December 31th 2019 were retrospectively analyzed. The TFR of the patients and the factors affecting it were analyzed. The median duration of TKI administration was 72 (range 35-173) months in the 35 patients. Among these patients, 8 had experienced TKI dose reduction or suspension. All the enrolled patients have achieved at least MMR. The median time for these patients achieving MMR was 15 (range 3-75) months after administration of TKI, and for MMR maintenance before TKI suspension was 55 (range 13-164) months. After TKI withdrawal the median follow up time was 20.3 (range 3-57.9) months, 22 out of 35 patients kept TFR, among them, 2 （5.71%） patients restarted TKI after 12 month suspension, and maintained MMR during suspension. 13 （37.1%）patients lost MMR, among them, 9 patients restarted TKI treatment, and 5 of them achieved MR4.0 after the median duration of 3(2-5) month. No patients were found to have disease progression. The estimated TFR rate was 57.8% and 51.8% at 12 and 24 months after discontinuation, respectively. Other clinical characteristic related to relapse were also analyzed, including the cumulative TKI administration duration, cumulative MMR duration, time to achieve MMR, median age at diagnosis, risk stratification by Sokal score, TKI dose reduction and discontinuation history, and second-generation TKI administration before stopping TKI, however, no statistical difference was found. TKI discontinuation is practical for CML patients in our center.

Profiles of NK cell subsets are associated with successful tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia and changes following interferon treatment.

Recent studies have shown that approximately 50% of patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) therapy with a sustained deep molecular response (DMR) (BCR-ABL1IS ≤ 0.01%) can achieve treatment-free remission (TFR, stopping TKI without relapse) and that prior interferon (IFN)-α therapy and higher NK cell counts at and after TKI discontinuation are associated with TFR. We recently reported that post-TKI discontinuation of IFN-α therapy could prevent molecular relapse (MR, BCR-ABL1IS > 0.1%). Here, we evaluated whether NK cells are associated with MR and investigated the effects of post-TKI discontinuation IFN-α therapy on lymphocyte subsets. A total of 34 patients measuring blood lymphocyte subclasses were included. In the 22 patients who did not receive IFN-α therapy, at 1month after TKI discontinuation, the nonrelapsed patients showed a significantly higher proportion and count of NK cells than the relapsed patients. In particular, the proportion and count of CD56dim NK cells were significantly higher in the nonrelapsed patients than in the relapsed patients. In the 12 patients who received IFN-α therapy, the level of CD56bright NK cells increased significantly after 3 and 6months of IFN-α therapy. In summary, NK cells, in particular CD56dim NK cells, were associated with MR after TKI discontinuation in patients with CML. Additionally, IFN-α therapy gradually increased the level of CD56bright NK cells in patients with CML.

Map3k8/COT1/Tpl2 Drives Resistance to Bcr-Abl1 Inhibition through Activation of MEK-ERK and NF-Kb Pathways

