Phase Chronic Myeloid Leukemia Patients Research Articles

Peripheral blood quantitation of CD26 positive leukemic stem cells as a predictor of tyrosine kinase inhibitor response in chronic myeloid leukemia.

Leukemic stem cells (LSCs) are the transcriptionally low/silent cells which are resistant to the tyrosine kinase inhibitor. These have been found to play a pivotal role in disease relapse in chronic myeloid leukemia (CML) cases. The present study evaluated the correlation of absolute CML-LSC count in the peripheral blood (PB) at diagnosis and achievement of major molecular response (MMR) at 12 months in patients of CML-CP. This was a prospective, observational, non-interventional single center study including newly diagnosed adult (>18 yrs) CML-CP patients. Absolute CD26 + CML-LSC quantification was done by multiparametric flow cytometry. Patients were treated with Imatinib treatment and subsequently monitored at 3-month intervals for BCR::ABL transcript levels. MMR was defined as a BCR::ABL1 transcript level of less than 0.1% on international scale. A total of 89 patients were enrolled in the study out of which 40.5% achieved MMR at 12 months. There was a significant difference in the median absolute CML-LSC count of the patients who achieved MMR at 12 months as compared to those who did not (58.5 vs 368.1 cells/μL; p value <0.001). Using a ROC analysis, a count of <165.69 CML LSC/μL was identified to have a sensitivity of 83.8% and specificity of 72.4%, in predicting the MMR at 12 months. Absolute CML-LSC count at diagnosis in the PB predicts the MMR achievement at 12 months. An absolute count of less than 165 cells/μL is highly predictive of achieving MMR at 12 months.

Retraction: Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era.

Retraction: Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era.

The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment

To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance

Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.

Kronik Miyeloid Lösemi Hastalarının Tanı Sırasındaki Hemoglobin, Lökosit ve Trombosit Düzeylerinin Sağkalım Sonuçlarına Etkisi

Background:Since the development of tyrosine kinase inhibitors (TKIs), the prognosis for chronic myeloid leukemia (CML) has significantly improved. Several predicted prognostic scores and indicators at diagnosis have been used to predict the prognosis of chronic phase chronic myeloid leukemia (CML-CP) during the TKI period. When CML patients are first diagnosed, hemogram parameter aberrations are rather prevalent in clinical practice, although it is still unknown how those parameters affect the prognosis. This study aims to evaluate the hemogram parameters at diagnosis on the survival outcomes of CML-CP patients. Materials and Methods:One hundred thirty-seven patients who were diagnosed with CML-CP and received treatment were assessed between the years 2006 and 2020. Results:There were 65 (47.4%) males and 72 (52.6%) females with a median age of 50 (range: 18-78) years at diagnosis. Median hemoglobin level was 12.1 gr/dL (4.3-17.4), leucocyte count was 66.2 ×109 /L (7.5-520.2), and thrombocyte count was 362 ×109 /L (18-3.496) for all patients. The median progression-free survival (PFS) was 16.7 months 16.7 (2.0-106.4) and the median overall survival (OS) was 63.8 months (0.43-166.2) for all patients. Conclusion:This study is valuable in terms of predicting the prognosis of CML patients with hemoglobin, leukocyte, and platelet values at the time of diagnosis. While emphasizing the importance of platelet count at the time of diagnosis, similar to the previously defined risk scores, it showed that leukocyte and hemoglobin values at the time of diagnosis did not have a statistically significant effect on OS and PFS.

Ascites does not accompany pleural effusion developing under dasatinib therapy in patients with CML-CP.

Pleural effusion (PE) is the most frequent pulmonary complication of dasatinib, a tyrosine kinase inhibitor (TKI). Concurrent pericardial effusions have been reported in about one-third of the cases. In this study, we aimed to investigate ascites generation in chronic-phase chronic myeloid leukemia (CML-CP) patients developing PE under dasatinib. We conducted a cross-sectional study to evaluate whether pericardial effusion and ascites accompany PE inCML-CP patients treated with dasatinib. For this purpose, consecutive patients with CML-CP who developed PE underdasatinib therapy have been evaluated with chest X-ray, transthoracic echocardiography, and abdominal ultrasonography. There were seven patients, and the median age was50 years (range, 31-73 years). Most of patients were male(n=5). All patients received imatinib as first-line TKI. Sixpatients received dasatinib following imatinib failure in second line. The median duration from dasatinib initiation to PE generation was 58months (range, 8-135months). Consequently, four patients had grade 1 pericardial effusion, and no patient had ascites. In our small study, dasatinib-related PE was associated with low-grade pericardial effusion but no ascites. There are hypothetical explanations of this phenomenon including the simultaneous activation/inhibition of kinases; however, more research needs to be performed on this topic.

The Mozart effect in chronic myeloid leukaemia.

Clinical research has not been able to establish whether the differences between first- and second-generation BCR-ABL 1 kinase inhibitors are clinically relevant with regard to outcome. In the study by Alcazer etal., a relevant difference seems to emerge-paradoxically in the absence of the drugs-as demonstrated by differences in the relapse kinetics after cessation of therapy. Commentary on: Alcazer etal. Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients. Br J Haematol 2024;204:1536-1539.

