Risk Of Chronic Myeloid Leukemia Research Articles

Abstract LB415: Association between waist circumference, body mass index, high-density lipoprotein cholesterol level, and risk of chronic myeloid leukemia

Abstract Advances in the treatment of chronic myeloid leukemia (CML) have resulted in increased prevalence. However, a more comprehensive understanding of its pathogenesis and epidemiology is necessary. Recent studies suggested the association between altered lipid metabolism and carcinogenesis, prompting an investigation of the relationship between metabolic disorders and incidence of CML. Thus, we conducted a study to examine the association between waist circumference, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), and the incidence of CML.Using data from the Korean National Health Insurance Service from 2009 to 2017, a competing risks regression was conducted to examine the hazard ratios of CML in 3,879,560 individuals aged 20 years and above. During a mean of 10.13±1.24 years of follow-up, there were a total of 848 cases of CML, including 539 male and 309 female patients.1) Individuals in the group with a waist circumference equal to or greater than 100cm had the greatest risk of CML (adjusted hazard ratio [aHR], 95% CI = 1.593, 1.058-2.398), compared to those with a waist circumference from 80 to less than 85cm.2) Those with a BMI less than 18.5 showed the lowest incidence of CML ([aHR], 95% CI = 0.509, 0.278–0.931) in comparison to the reference population with a BMI between 18.5 and 22.9.3) Individuals in the highest quartile of HDL-C had the lowest risk of CML ([aHR], 95% CI = 0.795, 0.657–0.961) compared to those in the lowest HDL-C quartile.A large waist circumference was significantly associated with increased risk of CML, whereas a low BMI and high HDL-C were associated with a reduced risk of CML. This suggests that a large waist circumference may be an independent risk factor of CML, whereas a low BMI and high HDL-C may be association with a protective effect against CML. Table 1. Risk of chronic myeloid leukemia by subgroups of waist circumference, bodey mass index, and high-density lipoprotein cholesterol level. Waist circumference (cm) N Case Duration IR (1000,000 PY) HR (95% CI) Model 1 Model 2 Model 3 Model 4 Model 5 <80.0 1,424,747 236 14493864.7 16.2830 0.644 (0.533, 0.778) 0.858 (0.707, 1.041) 0.859 (0.707, 1.045) 0.836 (0.662, 1.055) 0.853 (0.675, 1.078) 80.0 - 84.9 921,040 193 9344290.4 20.6540 0.816 (0.669, 0.995) 0.876 (0.718, 1.069) 0.876 (0.717, 1.069) 0.866 (0.705, 1.063) 0.843 (0.685, 1.037) 85.0 - 89.9 769,528 197 7785119.0 25.3050 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.) 90.0 - 94.9 451,608 116 4551043.2 25.4890 1.008 (0.801, 1.267) 0.963 (0.766, 1.212) 0.965 (0.767, 1.215) 0.976 (0.771, 1.234) 1.016 (0.802, 1.286) 95.0 - 99.9 201,541 68 2022854.6 33.6160 1.329 (1.009, 1.751) 1.267 (0.962, 1.670) 1.274 (0.966, 1.681) 1.302 (0.970, 1.747) 1.401 (1.044, 1.880) ≥100 111,096 38 1108876.8 34.2690 1.356 (0.958, 1.919) 1.352 (0.955, 1.915) 1.365 (0.962, 1.938) 1.421 (0.959, 2.105) 1.593 (1.058, 2.398) Model 1 was not adjusted.Model 2 was adjusted for age and sex.Model 3 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease.Model 4 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and BMI (Continuous).Model 5 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and BMI (5 level). Body mass index N Case Duration IR (1000,000 PY) HR (95% CI) Model 1 Model 2 Model 3 Model 4 Model 5 <18.5 143,144 11 1421140.8 0.0077 0.410 (0.225, 0.749) 0.496 (0.272, 0.906) 0.505 (0.276, 0.921) 0.586 (0.319, 1.077) 0.509 (0.278, 0.931) 18.5 - 22.9 1,512,449 290 15308105.8 0.0189 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.) 23.0 - 24.9 955,515 239 9697732.1 0.0246 1.300 (1.096, 1.543) 1.131 (0.952, 1.343) 1.120 (0.942, 1.331) 0.998 (0.828, 1.203) 1.060 (0.873, 1.287) 25.0 - 29.9 1,130,207 274 11476143.9 0.0239 1.260 (1.068, 1.486) 1.075 (0.910, 1.269) 1.060 (0.895, 1.256) 0.842 (0.675, 1.051) 0.878 (0.699, 1.104) ≥30.0 138,245 34 1402926.2 0.0242 1.280 (0.897, 1.826) 1.234 (0.865, 1.761) 1.218 (0.849, 1.747) 0.786 (0.500, 1.236) 0.765 (0.483, 1.211) Model 1 was not adjusted.Model 2 was adjusted for age and sex.Model 3 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease.Model 4 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and waist circumference (Continuous).Model 5 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and waist circumference (5 level). HDL-C level N Case Duration IR (1000,000 PY) HR (95% CI) Model 1 Model 2 Model 3 Model 4 Q1 (Lowest) 1,007,163 277 10156736.52 0.0273 1 (Ref.) 1 (Ref.) 1 (Ref.) 1 (Ref.) Q2 910,627 202 9242549.22 0.0219 0.802 (0.669, 0.961) 0.851 (0.710, 1.021) 0.853 (0.711, 1.023) 0.851 (0.709, 1.021) Q3 979,148 177 9948872.05 0.0178 0.653 (0.540, 0.788) 0.720 (0.596, 0.870) 0.724 (0.598, 0.876) 0.721 (0.596, 0.873) Q4 (Highest) 982,622 192 9957890.96 0.0193 0.708 (0.589, 0.851) 0.789 (0.656, 0.949) 0.798 (0.660, 0.965) 0.795 (0.657, 0.961) Model 1 was not adjusted.Model 2 was adjusted for age and sex.Model 3 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and BMI (5 level).Model 4 was adjusted for age, sex, household income, smoking, alcohol consumption, regular exercise, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and dyslipidemia medication. HDL-C high-density lipoprotein cholesterl, IR incidence rate, PY person-years, HR hazard ratio, CI confidence interval. Citation Format: Ka Young Kim, Kyung Do Han, Sung-Eun Lee. Association between waist circumference, body mass index, high-density lipoprotein cholesterol level, and risk of chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB415.

