The treatment of chronic myeloid leukemia (CML) was revolutionized with the advent of the first-generation tyrosine kinase inhibitors (TKIs), but drug resistance developed during treatment, leading to the development of the second-generation (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKI. Compared with previous treatment regimens, specific TKI can significantly improve the response rate, overall survival rate and prognosis of CML. Only a few patients with BCR-ABL mutation are insensitive to the second-generation TKIs, so it is suggested to select the second-generation TKIs for patients with specific mutations. For patients with other mutations and without mutations, the second-generation TKI should be selected according to the patient's medical history, while the third-generation TKIs should be selected for mutations that are insensitive to the second-generation TKIs, such as T315I mutation that is sensitive to ponatinib. Due to different BCR-ABL mutations in patients with different sensitivity to the second and third-generation TKIs, this paper will review the latest research progress of the efficacy of the second and third-generation TKIs in CML patients with BCR-ABL mutations.
Humans ; Antineoplastic Agents/pharmacology* ; Dasatinib/pharmacology* ; Drug Resistance, Neoplasm/genetics* ; Fusion Proteins, bcr-abl/genetics* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Mutation ; Protein Kinase Inhibitors/therapeutic use*

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.
Humans ; Male ; Adolescent ; Adult ; Female ; Protein Kinase Inhibitors/therapeutic use* ; Tyrosine Protein Kinase Inhibitors ; Treatment Outcome ; Retrospective Studies ; Dasatinib/therapeutic use* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Thrombocytopenia

OBJECTIVE: To analyze the efficacy and safety of flumatinib in the treatment of patients with chronic myeloid leukemia (CML). METHODS: The clinical data of 56 CML patients treated with flumatinib from January 2020 to December 2021 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. Patients were divided into three groups: 35 new diagnosed CML patients treated with flumatinib (group A), 10 patients with imatinib/dasatinib intolerance (group B) and 11 patients with imatinib/dasatinib resistance (group C) switched to flumatinib treatment, respectively. The molecular response and adverse effects of flumatinib treatment were evaluated. RESULTS: In group A, the early molecular response (EMR) at 3 months was 40.0%, and the major molecular response (MMR) at 6 and 12 months was 43.7% and 46.2%, respectively. In group B, the EMR was 50.0% at 3 months, and the MMR was 70.0% and 66.2% at 6 and 12 months, respectively. Among evaluable patients, 6 cases in group B achieved molecular response of 4.5 (MR4.5) at 12 months after switching to flumatinib treatment. In group C, 3 cases who switched from imatinib resistance to flumatinib achieved MR4.5 at 12 months, but 2 cases who switched from dasatinib resistance to flumatinib failed. Subgroup analysis showed significant differences in EUTOS long-term survival (ELTS) scores for patients in the medium-risk/high-risk group compared with those in the low-risk group for 3-month EMR (18.8% vs 57.9%), 6-month MMR (15.4% vs 63.2%) and 12-month MR4.5 (15.4% vs 69.2%) (P =0.036, P =0.012,P =0.015). The most common adverse effect in group A was thrombocytopenia, accounting for 54.5%, and 22.8% (8/35) patients discontinued the drug due to haematological adverse effects. Compared with patients who did not discontinue the drug or whose recovery time from discontinuation due to haematological toxicity was <1 month, patients whose recovery time from discontinuation was ≥1 month had a significantly worse 3-month EMR, 6-month MMR and 12-month MR4.5 (P =0.028, P =0.021, P =0.002). CONCLUSIONS Flumatinib has better molecular response and tolerance in patients with primary, imatinib/dasatinib-intolerant or resistant CML. Medium-risk/high-risk in ELTS score and time to recovery from discontinuation due to haematological toxicity ≥1 month are important factors influencing achievement of better molecular response in flumatinib treatment.
Humans ; Imatinib Mesylate/therapeutic use* ; Dasatinib/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use* ; Retrospective Studies ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Benzamides/therapeutic use* ; Chronic Disease ; Treatment Outcome ; Antineoplastic Agents/therapeutic use*

