Risk Of Chronic Myelogenous Leukemia Research Articles

Co-Diagnosis of Sickle Cell and Chronic Myelogenous Leukemia: Exploratory Analysis from a Nationally Representative Database

Background: Chronic myelogenous leukemia (CML) developing in patients with sickle cell disease (SCD) has been reported infrequently in case studies to date (1). Prevalent thought relates its infrequency to the shortened life expectancy in the SCD population. However, with advancements in medical care, longevity of these patients has been increasing. Resultingly, risk factors for CML related to their disease and its treatments may accumulate, including chronic inflammation, heightened cell turnover, iron overload, immunomodulation from frequent transfusions, blood and marrow transplantation, and hydroxyurea use (2,3). Most specifically, the elevated and continuous inflammatory cell stimulation due to vaso-occlusion may enhance changes in granulocytic cell differentiation, increasing the risk for CML (3). By leveraging a nationwide database, we aim to describe characteristics associated with the development of CML in SCD patients. Methods: Hospitalizations for SCD and CML were identified using ICD-10 coding from the 2020 National Inpatient Sample (NIS). Those hospitalizations with a co-diagnosis of SCD and CML were included in this study, and further evaluated for demographics, comorbidities, transfusion status, length of stay, mortality, and charges during admission. The NIS is the largest all-payer inpatient database in the US and approximates a 20% stratified sample of inpatient discharges from >5000 hospitals across 48 states (98% of U.S. population). Sampling weights were applied to generate nationally representative estimates. Results: In the 2020 NIS sample upon weighting, there were 60 hospitalizations with a co-diagnosis of SCD and CML. The vast majority of these patients presented with active CML (92%) and in sickle cell crisis (83%). Overall, half of the sample comprised those patients who were between the ages of 29.5-49 years old, with a median age of 40.5. Fifty percent (n=30) of the hospitalizations were female; 92% (n=55) were African American; 58% were hospitalized in the Southern region; 25% in the West, and 17% in the Northeastern United States. The majority of hospitalizations (92%) occurred in teaching hospitals and 83% were in large-bed size hospitals. Common comorbidities were similar to that expected in the general SCD population, including history of transient ischemic attack (42%), history of pulmonary embolism/venous thromboembolism (42%), chronic kidney disease (33%), anemia (33%), and pulmonary hypertension (33%). Seventeen percent of patients had a transfusion during the hospitalization (n=15). The mean length of stay among these hospitalizations was 4.25 days. There were no deaths during these hospitalizations. Mean charges during hospitalization were $53,973. Conclusion: Previously observed in rare case studies, here we present an exploratory analysis from a national inpatient database demonstrating a population of 60 adult patients with SCD and a co-diagnosis of CML. Specifically, we observe concomitant development of CML in the SCD patient population correlated with a younger age (median age 40.5) than expected compared to traditional CML patients (median age 64). There is some evidence to suggest that chronic inflammation associated with sickle cell with extended life expectancies and treatment burden may be associated with myeloid cancers. These studies will need to be followed up with prospective analyses to investigate a potential increased risk of CML in the SCD population. Literature Cited: 1. Chen L et al., Chronic myelogenous leukemia in sickle cell anemia. Arch Pathol Lab Med. 2005;129(3):423-424. doi:10.5858/2005-129-423-CMLISC 2. Brunson A et al., Increased risk of leukemia among sickle cell disease patients in California. Blood. 2017;130(13):1597-1599. doi:10.1182/blood-2017-05-78323. 3. Stankovic et al., Chronic myeloid leukaemia and sickle cell disease: could imatinib prevent vaso-occlusive crisis?. Br J Haematol. 2011;155(2):271-272. doi:10.1111/j.1365-2141.2011.08670.x

Association of Interferon Gamma +874T/A Polymorphism and Leukemia Risk: A Meta-Analysis.

Interferon gamma (IFN-γ) has antitumor and antiproliferative effects, and previous studies indicated IFN-γ +874T/A (rs2430561) polymorphism were related to the risk of many types of cancer. However, the association between IFN-γ +874T/A polymorphism and leukemia risk remained controversial.We performed a comprehensive meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (PRISMA). Electronic database of Embase, Pubmed, and the Cochrane Library were searched for eligible articles published up to December 13, 2015. The association between genetic polymorphisms and leukemia risk was measured by odds ratios (ORs) and its corresponding 95% confidence intervals (CIs).A total of 8 studies amounting to 420 patients and 767 control subjects were retrieved for this study. Although associations between IFN-γ +874T/A polymorphism and overall leukemia risks were lacking, decreased chronic lymphocytic leukemia (CLL) risk was detected in the allelic model (T vs A, OR=0.660, 95%CI = 0.483–0.902, P = 0.009, I2 = 0.0% and P = 0.863 for heterogeneity), the codominant model (TT vs AA, OR = 0.472, 95%CI = 0.247–0.902, P = 0.023, I2 = 0.0% and P = 0.994 for heterogeneity), and dominant model (TT + TA vs AA, OR = 0.457, 95%CI = 0.285–0.734, P = 0.001, I2 = 40.3% and P = 0.195 for heterogeneity) by using fixed-effect model separately. On the contrary, results indicated T carries have an increased chronic myelogenous leukemia (CML) risk in dominant model (TT + TA vs AA, OR = 1.783, 95%CI = 1.236–2.573, P = 0.002, I2 = 19.0% and P = 0.295 for heterogeneity).This study suggests IFN-γ +874T/A polymorphism are related to CML and CLL risk. In addition, our work also points out IFN-γ +874T/A polymorphism may play dual contrasting role in leukemia risk.