The role of gene expression hypoxia-inducible factor-1a and serum level monocyte chemoattractant protein-1 in the incidence of chronic myeloid leukemia in Iraqi patients

Abstract: BACKGROUND: Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy described by a translocation between chromosomes 9 and 22. There are many factors genetic or nongenetic effect on disease progression such as growth factors and transcription factors act as oncogenes or tumor suppressor genes. OBJECTIVES: The purpose of this research was to investigate the role of hypoxia-inducible factor (HIF1A) gene expression with CML, as well as the role of monocyte chemoattractant protein-1 (MCP-1) as a predictive biomarker on disease progression. MATERIALS AND METHODS: The current study consists of three groups: first group includes 50 newly diagnosed CML patients (females 22 and males 28), second group consists of 50 CML patients treated with tyrosine kinase inhibitor (TKI) with a complete molecular response (p210 BCR-ABL transcript levels ≤0.1% IS) (female 25 and male 25), and third group included another 50 apparently healthy volunteers (female 20 and male 30). The patients were admitted from the National Center of Hematology/Mustansiriyah University. All patients are diagnosed according to a complete blood count (CBC), a bone marrow examination, and a BCR-ABL gene test. RESULTS: Reverse transcription-quantitative polymerase chain reaction was applied to assess the expression levels of the HIF-1A gene and serum level of MCP1 by enzyme-linked immunosorbent assay. The results displayed downregulated of the HIF1A gene messenger RNA in CML patients in comparison to the controls group, as well as no statistically significant link was discovered when the fold of expression was correlated with the age and gender of CML patients. CONCLUSION: HIF1-alpha gene has an important role in pathological pathways such as angiogenesis. According to this study, HIF1-alpha gene is not an appropriate prognostic biomarker for detecting the risk of CML as well as MCP1 is thought to be a predictor of CML progression.

The Relationship between Telomere Length and Epigenetic Aging with Hematologic Diseases Risk: A Multivariable Mendelian Randomisation Study

Introduction: Aging is a complex phenomenon that involves multifaceted changes, including significant alterations in telomere length and epigenetic aging. When aging affects the hematopoietic system, it leads to a gradual increase in mutations in hematopoietic stem cells, making individuals more susceptible to the development of hematologic diseases. However, due to the limitations of observational studies, such as potential confounding factors and reverse causality, the precise causal direction and magnitude of the relationship between telomere length, epigenetic aging, and the incidence of hematologic diseases remain uncertain. Therefore, we conducted an investigation to determine the causal relevance of telomere length and epigenetic aging in relation to hematologic diseases using Mendelian randomization (MR). Methods: Firstly, we conducted a 2-sample single-variable Mendelian randomization (SVMR) study to examine the genetically predicted effects of telomere length and epigenetic age acceleration, as measured by HannumAge, Horvath Intrinsic Age, PhenoAge, GrimAge, and DNAm PAI-1 (DNA methylation-estimated plasminogen activator inhibitor-1) levels, on multiple hematologic diseases, including anemia, lymphoma, leukemia, myeloproliferative diseases, and hemostasis and coagulation diseases. Additionally, we used lasso regression to exclude multicollinearity in SNPs and subsequently performed multivariable MR using the screened SNPs to adjust for statistically significant risk factors, and MR Bayesian model averaging was performed to rank the significant risk factors based on their genetic evidence (Figure A). Results: Summary data were available for 19 malignant hematological neoplasms and 35 non-malignant hematological disorders, corresponding to 70,813 cases and 12,253,012 controls. Increased telomere length due to germline genetic variation was generally associated with increased risk for hematologic diseases. The strongest associations were observed for lymphoma, lymphoid leukaemia, Hodgkin lymphoma, chronic lymphocytic leukaemia, essential thrombocythaemia, unspecified types of non-Hodgkin lymphoma, multiple myeloma, Non-follicular lymphoma, unspecified iron deficiency, leukaemia, while higher levels of telomere length was associated with a reduced risk of pernicious anaemia (Figure B). Meta-analyzed IVW MR findings suggested that higher PhenoAge acceleration was associated with increased risks of myeloid leukemia, chronic lymphocytic leukemia, and lymphoid leukemia. Conversely, higher PhenoAge acceleration was linked to reduced risks of unspecified disorders of white blood cells and unspecified coagulation defects. Similarly, SVMR showed genetic predisposition for GrimAge acceleration to be associated with increased risks of amyloidosis, unspecified anemias, and myeloid leukemia. Conversely, genetically predicted GrimAge acceleration was associated with reduced risks of hemorrhagic anemia, hemolytic anemias, and idiopathic thrombocytopenic purpura. Furthermore, our findings suggested that elevated HannumAge acceleration increased the risks of lymphoma, leukemia, and lymphoid leukemia.Conversely, higher HannumAge acceleration was associated with a reduced risk of chronic myeloid leukemia. Additionally, higher levels of DNAm PAI-1 were found to be associated with an increased risk of chronic myeloid leukemia. However, there was no evidence of causality between genetically predicted Intrinsic epigenetic age acceleration and the 19 malignant hematological neoplasms and 35 non-malignant hematological disorders mentioned (Figure C). We utilized MVMR-LASSO to estimate the combined effects of telomere length and five epigenetic clocks on hematologic diseases. After adjusting for epigenetic aging, we observed a significant positive association between telomere length and various hematologic diseases, including leukemia, lymphoid leukemia, chronic lymphocytic leukemia, lymphomas, Hodgkin lymphoma, non-follicular lymphoma, unspecified types of non-Hodgkin lymphoma, essential thrombocythemia, and multiple myeloma (Figure D&E). Conclusion: Longer telomeres and epigenetic aging may increase the risk of developing most hematologic malignancies, while simultaneously raising or decreasing the risk of certain non-malignant hematologic diseases.

