High Risk Of Acute Myeloid Leukemia Research Articles

Autoimmune Diseases, Infections, Use of Antibiotics and the Risk of Acute Myeloid Leukemia: A National Population-Based Case-Control Study

Background.Studies have suggested that chronic autoimmune diseases and infections increase the risk of myeloid malignancies. However, due to the strong association between exposure to cytotoxic agents and subsequent acute myeloid leukemia (AML) and a lack of clinical data in previous studies, it remains unclear whether the reported risk is caused by e.g. cytotoxic and immune modulating agents given to treat a variety of autoimmune diseases.MethodsTo investigate if acute and chronic inflammation per se increase the risk of AML or whether this association are explained by preceding cytotoxic therapy or hematological diseases, we conducted a nationwide case-control study using the Danish National Acute Leukemia Registry. We identified 3165 AML patients diagnosed 2000-2013 Patients were matched to population controls on sex and age through the Danish National Registry of Patients. To avoid recall bias, we retrieved individual-level information on inflammation measured as autoimmune disease, infections, and use of antibiotics through the Danish National Registry of Patients and the Danish National Health Service Prescription Database.We used conditional logistic regression analysis to compute odds ratios for AML. To avoid reverse causation, we ignored exposures ≤3 years before AML diagnosis/index date. Results were stratified by AML type (de novo AML, secondary AML or therapy-related AML), sex, and age. Results were given with 95% confidence intervals (CI).ResultsThe median age was 68.8 years (range 15-99) and 55% of the cases were men. Among cases, 74.1% had de novo AML, 19.1% had sAML, and 6.8% had tAML. Only 3.5% had APL.Overall, 239 (7.6%) of patients and 1847 (5.8%) of controls had an autoimmune disease diagnosis more than 3 years before their AML diagnosis or the index date. Having an autoimmune disease was associated with an overall increased risk of AML (OR 1.3 (CI=1.2-1.5)). However, the risk was only increased for sAML and tAML (OR 2.1 (CI=1.7-2.6)), and not for de novo AML (OR 1.1 (CI=0.9-1.3)).The association between infections and AML overall and by AML type is shown in Figure 1.Any hospitalization-requiring infection was associated with a higher risk of AML (OR 1.2 (CI=1.1-1.4)). Stratified by type of AML, this association was explained by a high risk of sAML/tAML (OR 1.8 (CI=1.5-2.2)) and not by de novo AML (OR 1.1 (CI=0.9-1.2)).To capture community-acquired infections, we used antibiotic prescriptions. Overall, 2539 (80.2%) of patients and 24,676 of controls had redeemed more than one prescription for antibiotics >3 years before their AML diagnosis/index date. Prior use of antibiotics was associated with a higher risk of AML (OR 1.2 (CI=1.1-1.3)). However as for infections, the association was only evident for sAML/tAML (OR 1.8 (CI=1.5-2.2)), whereas the risk of de novo AMLwas not increased (OR 1.0 (CI=0.9-1.1)).In a subgroup analysis of individual autoimmune diseases, only gastrointestinal disease was associated with de novo AML (GI autoimmune disease: de novo AML: OR 1.5 (CI=1.0-2.1), sAML/tAML: OR 1.5 (CI=0.9-2.7)). Of infections, only gastrointestinal infections were associated with de novo AML (de novo AML: OR 1.5 (CI=1.1-2.0), sAML/tAML: OR 1.8 (CI=1.1-2.9)).ConclusionThis large population-based study using high-quality data shows that use of antibiotics, infections, and autoimmune diseases are not per se associated with AML.Only gastrointestinal autoimmune disease and gastrointestinal infections were associated with increased risk of de novo AML. Though, we cannot rule out the possibility that infections or autoimmune diseases in the gastrointestinal tracts cause immune-related/inflammation-driven leukemogenesis, these findings are likely coincidental or explained by therapeutic immune-modulating agents increasing both risk of infections and AML.In summery, our results indicate that in patients without prior hematological disease or exposure to cytotoxic therapy, inflammation plays - if any - only a minor role in leukemogenesis. [Display omitted] DisclosuresØstgård:Pfizer: Other: Travel expences; The Danish Cancer Society: Research Funding. Nørgaard:Program for Clinical Research Infrastructure (PROCRIN): Research Funding. Pedersen:Program for Clinical Research Infrastructure (PROCRIN): Research Funding. Østgård:Lilly: Consultancy; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy. Schöllkopf:Pfizer: Other: Travel expences; Teva: Other: Travel expences; Karyopharm Therapeutics: Research Funding. Severinsen:ARIAD: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Jensen:The Dagmar Marshall Foundation: Research Funding; The Danish Acute Leukemia Group: Research Funding.

