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

Nilotinib-loaded gelatin methacryloyl microneedles patch for the treatment of cardiac dysfunction after myocardial infarction / 生物医学工程学杂志

The study aimed to evaluate the therapeutic effect of nilotinib-loaded biocompatible gelatin methacryloyl (GelMA) microneedles patch on cardiac dysfunction after myocardial infarction(MI), and provide a new clinical perspective of myocardial fibrosis therapies. The GelMA microneedles patches were attached to the epicardial surface of the infarct and peri-infarct zone in order to deliver the anti-fibrosis drug nilotinib on the 10th day after MI, when the scar had matured. Cardiac function and left ventricular remodeling were assessed by such as echocardiography, BNP (brain natriuretic peptide) and the heart weight/body weight ratio (HW/BW). Myocardial hypertrophy and fibrosis were examined by WGA (wheat germ agglutinin) staining, HE (hematoxylin-eosin staining) staining and Sirius Red staining. The results showed that the nilotinib-loaded microneedles patch could effectively attenuate fibrosis expansion in the peri-infarct zone and myocardial hypertrophy, prevent adverse ventricular remodeling and finally improve cardiac function. This treatment strategy is a beneficial attempt to correct the cardiac dysfunction after myocardial infarction, which is expected to become a new strategy to correct the cardiac dysfunction after MI. This is of great clinical significance for improving the long-term prognosis of MI patients.

Mining and analysis of adverse drug events signals of nilotinib based on FDA adverse event database / 中国药房

OBJECTIVE To provide a reference for safe drug use in clinic. METHODS ADE reports related to nilotinib from the first quarter of 2007 to the fourth quarter of 2022 were collected from the US FDA adverse event reporting system database. The reporting odds ratio （ROR） and proportional reporting ratio （PRR） of disproportionality measures were used to mine potential ADE signals，which were compared with drug instruction and related case report， and were screened and analyzed according to the designated medical events （DME） list formulated by the European Medicines Agency. RESULTS Totally 23 332 cases of ADE with nilotinib as the primary suspected drug were reported. A total of 359 positive signals were obtained，involving 24 system organ classes （SOC），mainly concentrated in various examinations，heart organ diseases，vascular and lymphatic diseases，all kinds of nervous system diseases，etc. Among them，ADEs such as vertebral artery stenosis，coronary artery stenosis，arterial disease，liver infection and the second primary malignant tumor were not mentioned in the instructions. Seven DMEs were detected，of which bone marrow failure，pulmonary hypertension and deafness were not mentioned in the drug instruction. CONCLUSIONS The common ADE signals of nilotinib excavated in this study are consistent with the instructions. In clinical use，special attention should be paid to DME not mentioned in the instructions such as bone marrow failure，pulmonary hypertension and deafness； cardiac function， blood glucose and blood lipid indexes should be monitored closely.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

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.

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.

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.

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.

Comparison of nilotinib vs imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase / 中华血液学杂志

Objective: To compare the cytogenetic and molecular responses, outcomes and severe hematologic toxicity of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) . Methods: Newly diagnosed CML-CP patients were consecutively recruited from January 2006 to December 2018 who received nilotinib and imatinib as first-line treatment. Clinical data were retrospectively analyzed. Results: A total of 524 patients were classified into 439 (83.8%) receiving imatinib and 85 (16.2%) receiving nilotinib. Comparing with imatinib group, patients in nilotinib group were much younger (P=0.019) and more with intermediate and high Sokal risks (P<0.001) , WBC ≥100×10(9)/L (P<0.001) , HGB<120 g/L (P<0.001) , blast cells in bone marrow (P=0.026) , splenomegaly (P<0.001) by physical examination at diagnosis, and longer interval from diagnosis to TKI treatment (P=0.003) . With a median TKI duration of 57 (range 3-153) months, the probabilities of complete cytogenetic response (CCyR) (P=0.011) , major molecular response (MMR) (P=0.001) and MR(4.5) (P=0.046) were much higher in nilotinib group than those in imatnib according to each risk group. There is no statistical significance on probabilities of failure free survival (FFS) , progression free survival (PFS) and overall survival (OS) at 6 years between the two groups. Multivariate analyses showed that imatinib was an adverse factor associated with achieving CCyR (OR=0.6, 95% CI 0.5-0.8, P=0.001) , MMR (OR=0.6, 95% CI 0.5-0.9, P=0.032) and MR(4.5) (OR=0.6, 95%CI 0.5-0.9, P=0.032) and poor FFS (OR=1.9, 95%CI 1.0-3.4, P=0.041) . In addition, Sokal score was an independent factor affecting cytogenetic and molecular responses, treatment failure, disease progression and survival. Male, WBC ≥100×10(9)/L or HGB<120 g/L at diagnosis were significantly associated with lower cytogenetic and molecular response rates and/or poor FFS. The severe hematologic adverse events were not associated with different TKIs. Conclusions: Nilotinib reaches to the faster and deeper cytogenetic and molecular responses and significantly improves FFS than imatinib in newly diagnosed patients with CML-CP.

