Chinese Chronic Myeloid Leukemia Patients Research Articles

Adherence to tyrosine kinase inhibitor and clinical outcomes in patients with chronic myeloid leukemia

PurposeTo ensure optimal care for patients with chronic myeloid leukemia (CML), adherence to tyrosine kinase inhibitors (TKIs) has emerged as a critical component. The objective of this study was to assess the impact of TKIs adherence on clinical outcomes in a cohort of Chinese CML patients who received treatment with TKIs. MethodsThis retrospective study employed a cross-sectional design utilizing questionnaires to assess adherence to TKIs in a sample of 398 patients diagnosed with CML. Adherence was measured using the Morisky Medication Adherence Scale (MMAS-8), which dichotomizes patients into low, medium, and high adherence groups. ResultsOf the patients included in this study, 34.2% were classified as highly adherent, with 43.2% and 22.6% of patients categorized as having medium and low adherence, respectively. Compared to the low-adherence group, patients in the medium- and high-adherence groups exhibited significantly higher rates of achieving major molecular response (MMR) and lower rates of switching TKIs. Moreover, patients who failed to adhere to TKIs treatment demonstrated significantly lower event-free survival and failure-free survival compared to those in the high-adherence group. Notably, regular molecular monitoring and utilization of the “CML Academy” mobile application were positively associated with increased TKI adherence. On the other hand, patients receiving third-generation or above first-line TKIs treatment displayed reduced adherence. ConclusionThe findings suggest that high adherence to TKIs treatment confers clinical benefits to patients with CML. Accordingly, the implementation of effective guidance and intervention measures aimed at promoting adherence to TKIs therapy in real-world settings is imperative.

Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China.

Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China. We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy. The median age was 46 years (interquartile range: 33-55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%). This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.

Imatinib dose optimization based on therapeutic drug monitoring in Chinese patients with chronic-phase chronic myeloid leukemia.

Imatinib treatment often produces various adverse reactions in patients with chronic myeloid leukemia (CML), and increasing patients are pursuing dose optimization. In this study, the authors aimed to explore imatinib dose optimization based on therapeutic drug monitoring (TDM) in CML patients. The relationship between imatinib concentration and clinical response and adverse reactions was evaluated, then the dose-reduction data in 110 Chinese CML patients was also explored. Patients with a major molecular response (MMR) had higher imatinib plasma concentration compared with those not achieving MMR (1473.70±419.13 vs. 985.8±213.32ng/ml) when receiving 400mg daily. Imatinib concentration >1000ng/ml predicted improved event-free survival and failure-free survival. In addition, imatinib concentration was significantly correlated with leukopenia or neutropenia, diarrhea, edema, and rash. Patients receiving imatinib concentration >1685ng/ml were more susceptible to diarrhea and those with levels >1575ng/ml were more susceptible to periorbital and limb edema. Thirty-nine (35.5%) patients underwent low-dose therapy and seven (6.4%) patients received discontinuation therapy. Patients with a higher imatinib concentration were more likely to maintain MMR or deep molecular response after dose reduction. No significant difference in molecular relapse-free survival rate was observed between the low-dose and standard-dose groups over 1year and 2years. Furthermore, most adverse reactions significantly improved after dose reduction. Imatinib concentration was closely associated with clinical response and adverse reactions, suggesting that dose optimization based on TDM might achieve beneficial clinical outcomes. Dose reduction based on TDM is feasible and safe for patients exhibiting optimal response, which could improve adverse reactions.

Burden of tyrosine kinase inhibitor failure in Chinese chronic myeloid leukemia patients: a systematic literature review.

Aim: To conduct a systematic literature review of real-world evidence on the burden of tyrosine kinase inhibitor (TKI) failure in Chinese patients with chronic myeloid leukemia (CML). Methods: We identified 155 references in Chinese- and English-language journals from 2001 to 2021. Results: The age-adjusted mortality rate in Chinese CML patients was decreasing. Imatinib treatment had a higher annual treatment failure risk than nilotinib (0.199 vs 0.041). Patients with TKI treatment failure tended to be young (median: 38.6years), have progressive disease (44.3%) and harbor BCR-ABL1 mutations (51.6%). The disease burden of TKI treatment failure included reduced health outcomes and increased health resource utilization and costs. Conclusion: CML relapse cases could continuously rise in China due to increasing TKI treatment failure over extended survival.