Association of Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T (rs1801133) polymorphism among Sudanese patients with chronic myelogenous leukemia

Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. Objectives: The current study aimed to determine the association between MTHFR C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Material and methods: This are hospital based cross sectional case control study, a total of 170 Sudanese subjects were enrolled, and 75 patients with chronic myeloid leukemia and 75 age- and sex matched healthy volunteers as a control group. Genomic DNA was extracted by sodium chloride method and The SNPs genotypes were determined using polymerase chain reaction followed by restriction fragment length polymorphism method. (PCR- RFLP). Data of this study were collected using a structured interview questionnaire and analyzed by statistical package for social sciences (version 21). Results: The frequency of the CC genotype was higher in the control group compared with patients (100%,96%), while of the CT genotype was higher in the case (4%) than in control (0.0%); the TT genotype was absent in both study groups, the frequencies T and C allele were 0.02 and 0.98 in CML patient group and 0.00, 0.100 respectively in the control group. There was no clinically significant association between age (P.value= 0.3), gender (P.value= 0.4) and genotype, also there was no statistically significant association when compare case with control genotype (p. value 0.08). Conclusion: C677T MTHFR polymorphism is not associated with the risk of CML among the Sudanese population

Association of ABCB1, ABCG2 drug transporter polymorphisms and smoking with disease risk and cytogenetic response to imatinib in chronic myeloid leukemia patients

BackgroundDespite acceptable results of imatinib in the treatment of chronic myeloid leukemia (CML), some patients fail to acquire a complete cytogenetic response (CCyR), which may be caused by polymorphisms in the pharmacogenetic genes. The study aimed to evaluate the association of two polymorphisms in the ABCB1 and ABCG2 genes with cytogenetic response to imatinib and the risk of CML development. MethodsWe genotyped ABCB1 (c .2677G/T/A) and ABCG2 (c .421C/A) polymorphisms by PCR-RFLP, T-ARMS-PCR methods in 111 patients with CML and 102 sex- and age-matched healthy subjects. CCyR was determined by standard chromosome banding analysis (CBA). ResultsAnalysis of polymorphisms showed significant association of ABCG2 c.421CA genotype (p < 0.0001; OR = 0. 17), and ABCG2c.421A allele (p < 0.0001; OR = 0.31) with decreased risk of CML. Moreover, ABCB1c.2677GT- ABCG2c.421CC combined genotype (p = 0.017; OR = 4.20) was associated with increased risk of CML. Analysis of the joint effect of SNP-smoking combination showed that smoker subjects with the ABCB1c.2677GG/GT (p = 0.001; OR = 15.96, p = 0.001; OR = 8.13, respectively) or ABCG2c.421CC genotypes (p = 0.001; OR = 5.82) had the increased risk of CML, while the risk of the CML in non-smokers carrying the ABCG2c.421CA (p < 0.0001; OR = 0. 18) genotype was strongly decreased compared with reference group. Regarding drug response, ABCG2c.421 CC/CA genotypes in the smoker patients were associated with an increased risk of resistance to imatinib (p < 0.0001; OR = 7.02, p = 0.018; OR = 4.67, respectively). ConclusionOur results suggest the impact of ABCG2c .421C/A polymorphism on CML development, and smoking may have a synergistic role in the risk of CML and resistance to imatinib.

Impact of Methionine Synthase Reductase Polymorphisms in Chronic Myeloid Leukemia Patients.

