Response to Tyrosine Kinase Inhibitors in Patients with BCR-ABL1 Positive Chronic Myeloid Leukemia; 13.5 Years’ Experience at Patan Hospital, Nepal

Background:Since the advent of Tyrosine Kinase Inhibitor (TKI), well controlled studies in developed world have shown that the life expectancy of patients with CML is comparable to normal people without the disease. But long-term follow up studies are lacking in resource poor setting. Methods:This is a retrospective follow up study looking at the molecular response and resistance to Tyrosine Kinase Inhibitors (TKI) in patients enrolled in the Max Access Program since February 2003 till March 2017. Patients with twoor more BCR-ABL1 levels by Karyotyping/ fluorescent in situ hybridization (FISH) / reverse transcriptase polymerase chain reaction (RT-PCR) were included. At baseline, complete blood count (CBC), renal function test (RFT), and liver function test (LFT) were evaluated. Bone marrow aspiration and biopsy for morphology, cytogenetic analysis by Karyotyping/FISH and/or molecular analysis by RT-PCR were also done if these tests were not performed earlier. FISH or RT-PCR was done on peripheral blood every 3–12 months as necessary if the patient could afford. Patients with warning response/failure underwent BCR-ABL1 Resistance Mutation Analysis (IRMA).Results:Three hundred and forty six (346) patients had two or more BCR-ABL1 monitoring tests done. Optimal response was seen in 49.42%. Similarly, suboptimal response and failure were seen in 16.5% and 34% respectively. Overall Survival is 89.6% (at 1.8 -165 months, mean 62 months) . If only CML related events is considered survival is 95.9%. Seventy seven (77) patients with a total of 80 BCR-ABL1 domain Imatinib Resistance Mutation Analyses (IRMA) showed 19 different types of mutations with the most common being T315I mutation (8 and 19.5%). About 22.25% of the total patients showed resistance to Glivec out of which 10.98% showed mutations. Nine patients underwent trial for treatment free response (TFR) and 5 of them relapsed between 2-8 months.Conclusions:Despite all the odds of having financial problem, accessibility problem due to distances, transportation, etc. and difficulty monitoring with routine BCR-ABL1 and IRMA, our findings show that the outcome of TKI therapy in our CML patients is comparable to well controlled studies done elsewhere. Overall survival, molecular and cytogenetic responses and mutations in our patients who developed resistance as well as TFR are also similar to other studies. The resistance rate of 22.25% is slightly higher compared to other studies in developed world. This is mainly because of poor monitoring due to unavailability of the test including IRMA in our country and affordability until 2012. It proves that TKI is very effective in CML even in a resource-poor, developing country

Development and validation of liquid chromatography-tandem mass spectrometry method to quantify dasatinib in plasma and its application to a pharmacokinetic study

Abstract Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice.

Dasatinib-Related Pulmonary Toxicity / Toxicidad pulmonar por dasatinib

ABSTRACT 70-year-old male patient with chronic myeloid leukemia receiving treatment with dasatinib develops respiratory failure associated with pulmonary toxicity related to such drug.

RESUMEN Paciente de sexo masculino, 70 años, con leucemia mieloide crónica en tratamiento con dasatinib, desarrolla insuficiencia respiratoria asociada a toxicidad pulmonar por dicho fármaco.

Toxicidad pulmonar por dasatinib / Dasatinib-Related Pulmonary Toxicity

Paciente de sexo masculino, 70 años, con leucemia mieloide crónica en tratamiento con dasatinib, desarrolla insuficiencia respiratoria asociada a toxicidad pulmonar por dicho fármaco.

70-year-old male patient with chronic myeloid leukemia receiving treatment with da satinib develops respiratory failure associated with pulmonary toxicity related to such drug.

Analysis of the Curative Effect and Influencing Factors of Nilotinib Second-line and Dasatinib Third-line on Chronic Myelogenous Leukemia Failed First-line and Second-line Treatment / 中国实验血液学杂志

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.