Real-World Efficacy and Safety of China-Made Flumatinib Mesylate in the Treatment of Chronic Myeloid Leukemia in Chronic Phase

To evaluate the efficacy and safty of China-made flumatinib mesylate in the treatment of chronic myeloid leukemia in chronic phase (CML-CP). 42 CML-CP patients treated with Chinese produced flumatinib (oral, 600 mg, 1/d) were included in the study, including 14 newly diagnosed patients and 28 patients underwent conversion therapy. The hematological, cytogenetic and molecular response and safety were observed and evaluated after 3, 6 and 12 months of treatment. 35 patients were treated for more than 3 months, among which 31 patients were treated for more than 6 months and 17 patients were treated for more than 12 months. After 3 months of treatment, 33 patients underwent hematological, cytogenetic and molecular examination. Of these, 32 patients achieved complete hematological response (CHR), 13 patients achieved complete cytogenetic response (CCyR), 20 patients showed BCR-ABLIS≤10% and 7 patients reached major molecular response (MMR). After 6 months of treatment, all 30 patients who could evaluate efficacy achieved CHR, of which 17 patients achieved CCyR, 18 patients showed BCR-ABLIS≤1% and 16 patients reached MMR. After 12 months of treatment, all 17 patients were evaluated for efficacy, all achieved CHR, 10 patients obtained CCyR, 7 patients reached MMR. Grade III or IV thrombocytopenia, leukopenia and anemia occurred in 7, 2 and 1 patients, respectively. The non-hematological adverse reactions were diarrhea in 6 cases, renal function damage in 4 cases, rash and pruritus in 3 cases, liver function damage in 3 cases, nausea in 1 case, fever in 1 case, bone/joint or muscle pain in 1 case. In the real world, China-made flumatinib mesylate has a positive short-term efficacy and reliable safety in the treatment of CML-CP patients, whether as first-line treatment or second- and third-line conversion therapy.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study

BackgroundThere are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. Patients and MethodsData from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. Results2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). ConclusionNilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

Clinical Efficacy and Safety of Flumatinib in the Treatment of Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

To explore the clinical efficacy and safety of flumatinib mesylate produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). 32 newly diagnosed CML-CP patients admitted to the Hematology Department of the Affiliated Hospital of Southwest Medical University from March 1, 2020 to March 31, 2022, who had never received any tyrosine kinase inhibitor (TKI) were included in the study. The patients were treated by flumatinib mesylate 600mg once daily. The hematologic, cytogenetic and molecular responses were assessed at 3-, 6- and 12-month, and adverse effects of the drug were evaluated. 31 patients were treated with flumatinib for≥3 months, of which 24 patients were treated for ≥6 months and 14 patients were treated for≥12 months. At 3rd month of treatment, 30 out of 31 patients achieved complete hematologic response (CHR); 24 patients underwent cytogenetic testing and 22 cases achieved major cytogenetic response(MCyR), of which 21 cases achieved complete cytogenetic response (CCyR); Among 25 patients who underwent molecular testing, 22 patients had BCR-ABLIS≤10%, including 10 patients with BCR-ABLIS≤0.1%, and 6 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 23 out of 24 patients achieved CHR; 17 patients underwent cytogenetic testing and all achieved CCyR; Among 23 patients who underwent molecular testing, 20 patients had BCR-ABLIS≤1%, including 16 patients with BCR-ABLIS≤0.1% and 12 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 14 patients achieved CHR and CCyR; Among them, 10 patients had BCR-ABLIS≤0.1%, including 9 patients with BCR-ABLIS≤0.01%. The grade Ⅲ/Ⅳ leukopenia, thrombocytopenia and anemia rates in the patients were 13.3%, 20.0% and 3.3%, respectively. One patient stopped flumatinib therapy due to severe and persistent hematologic toxicity. The major non-hematologic adverse events were abnormal liver function (20%), diarrhea (10%), bone/joint pain (10%), muscle spasm (10%), rash (6.7%), acute kidney injury (6.7%) and nausea(3.3%), most of which were grade I-II. No patient experienced grade Ⅳ non-hematologic adverse events. No drug toxicity-related death occurred. Flumatinib mesglate, as the first-line treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.

Safety and Efficacy of TKIs in very Elderly Patients (≥75 Years) with Chronic Myeloid Leukemia.