Treatment status of tyrosine kinase inhibitors in Chinese patients with chronic myeloid leukemia in 2020

目的调查中国慢性髓性白血病（CML）患者的治疗现状。方法横断面研究，2020年4月末至5月中旬，以填写调研问卷的形式在全国范围内调研CML患者，分析酪氨酸激酶抑制剂（TKI）一线选择、目前用药、药物转换和获得主要分子学反应（MMR）的比例及其影响因素。结果2933份来自全国31个省市自治区CML受访者的问卷可供分析，男性1683例（57.4％），中位年龄38（16～87）岁。一线选择：伊马替尼2481例（84.6％），原创性新药（原研药）1803例（61.5％）。填写问卷时用药：伊马替尼1765例（60.2％），原研药1791例（61.1％）。共1185例（40.4％）受访者曾经历TKI药物转换。1944例初发慢性期受访者TKI中位治疗45（3～227）个月，1417例（72.9％）获得≥MMR的疗效。多因素分析显示，城镇户籍（OR＝0.6，95％CI 0.5～0.8，P<0.001）、≥大学学历（OR＝0.5，95％CI 0.4～0.7，P<0.001）和进展期（OR＝0.5，95％CI 0.3～0.8，P＝0.001）受访者更少首选仿制TKI，而来自中部地区受访者比东部地区更多首选国产仿制TKI（OR＝1.7，95％CI 1.4～2.0，P<0.001）。进展期受访者更多首选二代TKI（OR＝5.4，95％CI 3.6～8.2，P<0.001），≥60岁受访者更少首选二代TKI（OR＝0.4，95％CI 0.2～0.7，P＝0.002）。诊断时处于进展期（OR＝2.2，95％CI 1.6～3.2，P<0.001）、首选伊马替尼（OR＝2.0，95％CI 1.6～2.6，P<0.001）、首选国产仿制药（OR＝1.3，95％CI 1.1～1.6，P＝0.002）、诊断距开始TKI治疗的时间更长（OR＝1.2，95％CI 1.1～1.2，P<0.001）和服用TKI的时间更长（OR＝1.1，95％CI 1.0～1.1，P<0.001）与药物转换比例增高显著相关。城镇户籍（OR＝0.7，95％CI 0.6～0.8，P<0.001）、获≥MMR（OR＝0.6，95％CI 0.5～0.8，P<0.001）和疗效未知（OR＝0.7，95％CI 0.6～0.9，P＝0.003）与药物转换比例低显著相关。女性（OR＝1.4，95％CI 1.1～1.7，P＝0.003）、城镇户籍（OR＝1.6，95％CI 1.3～2.0，P<0.001）、初始服用伊马替尼（OR＝1.4，95％CI 1.1～1.9，P＝0.016）和TKI治疗时间更长（OR＝1.2，95％CI 1.2～1.3，P<0.001）与获得≥MMR显著相关，而年龄≥60岁（OR＝0.7，95％CI 0.4～1.0，P＝0.047）和药物转换（OR＝0.6，95％CI 0.5～0.7，P<0.001）与未获得MMR显著相关。结论截至2020年，中国CML患者中大多数首选并持续服用伊马替尼，半数以上服用原研药。社会人口学特征和疾病分期影响了患者的TKI选择、药物转换和治疗反应。

PCN50 Disease Burden of Chronic Myeloid Leukemia UNDER Current Treatment Pattern in China

To estimate the disease burden of Chronic Myeloid Leukemia (CML) under current treatment pattern in China. A decision-analytic model was constructed to simulate the Chinese patients with CML and the age and gender-matched Chinese general population over lifetime time horizon for the differences in overall survival, quality-adjusted life years (QALY), and lifetime direct medical costs. Literature search was conducted to identify appropriate evidence to estimate the model variables. Base case analysis and sensitivity analysis were conducted for the point estimations and uncertainty of the disease burden of CML. The Chinese CML patients were associated with reduced average overall survival by 6.878 years (26.555 years vs. 33.433 years), reduced average QALY by 7.390 QALY (23.281 QALY vs. 30.671 QALY), and increased average life-time direct medical costs by ¥837,811 (¥1,014,394 vs. ¥176,583) under current treatment pattern. The reduced QALY associated with CML was highly sensitive to first-line treatment effect of imatinib for the chronic phase of CML (change: 1.818 QALY), utility of disease remission (change:1.809 QALY), the rate of allogeneic stem cell transplantation (difference: 1.624 QALY), and best supportive care rate (difference: -1.082). The lifetime direct medical costs associated with CML was highly sensitive to the rate of first-line imatinib treatment (change: ¥-141,906), mortality of blast phase of CML (change: ¥-130,926), and effects of first-line imatinib treatment (change: ¥-91,115). The probabilistic sensitivity analysis with 5,000 Monte Carlo simulations estimated the median and 95% credible interval of reduced QALY ( -7.399 QALY, -8.555 to -6.338 QALY) and increased lifetime direct medical costs (¥844,685, ¥748,593 to ¥964,283). The disease burden of CML in Chinese patients was mainly characterized with reduced overall survival, reduced QALY, and increased medical costs that were highly sensitive to first-line treatment with imatinib, stem cell transplantation rate, and mortality of blast phase of CML.