Highlights What are the main findings? Our objective was to determine the relationship between the methionine synthase reductase polymorphisms (MTRR and MTR) and the risk of developing chronic myeloid leukemia (CML) in Sudanese Patients. What is the implication of the main finding? Here, we report that the heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with a decreased risk of developing CML in the Sudanese population asa protective factor.Our findings will help to increase the understanding of MTRR A66G polymorphism and its association with CML risk in the Sudanese population. Introduction： Metabolism methionine and of folate play a vital function in cellular methylation reactions, DNA synthesis and epigenetic process.However, polymorphisms of methionine have received much attention in recent medical genetics research. Objectives: To ascertain whether the common polymorphisms of the MTRR (Methionine Synthase Reductase) A66G gene could play a role in affecting susceptibility to Chronic Myeloid Leukemia (CML) in Sudanese individuals. Methods: In a case-controlled study, we extracted and analyzed DNA from 200 CML patients and 100 healthy control subjects by the PCR-RFLP method. Results: We found no significant difference in age orgender between the patient group and controls. The MTRR A66G genotypes were distributed based on the Hardy-Weinberg equilibrium (p > 0.05). The variation of MTRR A66G was less significantly frequent in cases with CML (68.35%) than in controls (87%) (OR = 0.146, 95% CI = 0.162–0.662, p < 0.002). Additionally, AG and GG genotypes and G allele were reducing the CML risk (Odds ratio [OR] = 0.365; 95% CI [0.179–0.746]; p = 0.006; OR = 0.292; 95% CI [0.145–0.590]; p = 0.001 and OR = 0.146; 95% CI [0.162–0.662]; p = 0.002 and OR = 2.0; 95% CI [1.3853–2.817]; respectively, (p = 0.000)). Conclusions: Our data demonstrated that heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with decreased risk of developing CML in the Sudanese population.

[Survey and analysis of the concerns of patients with chronic myeloid leukemia in China in 2021].

Objective: To investigate the concerns of adult patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy in China. Methods: A cross-sectional questionnaire including 23 issues of concern was filled by patients with CML nationwide from August to September 2021. The results were compared with those from 2015 to 2016. Results: Data from 952 questionnaires were analyzed. The five most concerned issues were "TKI-related adverse effects and management" (66%) , "stopping TKI therapy" (46%) , "CML risk assessment" (46%) , "TKI dose reduction" (42%) , and "restrictions in daily life activities" (41%) . Compared with the results from 2015 to 2016, patients paid more attention to "TKI-related adverse effects and management" , "monitoring" , and "interpretation of laboratory reports" (all P<0.01) . Concerns of "TKI reimbursement policies" , "price reduction of TKIs" , and issues related to generic TKIs decreased significantly (all P<0.01) . Multivariate analysis showed that female patients (OR=1.8, 95% CI 1.4-2.5, P<0.001) , elderly patients (OR=1.0, 95% CI 1.0-1.0, P<0.001) , or patients with bachelor's degree or higher (OR=1.8, 95% CI 1.3-2.4, P<0.001) were more concerned with "TKI dose reduction" than others. Patients with a bachelor's degree or higher (OR=1.6, 95% CI 1.2-2.2, P=0.002) paid more attention to "CML risk assessment" , whereas those currently receiving a second- or third-generation TKI therapy (OR=1.9, 95% CI 1.3-2.6, P<0.001) were more concerned about "TKI resistance" . Conclusion: Patients with CML paid the most attention to "TKI-related adverse effects and management" , "stopping TKI therapy" , "CML risk assessment" , "TKI dose reduction" , and "restrictions in daily life activities" . Patients' sociodemographic covariates and treatment status were associated with their concerns.

The Impact of CYP3A5, CYP1A1, GSTM1, GSTT1, GSTP1 and TPMT Gene Polymorphisms on the Risk of Chronic Myeloid Leukemia

Polymorphisms  in  the  genes  encoding  drug  metabolising  enzymes  (DME)  cause  inter-individual  variations  in metabolising exogenous and endogenous substances, which has been related to the risk of various diseases. The present study was conducted to investigate the association of CYP1A1, GSTM1, GSTT1, GSTP1 and CYP3A5 and TPMT gene polymorphisms with susceptibility to chronic myeloid leukemia (CML). 89 samples of CML patients and 135 control samples were included in this study. Genotyping of CYP1A1, GSTM1, GSTT1, GSTP1 and CYP3A5 and TPMT gene polymorphisms was performed by a Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP). The frequency of GSTM1 null genotype was found to be significantly higher among chronic myeloid leukemia (CML) patients vs controls (39% vs 18.5%, respectively) with a 2.85-fold increased risk for CML. The frequency of GSTT1 null was found to be significantly lower in CML patients vs controls (26% vs 40.7%). Under the dominant inheritance model, GSTP1 gene polymorphism was significantly associated with reduced risk of CML. Moreover, CYP3A5 * 6 and TPMT * 2 alleles were absent among CML patients and the control group. GSTM1 null genotype was found to be associated with an increased risk of CML whereas TPMT * 2 and CYP3A5 * 6 alleles were absent in the population of Punjab.

Association of TP53 P72R and MDM2 SNP309 variants with susceptibil-ity to chronic myeloid leukaemia development in Algerian population: TP53 P72R C allele is a strong risk marker and MDM2 SNP309 G allele has a protective effect

Chronic myeloid leukaemia is a monoclonal myeloproliferative syndrome, whose development is related to disturbance of growth, survival, and apop-totic pathways, such as MDM2-p53 pathway, mainly due to the abnormal kinase activity of BCR-ABL. A lot of work has to be done to understand chron-ic myeloid leukaemia genetic predisposition. This is a pilot study that search-es for association between TP53 P72R variant (rs1042522); and MDM2 T309G variant (rs2279744), and the risk of chronic myeloid leukaemia occur-rence in the Algerian population. It is a case-control study using DNA sam-ples of 74 Algerian chronic myeloid leukaemia patients and 104 healthy con-trol individuals. Our results attested that TP53 P72R C allele (Pro) was strong-ly associated with increased risk of chronic myeloid leukaemia, and that TP53 P72R homozygous CC genotype should be a genetic susceptibility factor in the pathogenesis of chronic myeloid leukaemia independently of age and of gender. Furthermore, MDM2 SNP309 TT genotype was moderately associat-ed with a risk of chronic myeloid leukaemia occurrence. In conclusion, our data suggest that, in Algerian population, TP53 P72R C allele (Pro) could be a possible biomarker of chronic myeloid leukaemia susceptibility, and that MDM2 SNP309 TT genotype seems to be a low penetrance risk factor of chronic myeloid leukaemia susceptibility.