While the outcomes of chronic phase chronic myeloid leukemia (CP-CML) patients aged over 65 years have been extensively evaluated in real-life experiences, limited data exist for the very elderly population (i.e., aged ≥ 75 years), especially for next-generation tyrosine kinase inhibitors (TKIs). In this retrospective study, we sought to evaluate the safety and efficacy of TKIs in this particular setting of patients. We conducted a retrospective analysis of a multicenter cohort of 123 newly diagnosed CP-CML very elderly patients. The median age at diagnosis was 80 years (range: 75-96). In the first line, 86.1% of patients received imatinib, 7.1% dasatinib, 5.6% nilotinib, and 0.81% received bosutinib. A total of 31 patients (25.2%) switched to second-line therapy, nine patients to a third line, and one patient to a fourth line of therapy. Resistance to treatment was the primary reason for switching therapy in both the first (64.5%) and second lines (77.7%). At diagnosis, reduced doses were administered in 36.5% of patients, in 61.2% in the second line, and in all patients in subsequent lines of therapy. In the first-line setting, 71.9% of patients achieved an early molecular response (EMR, i.e., 3-month BCR::ABL1IS < 10%); at 6, 12, and 24 months, MR3 was reached by 35.7%, 55.7%, and 75.0% of patients, respectively, with 16.6%, 35.7%, and 51.7% achieving a deep molecular response (DMR) at the same time points. Treatment-free remission (TFR) was successfully attempted in 11 patients. During the follow-up period, adverse events (AEs) were observed in 78.8% of patients, including 22 cases of cardiovascular AEs. Toxicity grade ≥ 3 was more commonly observed in patients treated with standard doses of TKIs compared to reduced doses (p = 0.033). Overall, the median follow-up was 46.62 months (range: 1.8-206.2), and 43 patients died due to non-CML-related causes. Three patients died due to disease progression to advanced (n = 1) and blastic (n = 2) phases. The 5-year overall survival (OS) for the entire cohort was 71.9% (95% CI: 0.63-0.81), with no significant difference between the patients treated with standard doses of TKIs compared to those treated with reduced doses (p = 0.35). TKIs appear to be safe and effective even in very elderly CML patients, and dose optimization strategies yield satisfactory molecular responses for adequate disease control with an improved safety profile.

Evaluating Effectiveness and Safety of Flumatinib for Chronic Phase Chronic Myeloid Leukemia in (CML-CP) without Optimal Response (Warning, Failure) to Imatinib or/and Dasatinib

Introduction Flumatinib is a novel second-generation BCR-ABL1 targeted kinase inhibitors (TKI) with better efficacy and safety than first generation TKIs in first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). In the previous phase III study, newly diagnosed CML-CP patients receiving flumatinib achieved higher treatment responses and safety than imatinib. When it comes to the patients not achieving the optimal response to TKIs, flumatinib is potentially a better option, nonetheless the robust evidence is unavailable. This study reports the effectiveness and safety of switching to flumatinib in patients who have not achieved the optimal molecular response to imatinib or/and dasatinib. Methods This prospective, multicentre study enrolled Philadelphia Chromosome-Positive (Ph+) CML-CP patients aged ≥18 years and who failed to achieve the optimal response with imatinib or/and dasatinib between March 2021 to October 2022. All patients were treated with flumatinib 600 mg once a day and followed up to 24 months. The primary endpoint of the study was rate of major molecular response (MMR) at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]) and safety was the secondary endpoint assessed with CTCAE 4.03 version. In addition, the optimal molecular response in either the warning or failure patients was evaluated at 3, 6 and 12 months respectively, after switching to flumatinib, and the difference in effectiveness was also analyzed from the available mutation subtypes. Results Overall, 94 patients with Ph+ CML-CP were included in the study. The median (range) age of the patients were 53 (19.0-84.0) years old and 61.7% of the patients were males. A total of 38 (40.4%) patients reported warning response from the previous TKIs whereas 56 (59.6%) of patients reported treatment failure to the previous TKIs. Seventy-seven (81.9%) patients have been treated with one TKI, either imatinib or dasatinib, and 17 (18.1%) have been treated with both prior to the study. Overall, 25 (54%) patients achieved MMR at 12-months follow-up compared to the baseline (Figure 1). The rates of optimal molecular response at 3- and 6-months were also improved compared to the baseline. The optimal molecular response was 76(88%) at 3 months, and 52(73%) at 6 months. Subgroup analysis with previous response to TKIs revealed that flumatinib improved the rates of optimal molecular response in both warning and failure groups. Switching to flumatinib from imatinib or/and dasatinib have been reported with an enhanced optimal molecular response in patients who experienced warning compared with those who had treatment failure after the TKIs with 38 (100%) vs 38 (79%), 29 (91%) vs 23 (59%) and 15 (68%) vs 10 (42%) at 3-, 6- and 12-months respectively (Figure 2). Similarly, the rates of optimal molecular response were improved in patients without mutations compared to those having mutations, 65 (90%) vs 9 (75%) at 3 months, 46 (77%) vs 5 (56%) at 6 months and 23 (59%) vs 1 (20%) at 12 months respectively. The most common adverse events (AEs) were diarrhea in 17 (18%), rash in 11 (12%), bloating in 11 (12%), and thrombocytopenia in 11 (12%) patients. Common hematological AEs of grade 3/4 were thrombocytopenia in 7 (7%), anemia in 3 (3%) and leucopenia in 1 (1%) patients. Conclusion For Ph+ CML-CP patients without the optimal molecular response in previous imatinib or/and dasatinib, flumatinib is a better alternative to the existing treatments. In addition, if the patients were switched to flumatinib earlier, the optimal response was achieved faster. The grade 3/4 AEs were mainly hematologically related, whereas the gastrointestinal events were mostly of grade 1-2.