Clinical efficacy and safety of imatinib treatment in children and adolescents with chronic myeloid leukemia

Chronic myeloid leukemia (CML) is relatively rare in childhood and few studies have reported the clinical use of imatinib (IM) in pediatric CML. In this study, we evaluated the efficacy and tolerability of IM in children and adolescents with CML.We investigated 21 patients under 18 years of age with newly diagnosed CML and treated with IM in Children's Hospital of Chongqing Medical University between May 2014 and February 2018. The disease was staged according to the European LeukemiaNet criteria and the IM dose was determined based on the disease stage. Cumulative responses and survival probabilities were estimated according to the Kaplan–Meier method.The estimated complete hematologic response rate of chronic phase-chronic myeloid leukemia (CML-CP) was 89.5% at 3 months. The complete cytogenetic response rates increased with time, reaching 47.4%, 73.7%, and 80.3% at 6, 12, and 24 months, respectively. The cumulative major molecular response rates were 42.1% and 76.3% at 12 and 24 months, respectively. With a median follow-up time of 33.8 months (range, 3.2–61.7 months), the estimated 2-year overall survival (OS) rate for CML was 95.2% (95% confidence interval [CI], 70.7%–99.3%). None of the CML-CP patients progressed to the accelerated phase or had a blast crisis. The 2-year OS and progression-free survival rates for the CML-CP cohort were both 100%, while the estimated 2-year event-free survival rate was 68% (95% CI, 42.1%–84.2%). None of the patients in this group had treatment-related deaths or IM discontinuation due to drug toxicities, and only 1 patient had a grade III–IV nonhematologic adverse event. Overall, anemia was the most common adverse effect and 42.9% of patients had a decrease in bone mineral density.IM was effective and the adverse effects were well-tolerated throughout the follow-up period in Chinese CML patients under 18 years of age.

Validation of the EUTOS Long-Term Survival Score in Chinese Chronic Myeloid Leukemia Patients Treated with Imatinib: A Multicenter Real-World Study.

PurposeTo validate the clinical efficacy of the recently developed EUTOS long-term survival (ELTS) score in a real-world setting.Patients and MethodsA total of 479 chronic myeloid leukemia (CML) patients treated with frontline imatinib between January 2010 and December 2017 were enrolled in this retrospective study. The ELTS score was evaluated on the end-points including complete cytogenetic response (CCyR), progression-free survival (PFS), overall survival (OS) and CML-related death, and the efficiency of the ELTS score was further compared with the historical Sokal, Hasford, EUTOS scores.ResultsWith a median follow-up of 69 months (range, 9–112 months), 462 evaluable patients were stratified into the ELTS low-risk (n = 230), ELTS intermediate-risk (n = 168) and ELTS high-risk (n = 64) groups. For the regular assessment indicators like CCyR, PFS and OS, the ELTS scoring system could effectively identify the corresponding risk groups, similarly with the results provided by previous scoring systems. With respect to the CML-related death, the ELTS score could accurately identify a high-risk group with a significantly higher risk of dying of CML, and the 5-year cumulative incidence occurred in the ELTS high-, intermediate-, and low-risk groups was 11% (95% CI: 3–19%), 5% (95% CI: 1–9%) and 2% (95% CI: 0–4%), respectively. Most notably, the ELTS score outperformed the Sokal, Hasford and EUTOS scores without statistical difference among different risk groups.ConclusionThe ELTS score could effectively predict the prognosis of imatinib-treated CML patients in real-life settings.

Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety.

Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). In 2007, a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients. This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment. The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total = 140 mg/ day), respectively. The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1% (versus 50.8% at 18 months), and the median time to MCyR was 12.7 weeks. All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response. The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64% (16/25), with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up; the median time to CHR was 16.4 weeks. The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months. The most frequently reported AEs (any grade) included pleural effusion, headache, and myelosuppression. These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.

Monitoring and Analysis of Chinese Chronic Myeloid Leukemia Patients Who Have Stopped Tyrosine Kinase Inhibitor Therapy.

Discontinuation of tyrosine kinase inhibitor (TKI) therapy after achieving a persistent deep molecular response (DMR) is an urgently needed treatment goal for chronic myeloid leukemia (CML) patients and has been included in the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2017) for CML. Indeed, various studies have confirmed the feasibility of discontinuing TKI therapy. In this study, we analyzed data from 45 CML patients who had discontinued TKI therapy. Univariate analysis was performed to predict factors that were potentially related to treatment-free remission (TFR) and identify the differences between early relapse and late relapse. Out of the 45 patients, 20 exhibited molecular relapse after a median follow-up of 18 months (range, 1-54 months), and the estimated TFR at 24 months was 40%. The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes. Our results indicate that TKI discontinuation could be successfully put into practice in China.

Retrospective Analysis of Chinese Chronic Myeloid Leukemia Patients Who Have Stopped Tyrosine Kinase Inhibitors

BackgroundAlthough life-long tyrosine kinase inhibitors (TKIs) therapy is still the consensus recommendation, TKIs discontinuation has yet been proven in part of the patients who sustain the long-term treatment-free remission (TFR) which has become a new endpoint and is an emerging goal in the management of chronic myeloid leukemia (CML) currently. In the last ten years, constant clinical trials have demonstrated that about 40%-50% patients with stable deep molecular response for a long period time stayed in TFR after stopping TKIs.MethodsWe retrospective analyzed 109 CML patients who have stopped TKIs in seven centers. They were included according to the unified standard. Rates of TFR were calculated by Kaplan-Meier analysis and stratified groups were compared with the log-rank test. COX univariate analysis was used to predict the potential factors on relapse after discontinuation.ResultsClinical features of the 93 patients were included in this work. 39 of 93 patients lost major molecular remission (MMR) after a median follow-up of 15 months and the estimated TFR was 52.6%. 31 of 39 patients who met the definition of molecular relapse resumed TKIs treatment immediately and regained the response with an average time to MMR of 4.34 months (range, 1-12 months). No significant difference was found in median course of imatinib therapy between the TFR group and the relapse. Similarly, time to MMR, age, gender and Sokal risk also showed no difference between the two groups. History of withdrawal is the only statistically significant factor in this retrospective analysis.ConclusionIn summary, this is the first report to prove that TKIs might be safely stopped in partial Chinese CML patients. DisclosuresNo relevant conflicts of interest to declare.

Chronic myeloid leukemia patients and treatment-free remission attitudes: a multicenter survey.

BackgroundTreatment-free remission (TFR) is becoming an essential goal for chronic myeloid leukemia (CML) patients in clinical practice. Few studies have emphasized patient attitudes or preferences about discontinuing tyrosine kinase inhibitors treatment. This study aimed to evaluate the characteristics of Chinese CML patients and their views and perspectives on TFR.MethodsA total of 329 CML patients participated in this multicenter, questionnaire-based, standardized, semi-structured, interview-guided, open-ended, cross-sectional study. Information about demographics, diagnosis information, treatment history, quality of life (QoL), and TFR preference was collected.ResultsThe adherence rate was 50% (N=163) and sex dependent (males, OR=2.24, 95% CI=1.40–3.58). Physical activity, symptom burden, mood impact, and daily impact were found to be better among adherent patients. Thirty-four percent of the patients were willing to attempt TFR positively. The reasons for preferring TFR were due to side effects (56%) followed by high cost (52%), inconvenience (42%), and pregnancy need (41%). Multivariate analysis indicated that patients who were younger (OR=0.96, 95% CI=0.94–0.99) with shorter disease duration (OR=0.90, 95% CI=0.82–0.98) and higher disease symptom burden (OR=1.08, 95% CI=0.98–1.21) were more likely positive about TFR.ConclusionPatients who were younger with shorter disease duration and higher disease symptom burden were more likely to try TFR. They expressed several perceived noncost factors of TFR. Our data may help promote the management of CML and designing of clinical trials for TFR in some developed regions of China.