OBJECTIVE: To evaluate the efficacy of the second-line nilotinib and third-line dasatinib on chronic myelogenous leukemia (CML) with failed first- and second-line treatments, and analyze the influencing factors of the efficacy. METHODS: Selected 83 patients in The Third People's Hospital of Kunshan City, Jiangsu Province with CML who were treated with nilotinib as the second-line treatment after the failure of the first-line treatment with imatinib as the second-line treatment group (referred to as the second-line group) from January 2014 to December 2018, and 61 CML patients who were treated by dasatinib as the third-line treatment group (referred to as the third-line group) after the failure of the second-line treatment with nilotinib; the first-line treatment with imatinib failed, but due to various reasons, the patients were fully after being informed of the possible serious consequences of not changing the drug treatment, 37 CML patients who were still required to continue imatinib treatment served as the control group. The hematological, genetic and molecular responses of each group were compared for 3, 6, and 24 months of treatment. LogistiC regression was used to analyze the factors affecting the second and third line curative effects. RESULTS: The three groups had statistically significant differences in the rates of achieving CHR, MCyR, and MMR at 3, 6, and 12 months of treatment (P<0.05). Compared the two groups, the CHR rates of the second-line group at 3, 6, and 12 months of treatment were 100.00%, 97.59%, and 95.18%, respectively; higher than the third-line group's 90.16%, 86.89%, 83.61% and the control group's 83.78%, 75.68% and 72.97%; the CHR rate of the third-line group was higher than that of the control group at 6 and 12 months of treatment. The rates of reaching MCyR at 3, 6, and 12 months after treatment in the second-line group were 87.95%, 93.98% and 93.98%, respectively, while those in the third-line group were 80.33%, 88.52% and 86.89%, which were higher than those of the control group of 67.57%, 64.86% and 48.65%. The rates of achieving MMR at 3, 6, and 12 months of treatment in the second-line group were 19.28%, 33.72% and 60.24%, respectively, and those in the third-line group were 11.48%, 26.23% and 49.18%, which were higher than those of the control group of 0.00%, 2.70% and 0.00%; The rate of reaching MMR within 12 months of treatment in the second-line group was higher than that of the third-line group, and the differences was statistically significant (P<0.05). There was no significant difference in the rate of reaching MCyR between the second-line group and the third-line group at 3, 6, and 12 months, and the rate of reaching MMR at 3 and 6 months (P>0.05). The incidence of nausea and vomiting among the three main non-hematological adverse reactions, and the incidence of grade 1~2 anemia among the hematological adverse reactions were statistically significant (P<0.05). There was no significant difference in the incidence of rash, eyelid edema, diarrhea, thrombocytopenia, leukopenia and neutropenia in the three groups (P>0.05). The incidence of nausea and vomiting and grade 1~2 anemia in the second-line group and the third-line group were higher than that of the control group, and the difference was statistically significant (P<0.05). There were statistically significant differences in Sokal score, medication compliance, and hematological adverse reactions between the MMR group and the non-MMR group (P<0.05). Logistic regression analysis showed that dose reduction or withdrawal during the treatment period, and grade 3~4 hematological adverse reactions were the main factors affecting the second and third line curative effects (OR=22.160, 2.715, 95% CI=2.795-93.027, 1.882-48.834). CONCLUSION The second-line nilotinib and the third-line dasatinib have a better effect on CML patients who have failed the first and second-line treatments. Grade 3~4 hematological adverse reactions, dose reduction or withdrawal are risk factors that affect the efficacy of second and third-line treatments.
Antineoplastic Agents/therapeutic use* ; Dasatinib/therapeutic use* ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Protein Kinase Inhibitors/therapeutic use* ; Pyrimidines/therapeutic use* ; Treatment Outcome

Objective: To explore the impacts of socio-demographic and clinical co-variates on treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) and identified the predictive models for them. Methods: Data of newly diagnosed adult patients with CML-CP receiving first-line TKI and having complete socio-demographic data and clinical information were reviewed. Cox model was used to identify the independent variables associated with complete cytogenetic response (CCyR) , major molecular response (MMR) , molecular response 4 (MR(4)) and molecular response 4.5 (MR(4.5)) , as well as failure-free survival (FFS) , progression-free survival (PFS) , overall survival (OS) and CML-related OS. Results: A total of 1414 CML-CP patients treated with first-line imatinib (n=1176) , nilotinib (n=170) or dasatinib (n=68) were reviewed. Median age was 40 (18-83) years and 873 patients (61.7% ) were males. Result of the multivariate analysis showed that lower educational level (P<0.001-0.070) and EUTOS long-term survival intermediate or high-risk (P<0.001-0.009) were significantly associated with lower cumulative incidences of CCyR, MMR, MR(4) and MR(4.5), as well as the inferior FFS, PFS, OS and CML-related OS. In addition, those who were males, from rural households, had white blood cells (WBC) ≥120×10(9)/L, hemoglobin (HGB) <115 g/L and treated with first-line imatinib had significantly lower cumulative incidences of cytogenetic and/or molecular responses. Being single, divorced or widowed, having, rural household registration, WBC≥120×10(9)/L, HGB<15 g/L, and comorbidity (ies) was significantly associated with inferior FFS, PFS, OS, and/or CML-related OS. Thereafter, the patients were classified into several subgroups using the socio-demographic characteristics and clinical variables by cytogenetic and molecular responses, treatment failure and disease progression, as well as overall survival and CML-related OS, respectively. There were significant differences in treatment responses and outcomes among the subgroups (P<0.001) . Conclusion: Except for clinical co-variates, socio-demographic co-variates significantly correlated with TKI treatment responses and outcomes in CML-CP patients. Models established by the combination of independent socio-demographic and clinical co-variates could effectively predict the responses and outcome.
Adult ; Antineoplastic Agents/therapeutic use* ; Dasatinib/therapeutic use* ; Demography ; Humans ; Imatinib Mesylate/therapeutic use* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Male ; Protein Kinase Inhibitors/therapeutic use* ; Retrospective Studies ; Treatment Outcome