The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Myeloid Leukemia Risk in Turkish Patients

Interleukin-18 (IL-18) is a cytokine which belongs to the interleukin-1 superfamily and secreted by various immune and non-immune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between -137G/C (rs187238) IL-18 gene polymorphism and susceptibility to chronic myelogenous leukemia(CML) in Turkish patients. The frequencies of polymorphism -137G/C were studied in thirty chronic myelogenous and thirty healthy individuals. The genotyping was performed by polymerase chain reaction and DNA sequencing analysis. Significant associations were detected between the IL-18 rs187238 (G/C) polymorphism and CML patients. A higher prevalence of the C allele was found in CML cases with respect to controls (p<0.05). The GC heterozygote and CC homozygote genotypes are associated with the risk of CML when compared with controls (OR, 1.9023; 95% CI, 0.6171-5.8636 for GC genotype and OR, 10.3585; 95% CI, 0.5326-201.4622 for CC genotype). These results indicate that individuals that are either heterozygote (GC) or homozygote for CC genotype are associated with the development of chronic myelogenous leukemia in Turkish population. Further large-scale studies combined with haplotype and expression analysis are required to validate the current findings. DisclosuresNo relevant conflicts of interest to declare.

Influence of CYP1A1, GST polymorphisms and susceptibility risk of chronic myeloid leukemia in Syrian population

In the present study, we investigated the associations of polymorphisms in cytochrome P450 gene (CYP1A1), glutathione S-transferase genes (GSTM1 and GSTT1) with chronic myelogenous leukemia (CML). A total of 126 patients with CML and 172 healthy volunteers were genotyped, and the DNA was isolated from their blood samples. The polymorphisms were assessed by polymerase chain reaction (PCR) restriction fragment length polymorphism-based methods and multiplex PCR. Logistic regression analyses showed significant risk of CML associated with CYP1A1 Val allele [odds ratio (OR) 3.3, 95% confidence intervals (CI) 1.96-5.53], (p < 0.0001) while CYP1A1 Val/Val homozygotes were observed only in the CML patients. There was statistically significant difference in the frequency of GSTM1 and GSTT1 null genotypes. The GSTT1-null genotype was slightly higher in 27% of CML cases and 16.7% of controls (OR 1.98, 95% CI 1.12-3.5) (p < 0.020). The GSTM1 null was higher in 42.8% of CML cases and 22.7% of controls (OR 2.55, 95% CI 1.54-4.22) (p < 0.00024). The individuals carrying CYP1A1 Ile/Val (AG) and GSTM1 null genotype have 9.9 times higher risk to be CML than those carrying CYP1A1 Ile/Ile (AA) and GSTM1 present genotype (OR 9.9, 95% CI 2.7-36.3) (p < 0.0001). This suggests that the association of the GSTM1 null genotype, either alone or in combination with GSTT1 null, with CYP1AI heterozygous leads to the CML risk.

MTHFR genetic polymorphisms may contribute to the risk of chronic myelogenous leukemia in adults: a meta-analysis of 12 genetic association studies

Chronic myelogenous leukemia (CML) is a complex disease with a genetic basis. The genetic association studies (GASs) that have investigated the association between adult CML and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the association of these polymorphisms with adult CML risk. A literature search for eligible GAS published before September 15, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases. Pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. All analyses were performed using the Stata software, version 12.0. Twelve case-control studies were included in this meta-analysis with a total of 932 CML patients and 3,465 healthy controls. For MTHFR C677T (dbSNP: rs1801133, C>T), though the pooled ORs were not significant in the overall population, all the ORs greater than 1 suggested an increased risk of CML for carriers of the risk allele. However, stratified analysis based on genotyping method revealed a significant association in the PCR-restriction fragment length polymorphism (RFLP) subgroup, possibly as a result of heterogeneity. For MTHFR A1298C (dbSNP: rs1801131, A>C), the combined results showed that carriers of the C allele may be associated with a decreased risk of adult CML. Stratified analysis showed that the magnitude of this effect was especially significant among Asians, indicating ethnicity differences in adult CML susceptibility. This meta-analysis shows that the C allele of MTHFR A1298C may be associated with a decreased risk in adult CML, especially among Asians, while MTHFR C677T may not be associated with adult CML risk. However, the development of adult CML may be the result of gene-gene and gene-environment interactions, which should be considered in future individual GAS and subsequent meta-analyses.