The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a manageable, chronic disease with long-term survival exceeding 85%, but discontinuation of TKI in patients who achieve deep molecular remissions results in a 50% relapse rate. The relapses are believed to be caused by Bcr-Abl1-expressing hematopoietic stem cells (CML stem cells) which are independent of the Bcr-Abl1 kinase activity for their survival. Signaling pathways, including PI3K/AKT, Wnt/β-catenin, JAK/STAT, and Hedgehog/SMO, are crucial for CML stem cell self-renewal and survival in the presence of TKI. Eradication of these cells poses the greatest current challenge.We previously described a Bcr-Abl1-independent model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentration of IM displayed reduced Bcr-Abl1 protein and activity levels (Chorzalska et al., Leukemia 2014). Quantitative phosphoproteomic analysis of these IM-resistant cells (IMRC) identified 2,593 phosphopeptides showing significant differences in abundancies in comparison to IM-sensitive cells. Functional analysis of identified phosphopeptides pointed to MEK-ERK pathway as a highly dysregulated cascade in IMRC (Chorzalska et al., Stem Cell Dev, 2017). Within the list of identified phosphopeptides, we assessed the abundancy of 222 MEK-ERK pathway-specific core interactor peptides (as listed in MEK-ERK superpathway in Pathcards), and identified the Map3k8-derived phosphopeptide as the most abundant one in IMRC (Fig. 1A). Map3k8, also known as Tumor Progression Locus (Tpl2) or Cancer Osaka Thyroid (COT1), links the MEK-ERK and NF-κB signaling and drives resistance to Raf inhibition in melanoma, but its role in chemoresistance of CML stem cells has not been explored.Using RT-PCR assays in CML CD34+ cells cultured with IM for 7 days, we found a 2-fold increase in MAP3K8 transcriptsand a 1.7-fold increase in transcripts of its binding partner NFKB1 (NF-κB1; Fig. 1B). IMRC also showed increased expression of Map3k8 and NF-κB1 protein levels, and increased activity of the NF-κB signaling components: NF-κB inhibitor - IκB and IκB kinase - IKKα/β (Fig. 1C). Immunoblotting evaluation of the Map3k8-dependent effect on MEK-ERK signaling indicated no significant difference between IMRC and control cells in the activity of Raf module, with exception of C-Raf Ser289/296/301 inhibitory sites associated with a MEK-ERK negative feedback loop (Fig. 1D). Evaluation of the downstream effectors of Raf showed no difference in MEK1 and decrease in MEK2 abundance, and enhanced phosphorylation of MEK1/2. IMRC also showed higher ERK1 and lower ERK2 abundance, and no significant change in the stoichiometry of ERK1/ERK2 phosphorylation at Thr202/Tyr204 (Fig. 1D). To identify other upstream mediators of MEK phosphorylation, we evaluated the activity of Src Family Kinases (SFKs) and found a marked increase in phospho-SFKs in IMRC (Fig. 1E).Considering the observed upregulation of SFKs, MEK and NF-κB signaling in Map3k8-overexpressing IMRC, we investigated apoptotic effects of the SFKs inhibitor dasatinib, the MEK inhibitor U0126, and the IKK inhibitor PS-1145, individually and in combination. The SFKs and IKK inhibitors, as single agents or combined, induced only a modest (35%) increase in apoptosis. Conversely, the combination of SFKs+MEK inhibitors decreased survival of IMRC by nearly 50%, whereas the triple SFKs+MEK+IKK inhibition killed 65% of IMRC within 48h of incubation (Fig. 1F). In addition, the combination of three inhibitors SFKs+MEK+IKK significantly decreased the phosphorylation of MEK, ERK, SFKs and NF-κB, surpassing the effect of a dual SFKs+MEK or SFKs+IKK inhibition (Fig. 1G). The effect of SFKs, MEK and IKK inhibitors on the capacity of CML CD34+ cells to form colonies in methylcellulose assays was also evaluated. The dual SFKs+MEK inhibition reduced the colony number by 70%, while the triple SFKs+MEK+IKK inhibition decreased it by about 80% (Fig. 1H). Finally, CML CD34+ cells cultured for 7 days in the presence of SFKs+MEK+IKK inhibitors showed significant reduction of MAP3K8 transcript levels (Fig. 1I).In conclusion, combined inhibition of SFKs, MEK and NF-κB attenuates the survival of IM- resistant CML cell line and CML stem/progenitor cells, and a combination of relevant inhibitors may offer a new therapeutic option for overcoming the TKIs resistance in CML patients. [Display omitted] DisclosuresReagan:Teva: Membership on an entity's Board of Directors or advisory committees.

Interferon-α may help prevent molecular relapse of chronic myeloid leukemia after the discontinuation of tyrosine kinase inhibitors.