Changing Treatment May Affect the Predictive Ability of European Treatment Outcome Study Scoring for the Prognosis of Patients with Chronic Myeloid Leukemia.

Objective:Previous studies compared the predictive ability of the European Treatment Outcome Study (EUTOS), Sokal, and Hasford scoring systems and demonstrated inconsistent findings with unknown reasons. This study was conducted to determine a useful scoring system to predict the prognosis of patients with chronic myeloid leukemia (CML) and identify the probable factors that affect the scoring.Materials and Methods:This is a retrospective cohort study. The predictive ability of EUTOS and the factors that affect scoring were analyzed in 234 Chinese chronic-phase CML patients treated with frontline imatinib, including a few patients temporarily administered hydroxyurea for cytoreduction before imatinib. Patients were stratified into different risk groups according to each scoring system to assess the treatment outcomes and the predictive ability of EUTOS scores between patients who received imatinib during the entire follow-up period and patients who received altered treatment because of intolerance, progression, and treatment failure.Results:Sixty-one (26.0%) patients received altered treatments during the follow-up. In the EUTOS low- and high-risk groups, the 5-year overall survival was 94.6% and 84.7% (p=0.011), 5-year event-free survival was 92.6% and 77.6% (p=0.001), and 5-year progression-free survival (PFS) was 95.3% and 82.4% (p=0.001), respectively. The predictive ability of EUTOS was better than that of the Sokal and Hasford scores (p=0.256, p=0.062, p=0.073) without statistical significance. All three scoring systems were valid in predicting early optimal response. Kaplan-Meier analysis showed a high association between overall PFS and the EUTOS scores in the standard-dose imatinib group (p<0.001).Conclusion:This study suggests that the EUTOS scoring system could predict the outcome of chronic-phase CML patients treated with standard-dose imatinib. Altered treatment is a crucial factor that affects the prognostic impact of EUTOS scoring. Achieving complete cytogenetic response at 18 months is an essential factor in predicting the prognosis of patients with CML.

Long-Term Safety of Dasatinib in Chinese Chronic Phase Chronic Myeloid Leukemia Patients with Imatinib-Resistance or -Intolerance: Results from a 6-Year Follow-up of a Multicenter Phase II Study

Background:The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) has turned chronic myeloid leukemia (CML) from a fatal disease into a controllable chronic condition. Most CML patients, especially those who were in chronic phase (CP), now may require life-long TKIs therapy. Thus, the long-term safety of TKIs is of great importance. Dasatinib is a second-generation TKI that has been approved in China in 2011 as a treatment for imatinib-resistant or -intolerant CML. Previously we have reported safety findings from the Chinese dasatinib registration study after 4 years of follow-up. The results showed that dasatinib was well tolerated, with a low rate of discontinuation and a safety profile that supported previous data from large Phase 3 clinical trials (CA180-034)[1]. Here we present the safety results from the 6-year follow-up of 59 CML-CP patients in this pivotal Chinese studyAims:To evaluate the long-term safety of dasatinib in Chinese CML-CP patients who were resistant to or intolerant of imatinib after 6 years of follow-up. Important endpoints included the incidence and severity of adverse events (AEs) and treatment discontinuation due to drug-related AEs.Methods:This was an open-label, single-arm phase 2 clinical study conducted at 10 centers in China. Adult, Chinese CML patients with imatinib-resistant or -intolerant were recruited. CML-CP patients received oral dasatinib of 100mg/d, until disease progression or intolerable toxicity. Follow-up visits were scheduled at least every 4 weeks until all study-related toxicities returned to baseline or ≤ National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 Grade 1, stabilized or were irreversible.Results:A total of 140 patients were enrolled, 59 of whom had CML-CP. After 6 years of follow-up, 61% (36/59) of patients with CML-CP remained on treatment. Between the 4- and 6-year follow-up, there were no further deaths on the study and no more patients with CML-CP discontinued treatment due to drug-related AEs.Overall, drug-related AEs of any grade were experienced by 74.6% (44/59) of patients with CML-CP, of which 3 patients experienced drug-related AEs after 4-year follow-up (Table). 20.3% (12/59) of patients with CML-CP experienced drug-related, Grade 3-4 AEs and 16.9% (10/59) experienced drug-related serious AEs (Table). 16.9% (10/59) of patients experienced haematological AEs (Grade 3-4, 11.9%, 7/59) and none of the 10 cases happened after 4-year follow-up. The most frequently reported drug-related AEs for CML-CP patients remained pleural effusion (25.4%, 15/59; Grade 3-4, 3.4%, 2/59) and 1.7% (1/59) of the patients discontinued dasatinib treatment due to pleural effusion. Only 1 new case of pleural effusion occurred between 4-year and 6-year follow-up and no more Grade 3-4 pleural effusion has been observed after 4-year follow-up. Pulmonary hypertension were experienced by 8.5% (5/59) patients. Only 1 new case of pulmonary hypertension happened between 4-year and 6-year follow-up and no more Grade 3-4 pulmonary hypertension occurred after 4-year follow-up. Between 4-year and 6-year follow-up, 1 patient (1.7%) experienced Grade 1-2 pulmonary arterial hypertension and this was the only case of pulmonary arterial hypertension observed in the study. Deep vein thrombosis (1.7%, 1/59) occurred to 1 patient in 4-year follow-up and no more cases of deep vein thrombosis occurred between 4-year and 6-year follow-up.Conclusion:The safety profile of dasatinib after 6-year follow-up was consistent with the results from 4-year follow-up, which confirmed the long-term safety of dasatinib in the treatment for Chinese CML-CP patients with imatinib-resistance or -intolerance. Pleural effusion remained the most common adverse event during long-term follow up. As TKI-associated vascular AEs (VAEs) is drawing more and more attention in recent years, we have evaluated their incidence in our study and the results showed that the risk of VAEs remained low with long-term dasatinib treatment.Acknowledgment: BMS funded this research and medical writing support.Reference[1] Huang XJ, Hu JD, Li JY, et al. Four-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukaemia receiving dasatinib: efficacy and safety. Poster (#54229) presented at the 19th European Haematology Association Annual Congress; 12-15 June 2014; Milan, Italy DisclosuresNo relevant conflicts of interest to declare.