Can Polymorphisms In Oxidative Stress Related Genes Be a Risk Factor For CML?

Oxidative stress (OS) is recognized to be a evident feature in cancer development and progression. Indirect evidences suggest a role for oxidative stress (OS) in Chronic Myelogenous Leukemia (CML) etiology and pathogenesis. OS, resulting from an imbalance between Reactive Oxygen Species (ROS) production and antioxidant defenses, contributes to cell damage, apoptosis and ineffective hematopoiesis. The antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) are important components of cell defense against OS, and polymorphisms in the genes may contribute to differences in susceptibility of individuals to oxidative damage since it can lead to reduced protection against OS.In the present study we set to investigate the influence of polymorphisms of oxidative stress related genes, namely SOD1 (A251G), SOD2 (Ala16Val), COX2 (G-765C), CAT (C-262T) and NADPH oxidase p22 phox (C242T), as a risk factor for CML development and also as a prognostic risk marker in CML patients.Our study population consisted of 48 patients diagnosed with CML and the same number of healthy controls. Diagnosis was set according to international criteria. The genetic polymorphisms of SOD1 (A251G), SOD2 (Ala16Val), COX2 (G-765C), CAT (C-262T) and NADPH oxidase p22 phox (C242T) were assessed by RFLP-PCR. The patient group median age was 51 years (18-86), gender M/F=27/21. The strength of association between polymorphisms and CML risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (CI95%) and Kaplan-Meier survival analysis will be assessed to investigate the prognostic importance of these polymorphisms.Our preliminary results show a higher wild type allelic frequency of SOD1 (94%), COX2 (80%), CAT (82%) and NADPH oxidase p22 phox (67%) polymorphism and a higher variant allelic frequency SOD2 (52%) in CML patients, compared to controls. In these patients the predominant genotype was AA (88%), CG (52%), GG (67%), CC (73%) and CT (46%), respectively for SOD1, SOD2, COX2, CAT and NADPH oxidase p22 phox. Besides that, individuals with CC genotype of NADPH oxidase p22 phox and with TT genotype of CAT have an increase risk for CML about 2,3636-fold (CI95% 1,0346-5,3997; p=0,032) and 12,368-fold (CI95% 1,5151-100,9687; p=0,0076), respectively.These preliminary results show that CAT (C-262T) and NADPH oxidase p22 phox (C242T) genetic polymorphisms might be related with CML development and may be a novel genetic markers for CML susceptibility. Disclosures:No relevant conflicts of interest to declare.

Medical conditions and risk of adult myeloid leukemia

Although a few previous studies have reported positive associations between adult myeloid leukemia and a history of certain medical conditions, the etiology of most cases remains largely unknown. Our purpose was to examine associations between certain medical conditions and adult myeloid leukemia. Using logistic regression, we evaluated associations between 16 self-reported medical conditions and myeloid leukemia in a case-control study of 670 cases [including 420 acute myeloid leukemia (AML) and 186 chronic myelogenous leukemia (CML)] and 701 population-based controls. We observed significant positive associations between AML and ulcerative colitis (odds ratio (OR) = 3.8; 95 % confidence interval (CI), 1.1-13) and between CML and peptic ulcer (OR = 2.0; 95% CI, 1.1-3.8). A personal cancer history increased both AML (OR = 2.6; 95% CI, 1.7-3.9) and CML (OR = 3.5; 95% CI, 2.0-5.8) risk even after excluding individuals who reported prior radiation and/or chemotherapy treatment. Certain inflammatory medical conditions and a personal history of cancer, independent from therapy, are associated with an increased risk of myeloid leukemia.

Meta-analysis of human leukocyte antigen genetic polymorphisms and susceptibility to chronic myelogenous leukemia in Chinese population

Human leukocyte antigen (HLA) genetic polymorphisms are assumed to be correlated to the risk of chronic myelogenous leukemia (CML) in various ethnicities. Up to now, no clear consensus has been reached. Our goal is to address this issue in Chinese population. By searching the data in PubMed, Embase and four Chinese databases (prior to July 2010), the association of HLA genetic polymorphisms with CML has been fixed as the research objective. We studied a totality of 12 studies, comprising 2281 CML cases and 41000 health controls. The data demonstrated that HLA-A*11, A*74, HLA-B*40, B*47, B*55 and B*81 alleles were correlated with the increasing risk of CML. Nevertheless, HLA-DRB1*13 allele seemed to contribute to the genetic protection to CML. Conclusively we suggested that certain HLA alleles might be in association with the pathogenesis of CML in Chinese population. Due to little statistical scale, larger studies and particularly in a mono-people background, our hypothesis need to be further investigated in the future.