Background:Currently, the goal of chronic myeloid leukemia (CML) treatment is normal survival and good quality of life without life-long treatment, namely, “treatment-free remission” (TFR). At present, approximately only 50% of patients with CML with a deep molecular response are able to discontinue tyrosine kinase inhibitor (TKI) without experiencing molecular relapse [MR; loss of major molecular response (MMR)]. In addition, prior interferon (IFN) treatment is associated with a higher rate of TFR.Methods:We aimed to evaluate the feasibility of TKI discontinuation in Chinese patients with CML and determine whether IFN could prevent MR when used after TKI discontinuation in patients with 0.0032% <BCR-ABLIS ⩽0.1%. Therefore, we retrospectively analyzed the data of patients with CML who discontinued TKI treatment at our center.Results:Forty-nine patients who discontinued TKI therapy after achieving MR 4.5 were included in this study, and the median follow-up time from TKI discontinuation was 27 (7, 75) months. Nineteen patients eventually lost MMR, and the TFR rate of the 49 patients was 67% (95% confidence interval 53.6%, 80.3%) at 12 months. The duration of MR 4.5 ⩾54 months and duration of imatinib ⩾85 months were significantly associated with a higher TFR rate. Of the 22 patients with 0.0032% <BCR-ABLIS ⩽0.1%, 12 received IFN-α treatment. The median IFN-α therapy duration was nine (2, 18) months, and three patients eventually lost MMR. Three patients discontinued IFN-α after 2, 2.5, and 10 months, and maintained MMR for 9, 8, and 11 months after IFN discontinuation, respectively. Of the 10 patients not receiving IFN-α treatment, eight eventually lost MMR. The MR-free survival rate was significantly different between the patients treated with and those treated without IFN-α over 24 months (70.7% versus 15.0%, p = 0.002).Conclusion:These results indicate that after TKI discontinuation, IFN-α can be administered to patients with 0.0032% <BCR-ABLIS ⩽0.1%, which may help prevent MR.

CML-085: Discontinuation of Tyrosine Kinase Inhibitor (TKI) Treatment in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in US Clinical Practice Following Updates to NCCN CML Practice Guidelines

Context NCCN CML practice guidelines were updated in 11/2016 and 11/2019 to incorporate criteria for TKI discontinuation in patients with CML-CP. Objective To describe TKI discontinuation practices in the US following updates to NCCN CML practice guidelines and compare them to a previously conducted study (Ritchie et al. Leuk Lymphoma. 2019). Patients Using an online case report form by US oncologists/hematologists, patient charts were abstracted (11/2019-12/2019) from adult patients with CML-CP that discontinued TKIs (1/2017-12/2018) after achieving adequate responses. Physicians' assessment of adequate response (TKI duration, molecular response (MR), and MR duration) and relapse were described. Results 153 patient charts were obtained from 61 physicians (academic: 43%; community-based practices: 57%), mostly from large practices (57%), with over 10 years (y) of experience following subspecialty training (59%). They had treated a median of 30 patients with CML-CP in the last 2y. Most (56%) did not have access to precise tests used to detect BCR-ABL1 of ≥4.5 log when attempting TKI discontinuation. Patients that discontinued TKIs had the following characteristics: mean age 56 y, 60% male, 69% white, 96% with TKI discontinuation in first-line. Besides achieving adequate responses, the most common reasons for TKI discontinuation were patient request (54%) and adverse events (18%). Results from physicians' assessment of adequate response for TKI discontinuation were as follows: most patients had ≥3 y of TKI therapy (academic: 57%; community: 43%); most patients had MR4 (academic: 31%; community: 45%) or MR4.5 (academic: 48%; community: 30%); more patients had ≤1 y duration of MR (academic: 36%; community: 61%) than 2 y (academic: 25%; community: 17%), and ≥3 y (academic: 39%; community: 22%). 21% of patients (academic: 12%; community: 30%) relapsed after TKI discontinuation (treatment-free remission [TFR] failure; 66% relapsed within 1 y). Conclusion TKI discontinuation is mainly attempted in patients on first-line therapy (similar to Ritchie et al. 2019) and is being practiced without tools required to accurately monitor response. Despite updates to NCCN CML practice guidelines, there is heterogeneity in US practice regarding TKI discontinuation. In order to improve long-term TFR rates, broader application of practice guidelines is needed for optimal TKI discontinuation, particularly in community-based practices. Study sponsored by Novartis Pharmaceuticals Corporation. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved.