Effect of nilotinib on pregnancy outcome in female patients with chronic myeloid leukemia / 中华血液学杂志

Objective: To observe the pregnancy outcome among patients with chronic myeloid leukemia (CML) treated with Nilotinib (NIL) . Methods: Clinical data of pregnancy delivery in CML patients treated with NIL from March 2015 to January 2019 were retrospectively collected. Results: A total of 11 patients were recruited with median pregnancy age 28 (25-40) years. The median duration of NIL treatment before pregnancy was 34 (3-48) months. There were 12 pregnancies, included 2 planned ones and 10 (83.3%) unplanned. In the 10 unplanned patients, 9 (90.0%) received NIL 600 mg/d. The median exposure time were 4 (4-7) weeks. In eight patients with delivery outcomes, 5 cases had well-developed babies, 2 had spontaneous abortion and 1 case with an baby of syndactyly deformity, whose mother was exposed to NIL 600 mg/d for 7 weeks in the early trimester of pregnancy. Seven infants were 4 boys and 3 girls with the median height at birth 50 (41-54) cm and median weight 3.2 (3.0-4.6) kg. They all grew with a normal pattern and well developed. Now the median age is 19 (4-41) months. The disease status during 12 pregnancies included 3 cases in CMR, 2 cases in MR(4.0), 3 cases in MMR, 4 cases not acquiring MMR. The median time of drug discontinuation was 35 (15-36) weeks during pregnancy. No patient lost CHR during this period. Conclusions: Female CML patients exposed to NIL 600 mg/d for 4 weeks in early pregnancy can give birth to normal babies, but there is still a risk of spontaneous abortion and congenital malformations.

Effect of nilotinib on silicon dioxide-induced proliferation and collagen synthesis in HFL-1 cells / 中国职业医学

OBJECTIVE: To observe the effects of nilotinib on silicon dioxide(SiO_2)-induced cell proliferation and collagen synthesis in human fetal lung fibroblast-1(HFL-1) cells and to explore the related mechanism. METHODS: ⅰ) HFL-1 cells were induced with different doses of SiO_2 suspension(0, 5,10, 25, 50 and 100 mg/L) for 24.0 hours. The expression of transforming growth factor-β1(TGF-β1), C-Abl, and platelet-derived growth factor receptor(PDGFR) was detected by Western blot, and the dose of SiO_2 in subsequent experiments was screened. ⅱ) HFL-1 cells were randomly divided into 6 groups: 1) the control group: no treatment; 2) the solvent control group: cells were treated with 0.10% dimethyl sulfoxide; 3) the SiO_2 stimulation group: cells were induced with SiO_2 suspension at a dose of 50 mg/L for 24.0 hours; 4)-6) the nilotinib groups: cells were induced with SiO_2 suspension at a dose of 50 mg/L for 24.0 hours and treated with nilotinib at the concentration of 5, 10, or 15 mmol/L for 24.0 hours. Cell proliferation was detected by MTS assay. The TGF-β1 protein secreted by cells was measured using enzyme linked immunosorbent assay. The expression of TGF-β1, C-Abl, platelet derived growth factor(PDGF), PDGFR and collagen typeⅠproteins was measured by Western blot. RESULTS: ⅰ) The dose of the SiO_2 in the experiments was set to 50 mg/L. ⅱ) The cell proliferation rate of HFL-1 cells in the SiO_2 stimulation group and the 3 nilotinib groups was higher than that in control group and solvent control group(P<0.05). The proliferation rates of HFL-1 cells in 10 and 15 mmol/L nilotinib groups were lower than that in SiO_2 stimulation group(P<0.05). The level of TGF-β1 and the protein relative expression levels of TGF-β1, collagen typeⅠ, C-Abl, PDGFR and PDGF in HFL-1 cells of SiO_2 stimulation group were higher than those in control group and solvent control group(P<0.05). The above indexes of HFL-1 cells in 15 mmol/L nilotinib group were lower than that in SiO_2 stimulation group(P<0.05); the above indexes of HFL-1 cells in 5 mmol/L nilotinib group were not significantly different from those in SiO_2 stimulation group(P>0.05). The level of TGF-β1 and the relative expression level of C-Abl protein in HFL-1 cells of 10 mmol/L nilotinib group were lower than those in SiO_2 stimulation group(P<0.05). CONCLUSION: Nilotinib can inhibit the proliferation of HFL-1 cells and reduce the expression of collagen typeⅠprotein induced by SiO_2. This process may be achieved by inhibiting tyrosine kinase-mediated signaling pathway.