Preparation and characterization of dasatinib albumin micelles / 中国药科大学学报

@#In this study, a polyethylene glycol and dodecaldehyde modified bovine serum albumin (PEG-DSA) was developed, and its feasibility as a new high-efficiency micellar carrier for dasatinib (DAS) was explored.Circular dichroism, 1H NMR, elemental analysis, FT-IR and other methods were used to characterize the material structure and the single factor method was used to optimize the process of PEG-DSA/DAS micelles and non-PEGylated control micelles DSA/DAS.The results indicated that the optimal formulation was obtained with a mass ratio of 4∶1 between PEG-DSA and DAS, with average particle size of (37.21 ± 0.21) nm, polydispersion index (PDI) of (0.24 ± 0.04), Zeta potential of ? (15.68 ± 0.19) mV, drug loading (DL) capacity of (10.22 ± 0.34) %, and encapsulation efficiency (EE) of (42.73 ± 1.15) %. Compared with the currently reported nano-formulations of DAS, the drug loading of PEG-DSA/DAS micellar formulations was significantly increased with potential for further development.

Efficacy of second-line therapy with dasatinib in the treatment of chronic myeloid leukemia / 中国基层医药

Objective:To investigate the clinical efficacy of second-line therapy with dasatinib in the treatment of chronic myeloid leukemia.Methods:Sixty patients with chronic phase chronic myeloid leukemia who received treatment in Hongqi Hospital of Mudanjiang Medical University between January 2015 and January 2021 were included in this study. They were randomly divided into control and observation groups, with 30 patients in each group. The control group was treated with conventional chemotherapy, and the observation group was treated with conventional chemotherapy combined with oral dasatinib. All patients were treated for 6 months. Clinical efficacy, immune function indexes, quality of life score, and incidence of adverse reactions (abnormal liver function, rash, fatigue, peripheral edema, nausea and vomiting, alopecia) were compared between the two groups.Results:Objective response rate (ORR) in the observation group was significantly higher than that in the control group [83.33% (25/30) vs. 53.33% (16/30), χ2 = 6.23, P < 0.05). Before treatment, there were no significant difference in immune function indicators between the two groups ( t = 0.03, 0.20, 0.44, all P > 0.05). After treatment, CD 4/CD 8, CD 3+ and natural killer cells in the observation group were (1.03 ± 0.32), (43.77 ± 6.62)%, (31.12 ± 3.38)%, respectively, which were significantly higher than (0.74 ± 0.28), (35.79 ± 6.27)%, (28.22 ± 2.84)% in the control group ( t = 3.69, 4.78, 3.60, all P < 0.05). The scores of social functioning, material well-being life, mental health, somatic health in the observation group were (85.48 ± 6.25) points, (80.12 ± 6.34) points, (79.94 ± 6.48) points, and (77.92 ± 5.81) points, respectively, which were significantly higher than (72.79 ± 5.89) points, (63.47 ± 5.82) points, (68.87 ± 6.08) points, (63.14 ± 6.12) points in the control group ( t = 7.91, 10.59, 6.82, 9.59, all P < 0.05). The incidence of adverse reactions in the observation group was significantly lower than that in the control group [16.67% (5/30) vs. 40.00% (12/30), χ2 = 4.02, P < 0.05). Conclusion:Second-line therapy with dasatinib for chronic phase chronic myeloid leukemia is effective and safe. It can effectively improve the efficacy and safety of chemotherapy and can also improve immunological function and quality of life.

Effects of Dasatinib on the Maturation of Monocyte-Derived Dendritic Cells Derived from Healthy Donors and Chronic Myelogenous Leukemia Patients / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of dasatinib on the maturation of monocyte-derived dendritic cells (moDCs) derived from healthy donors (HDs) and chronic myelogenous leukemia (CML) patients.@*METHODS@#Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=10) and CML patients (n=10) who had got the remission of MR4.5 with imatinib treatment. The generation of moDCs from PBMCs was completed after 7 days of incubation in DC I culture medium, and another 3 days of incubation in DC II culture medium with or without 25 nmol/L dasatinib. On the 10th day, cells were harvested and expression of molecules of maturation related marker were assessed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as DCs in the fluorescence-activated cell storting (FACS) analyzing system, then the expression of CD83, CD40 or HLA-DR in this population was analyzed respectively.@*RESULTS@#The proportion of CD80+CD86+ cells in total cells didn't show a statistical difference between HD group and patient group (89.46%±9.70% vs 87.39%±9.34%, P=0.690). Dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.008) and HLA-DR (P=0.028) on moDCs derived from HDs compared with the control group, while the expression of CD83 on moDCs didn't show a significant difference between dasatinib group and the control group (P=0.428). Meanwhile, dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.023), CD83 (P=0.038) and HLA-DR (P=0.001) on moDCs derived from patients compared with the control group.@*CONCLUSION@#For CML patients, the same high proportion of moDCs as HDs can be induced in vitro, which provides a basis for the application of DC-based immunotherapy strategy. Dasatinib at the concentration of 25 nmol/L can efficiently promote the maturation of moDCs derived from HDs and CML patients in vitro. Dasatinib shows potential as a DC adjuvant to be applied in DC-based immunotherapy strategies, such as DC vaccine and DC cell-therapy.