Clinical analysis on outcomes in patients with chronic myeloid leukemia in chronic phase after tyrosine kinase inhibitors discontinuation and their influencing factors

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

BCL2L11 (BIM) Deletion Polymorphism Is Associated with Molecular Relapse after ABL Tyrosine Kinase Inhibitor Discontinuation in Patients with Chronic Myeloid Leukemia with Complete Molecular Response

Abstract Background: The inhibition of BCR-ABL1 kinase with tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of chronic myeloid leukemia (CML). Recently, it has been recognized that some CML patients with a complete molecular response (CMR) are able to maintain treatment-free remission (TFR) after discontinuation of TKIs. However, no predictive prognostic factors for successful discontinuation of the treatment have yet been identified. We set out to further clarify the role of predictive biomarkers in molecular relapse and non-relapse after ABL TKI discontinuation. Materials and methods: Patients in sustained CMR (MR 4.5) undergoing TKI therapy were eligible for inclusion in the study. Molecular relapse was defined as loss of major molecular response (MMR) of at least one point. Genomic DNA was obtained from whole blood using a DNA Extractor WB Kit (Wako, Osaka, Japan), and was subjected to polymerase chain reaction (PCR) amplification using primers designed to detect a deletion site (2903 bp) in intron two of the BCL2L11 gene (forward: 5′-AATACCACAGAGGCCCACAG-3′; reverse: 5′-GCCTGAAGGTGCTGAGAAAG-3′) and JumpStart RedAccuTaq LA DNA polymerase (Sigma Aldrich, St. Louis, MO, USA). Results: 32 CML patients (17 men, 15 women, median age 58.4 years) were included in this study (Sokal category; low 24, intermediate 7, high 1). Six patients were treated with IFNα before TKI treatment, and 3 were treated with IFNα after stopping TKI. Median duration from TKI initiation to discontinuation was 79.3 months (range; 22 to 138 months); median duration of CMR before TKI discontinuation was 47.3 months (range; 5 to 97 months). Seven patients showed loss of MMR; 6 relapsed within 6 months and one showed late relapse at 25 months after discontinuation. The cumulative incidence of MMR loss was estimated as 18.8% at 12 months and at 24 months. Fluctuation of BCR-ABL transcript levels below the MMR threshold (&gt; two consecutive positive values) was observed in 6.25% of patients at 24 months after ABL TKI discontinuation. Treatment-free remission was estimated as 81.2% at 12 months and at 24 months. The median period of restoration of second CMR was 6.0 months in re-treated patients. No patient died during the follow-up period. TKI-free remission was estimated as 78.1% at 30 months. There was only a significant difference in BCL2L11 (BIM) deletion polymorphism between the patients who maintained and those who lost MMR (p = 0.0253). No significant difference was observed in prior IFNα therapy, time to complete cytogenetic response (CCyR), time to MMR, and time to CMR between relapsing and non-relapsing patients. Conclusion: Our study shows a specific association between BCL2L11 (BIM) deletion polymorphism and clinical outcome after ABL TKI discontinuation in patients with long-lasting molecular undetectable residual disease. BCL2L11 (BIM) deletion polymorphism may predict relapse after ABL TKI discontinuation, which may have an impact on future ABL TKI discontinuation trials. These results further illustrate the importance of single nucleotide polymorphisms in successful long-term treatment of CML. Disclosures Ohyashiki: Bristol-Myers Squibb KK : Research Funding, Speakers Bureau; Novartis KK: Research Funding, Speakers Bureau.