Comparison of nilotinib vs imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase / 中华血液学杂志

Objective@#To compare the cytogenetic and molecular responses, outcomes and severe hematologic toxicity of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) .@*Methods@#Newly diagnosed CML-CP patients were consecutively recruited from January 2006 to December 2018 who received nilotinib and imatinib as first-line treatment. Clinical data were retrospectively analyzed.@*Results@#A total of 524 patients were classified into 439 (83.8%) receiving imatinib and 85 (16.2%) receiving nilotinib. Comparing with imatinib group, patients in nilotinib group were much younger (P=0.019) and more with intermediate and high Sokal risks (P<0.001) , WBC ≥100×109/L (P<0.001) , HGB<120 g/L (P<0.001) , blast cells in bone marrow (P=0.026) , splenomegaly (P<0.001) by physical examination at diagnosis, and longer interval from diagnosis to TKI treatment (P=0.003) . With a median TKI duration of 57 (range 3-153) months, the probabilities of complete cytogenetic response (CCyR) (P=0.011) , major molecular response (MMR) (P=0.001) and MR4.5 (P=0.046) were much higher in nilotinib group than those in imatnib according to each risk group. There is no statistical significance on probabilities of failure free survival (FFS) , progression free survival (PFS) and overall survival (OS) at 6 years between the two groups. Multivariate analyses showed that imatinib was an adverse factor associated with achieving CCyR (OR=0.6, 95% CI 0.5-0.8, P=0.001) , MMR (OR=0.6, 95% CI 0.5-0.9, P=0.032) and MR4.5 (OR=0.6, 95%CI 0.5-0.9, P=0.032) and poor FFS (OR=1.9, 95%CI 1.0-3.4, P=0.041) . In addition, Sokal score was an independent factor affecting cytogenetic and molecular responses, treatment failure, disease progression and survival. Male, WBC ≥100×109/L or HGB<120 g/L at diagnosis were significantly associated with lower cytogenetic and molecular response rates and/or poor FFS. The severe hematologic adverse events were not associated with different TKIs.@*Conclusions@#Nilotinib reaches to the faster and deeper cytogenetic and molecular responses and significantly improves FFS than imatinib in newly diagnosed patients with CML-CP.

Effect of nilotinib on pregnancy outcome in female patients with chronic myeloid leukemia / 中华血液学杂志

Objective@#To observe the pregnancy outcome among patients with chronic myeloid leukemia (CML) treated with Nilotinib (NIL) .@*Methods@#Clinical data of pregnancy delivery in CML patients treated with NIL from March 2015 to January 2019 were retrospectively collected.@*Results@#A total of 11 patients were recruited with median pregnancy age 28 (25-40) years. The median duration of NIL treatment before pregnancy was 34 (3-48) months. There were 12 pregnancies, included 2 planned ones and 10 (83.3%) unplanned. In the 10 unplanned patients, 9 (90.0%) received NIL 600 mg/d. The median exposure time were 4 (4-7) weeks. In eight patients with delivery outcomes, 5 cases had well-developed babies, 2 had spontaneous abortion and 1 case with an baby of syndactyly deformity, whose mother was exposed to NIL 600 mg/d for 7 weeks in the early trimester of pregnancy. Seven infants were 4 boys and 3 girls with the median height at birth 50 (41-54) cm and median weight 3.2 (3.0-4.6) kg. They all grew with a normal pattern and well developed. Now the median age is 19 (4-41) months. The disease status during 12 pregnancies included 3 cases in CMR, 2 cases in MR4.0, 3 cases in MMR, 4 cases not acquiring MMR. The median time of drug discontinuation was 35 (15-36) weeks during pregnancy. No patient lost CHR during this period.@*Conclusions@#Female CML patients exposed to NIL 600 mg/d for 4 weeks in early pregnancy can give birth to normal babies, but there is still a risk of spontaneous abortion and congenital malformations.