A survey on tyrosine kinase inhibitor treatment in patients with chronic myeloid leukemia in China: from patients'perspective

目的评估中国慢性髓性白血病（CML）患者接受酪氨酸激酶抑制剂（TKI）治疗的现状，并分析相关影响因素。方法2014年5月至11月，在全国范围内向正在接受TKI治疗的成年CML患者发放并收集无记名调查问卷。结果共收集1 038份问卷，949份可供评估。949例受访者中，男549例（58%），中位年龄41(18~88）岁，623例（66%）为城镇户籍，449例（47%）具有大学及以上学历。888例（94%）的受访者初诊时处于慢性期，其中690例（78%）在诊断1年内开始用TKI治疗。794例（84%）服用伊马替尼，768例（81%）服用原研药。TKI中位治疗时间为3（<1~13）年，可评估TKI治疗反应的受访者中，85%（708/834）获得完全细胞遗传学反应（CCyR），46%（397/859）获得完全分子学反应（CMR）。多因素分析显示，女性（OR=1.8, 95% CI 1.1~2.8，P=0.019和OR=1.5, 95% CI 1.1~2.0，P=0.015）、TKI治疗时间>3年（OR=4.1，95% CI 2.6~6.5，P<0.001和OR=3.7, 95% CI 2.7~5.1，P<0.001）和服用伊马替尼（OR=2.1, 95% CI 1.2~3.7，P=0.007和OR=3.3, 95% CI 2.1~5.1，P<0.001）是有利于获得CCyR和CMR的共同独立因素。此外，大学及以上学历（OR=2.0, 95% CI 1.3~3.1，P=0.003）、确诊1年内开始TKI治疗（OR=2.4, 95% CI 1.5~3.8，P<0.001）和服用原研药（OR=2.4, 95% CI 1.4~4.0，P=0.001）是有利于获得CCyR的独立因素。787例（83%）受访者付费服用TKI，每年TKI中位自付金额为7.20（0.24~37.00）万元。884例报告了TKI治疗中的最大障碍的受访者中，534例（62%）报告“经济负担”，仅152例（17%）报告“不良反应影响生活质量”。结论在当今中国，绝大多数CML患者服用伊马替尼，TKI治疗结果满意，但经济负担重是TKI治疗中的主要障碍。

SF3B1 mutation is a rare event in Chinese patients with acute and chronic myeloid leukemia