Combined GSTT1 Null, GSTM1 Null and XPD Lys/Lys Genetic Polymorphisms and Their Association with Increased Risk of Chronic Myeloid Leukemia.

PurposeGlutathione S-transferases (GSTT1 and GSTM1) are instrumental in detoxification process of activated carcinogens. Nucleotide excision repair is carried out by DNA helicase encoded by xeroderma pigmentosum group D (XPD) genes and aberrations in the XPD gene predisposes to increased risk of cancer. The present study aimed to investigate GSTT1, GSTM1 and XPD polymorphisms in newly diagnosed chronic myeloid leukemia (CML) patients and to examine the association of these polymorphisms with the risk of developing CML.Patients and MethodsThis case–control study was carried out from June 2019 to August 2021 involving 150 newly diagnosed patients with CML and an equal number of randomly selected age- and sex-matched healthy individuals. A multiplex-PCR assay was used to genotype GSTT1 null and GSTM1 null polymorphisms. XPD gene polymorphism was detected by PCR-RFLP using predesigned gene-specific primers.ResultsGSTT1 and GSTM1 null polymorphisms were detected in 42.7% and 61.3% of cases, respectively, compared to 18% and 35.3% for controls. The combination of both GST null polymorphisms revealed a significant association with CML. Frequencies of XPD Lys751Gln genotypes in cases were 62.7% heterozygous Lys/Gln, 24% homozygous Lys/Lys and 13.3% homozygous Gln/Gln, while in the controls were 74.7%, 20%, and 5.3%, respectively. Significant differences were also noted regarding the combination of GSTT1/GSTM1 null with XPD Lys/Lys, and GSTM1 null with XPD Lys/Lys.ConclusionIn conclusion, GSTT1 null, GSTM1 null and XPD polymorphisms showed positive association with the risk of development of CML. Furthermore, age and gender did not exhibit any association with the studied polymorphisms, while CML phases were associated with GSTT1 null polymorphism.

Age- and Gender-Independent Association of XRCC1 Arg399Gln Polymorphism with Chronic Myeloid Leukemia.

PurposeDNA damage to hematopoietic progenitor cells is an essential factor for leukemia development as a failure of the host DNA repair system to fix errors in DNA. This study aimed to assess the association of XRCC1 gene polymorphisms including Arg194Trp, Arg399Gln, and Arg280His with the risk of development of CML in Sudanese population.Patients and MethodsThe present study was conducted on 186 newly diagnosed patients with CML, aged 19–70 years (118 males and 68 females; mean age of 46.15±13.91 years) and 186 normal healthy controls (123 males and 63 females; mean age of 44.94±8.97 years). Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the XRCC1 (Arg194Trp, Arg399Gln, and Arg280His) gene polymorphisms.ResultsThe genotypic frequencies of Arg399Gln polymorphism in cases were 131 (70.4%) homozygous Arg/Arg, 46 (24.7%) homozygous Gln/Gln, and 9 (4.8%) heterozygous Arg/Gln as compared to the controls ie, 153 (82.3%), 73 (14.5%), and 6 (3.2%), respectively. The Arg399Gln variant genotypic frequencies significantly differed between the cases and controls (χ2 = 7.249, P = 0.027). By comparison, no statistically significant difference was observed in the variant genotype frequencies between the cases and controls in terms of Arg194Trp and Arg280His polymorphisms.ConclusionXRCC1 Arg399Gln gene polymorphism might have an important role in increasing the risk of chronic myeloid leukemia among Sudanese patients. Furthermore, all tested three polymorphisms showed no association of risk of the development of CML with age and gender.

NATURAL KILLER CELLS PHENOTYPE CORRELATES WITH TYROSINE KINASE INHIBITORS TREATMENT RESPONSE IN CHRONIC MYELOID LEUKEMIA PATIENTS