Objective: To evaluate the outcomes and identify the prognostic factors of childhood acute lymphoblastic leukemia (ALL) treated with Chinese Children's Cancer Group study ALL-2015 (CCCG-ALL-2015) protocol. Methods: There were two randomization studies in CCCG-ALL-2015 study. A total of 7 640 newly diagnosed ALL patients in 20 hospitals of multi-institutional study group between January 2015 and December 2019 were treated with unified protocol. CCCG-ALL-2015 protocol featured risk-directed therapy based on morphology, immunophenotype, and genetic features, and adjusted according to minimal residual disease (MRD) assay on day 19 and day 46 of induction, which totally omitted prophylactic cranial irradiation. Two randomized controlled trails were designed. Children with Philadelphia chromosome-positive ALL (Ph⁺ALL) were randomly treated with dasatinib (Ph-D group) or imatinib (Ph-I group). During the latter half of continuation therapy, children were randomly treated with seven pulses of vincristine plus dexamethasone (group A) or not (group B). The survival rates of different groups were compared. Event-free survival (EFS) and overall survival (OS) curves were estimated according to the Kaplan-Meier method and compared by Log-rank test. Cox proportional hazards model was used for multivariate analysis. Results: Of the 7 640 enrolled patients, there were 4 521 males and 3 119 females, 7 508 (98.3%) entered complete remission. The 5-year EFS was 60.1% (95%CI 49.8%-72.5%) in the Ph-D group and 39.4% (95%CI 26.9%-57.7%) in the Ph-I group (χ²=5.00, P=0.020). Between patients with lower risk (LR) and intermediate and higher risk (I/HR) treated with (group A) or without (group B) additional pulse of vincristine plus dexamethasone, there were no difference in 5-year EFS and OS. The one-sided 95% upper confidence bound for the difference in 5-year EFS and OS were 0.02 and 0.01 for LR, 0.05 and 0.01 for I/HR, establishing non-inferiority, lower than 0.05. The follow-up time was 3.5 (2.4,4.8) years. The 5-year OS was 90.9% (95%CI 90.2%-91.7%), and EFS was 80.1% (95%CI 79.0%-81.2%). The 5-year cumulative risk of any relapse was 15.3% (95%CI 14.3%-16.3%).The cumulative risk of isolated central nervous system (CNS) relapse was 1.9% (95%CI 1.6%-2.2%), and any CNS relapse 2.7% (95%CI 2.3%-3.1%). The 5-year cumulative risk of death during remission was 1.3% (95%CI 1.0%-1.6%). In the multivariate analysis, the independent factors associated with inferior EFS of patients with B-ALL were age≥10 years, male sex, white blood cell count ≥50×10⁹/L, CNS2 or CNS3 status, BCR-ABL fusion, KMT2A rearrangements, without ETV6-RUNX1 fusion and the presence of MRD>0.01% at day 19 or 46 (all P<0.05). Among patients with T-ALL, the significant predictors for lower EFS were the BCR-ABL1 fusion and MRD≥0.10% at day 46 (both P<0.05). Conclusions: Patients treated with CCCG-ALL-2015 protocol without the use of prophylactic cranial irradiation have favorable outcomes, and the cumulative risk of isolated CNS relapse and cumulative risk of death during remission are low. Intensive chemotherapy including dasatinib yield superior results compared to imatinib in the treatment of Ph⁺ALL. Vincristine plus dexamethasone pulses can be omitted for ALL children without decrease in treatment ontcome during the latter half of continuation therapy.
Antineoplastic Combined Chemotherapy Protocols ; Child ; China/epidemiology* ; Core Binding Factor Alpha 2 Subunit ; Dasatinib/therapeutic use* ; Dexamethasone/therapeutic use* ; Disease-Free Survival ; Female ; Humans ; Imatinib Mesylate/therapeutic use* ; Male ; Neoplasm, Residual ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Prognosis ; Recurrence ; Treatment Outcome ; Vincristine/therapeutic use*