ObjectiveSomatic mutations of SF3B1 gene have recently been identified in myelodysplastic syndrome and chronic lymphocytic leukemia. The frequency and clinical relevance of SF3B1 mutations have been rarely studied in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The present study was aimed to analyze the frequency of SF3B1 mutations in AML and CML. Designs and methodsHigh-resolution melting analysis (HRMA) was established to detect the mutation hotspots (codon E622, H662, K666, and K700) of SF3B1 gene in 275 AML and 81 CML patients. ResultsHeterozygous SF3B1 mutations were detected in three AML patients by HRMA. Direct DNA sequencing identified one K666T, one K666N and one K700E mutations. All three AML patients had normal karyotypes. One case also had NPM1 and DNMT3A mutations, one had FLT3 internal tandem duplication and DNMT3A mutations, and the other had NPM1 mutation. No SF3B1 mutations were detected in CML patients. ConclusionsSF3B1 mutation is a rare molecular event in Chinese AML and CML patients.

Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through β-catenin signaling

Sonic hedgehog (Shh) signaling plays an important role in many human cancers and cancer stem cells. Here we investigate the activity and functional role of Shh signaling in chronic myeloid leukemia (CML) and leukemia progenitor cells. Differential activation of Shh signaling was found in about 50% CML chronic phase samples, about 70% of CML accelerated phase samples, and >80% CML blast crisis phase samples. Deregulated activation of Shh signaling was observed in CD34(+) and c-kit(+) leukemia progenitor cells. Stimulation of Shh signaling with exogenous Shh peptide induced expansion of CD34(+) and c-kit(+) progenitor cells (p < 0.05), inversely, blocking the pathway with signal inhibitor induced cell apoptosis (p < 0.05). Low level of Shh protein was observed in CML bone marrow stromal cells, and CD34(+) progenitor cells are less sensitive to exogenous Shh peptide and more sensitive to cyclopamine than CD34(-) cells (p < 0.05), implying cell-autonomous activation of Shh signaling play a predominant role in progenitor cells. Coactivation of Shh and β-catenin signaling was found in CD34(+) and c-kit(+) progenitor cells. Administration of Shh-neutralizing antibody or Wnt3a-neutralizing antibody in c-kit(+) progenitor cells induced cell apoptosis; however, Wnt3a peptide could salvage cell apoptosis, while Shh peptide failed to revert anti-Wnt3a-induced cell apoptosis. C-MYC, GLI1, BCL-2, and P21 were also found to be downstream targets of Shh signaling, mediating apoptosis or G(2)/M cell cycle arrest of progenitor cells. Our results demonstrate that autoactivated Shh signaling provides survival and proliferative cues in CML progenitor cells through downstream β-catenin signaling, suggesting a novel therapeutic approach in CML.

Tyrosine Kinase Inhibitor Imatinib Mesylate Induces Generalized Skin Hypopigmentation In Chinese Patients with Chronic Myelogenous Leukemia.