Real World Population- Based Data from Nationwide Registry Support the Existence of Accelerated Phase in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients Even in Tyrosine Kinase Inhibitors (TKIs) Era

Background For decades, CML has been considered to be a triphasic disease recognizing 3 distinct stages: chronic phase (CP), accelerated phase (AP), and blast crisis (BC). Since the discovery of TKIs, the prognosis of CML patients has rapidly improved and less than 10% of patients diagnosed in CP experience disease progression on the therapy. Based on low incidence of CML progression and the fact that CML biological behavior seems biphasic, the new WHO 2022 classification of CML deemed AP less relevant and suggested the omission of AP. Many experts, however, still advocate for its inclusion in CML classification (e.g. ELN 2020, ICC 2022, NCCN 2023), even though the universal definition of AP is not established and differs in between publications. Methods This retrospective, real-world study is based on the Czech nationwide CML registry INFINITY with the data of newly diagnosed CML patients who agreed and provided their written consent. Recruited subjects were adult patients diagnosed in years 2005 - 2022 with sufficient data to determine the phase of the disease at diagnosis and follow-ups to assess their overall survival (OS), disease specific survival (DSS) and progression-free survival (PFS). The phase of the disease at the time of diagnosis was determined using the classification according to ELN 2020, ICC 2022, WHO 2016, and WHO 2022. Whenever CP was established, EUTOS Long-Term Survival (ELTS) score was calculated, assigning the patient to low risk (LR), intermediate risk (IR) and high risk (HR) group. OS and PFS are defined according to published guidelines. DSS is defined as the time from diagnosis to death due to CML disease or CML treatment. Results During the studied time period, 1660 new cases of CML were reported in INIFINITY registry. Of them, 1500 patients had data sufficient to classify the phase of the disease at the time of the diagnosis according to ELN 2020 guidelines and WHO 2022 classification and 1395 patients had data to assess the phase according to WHO 2016 and ICC 2022 classifications. When using ELN 2020 guidelines, groups were assigned as follows: LR CP- 784 patients (52.3%), IR CP- 421 patients (28.1%), HR CP- 227 patients (15.1%), AP- 42 patients (2.8%), BC- 26 patients (1.7%). There were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, there were no significant differences. Calculated estimates of 5- and 10- year OS, respectively, were 92.5% and 87.2% for LR CP, 83.5% and 65.9% for IR CP, 76.9% and 65.5% for HR CP, 59.2% and 45.9% for AP, and 32.9% for BC, p= 0.031 for HR CP versus AP (Figure 1). In the case of WHO 2016 and ICC 2022 classifications, 714 (51.2%) patients were diagnosed in LR CP, 374 (26.8%) in IR CP, 154 (11.0%) in HR CP, 125 (9.0%) in AP, and 28 (2.0%) in BC. Again, there were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, only age at the time of diagnosis was significantly different. Calculated estimates of 5- and 10- year OS, respectively, were 93.2% and 87.5% for LR CP, 84.9% and 67.7% for IR CP, 80.0% and 69.5% for HR CP, 65.7% and 55.6% for AP, and 39.7% for BC. We also performed propensity score matching according to age for patients in HR CP and AP and calculated estimates of 5- and 10- year OS, respectively, were 85.4% and 74.4% for HR CP and 60.2%, and 52.0% for AP, p= 0.003 (Figure 2). Similar results were obtained when testing for PFS and DSS. Summary Real-world data obtained from 1500 patients diagnosed in Czechia over 17 years, in our opinion, support the need to recognize the existence of AP at the time of diagnosis, even though a singular definition of AP is not agreed upon. Patients in AP have worse survival scores (OS, DSS, PFS) compared to patients in CP and/or HR CP. Moreover, because ELTS risk score was calculated on patients in CP, it may not be suitable for patients in AP, which would be changed to CP according to the new WHO 2022 classification. In conclusion, based on the real-world data with long-term follow-up, we believe it would be reasonable to keep the AP as part of CML classification of newly diagnosed patients. This publication was supported by the grant number MUNI/A/1224/2022, Programme EXCELES, ID Project No. LX22NPO5102, and by the Ministry of Health of the Czech Republic grant number 00023736.

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

Backgrounds: Several studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive sufficient tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. The main factors affecting Treatment free remission (TFR) are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment. Aims: To investigate impact of longer duration of DMR, we analyzed the outcome of patients with CP-CML who maintained DMR for more than 6 years during TKIs treatment and discontinued TKIs. The clinical and molecular immunological application criteria were also investigated for safer and more successful TFR. Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. After discontinuation, molecular responses were monitored for up to six months per month, up to 12 months every two months, and every three months thereafter using the qRT-PCR method. In the case of relapse, defined as loss of major molecular response (MMR), the last TKI therapy was reintroduced and molecular responses after resumption were monitored monthly until achievement of MMR using qRT-PCR. Results: Altogether 116 patients (50 males and 66 females) discontinued TKI. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. Prior to discontinuation, all patients received TKIs for a median of 120.6 months (range, 113.9-127.3), and the duration of sustained MR4.5 was 75.0 months (range, 70.7-79.3). At the time of discontinuation, 93 patients (80.2%) were receiving their first TKI (70 imatinib, 13 nilotinib, 6 radotinib, and 4 dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. After a median follow-up from treatment discontinuation of 42.2 months (range, 35.3-49.1), 28 (24.1%) patients have lost their response at a median of 8.4 months (range, 4.9-11.9) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation and 7 (25.0%) patients lost MMR after 12 months from discontinuation. TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) re-achieved MMR with a median of 5.6 months (range, 4.0-7.2). By univariate analysis, a TKI treatment duration of 10 years or more was the only significant predictor for maintained response (P&amp;lt;0.048). Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.