Despite well-known Natural Killer (NK) cells antitumor activity, its potential in regulating Chronic Myeloid Leukemia (CML) is not fully stablished. Tyrosine kinase inhibitors (TKI) treatment, besides reducing BCR-ABL1 transcripts, seems to result in immunomodulation that partly restore the immune dysregulation of the disease. Numerical, functional and maturation defects might be associated with CML risk stratification, molecular response profile or even with resistance to treatment with TKI. Therefore, we aimed to immunophenotypically characterize frequency, subtypes and maturation profile of NK cells in CML patients, by Multiparametric Flow Cytometry (MFC), during monitoring of TKI treatment. 11 Peripheral Blood samples from patients with CML (Clinical Hospital of Ribeirão Preto - HCRP-USP) and 10 healthy donors (controls) were analyzed. Clinical, laboratory and ELN2017 risk stratification were assessed. NK cells were defined as CD19-CD3-CD56+ and: CD56brightCD16- (secretory), CD56dimCD16+ (cytotoxic), CD11b-CD27- (tolerant); CD27+CD11b- (immature secretor), CD27+CD11b+ (secretory) and CD11b+CD27- (cytotoxic). Based on molecular response levels assessed by BCR-ABL1 RT-qPCR, patients were classified in G1 (without loss of molecular response to the 1 st line of TKI; n = 3), G2 (loss of molecular response to 1 st line of TKI; n = 3) and G3 (loss of molecular response to 2 nd generation TKI; n = 5). Mann Whitney or Kruskal-Wallis tests (p < 0.05) were applied using SPSS (v.20). A higher frequency of lymphocytes in CML patients was observed when compared to controls (p = 0.0242), but no difference was found in the frequency of NK cells. G1 and G2 showed a higher frequency of NK cells than G3 (p = 0,7774). Even though no statistical significance was found, CD27-CD11b- and CD27+CD11b- NK cells showed a higher frequency, while CD27+CD11b+ NK cells showed a lower frequency in CML when compared to controls. Frequency of CD27+CD11b- NK cells was higher in G2 and G3 when compared to G1. G3 showed an immature profile with higher percentages of CD27-CD11b- and CD27+CD11b- NK cells when compared to controls, while the more mature CD27+CD11b+ NK cells showed a lower frequency in CML. Furthermore, a lower frequency of CD56brightCD16- (p = 0.0002) and CD56dimCD16+ (p = 0.0448) NK cells was observed in CML, as wells as the frequency of CD27-CD11b+ cytotoxic NK cells, consistent to what we found in G3 and supporting our hypothesis. We observed that patients with loss of molecular response in treatment with 1 st and 2 nd TKI generation presented an immature non-effective NK cell profile, with deficient cytotoxicity. This scenario might result in impaired tumor surveillance of CML, meaning that phenotypic changes in NK cells may directly affect risk stratification and treatment response in CML. However due to the small number of patients and the lack of a functional assay, it is not possible to confirm that the cytotoxic cell may actually be deficient. Our findings and further functional studies can contribute to a better understanding of the physiopathology, prognosis and monitoring of CML, response to TKI therapy, as well as help to define therapeutic strategies based on immunotherapy mediated by NK cells.

Health-Related Quality of Life and Symptom Burden in Chronic Myeloid Leukemia Patients Treated with First Line with Imatinib Versus Those Treated with Dasatinib: First Results of the Leonidas Study

Background:Selection of first line treatment in patients with chronic myeloid leukemia (CML) is one of the major challenges in routine practice. While a wealth of comparative clinical and efficacy data are available for the three tyrosine kinase inhibitors (TKIs) that can be used frontline, there is dearth of information on their effects on patients' health-related quality of life (HRQOL).Aim:The primary objective was to investigate HRQOL differences in patients receiving first line therapy with imatinib (IMA) versus those receiving therapy with dasatinib (DASA) in the real-world setting. The pre-specified primary endpoint of the protocol was the “impact on daily life scale” of the EORTC QLQ-CML24 questionnaire.Patients and methods:This was a matched case control study recruiting patients from 38 centers in Italy and Germany. Patients selection criteria included: being in first line treatment with IMA or DASA for no more than three years and, at least, in complete cytogenetic response at the time of study entry. All patients were invited by their treating physicians in the hospital to participate and all consenting patients were requested to complete a Health Survey Packet at home. Pre-paid reply envelopes were also provided with the request to send back completed Surveys to an independent coordinating Data Center. HRQOL was assessed with the EORTC QLQ-C30 and the CML disease specific EORTC QLQ-CML24. This latter questionnaire was specifically developed for CML patients and includes the following scales: 1) impact on daily life; 2) impact on worry/mood; 3) body image problems; 4) satisfaction with care and information; 5) satisfaction with social life; 6) symptom burden. In order to minimize selection bias when performing HRQOL comparisons between treatment groups, IMA patients were matched to DASA patients by 1:1 optimal pair propensity score (PS) matching. By such procedure, we identified the most similar IMA-DASA pairs as based on patients' characteristics at diagnosis: age, sex, family status, comorbidity, ECOG performance status, Sokal risk and previous treatment for CML. In addition, we further adjusted comparisons between matched treatment groups by potential post-diagnosis HRQOL confounders, including months from treatment start, any adverse event that led to drug interruption and taking drug(s) for other concurrent disease(s). Only patients for whom both drugs were available at time of diagnosis were considered for the matching procedures.Results:Between October 2014 and December 2016, 323 patients, of whom 223 in therapy with IMA and 100 in therapy with DASA were consecutively enrolled. Patients' compliance was 97% of patients (N=312/323) returning a valid Health Survey Packet to the coordinating Data center. At study participation, mean age of patients was 65 and 60 years for patients treated with IMA and DASA respectively. Median time of therapy was 1.3 years for both IMA and DASA. All results reported below derive from adjusted comparisons between the PS-matched IMA-DASA groups (94 patients each).Analysis of the primary endpoint revealed that IMA patients had a statistically significant higher score (i.e., worse outcome) on the impact on daily life scale (P=.005). Other two scales of the EORTC QLQ-CML24 were significantly better for patients treated with DASA, that is, satisfaction with social life (P=.001) and symptom burden (P=.001). For descriptive purposes, CML symptom prevalence of those included in the EORTC QLQ-CML24 symptom burden scale is depicted in Figure 1. Conversely, there were no apparent better outcomes for patients treated with DASA for most of the scales of the cancer generic EORTC QLQ-C30 questionnaire (data not shown). Inspection of cancer generic symptoms revealed that pain (P=.013) and diarrhea (P=.016) were better for patients treated with DASA while constipation was better for patients treated with IMA (P=.026).Conclusions:This study suggests that patients in treatment with first line DASA report a lower impact of therapy on their daily life, compared to their peers in treatment with IMA. Some benefits in terms of symptom burden, favoring patients treated with DASA, were also noted as measured by a CML disease specific HRQOL questionnaire. This information extends current knowledge on physician-reported safety and efficacy data of IMA and DASA and might help clinicians making more informed treatment decisions. [Display omitted] DisclosuresEfficace:Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Incyte: Consultancy; Lundbeck: Research Funding; Amgen: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Iurlo:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Abruzzese:Bristol Myers Squibb: Consultancy; ARIAD: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Breccia:TEVA: Speakers Bureau. Castagnetti:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Crugnola:Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Tiribelli:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Gaidano:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bosi:Janssen: Honoraria; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Pregno:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saussele:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Micro-RNA Biogenesis Genes (AGO1 and GEMIN4) Single Nucleotide Variants of Bad Prognosis and Poor Therapeutic Response in Egyptian Chronic Myeloid Leukemia Patients: Case–control Study