Combination of axitinib with dasatinib improves the outcome of a chronic myeloid leukemia patient with BCR-ABL1 T315I mutation / 中南大学学报(医学版)

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.

Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase / 中华血液学杂志

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 <CHR on the first-line TKI-therapy, the interval from diagnosis to switching to second-line TKI ≥18 months, AP or hematologic failure, or non-specific mutation of BCR-ABL kinase domain before second-line TKI therapy, developing severe hematologic toxicity during the second-line TKI therapy were variables associated with poor responses or outcomes on second-line TKI therapy. With a median follow-up of 6 (range, 3-129) months, the cumulative CHR, CCyR and MMR were 95.7%, 29.3%, and 18.6%, respectively in those receiving the third-line TKI therapy. The 2-year PFS and OS rates were 66.8% and 93.8%, respectively. The patients with an interval from diagnosis to starting TKI ≥6 months, achieving no cytogenetic response on the second-line TKI, the interval from diagnosis to starting second-line TKI ≥60 months, and progression to AP before the third-line TKI therapy had lower probabilities of responses and unfavorable outcomes.@*Conclusions@#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.

¿Qué resultados logran los pacientes que cursan con leucemia mieloide crónica actualmente? / What results do patients who currently have chronic myeloid leukemia achieve?

Resumen: ANTECEDENTES: La leucemia mieloide crónica es una neoplasia mieloproliferativa; los inhibidores de tirosin cinasa son fármacos eficaces en el tratamiento de esta enfermedad, en el ISSSTE se cuenta con imatinib, nilotinib y dasatinib. OBJETIVOS: Conocer el número de casos de leucemia mieloide crónica de 2005 a 2016, identificar las características clínicas, medir el grado de respuesta y la supervivencia. MATERIAL Y MÉTODO: Estudio retrospectivo, transversal, observacional y explicativo, efectuado de 2005 a 2016, en el que se incluyeron pacientes mayores de 18 años de edad, con diagnóstico de leucemia mieloide crónica, con cualquier fase de la enfermedad y en tratamiento con cualquiera de los inhibidores de tirosin cinasa. RESULTADOS: Se incluyeron 31 casos (55.2% mujeres); la mediana de edad fue 62 años. El 72.4% estaba en fase crónica, 27.6% en fase acelerada y ninguno en fase blástica. La respuesta hematológica fue de 94.1, 90 y 96%; la respuesta citogenética completa a 12 meses fue de 69.2, 60 y 57%; la respuesta molecular mayor se documentó en 62.9, 68.6 y 69.1% para imatinib, nilotinib y dasatinib, respectivamente. La supervivencia libre de enfermedad en este grupo a cinco años fue de 83%. La supervivencia global a cinco años fue de 94%. CONCLUSIONES: Independientemente del inhibidor prescrito se logran respuestas hematológicas superiores a 90%, citogenéticas completas en alrededor de 60% a 12 meses y moleculares mayores de 60% en un hospital del ISSSTE.