Somatic Mutations in Cancer-Related Genes Were Observed More Frequently in AYA CML Patients Compared to Elderly at Diagnosis, Whereas the Frequency Was Markedly Higher in Elderly Patients during TKI Treatment

CONCLUSIONS Several works showed that patients with chronic myeloid leukemia (CML) diagnosed at the age of 18 to 39 years (adolescent and young adults, AYAs), had a worse outcome of tyrosine kinase inhibitors (TKI) therapy compared to elderly patients. Only limited data on the molecular background differing AYA from the other age groups are available. To characterize the somatic mutation landscape of AYA CML patients in chronic phase at the time of diagnosis and follow-up in comparison to pediatric and elderly patients, and to follow their clonal evolution. Ph-positive acute lymphoblastic leukemia (Ph+ ALL) patients were included for comparison. Samples from the time of diagnosis (CML children N=18; AYA N=69; elderly N=70; Ph+ ALL children N=32, AYA N=13, elderly N=39) and TKI treatment follow-up (CML AYA N=69, elderly N=70) were analyzed with custom panel (22 whole genes, 40 selected exons). To follow the clonal evolution vital cells available from 10 CML patients were FACS sorted into populations of neutrophils, monocytes, T- and B-lymphocytes. Genomic BCR::ABL1 (g BCR::ABL1) and mutations were quantified using ddPCR in the sorted cells. At the time of diagnosis, a slightly higher frequency of somatic mutations was detected in AYA CML patients (28%, 19/69) compared to elderly (20%, 14/70) and children (11%, 2/18). The similar trend with markedly higher differences was observed in Ph+ ALL patients (62% 8/13 of AYA, 31% 12/39 of elderly, 22% 7/32 of pediatric). The most frequently mutated genes in AYA and elderly CML patients were identically ASXL1, DNMT3A, and TET2. Other mutated genes in AYA were FBXW7, IDH2, IKZF1 PHF6 and KDM6A, SETD2, SF3B1 in elderly. Considering the treatment response, a higher number of mutations at diagnosis were found in the AYA patients that responded optimally in follow-up (21%, 7/33) than in elderly 4% (1/26) and a slightly higher frequency of mutations in AYA patients who later failed on TKI (35%, 8/23) than in elderly 30% (13/43). In contrary, the frequency of acquired mutations or persisted mutations from diagnosis detected during TKI therapy was higher in elderly that failed on TKI therapy (67%, 29/43) than in AYA (52%, 12/23). The treatment failure was associated with de novo mutations in ABL1, RUNX1, TET2, ASXL1 in AYA and elderly CML patients, and in addition in IKZF1, and in DNMT3A, WT1, JAK2, respectively. Sorted cells were analyzed from the time of optimal response in 7 CML patients (+ diagnostic sample of 2 patients) with mutated ASXL1 in 6 patients, FBXW7 in 1 patient, DNMT3A in 1 patient and IDH2 in 1 patient. Samples from the time of therapy failure were available for sorting of 3 patients (+ diagnostic sample of 1 patient). All mutations were detected in g BCR::ABL1 positive neutrophiles and monocytes. The g BCR::ABL1 levels matched exactly with the levels of mutations except for 1 patient with ASXL1-mutated subclone (VAF 5%), which was found in g BCR::ABL1 positive cells. Similar data were found in patients with therapy failure. However, in one patient with secondary failure, the ASXL1 mutation detected at diagnosis disappeared. In all 10 CML patients, g BCR::ABL1 and mutations were not detected in T- and B- lymphocytes under the therapy. In diagnostic samples some g BCR::ABL1 and mutations positive T- and B- lymphocytes were found, but the levels were 3-4 log lower compared to levels in neutrophils and monocytes, which likely correspond to the contamination (purity check was done after sorting) than to the presence of a very small subset of physiological lymphoid cells. Of all age groups, AYAs had the highest number of mutations detected at the time of diagnosis with differences in the spectrum between CML and Ph+ ALL. A markedly higher de novo acquisition of mutations was observed in elderly CML patients during TKI treatment. Moreover, therapy failures were observed more frequently in elderly than in AYA CML patients. Clonal analysis of 10 CML patients outlined that myeloid, but not lymphoid stem/progenitor cells were mutated. Supported by MZCR NU21-07-00225

Single Cell Analysis of Genes Involved in Asymmetric Hematopoietic Stem Cell (HSC) Division in Chronic Myeloid Leukemia (CML) : Evidence of the Regulation of Tetraspanin CD63 during Leukemia Progression