BACKGROUND: Chronic myeloid leukemia (CML) is one of the most common hematological tumors. Gene candidate studies cleared the association of single genetic variants (SNVs) to the risk and progression in CML. MicroRNA biogenesis genes disruption contributes a fundamental role in carcinogenesis. AIM: We aimed to determine the association between rs636832 and rs2740348 SNVs of AGO1 gene and GEMIN4 gene, respectively, and the risk and prognosis in CML Egyptian patients with 5 years survival estimation. METHODS: The study was conducted on 110 newly diagnosed CML patients and 110 age and sex healthy matched controls. Real-time polymerase chain reaction utilizing TaqMan probes was operated to demonstrate genetic modalities of rs636832 and rs2740348. RESULTS: No significance difference was observed between the cases and controls regarding the genotypic and allelic frequencies for both variants. On the other hand, the rs636832 GG genotype was more evident at a younger age of diagnosis and associated with the poor grades of the Sokal and Eutos scores. As well, rs2740348 CC genotype was encountered in high Eutos score levels. Regarding the response therapy, rs636832 GG genotype was overrepresented in the resistance to Imatinib while rs2740348 CC genotype was prevalent in the resistance to both Imatinib and Nilotinib. Overall survival was of no statistical significance for both variants. CONCLUSION: Our study revealed that the major homozygous genotypes of both variants were associated with bad prognostic clinical scores and poor response to therapy but with no role in CML risk.

Association of DNA repair gene XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) polymorphisms with the risk of chronic myeloid leukemia: A case-control study in a South Indian population.

Xeroderma pigmentosum complementation group C (XPC), a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for the nucleotide excision repair pathway. Polymorphisms in the XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The present study aimed to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non-synonymous polymorphisms and susceptibility to chronic myeloid leukemia (CML) pathogenesis, disease progression and the response to targeted therapeutic regimen, imatinib mesylate. This case-control study included 212 cases and 212 controls, and the genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assays. Our results showed significant association of variant CT (odds ratio = 1.92, 95% confidence interval = 1.21-3.06, p =0.003) and TT (odds ratio = 2.84, 95% confidence interval = 1.22-6.71, p =0.007) genotypes in patients with the XPC Ala499Val polymorphism and CML risk. In addition, these genotypes were associated with CML progression to advanced phases (p =0.006), splenomegaly (p =0.017) and abnormal lactate dehydrogenase levels (p =0.03). XPC Lys939Gln was found to correlate with a poor response to therapy, showing borderline significant association with minor cytogenetic response (p =0.08) and a poor molecular response (p =0.06). Significant association of the Ala499Val and Lys939Gln polymorphisms with prognosis was observed (Hasford high risk, p = 0.031 and p = 0.019, respectively). Haplotype analysis showed a strong correlation of variant TC haplotype with poor therapy responses (minor cytogenetic response, p = 0.019; poor molecular response, p < 0.0001). In conclusion, our results suggest that XPC Ala499Val is a high-penetrance CML susceptibility polymorphism. Both polymorphisms studied are considered as genetic markers with respect to assessing disease progression, therapy response and prognosis in CML patients.

Role of Antioxidant Gene Polymorphisms in Risk and Prognosis of Chronic Myeloid Leukemia

Introduction: We aimed to investigate the possible role of antioxidant enzyme polymorphisms CAT -21A/T (rs7943316), CAT -262C/T (rs1001179), GPX1 -198C/T (rs1050450), MPO -463G/A (rs2333227), GSTM1 (rs366631) &amp; GSTT1 (rs17856199) with susceptibility to chronic myeloid leukemia (CML) and their association with tyrosine kinase inhibitor (TKI, imatinib) response.Methods: Six single nucleotide polymorphisms (SNPs) in antioxidant enzyme genes were genotyped in a total of 325 samples, of which 125 were from CML patients and 200 from healthy controls. The SNPs were correlated with various confounding variables lke BCR-ABL1 levels and tyrosine kinase domain mutation status in CML patients.Results: Genotyping results revealed statistically significant associations with CAT -21A/T (p=0.037) and GPX1 -198C/T (p=&lt;0.0001) polymorphisms with risk of CML. No associations were observed between CAT -262C/T, MPO -463G/A, GSTM1 &amp; GSTT1 polymorphisms and CML. The CAT -21A/T polymorphism conferred 2.95 folds increased risk of CML under co-dominant model (p=0.024) and 2.51 folds risk under dominant models (p=0.05). In addition, the haplotypes of CAT -21A/T and -262C/T polymorphisms, ATCC and ATCT conferred higher incidence of CML risk by 2.67 times (p=0.05) and 2.99 times (p=0.045). The GPX1 -198C/T polymorphism conferred significantly increased risk of CML under co-dominant model [CC vs CT (p=&lt;0.0001), CC vs TT (p=&lt;0.0001)] and dominant models [CC vs CT+TT (p=&lt;0.0001)]. The heterozygous GPX1 CT genotype frequency significantly elevated in poor molecular responders (p=0.005) and TKD mutation carriers (p=0.114) as compared to respective groups.Conclusions: Our results suggest that the reduced activity of antioxidant enzymes caused by the CAT -21A/T and GPX1-198C/T polymorphisms might contribute to increased risk of CML. In addition, the GPX1-198C/T polymorphism was associated with poor molecular response and acquired TKD mutations. Hence, the present study indicates that defective antioxidant defense system might have a strong influence on CML susceptibility and TKI (imatinib) response through oxidative stress.