Abstract: BACKGROUND: Chronic myeloid leukemia is a myeloproliferative disease; the most effective drugs in the treatment of this disease are imatinib, nilotinib and dasatinib. Those drugs are available at the ISSSTE. OBJECTIVES: To know the number of chronic myeloid leukemia cases, to identify the clinical characteristics and to measure the degree of response to tyrosine kinase inhibitors and the survival. MATERIAL AND METHOD: A retrospective, cross-sectional, observational and explanatory study was done from 2005 to 2016, including patients over 18 years of age, with a diagnosis of chronic myeloid leukemia; with any of the three phases of the disease and treatment with any of the tyrosine kinase inhibitors. RESULTS: There were included 31 cases (55.2% women); the median age was 62 years; 72.4% were in chronic phase, 27.6% in accelerated phase and none in the blast phase. The haematological response was of 94.1%, 90% and 96%; the complete cytogenetic response at 12 months was of 69.2%, 60% and 57% and the mayor mo- lecular response was of 62.9%, 68.6%, 69.1% of the patients treated with imatinib, nilotinib or dasatinib, respectively. Disease-free survival at 5 years was of 83% and global survival at 5 years was of 94%. CONCLUSION: Independently of the inhibitor prescribed, the hematologic response is achieved in more than 90%, the complete cytogenetics around 60% at 12 months and major molecular almost 60% in a ISSSTE hospital.

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

ABSTRACT Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

Management of chronic myeloid leukemia during pregnancy: a retrospective analysis at a single center

ABSTRACT We analyzed the management and outcomes of pregnancies of patients with chronic myeloid leukemia at a single center over fifteen years. Among the 203 CML female patients, there were ten pregnancies in seven women, all of them not planned. In three cases, the chronic myeloid leukemia diagnosis was made during pregnancy. Five patients received tyrosine kinase inhibitors in the first weeks of pregnancy and the drug was interrupted until delivery. One patient lost complete cytogenetic response, and two patients lost the hematological response. A patient with a stable major molecular response had two successful pregnancies without loss of response. There were four premature births. There were no maternal adverse events, fetal malformation or death. All patients received Interferon-alpha during gestation, and two received hydroxyurea for a short period. Leukapheresis was performed in two patients for hyperleukocytosis control. One patient with sickle cell disease died from disease progression six months after delivery. Conclusions: The tyrosine kinase inhibitors ministration should be interrupted during pregnancy. Patients should be advised to achieve a stable and deep molecular response if they plan to conceive, to avoid the risk of disease progression.

Paediatric chronic myeloid leukaemia: Is it really a different disease?

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.

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

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.

miR-103 targets PTEN to promote dasatinib resistance in lung cancer A549 cells via activating PI3K/AKT pathway / 中国肿瘤生物治疗杂志

@#Objective: To explore the mechanism of miR-103 targeting PTEN (gene of phosphate and tension homology deleted on chromsome ten) and activating PI3K/AKT signaling pathway to promote dasatinib (DASA) resistance in lung cancer cells. Methods: DASA-resistant tissues and non-resistant tissues (35 samples for each) from patients treated in Department of Thoracic Surgery, the First Affiliated Hospital of Kunming Medical University from April 2014 to January 2018 were collected for this study. Expression of miR-103 was detected in DASA-resistant tissues and cell lines of lung cancer by quantitative Real-time polymerase chain reaction (qPCR). The effect of miR-103 knock-down on the proliferation, invasion and epithelial mesenchymal transition (EMT) ofA549/DASA cells were measured by CCK-8 assay, Transwell and Wb, respectively. Subsequently, the dual luciferase reporter gene assay was used to verify whether PTEN was a target gene of miR-103. CCK-8, Transwell and Wb assay were further used to investigate the effect of miR103 on malignant biological behaviors of A549/DASA cells via regulating PTEN-PI3K/AKT signaling pathway. Results: miR-103 was highly expressed in DASA-resistant tissues andA549/DASAcells (P<0.01). Knockdown of miR-103 significantly inhibited the proliferation, invasion and EMT ofA549/DASAcells (P<0.05 or P<0.01).Additionally, dual luciferase reporter gene assay confirmed that miR103 directly targeted PTEN and down-regulated its expression (P<0.01). Mechanistically, over-expression of miR-103 targeted and down-regulated PTEN to promote cell viability, invasion and EMT via activating PI3K/AKT pathway (P<0.05 or P<0.01), and further up-regulated the DASA-resistance inA549/DASAcells. Conclusion: miR-103/PTEN/PI3K/AKT signaling pathway plays a certain role in regulating DASA resistance of lung cancer, and knockdown of miR-103 expression may reverse the resistance of A549/DASA cells to DASA.

Depigmentation in a Patient with Chronic Myeloid Leukemia during Chemotherapy with Dasatinib / 대한피부과학회지

No abstract available.