Tyrosine kinase inhibitor (TKI) therapies have profoundly changed the natural history and survival of CML patients. However, the majority of the patients remain on long-lasting therapies and switch one TKI to another, either because of intolerance or resistance. All TKI cessation trials showed approximately 50% of leukemia recurrence rates even after several years of TKI therapies, suggesting the persistence of residual leukemic stem cells in patients in deep molecular response (DMR). The resistance and persistence of CML HSC are related to intrinsic (BCR-ABL independent survival) or extrinsic (leukemic niche ) mechanisms some of which have been extensively studied. However, there has been no data with regard to the role of asymmetric cell division pathways in the persistence and progression of CML stem cell clone. Indeed, During asymmetric division process of hematopoietic stem cells, some proteins are differently segregated between daughter HSCs such as endosome associated tetraspanin proteins (CD53, CD63) and mitochondria-associated fission regulator Dynamin related protein-1(DRP1). Similarly, it has been shown that asymmetric organelle inheritance can influence HSC decisions towards differentiation versus self-renewal. Interestingly, the tetraspanin CD63 is known to be involved in the quiescence of human and murine HSC via activation of TGF-beta pathway, CD63 hi cells exhibiting increased self-renewal potential after the asymmetric division with reduced differentiation potential. Materials and Methods We have analyzed the transcriptome performed in a cohort of CML patients in chronic phase (CP) and blast phase (BP) (GSE4170) as well as in a validation cohort of RNA-sequencing (GSE100026). Similarly, single cell transcriptome analysis of Lin- CD34+ CD38- CML progenitors (GSE76312) were included in the study evaluating the expression of genes involved in asymmetric cell division. We have then generated an asymmetric hematopoietic stem cell risk score using a panel of genes involved in the asymmetric division of HSCs and correlated these results with the transcriptome of the CML cohorts above. A pseudotime analysis was performed to evaluate single cell trajectories of the genes identified. Results To determine the potential role of asymmetric cell division markers in the progression of CML, we have analyzed the expression of several of these genes during CML progression in two independent transcriptome cohorts. The regulation concordance between the two distinct cohorts was principally observed on asymmetric molecules which were found to be down-regulated during blast crisis as compared to chronic phase. The regulation concordance between the two distinct cohorts was principally observed on asymmetric molecules down regulated during blast crisis as compared to chronic phase suggesting less of asymmetric properties during advanced phase of the disease. The down regulation in patients in blast crisis was confirmed at single cell level for the expression of SELL, CD63, NUMB, HK2 and LAMP2. CD63 expression has also been found to be of interest in CML chronic phase. Indeed, single cell neural network and deep learning in CP samples showed that the CD63 expression was the best asymmetric gene marker predicting a poor prognosis and this appeared to be induced by opposite regulation of HK2 and NUMB. In patients in CP-CML, the single cell trajectory reconstitution revealed the major regulatory role of CD63 highlighting a trajectory cluster implicating HSPB1, PIM2, ANXA5, LAMTOR1, CFL1, CD52, RAD52, MEIS1, PDIA3, all genes known to be involved also in hematopoietic malignancies such as myelodysplasia, AML and ALL. Conclusion We show here for the first time the identification of the expression of genes involved in the asymmetric division of CML HSC. Among these genes we identified the tetraspanin CD63 as being down-regulated during CML progression. The expression of the genes involved in the asymmetric HSC division should require further studies in CML, either to predict persistence of CML or progressive disease. Figure 1 : Single cell transcriptome of Lin- CD34+ CD38- CML progenitors in CP links CD63 expression to progressive disease. A/ Piechart of counts for chronic phase cells analyzed according to prognosis; B/ pseudotime transformation of single cell transcriptome according patient prognosis; C/ Pseudotime expression heatmap; D/ Pseudotime expression of CD63 in CP.

Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase Showing Clinical Resistance to Frontline Treatment with Second Generation Tyrosine Kinase Inhibitors. an Italian Prospective Study from the CML Campus