AbstractAbstract 4475Imatinib mesylate is a selective tyrosine kinase inhibitor targeting BCR-ABL fusion protein. In the therapy of either interferon refractory or newly diagnosed chronic myeloid leukemia (CML), imatinib significantly improved the prognosis of the disease, albeit with typically mild to moderate adverse effects. In recent years, increasing attention has been focused on the skin hypopigmentation developed after the initiation of imatinib therapy, especially in Asian countries such as India, with the incidence between 33% and 85%, though sparsely reported in western countries. The inhibition of c-kit by imatinib may be a possible explanation, but the exact mechanism for this hypopigmentation caused by imatinib and its potential risk in patients is poorly understood. Here we report our clinical observation of this side effect of imatinib therapy among Chinese CML patients in our institution, as well as a brief in vitro study aiming to investigate the mechanism of the hypopigmentory effect and evaluate its potential risk. Among 116 patients who took imatinib for CML therapy, 90 of them (77.6%) had reported to develop generalized hypopigmentation or whitening in the skin. This side effect usually developed within 3 months after initiation of imatinib, persistent during the therapy, and reversible upon imatinib discontinuation, according to our interviews and observation. More interestingly, in three of these CML patients who originally had vitiligo, the cosmetic appearance seemed to be improved during imatinib therapy due to the whitening effect on normal pigmented skin areas. To further confirm and understand this side effect, we examined the impact of imatinib on cultured normal human melanocytes derived from the foreskins of healthy Chinese adults. Melanocytes were treat with various concentrations of imatinib (1~16 μ M) for different periods of time (1~7 days). Cell proliferation and apoptosis were detected by cell counting kit-8 and flow cytometric assay, respectively. The melanogenic activity of the melanocytes was detected by melanin content assay and tyrosinase activity assay. Moreover, the role of stem cell factor (SCF) and its receptor c-kit in imatinib induced hypopigmentation were investigated. We found that imatinib not only concentration-dependently inhibited melanocyte proliferation in vitro (IC50=6.23 μ M), but also resulted in massive melanocyte apoptosis at concentrations higher than 8 μ M (P<0.01). Even at low concentrations (1-8 μ M), imatinib was able to cause decreases in total melanin content (P<0.05) and tyrosinase activity (P<0.05) which were responsible for skin pigmentation. In addition, imatinib (1-8 μ M) completely abrogated SCF (5 ng/ml) induced melanocyte proliferation (P<0.01) and melanogenesis (P<0.01), through the inhibition of the phosphorylation of c-kit receptor (Tyr 703 and Tyr 719) and the downstream signal transduction, which is pivotal for melanocyte proliferation and melanin synthesis after ultraviolet exposure. These results reveal that imatinib may cause destruction or dysfunction of melanocytes in patients through the inactivation of SCF/c-kit signaling, leading to inability of the skin to produce melanin and perform protection against ultraviolet radiation. Therefore, CML patients who take imatinib are necessarily to be warned for this side effect, and diminish the intensive exposure to sunlight. Although an ethnic or genetic basis for the prevalence difference can not be excluded yet, we tend to believe that the hypopigmentation effect of imatinib was probably underestimated in caucasian patients due to their light skin color. Since the melanocytes used in this study were all isolated from the skin samples of Chinese volunteers, further study may be done to determine whether the similar results can be achieved in primary melanocytes from other ethnic group. Disclosures:No relevant conflicts of interest to declare.

Characteristics of BCR–ABL kinase domain point mutations in Chinese imatinib-resistant chronic myeloid leukemia patients

To explore the characteristics of BCR-ABL kinase domain point mutations in Chinese chronic myeloid leukemia (CML) patients, a cohort of 127 patients with hematologic or cytogenetic resistance to imatinib are screened by direct sequencing. Mutations are found in 74 patients (58%). More patients with hematologic resistance show mutations compared to patients with cytogenetic resistance (70% vs 44%, p = 0.002), and more patients with acquired resistance present mutations compared to patients with primary resistance (68% vs 48%, p = 0.031). Frequencies of mutations were similar in early chronic phase (ECP), late chronic phase (LCP), accelerated phase, and blast phase (BP) patients (56%, 58%, 50%, and 69%, respectively; p > 0.05). Overall, 25 mutants are found in 21 amino acid sites, and four of them (I418V, E450A, E453L, and E455K) are first reported here. All patients with these four mutants either progress to or reenter the BP. The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255K, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance. ABL mutations are common in Chinese imatinib-resistant CML patients and are associated with clinical resistance. Chinese patients also seem to have unique profiles in the types and frequencies of some mutants, the disease phases of patients with T315I mutation, and the frequency of mutations in CP patients.

Efficacy and prognosis of chronic myeloid leukemia treated with imatinib mesylate in a Chinese population

There is limited data from developing countries on the current status of imatinib treatment for chronic myeloid leukemia (CML), thus we retrospectively analyzed 116 Chinese CML patients who received imatinib between 2003 and 2008. The response rates for 102 patients in chronic phase were: complete hematologic, 94.1%; complete cytogenetic, 69.6%; and complete molecular response, 54.9%. For 14 patients in the accelerated phase, the respective response rates were 85.7, 35.7 and 28.6%. The 3-year progression-free survival and 5-year overall survival were 73.3 and 74.8%. Although skin hypopigmentation occurs as the most common side effect (77.6%), imatinib is still well tolerated. In addition to the known pretreatment characteristics of spleen size, leukocyte and platelet counts, disease phase and Sokal scores, we found that delayed therapy, variant Philadelphia chromosome translocations and IM-related grade 3/4 leucopenia were associated with an inferior cytogenetic response. Four factors emerged as predictors of disease progression: molecular response, cytogenetic response, disease phase and disease duration prior to imatinib treatment, but only the latter three remained significant after multivariate analysis. The results indicate that the suboptimal outcome in Chinese patients is associated with delayed imatinib therapy, so the importance of the optimal treatment opportunity for CML should be emphasized.