Efficacy and safety of domestic dasatinib as second-line treatment for chronic myeloid leukemia patients in the chronic phase / 中华血液学杂志

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.

Clinical effect and safety of dasatinib combined with Chinese Children's Leukemia Group-acute lymphoblastic leukemia 2008 protocol in treatment of childhood Philadelphia chromosome-positive acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective@#To investigate the clinical effect and safety of dasatinib combined with Chinese Children's Leukemia Group-acute lymphoblastic leukemia (CCLG-ALL) 2008 protocol in treatment of childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).@*Methods@#The clinical data of 22 patients with Ph+ ALL who were newly diagnosed at the age of less than 15 years old in Fujian Medical University Union Hospital from January 2014 to December 2018 were retrospectively analyzed. All patients were treated with dasatinib combined with CCLG-ALL2008 protocol (high-risk group). The patients were assigned to two groups according to different starting times of oral dasatinib: the dasatinib-induced group (starting from day 15 of induction chemotherapy) and the dasatinib-consolidated group (starting with early consolidated chemotherapy). The early treatment response and 5-year event-free survival (EFS) rate were compared between the two groups.@*Results@#The differences of clinical characteristics and early efficacy of chemotherapy before treatment of dasatinib between the two groups were not statistically significant (both P > 0.05). The complete remission (CR) rate on day 33 of induction chemotherapy was higher in the dasatinib-induced group than that in the dasatinib-consolidated group [100% (10/10) vs. 75% (9/12)], but the difference was not statistically significant (χ 2= 2.895, P= 0.221). The rate of minimal residual disease (MRD) turned negative (<0.01%) on day 33 of induction chemotherapy in the dasatinib-induced group was significantly higher than that in the dasatinib-consolidated group [70% (7/10) vs. 17% (2/12)], and the difference was statistically significant (χ 2= 6.418, P= 0.027). The 3-year EFS rate was higher in the dasatinib-induced group than that in the dasatinib-consolidated group (88.9% vs. 63.5%), but the difference was not statistically significant (P= 0.163). The incidence of grade 3-4 infection in the dashatinib-induced group was lower than that in the dasatinib-consolidated group, and the difference was statistically significant [60% (6/10) vs. 100% (12/12), P= 0.029]. the other grade 3-4 adverse reactions related to the chemotherapy drugs mainly included hematological toxicity, diarrhea, abnormal liver function, edema and pleural effusion, but there was no significant difference between the two groups (all P > 0.05).@*Conclusions@#Dasatinib combined with CCLG-ALL2008 protocol in the treatment of children with Ph+ ALL has good efficacy and safety. Furthermore, the early use of dasatinib on day 15 of induction chemotherapy can enable patients to achieve deeper remission earlier and improve long-term efficacy.

Hipertensión pulmonar reversible y derrame pericárdico severo secundario a uso dasatinib: Reporte de caso / Reversible pulmonary hypertension and pericardial effusion secondary to use of dasatinib. Case report

Dasatinib es un potente inhibidor de la tinosina kinasa utilizado como tratamiento de segunda línea en pacientes con leucemia mieloide crónica, especialmente cuando se desarrolla resistencia o algún tipo de intolerancia a imatinib. A pesar de la aparente selectividad, pueden producirse efectos secundarios significativos. Los derrames pericárdicos son complicaciones frecuentes, que usualmente necesitan reducir la dosis o discontinuar el tratamiento. Por otro lado, la hipertensión pulmonar es un efecto adverso poco frecuente que puede aparecer a los 8 meses del inicio de la terapia. A continuación se presenta el caso de un paciente de 82 años que desarrolla derrame pericárdico crónico e hipertensión pulmonar reversible tras reducción de la dosis de Dasatinib.

Dasatinib is a potent tyrosine kinase inhibitor used as second line treatment for patients with chronic myeloid leukemia, particularly when resistance or some type of intolerance to imatinib has built up. Despite its apparent selectivity it can have significant side effects. Pericardial effusions are frequent complications and usually require dose reduction or treatment discontinuation. On the other hand, pulmonary hypertension is an infrequent side effect which may appear 8 months after initiating treatment. In the following we present the case of an 82 year old who developed a chronic pericardial effusion and pulmonary hypertension which were reversed upon reducing the dasatinib dose.