BACKGROUND: Frontline treatment with second generation tyrosine-kinase inhibitors (2G-TKIs) in patients with chronic myeloid leukemia in chronic phase (CP-CML) demonstrated higher efficacy as compared to imatinib therapy in inducing deeper molecular responses. However, its ability to reduce treatment failure and progressive disease is debated. Furthermore, limited information is currently available on the outcome of those CML patients showing clinical resistance to first-line treatment with a 2G-TKI. AIM: To describe the clinical outcome of CP-CML patients showing resistance to a frontline 2G-TKI and that switched to alternative TKIs therapy. PATIENTS AND METHODS: We performed this investigation on patients drawn from a web-based database (www.epiclin.it/lmc) used to collect clinical and biological data of CML patients enrolled in 24 Italian Hematology Centers from January 2013 onwards. Definitive information about first-line TKI treatment was available in 1277 prospective and consecutive CP-CML patients: 607 received imatinib and 670 dasatinib or nilotinib (2G-TKIs) as frontline therapy. Main inclusion criteria were: i) diagnosis of CP-CML; ii) first-line treatment with a 2G-TKI; iii) switch to second-line treatment in case of clinical resistance (i.e. failure according to ELN 2020 recommendations). Exclusion criteria was switch to second-line treatment for intolerance or for low adherence to therapy. Patients were treated according to the Center policy and the molecular data were obtained in accordance to the IS% parameters. RESULTS: Fifty-four CML patients met the inclusion/exclusion criteria and were identified as failure according to the ELN 2020 recommendations. The median age of these patients was 48.5 (20-81) years; male sex in 30 (55.5%) and female 24 (44.4%), Sokal risk score was low in 16 (29.6%), intermediate in 22 (40.7%) and high in 16 (29.6%) patients respectively;ELTS score was low in 26 (48.1%), intermediate in 14 (25.9%) and high in 14 (25.9%) patients. Additional chromosomal abnormalities were present at diagnosis in 4 out of 54 patients (7.4%: 3 additional Ph-chromosome and 1 trisomy 8). Nilotinib was administered in 27 (50%) and dasatinib in 27 (50%) of the patients.At 6 months, 30 out of 50 evaluable patients (60%) had BCR::ABL1 transcript values &amp;gt;1% and at 12 months 9 of 33 evaluable patients (28%) had BCR::ABL1 values still &amp;gt;1%. Second-line treatment after 2G-TKIs frontline failure started in all patients after a median time of 12 months (3-83) with ponatinib (30 pts, 55.5%), dasatinib (8 pts, 14.8%), nilotinib (4 pts, 7.4%), bosutinib (7 pts, 12.9%) or imatinib (5 pts, 9.2%).At 12 months the switch to second-line treatment induced the achievement of BCR::ABL1 values &amp;lt;1% in 45% of the evaluable cases. Eighteen patients (in which no mutations were found) switched to third-line treatment after a median time of 11 months (0-45) (ponatinib, 8 pts; nilotinib, 1 pt; dasatinib, 3 pts; imatinib, 3 pts; bosutinib, 1 pts; asciminib, 2 pts). MMR or a better response was reached by 6 of these patients and allogeneic stem-cell transplantation (SCT) was performed in 7 patients.Progression to CML advanced phase occurred in 8 pts. After a median follow-up of 59.9 months (15.6 - 99.3) 44 patients were still alive and death occurred in 10 pts (18.5%) (7 CML-related and 3 unrelated). Overall survival (OS) at 5 years was 82% (see Figure below). Indeed, OS at 5 years was 94% for the total 670 patients treated frontline with 2G-TKIs. In this population, 12 out of 32 observed deaths were CML-related and all were recorded in patients who changed TKI therapy, whereas in 19 cases the death was CML-unrelated and in 1 case was not specified. However, those patients who maintained the same therapy for 5 years showed an OS of 96%, whereas those who had to change treatment for any cause showed an OS of 89% at 5 years. CONCLUSION: Our findings, collected from the prospective cohort of the CML Italian observational registry, show that CP-CML patients failing frontline 2G-TKI therapy, despite a complex management, may have still an acceptable prognosis and survival due to the availability of both multiple TKI options and SCT.

Treatment-Free Remission after Ponatinib Cessation in Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients. the Ponastop Observational Study

Introduction: Ponatinib has proven its efficacy as salvage therapy for patients intolerant, or resistant (and ABL1T315I+ mutation) to at least 2 tyrosine kinase inhibitors (TKI) in CP-CML. Despite the unfavourable profile of such patients, some durable deep molecular response (DMR, i. e. MR 4 and MR4.5) might be observed, and it is arguable to propose a treatment-free remission (TFR) strategy to these patients, despite the fact that this is not currently recommended. The aim of this study is to analyse the results of TFR in CP-CML patients that have received ponatinib as last line of therapy for any reason. Methods: This a retrospective multicentric European analysis of CP-CML patients undergoing ponatinib at any dose for prior TKI-intolerance or -resistance and obtaining at least 2 years of MR4.5, assessed on at least 4 successive samples, and undergoing a treatment-free remission (TFR) procedure and follow-up. All BCR::ABL1 assessments have been performed in ELN reference laboratories and expressed in % on the international scale (IS). Loss of major molecular response (MMR i. e. BCR::ABL1 transcript ≥0.1% IS) on one datapoint was sufficient to consider relapse. Clinical information were extracted from individual patients' files. All patients have given their written agreement in participating to this observational study. Results: Fifteen cases could be collected and analysed with 27% males, 73% females of a median age of 43 (24-79) years at CML diagnosis and of 56 (30-83) at ponatinib cessation. All patients were in CP at diagnosis and at ponatinib cessation. None of these patients were harbouring additional chromosomal abnormalities at diagnosis or beyond. Sokal scores were low in 50%, intermediate in 25% and high in 25% of patients, ELTS scores were low in 64% and intermediate in 36% of patients. None of these patients has undergone allogeneic stem cell transplant. Three patients were ABL1T315I mutated. The median time between CP-CML diagnosis and ponatinib initiation was 52 (1.5-145) months, the median initial dose of ponatinib was 45 mg QD for 12 patients, 30 mg QD for 2 patients and 15 mg QD for 1 patient. One patient had 4 previous lines of TKI prior to ponatinib, 4 patients 3 prior lines, 5 patients 2 prior lines, 4 patients 1 prior line and 1 patient was in ponatinib first-line (EPIC trial). Thirteen arterial events occurred on ponatinib in these 15 patients, all prior to ponatinib cessation. At cessation, the median dose of ponatinib was 30 mg QD for 1 patient, 15 mg QD for 7 patients, 7.5 mg QD for 2 patients, and ≤ 6.4 mg QD for 4 patients. Ten (67%) patients were resistant to prior TKI before ponatinib, 3 were intolerant, 1 intolerant and resistant and 1 was in first-line ponatinib. The median ponatinib treatment duration prior to cessation was 71 (21- 124) months and the time from ponatinib initiation to sustained DMR was 14 (2-112) months. The median follow-up after cessation was 11 (2-55) months. One patient died in TFR of severe SARS-CoV2 lung infection 23 months after cessation. The median survival without MMR loss after ponatinib cessation was 69.26% at 12-months, 24-months and 54-months. Time to MMR-loss KM curve is presented in Figure 1. The four patients loosing MMR after ponatinib cessation resumed low dose ponatinib (≤ 15 mg QD) for 2 and asciminib (80 mg BID) for 2, three patients regained MMR (one non evaluable with too short follow-up). Conclusions: TFR attempt represents a strategy that can be applied to ponatinib patients in the setting of heavily pretreated CP-CML in a similar way as of less advanced CP-CML patients, with high success rates and no disease progression. If those data are confirmed by further studies and longer follow-up, TFR strategies might have to be considered also in previously heavily pre-treated patients.