OBJECTIVE: To study the influence of dasatinib treatment on body height in children with acute myeloid leukemia (AML). METHODS: A retrospective analysis was performed for the clinical data of 86 AML children aged <17 years. According to the treatment regimen, these children were divided into a conventional chemotherapy group and a dasatinib chemotherapy group. The 57 children in the conventional chemotherapy group were given conventional chemotherapy drugs without tyrosine kinase inhibitor, and the 29 children in the dasatinib chemotherapy group were given conventional chemotherapy drugs and dasatinib. The two groups were compared in terms of height standard deviation score (HtSDS) at the beginning of treatment and after treatment, as well as the change in HtSDS after 1 and 2 years of treatment. RESULTS: There was no significant difference in HtSDS between the conventional and dasatinib chemotherapy groups before treatment. Within the first two years of treatment, the dasatinib chemotherapy group had a similar change trend of HtSDS as the conventional chemotherapy group. Four children in the dasatinib chemotherapy group reached the final adult height during follow-up, which was significantly lower than the target height (P=0.044). In the conventional chemotherapy group, there was no significant difference between final adult height and target height. In the dasatinib chemotherapy group, the children in adolescence had a significant change in HtSDS after treatment (P=0.032). CONCLUSIONS Dasatinib treatment may affect the final height of children with AML, and the use of dasatinib after the beginning of adolescence may lead to growth disorder, but dasatinib treatment has little effect on body height in the short-term treatment.
Adolescent ; Body Height ; Child ; Dasatinib ; therapeutic use ; Growth Disorders ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Retrospective Studies

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and characterized by the formation of Philadelphia (Ph) chromosome. Recently, tyrosine kinase inhibitors (TKI) treatment greatly improved the prognosis of CML. However, the options may be limited when a patient develops traditional TKI resistance or gene mutation. Herein, we reported a case. A 38-year-old male CML patient developed a BCR-ABL1 gene mutation of T315I after 2.5 years of TKI treatment, including imatinib and dasatinib. We adjusted the treatment with the combined application of dasatinib and axitinib. BCR-ABL1 gene copies dropped down and achieved an early molecular response at 2 months later. Subsequently, he received hematopoietic stem cell transplantation. Axitinib and dasatinib were applied for another half year after the allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two years after the allo-HSCT, the BCR-ABL1 gene was still undetectable. It provided a successful example in treating CML patients carrying BCR-ABL1 T315I mutation via combination of axitinib with conditional TKI.
Adult ; Axitinib ; Dasatinib ; therapeutic use ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; Male ; Mutation ; Protein Kinase Inhibitors ; therapeutic use

Objective: To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) . Methods: From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed. Results: A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved The efficacy of dasatinib and nilotinib as second- or third-line TKI-therapy were active in the CML patients with TKI-resistance. The best response achieved on previous TKI-therapy, the disease phase before switching TKI, and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.
Dasatinib/therapeutic use* ; Female ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Pyrimidines/therapeutic use* ; Retrospective Studies ; Treatment Outcome

Objective: To investigate the efficiency and safety of domestic tyrosine kinase inhibitor (TKI) dasatinib (Yinishu) as second-line treatment for patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods: A retrospective analysis of clinical data of CML-CP patients who received domestic dasatinib as second-line treatment in the CML collaborative group hospitals of Hubei province from March 2016 to July 2018 was performed. The optimal response rate, the cumulative complete cytogenetic response (CCyR), the cumulative major molecular responses (MMR), progression free survival (PFS), event free survival (EFS) and adverse effects (AEs) of the patients were assessed at 3, 6 and 12 months of treatment. Results: A total of 83 CML-CP patients were enrolled in this study. The median follow-up time was 23 months. The optimal response rates at 3, 6 and 12 months in 83 CML-CP patients treated with dasatinib were 77.5% (54/71), 72.6% (61/75) and 60.7% (51/69), respectively. By the end of follow-up, the cumulative CCyR and MMR rates were 65.5% (55/80) and 57.1% (48/73), respectively. The median time to achieving CCyR and MMR was 3 months. During follow-up time, the PFS rate was 94.0% (79/83) and the EFS rate was 77.4% (65/83). The most common non-hematological AEs of dasatinib were edema (32.5%), rash itching (18.1%) and fatigue (13.3%). The common hematological AEs of dasatinib were thrombocytopenia (31.3%), leukopenia (19.3%) and anemia (6.0%). Conclusion: Domestic dasatinib was effective and safe as the second-line treatment of CML-CP patients and it can be used as an option for CML-CP patients.
Antineoplastic Agents ; Dasatinib/therapeutic use* ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Protein Kinase Inhibitors ; Retrospective Studies ; Treatment Outcome