Effects of GSTP1 Ile105Val polymorphism on both susceptibility and treatment response of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a multifactorial disease, which is caused by a complicated interaction between genetic and environmental agents. The Gluthation- S-transferase (GST) covers a family of multifunctional enzymes that involved in the detoxification of various toxic substances and anticancer drugs. Some polymorphisms in GSTs gene, could influence cancer susceptibility and drug resistance. The aim of the present study was to explore the influence of GSTP1 105 Ile/Val (rs1695) gene polymorphism on both CML susceptibility and response to Imatinib.DNA was extracted from blood samples by salting-out method; the Ile105Val polymorphism was genotyped in all participants (200 controls and 112 patients with chronic myeloid leukemia) by using PCR-RFLP method.The results of the present study revealed the absence of a significant association between GSTP1 105 Ile/Val gene polymorphism and CML risk, the variant allele Val was more frequent among controls (32%) than among patients (30)%). However, Hematologic response loss, cytogenetic resistance, side effects related to imatinib and none cytogenetic responders were more frequent among patients harboring val/val genotype compared with patients carrying Ile/ Ile and Ile/val genotypes.We have shown that this polymorphism is not associated with the risk of CML, but it influences the response of our patients treated by imatinib.

Glutathione S-transferase gene polymorphic sequence variations: Association with risk and response to Imatinib among Chronic Myeloid Leukemia patients of Kashmir.

Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We aimed to analyze relation of different GST gene sequence variants with susceptibility and response to Imatinib in CML. A total of 150CML cases and equal number of age and gender matched healthy controls were genotyped for five GST polymorphisms by multiplex-PCR and PCR-RFLP techniques. BCR-ABL1 transcripts were quantified by quantitative Real Time PCR (qRT-PCR). GSTT1, GSTO1, and GSTO2 SNPs revealed no association, while as GSTM1null genotype was observed to protect against the development of CML (OR=0.53, P=.01). GSTP1 variant genotypes AG (OR=2.1, P=.003) and GG (OR=5.6, P<.001), significantly associated with increased risk of CML. Combined genotype analysis showed protective impact of GSTT1present /GSTM1null (OR=0.44, P=.003) while as GSTT1present /GSTP1-GG (OR=6.92, P<.001) and GSTM1present /GSTP1-GG (OR=6.33, P<.001), significantly increased CML risk. GSTM1null genotype individually and in combination with GSTT1present associated with superior rate of major molecular response (MMR) and event free survival (EFS) (log-rank P=.029). GSTO2-AG+GG genotype associated with significantly inferior MMR rates at 3, 6, and 12months. Also, patients with GSTO2-GG genotype showed significantly reduced EFS (log-rank P=.025). Multivariate analysis confirmed GSTM1null as a better (HR:0.19, P=.029) and GSTO2-GG genotype as an independent poor prognostic factor (HR:2.29, P=.037). GSTM1null genotype seems to have a better prognostic role while GSTP1 variants significantly increase CML risk. Also, results support a correlation between disease outcome and GSTO2 polymorphism.

Impact of ABCB1 Gene Polymorphisms and Smoking on the Susceptibility Risk of Chronic Myeloid Leukemia and Cytogenetic Response.

Background:IM, a strong and selective TKI, has been approved as the front line of treatment in CML patients. In spite of satisfactory results of imatinib in the treatment of patients with CML, patients with treatment failure or suboptimal response developed resistance that might be because of pharmacogenetic variants. This study attempted to evaluate the influence of ABCB1 gene polymorphisms and smoking on CML risk and resistance to imatinib. Methods: ABCB1 (c.1236C>T, c.3435C>T) polymorphisms were genotyped in 98 CML patients and 100 sex- and age-matched healthy subjects by PCR-RFLP method, followed by sequencing. The patients were evaluated for cytogenetic response by the standard chromosome banding analysis in regular intervals. Results:Our results showed that c.1236CC genotype was significantly associated with imatinib resistance (OR = 3.94; p = 0.038). Analysis of the joint of SNP-smoking combination showed that smokers with c.1236TT/CT and c.1236CC genotypes had the increased risk of CML (OR = 6.04; p = 0.00 and OR = 4.95, p = 0.005) and treatment failure (OR = 5.36, p = 0.001 and OR = 15.7, p = 0.002), respectively. Smokers with c.3435TT/CT and c.3435CC genotypes also displayed the elevated risk of CML development (OR = 6.01, p = 0 and OR = 4.36, p = 0.011) and IM resistance (OR = 5.61, p = 0.001 and OR = 13.58, p = 0.002), respectively. Conclusion:Our findings suggest that c.1236CC genotype has clinical importance in the prediction of treatment outcome with IM, and smoking could have a synergistic role in CML risk and IM resistance.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.