A Predictive Scoring System for Therapy Failure of Tyrosine-Kinase Inhibitors in Patients with Chronic-Phase Chronic Myeloid Leukemia

Background In the latest version of WHO criteria (5th edition, 2022), accelerated-phase chronic myeloid leukemia (CML-AP) was re-defined as “high-risk” chronic-phase chronic myeloid leukemia (CML-CP). However, there is no robust predictive scoring system for therapy failure of tyrosine-kinase inhibitors (TKIs) in these newly-defined CML-CP patients. Objectives To develop and validate a predictive scoring system for TKI-therapy failure in CML-CP patients. Methods Data from 2,038 consecutive CML-CP patients according to the WHO 2022 criteria receiving initially TKI-therapy at one centre were interrogated as the training dataset to develop a predictive scoring system which was subsequently-validated in 4,640 patients from 76 other centres (validation dataset). TKI-therapy failure was defined by the 2020 European LeukemiaNet recommendation. Results In the training dataset, 1,591 patients (78%) initially received imatinib; 326 (16%), nilotinib; 85 (4%), dasatinib; and 36 (2%), flumatinib (a novel 2G-TKI made in China). Median TKI-therapy duration was 58 months (IQR, 33-90 months). 515 patients (27%) experienced therapy failure at a median of 9 months (IQR 3-12 months) on TKI-therapy. Multi-variable analysis indicated that older age, male sex, lower hemoglobin concentration, higher proportion of blood blasts and basophils, larger spleen size below the costal margin and high-risk additional cytogenetic abnormalities (ACAs) in Ph + cells were significantly-associated with higher cumulative incidence of therapy failure. Based on the optimal Fine-Gray regression model, a formula to calculate the therapy-failure risk score was established: “ Initial TKI-therapy failure risk score = 1.9321 × (Age/100) + 0.2950 × Sex (male = 1, female = 0) - 0.8589 × (HGB/100) 2 + 0.0979 × Blood blasts + 0.023× Blood basophils + 0.0521 × Spleen size below the costal margin + 0.5075 × high-risk ACAs (existing = 1, no = 0)” which divided patients into low- (score ≤ 0.0545; n = 908; 47%), intermediate- (0.0545 &amp;lt; score &amp;lt; 1.1662; n = 791; 41%) and high-risk (score ≥ 1.1662; n = 216; 12%) cohorts with 7-year cumulative incidences of therapy failure of 8% (95%CI, 4, 12%), 39% (35, 43%) and 80% (76, 84%; p &amp;lt; 0.001; Figure 1A). Sub-distribution hazard ratios (sHRs) for therapy failure (low-risk cohort as reference) were 3.2 (2.6, 4.1, p &amp;lt; 0.001) and 9.5 (7.4, 12.2; p &amp;lt; 0.001) for the intermediate- and high-risk cohorts. In the validation dataset, 4,640 patients were classified into the low- (n = 2,168; 47%), intermediate- (n = 2,093; 45%) and high-risk (n = 379; 8%) cohorts using the scoring system. 7-year cumulative incidences of therapy-failure were 10% (7, 13%), 36% (33, 39%) and 70% (66, 74%; p &amp;lt; 0.001; Figure 1B). sHRs (low-risk cohort as reference) were 3.4 (3.0, 3.9; p &amp;lt; 0.001) and 8.8 (7.5, 10.3; p &amp;lt; 0.001) for the intermediate- and high-risk cohorts. Time-dependent AUROC values for therapy failure using the predictive scoring system were 0.84-0.92 and 0.79-0.86 in the training and validation datasets. Moreover, patients identified as intermediate- or high-risk cohorts by the predictive scoring system receiving initial 2G-TKI-therapy had significantly-lower therapy failure rate than those receiving imatinib-therapy ( p-values = 0.002 and 0.017) both in the training and validation datasets. Conclusions We developed and validated a robust predictive scoring system for TKI-therapy failure in newly-defined CML-CP patients according to the WHO criteria (5th edition, 2022), which might help physicians decide appropriate therapy strategy.