Obesity and the risk of chronic myelogenous leukemia: is this another example of the neoplastic effects of increased body fat?

Obesity and the risk of chronic myelogenous leukemia: is this another example of the neoplastic effects of increased body fat?

Human leukocyte antigen class I alleles and the risk of chronic myelogenous leukemia: a meta-analysis

A number of different human leukocyte antigen (HLA) allele associations with chronic myelogenous leukemia (CML) have been previously reported. The specific associations reported in one population, however, are rarely replicated in other populations. We attempted to explore these associations by performing a meta-analysis of published studies. Following a Medline search, we identified four studies which presented raw data on all allele associations with CML (significant and non-significant). Meta-analysis of these revealed a significant risk association with the HLA-A*02 (pooled odds ratio 1.33, 95% confidence interval 1.10–1.61) allele and a significant protective effect with the HLA-B*35 allele (pooled odds ratio 0.64, 95% confidence interval 0.48–0.86). To our knowledge this is the first study to demonstrate the epidemiologic association between HLA-A*02 and the risk of CML, and we discuss this in the context of recent immunological studies reporting data on BCR–ABL fusion peptide presentation and subsequent immune response. Our findings suggest that individual epidemiological studies may lack statistical power, or may have other interfering factors which prevent the unmasking of overall associations. Meta-analyses of published studies may overcome these limitations and may prove useful in uncovering allele–disease associations.

Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies

Several genetic polymorphisms in the genes coding folate-metabolizing enzymes have been associated with susceptibility to hematology malignancies. We conducted a Korean population-based case–control study to examine the relationship between the polymorphisms of folate-metabolizing enzymes and the risk of AML (acute myelogenous leukemia), CML (chronic myelogenous leukemia), MDS (myelodyspastic syndrome), and ALL (acute lymphoblastc leukemia). The MTHFR 677TT genotype was associated with an increased risk for ALL (odds ratios (OR) = 1.77; 95% confidence intervals (CI) = 1.02–3.09, p = .044). The MTRR 66 AG genotype was associated with an increased risk for MDS (OR = 1.59; 1.06–2.38, p = .026) and the MTRR 66 GG genotype was associated with increased risk for AML (OR = 1.51; 1.03–2.23, p = .037). The TYMS 2R3R genotype was associated with a decreased risk for AML (OR = 0.76; 0.60–0.96, p = .022). The TYMS hap3 (2R-6bp) and hap4 (2R-0bp) were associated with decreased risk (OR = 0.69; 0.53–0.90, p = .006) and increased risk (OR = 1.65; 1.20–2.27, p = .002), respectively for AML. Hap C (677T-1298A) was associated with an increased risk (OR = 1.40; 1.02–1.92, p = .04) for ALL. The risk for ALL appears to be associated with the MTHFR 677 polymorphism. The results are supportive of a risk modification by folate polymorphisms in several hematologic malignancies in Korea. The pattern of results suggests that MDS was associated with the DNA methylation status and the risk for AML was associated with both the DNA synthesis and DNA methylation status.

MTHFR 677CC/1298CC genotypes are highly associated with chronic myelogenous leukemia: A case-control study in Korea

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism and DNA methylation. Studies on MTHFR polymorphism in leukemia have largely focused on the protective role of MTHFR polymorphism in acute lymphoblastic leukemia (ALL). We evaluated the C677T and A1298C polymorphisms using the TaqMan ® allelic discrimination assay in various malignancies. The study population included 115 subjects with chronic myelogenous leukemia (CML), 200 with acute myelogenous leukemia (AML), 196 with multiple myeloma (MM) and 434 healthy control subjects. The frequency of 1298CC was statistically significantly higher in subjects with CML than that of the controls (OR = 5.12, 95% CI: 1.75–14.9, P-value = .003). Of note, the frequencies of 677CC/1298CC genotype were statistically significantly higher in subjects with CML, AML and MM than that of the controls (OR = 8.8, 3.5, 3.83, P-value = .002, 0.036, 0.023, respectively). Our results demonstrate that the MTHFR 1298CC homozygote variant is strongly associated with an increased risk of CML, while MTHFR C677T does not significantly affect the risk of CML. Moreover, we demonstrated that MTHFR 677CC and 1298CC genotype might have combined effect on risk of CML, AML and MM and it is inferred that the A1298C may play a different role in carcinogenesis, depending on the types of organs involved, the types of disease entities and the genotype of C677T.