The Anti-fibrotic Effect of Nilotinib on Tenon's Capsule Fibroblasts in Vitro

PURPOSE: To evaluate the anti-fibrotic effects of nilotinib on the survival of cultured human Tenon's capsule fibroblasts (HTFs). METHODS: HTF primary cultures were obtained from samples following glaucoma surgery. Primarily cultured HTFs were exposed to 1, 5, 10, and 20 µM nilotinib for 24 hours. The effects of nilotinib on HTF proliferation and cell viability were determined using the 3-(4,5-dimethylthiazone-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, and apoptosis was determined by flow cytometry using annexin-V/propidium iodide (PI) double staining. Apoptosis-related proteins were detected by western blotting. RESULTS: The MTT assay showed that nilotinib induced an inhibition of HTF proliferation at concentrations of 10 and 20 µM (p < 0.001 and p < 0.001, respectively). Annexin V/PI double staining showed significantly increased apoptosis in cells treated with nilotinib. Nilotinib activated caspase-3, -9, and poly adenosine diphosphate ribose polymerase cleavage, and downregulated the expression of B-cell lymphoma-extra large and Bax, which indicated that nilotinib-induced apoptosis was partly mediated through the mitochondrial pathway. In addition, treatment with nilotinib decreased the expression of α-smooth muscle actin and transforming growth factor-β. CONCLUSIONS: Nilotinib decreased cell survival of cultured HTFs and induced mitochondria-mediated apoptosis. The results suggested that nilotinib may exert antiproliferative effects on HTFs, making it a possible agent to control postoperative fibrosis in patients undergoing glaucoma surgery.

Effect of stopping tyrosine kinase inhibitors during pregnancy on disease status and reproductive outcomes among patients with chronic myeloid leukemia / 中华血液学杂志

Objective: To explore the pregnancy outcome and disease status among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI) when they stopped TKI treatment during pregnancy. Methods: The clinical characteristics, reproductive outcomes and disease status of the patients who stopped TKI due to pregnancy between November 2004 to November 2017 were retrospectively collected. Results: A total of 14 CML patients in chronic phase (CML-CP), 12 patients were Sokal-low-risk. The median time of TKI treatment was 46.5 (15-123) months before the drug was stopped. The median age at the time of pregnancy was 29 (24-32) years. The median time of TKI exposure was 4 (0-9) weeks in 12 accidental pregnancies. Outcomes were available for 13 pregnancies, 9 cases (69.2%) delivered healthy babies, 1 case (7.7%) delivered polydactylia malformation baby, 3 cases (23.1%) had spontaneous abortion. The last one was still in pregnancy (no organ malformations were observed in color Doppler ultrasound). At the end of the follow up date, 10 children developed normal, the median age was 14 (0.7-65) months. Of the 14 patients who stopped TKI, 7 in complete molecular response (CMR), 3 in MR(4) (BCR-ABL(IS) <0.01%, ABL transcript >10 000), 2 in major molecular response (MMR), 2 in complete cytogenetic response (CCyR). The median time of TKI discontinuation during pregnancy was 33.5 (4-40) weeks. At the end of pregnancy, 4 cases were in CMR, 4 in MR(4), 1 in MMR and 4 in CCyR. No patients lost CCyR and complete hematologic remission. Conclusions: During the treatment of imatinib and Nilotinib, unplanned pregnancy may have a normal infant, but may lead to spontaneous abortion and congenital malformations. Female of CML-CP who had sustained and stable MMR at least 24 months and Sokal-low-risk had higher safety factor discontinued TKI during pregnancy, but still had a risk of increasing tumor load, so monitored the level of BCR-ABL of peripheral blood monthly during pregnancy is necessary.

Effect of stopping tyrosine kinase inhibitors during pregnancy on disease status and reproductive outcomes among patients with chronic myeloid leukemia / 中华血液学杂志

Objective@#To explore the pregnancy outcome and disease status among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI) when they stopped TKI treatment during pregnancy.@*Methods@#The clinical characteristics, reproductive outcomes and disease status of the patients who stopped TKI due to pregnancy between November 2004 to November 2017 were retrospectively collected.@*Results@#A total of 14 CML patients in chronic phase (CML-CP), 12 patients were Sokal-low-risk. The median time of TKI treatment was 46.5 (15-123) months before the drug was stopped. The median age at the time of pregnancy was 29 (24-32) years. The median time of TKI exposure was 4 (0-9) weeks in 12 accidental pregnancies. Outcomes were available for 13 pregnancies, 9 cases (69.2%) delivered healthy babies, 1 case (7.7%) delivered polydactylia malformation baby, 3 cases (23.1%) had spontaneous abortion. The last one was still in pregnancy (no organ malformations were observed in color Doppler ultrasound). At the end of the follow up date, 10 children developed normal, the median age was 14 (0.7-65) months. Of the 14 patients who stopped TKI, 7 in complete molecular response (CMR), 3 in MR4 (BCR-ABLIS <0.01%, ABL transcript >10 000), 2 in major molecular response (MMR), 2 in complete cytogenetic response (CCyR). The median time of TKI discontinuation during pregnancy was 33.5 (4-40) weeks. At the end of pregnancy, 4 cases were in CMR, 4 in MR4, 1 in MMR and 4 in CCyR. No patients lost CCyR and complete hematologic remission.@*Conclusions@#During the treatment of imatinib and Nilotinib, unplanned pregnancy may have a normal infant, but may lead to spontaneous abortion and congenital malformations. Female of CML-CP who had sustained and stable MMR at least 24 months and Sokal-low-risk had higher safety factor discontinued TKI during pregnancy, but still had a risk of increasing tumor load, so monitored the level of BCR-ABL of peripheral blood monthly during pregnancy is necessary.

A validated UPLC–MS/MS method for simultaneous determination of imatinib,dasatinib and nilotinib in human plasma / 药物分析学报

A sensitive, rapid, simple and economical ultra-performance liquid chromatography–tandem mass spectro-metric method (UPLC–MS/MS) was developed and validated for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma using gliquidone as internal standard (IS). Liquid-liquid extraction method with ethyl acetate was used for sample pre-treatment. The separation was performed on an Xtimate Phenyl column using isocratic mobile phase consisting of A (aqueous phase: 0.15% formic acid and 0.05% ammonium acetate)and B(organic phase:acetonitrile)(A:B=40:60,v/v).The flow rate was 0.25 mL/min and the total run time was 6 min. The multiple reaction monitoring (MRM) transitions, m/z 494.5→394.5 for imatinib, 488.7→401.5 for dasatinib, 530.7→289.5 for nilotinib and 528.5→403.4 for IS, were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity and good linearity over the concentration range of 2.6–5250.0 ng/mL for imatinib, 2.0–490.0 ng/mL for dasatinib,and 2.4–4700.0 ng/mL for nilotinib.The method showed acceptable results on sensitivity,specificity, recovery, precision, accuracy and stability tests. This UPLC–MS/MS assay was successfully used for human plasma samples analysis and no significant differences were found in imatinib steady-state trough concentra-tions among the SLC22A5?1889T>C or SLCO1B3 699G>A genotypes(P>0.05).This validated method can provide support for clinical therapeutic drug monitoring and pharmacokinetic investigations of these three tyrosine kinase inhibitors(TKIs).

The clinical analysis of frontline nilotinib vs imatinib therapies for newly diagnosed chronic myeloid leukemia in chronic phase / 中华内科杂志

Objective To compare the clinical efficacy and safety of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase ( CML-CP ) . Methods Until December 31st 2016, 18 patients using nilotinib and 83 using imatinib were recruited in our study.The efficacy and safety of two groups were evaluated .Results A total of 101 patients with CML-CP included 18 receiving nilotinib and 83 imatinib.The optimal response rates at 3, 6, 12 and 18 months in nilotinib and imatinib group were 88.9%(16/18) vs 57.3%(47/82) (P=0.012), 82.4%(14/17) vs 55.7%(44/79) (P=0.041), 9/12 vs 63.9% (39/61) (P=0.460), 6/9 vs 68.9% (31/45) (P=0.896) respectively.The optimal response rates by 3 months in low sokal risk group on nilotinib and imatinib were 9/9 vs 76.5%(26/34) (P=0.107), in intermediate and high sokal risk group were 7/8 vs 45.2%(14/31) (P=0.032).At the end of follow-up, the rate of major molecular response (MMR) in nilotinib group was 72.2%, which was higher than 56.6% in imatinib group (P=0.021).The rate of complete cytogenetic response ( CCyR ) in nilotinib group was 100%, which was higher than 71.1% in imatinib group (P =0.002).Progression free survival (PFS) rates in nilotinib and imatinib groups were 94.4%and 98.8%(P=0.019) respectively; whereas event free survival (EFS) rates were 88.9% and 48.2%(P=0.045).The incidence of drug related adverse reactions in nilotinib and imatinib was similar with only minor proportion of grade 3/4 adverse reactions .Conclusions Nilotinib achieves a deeper molecular response in a shorter time than imatinib in newly diagnosed patients with CML-CP, especially in patients with high risk outcome .Good safety is obtained in both groups so as to ensure a long-term administration and improving prognosis .