Dual biomarkers long non-coding RNA GAS5 and its target, NR3C1, contribute to acute myeloid leukemia

Acute myeloid leukemia (AML) is a complex hematological neoplasm with poor prognosis. At present, overwhelming evidence indicates that different genetic abnormalities are relevant to the pathogenesis of AML. Nevertheless, its exact molecular mechanism is still unknown. Recently, it was reported that lncRNAs play crucial roles in tumorigenesis. But, their role in the molecular pathogenesis of AML has not been extensively explored. GAS5, one of the earliest known lncRNAs, has an essential role in the formation and progression of multiple human cancers. It was recently demonstrated that GAS5 acts as a riborepressor of the Glucocorticoid receptor) GR) and abnormal levels of GAS5 may alter response of hematopoietic cells to glucocorticoids. GAS5 can have interaction with the GR that encoded by NR3C1 gene and inhibit its transcriptional activity.To test whether the genetic variants can be associated with AML risk, we genotyped rs55829688 (T > C) polymorphism in GAS5 and three NR3C1 SNPs namely rs6195, rs41423247 and rs6189/rs6190 in a population of 100 Iranian AML patients and 100 healthy subjects.The analysis of the data showed the frequency of alleles and genotypes of rs55829688 and rs6189/rs6190 polymorphisms did not differ between patients and healthy subjects. But, rs41423247 and rs6195 demonstrated a significant correlation with AML risk. The rs6195 was associated with higher AML susceptibility in the co-dominant (OR = 4.58, 95% CI = 2.11–9.981, P < .0001), dominant (OR = 4.55, 95% CI = 2.155–9.613, P < .0001), and over-dominant (OR = 4.43, 95% CI = 2.042–9.621, P < .0001) models. Also, the rs41423247 polymorphism was associated with higher risk of AML in co-dominant (OR = 2.07, 95% CI = 1.171–4.242, P = .012) and dominant (OR = 2.47, 95% CI = 1.192–5.142, P = .010) models. Furthermore, haplotype analysis (rs41423247, rs6189.rs6190, rs6195, and rs55829688 respectively) demonstrated that GGAT, CGGT, and GGGT haplotypes were associated with higher risk of AML in the studied population (p-values = .007, 0.042 and 0.044, respectively). The present study reveals a possible role for NR3C1 in the pathogenesis of AML.

New advances in treatment of elderly acute myeloid leukemia

Acute myeloid leukemia (AML) is a group of hematologic malignancy with high heterogeneity. Old people are at a high risk of AML with poor outcome, while compared with younger ones, chemotherapy of elderly patients were always limited by some conditions associated with aging, such as organ dysfunction, debility and more comorbidities. This article reviews the new advances in treatment of elderly AML in recent years, to provide reference on characteristics of elderly AML, evaluations of prognosis in elderly patients with AML, as well as treatment decision making. Key words: Leukemia, myeloid, acute; Elderly; Drug therapy, combination; Prognosis; Drugs, investigational

Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1-6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6-57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4-49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.

Acute myeloid leukemia (AML) in older women after adjuvant breast cancer therapy

560 Background: Adjuvant chemotherapy for breast cancer is associated with the development of secondary AML, but this risk in an older population has not been previously quantified. Methods: We queried data from the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database for women who were diagnosed with nonmetastatic breast cancer from 1992–1999. We compared the risk of AML in patients with and without adjuvant chemotherapy (C), and by differing C regimens. The primary endpoint was a claim with an inpatient or outpatient diagnosis of AML (ICD-09 codes 205–208). Risk of AML was estimated using the method of Kaplan-Meier. Cox proportional hazards models were used to determine factors independently associated with AML. Results: 36,904 patients were included in this observational study, 4,572 who had received adjuvant C and 32,332 who had not. The median patient age was 75.3 (66.0–103.3). The median follow up was 63 months (13–132). Patients who received C were significantly younger, had more advanced stage disease, and had lower comorbidity scores (p&lt;0.001). The unadjusted risk of developing AML at 10 years after any adjuvant C for breast cancer was 1.6% versus 1.1% for women who had not received C. The adjusted HR for AML with adjuvant C was 1.72 (1.16–2.54) compared to women who did not receive C. HR for radiation was 1.21 (0.86–1.70). HR was higher with increasing age but p&gt;0.05. An analysis was performed among women who received C. When compared to other C regimens, anthracycline-based therapy (A) conveyed a significantly higher hazard for AML HR 2.17 (1.08–4.38), while patients who received A plus taxanes (T) did not have a significant increase in risk HR1.29 (0.44–3.82) nor did patients who received T with some other C HR 1.50 (0.34–6.67). Another significant independent predictor of AML included GCSF use HR 2.21 (1.14–4.25). In addition, increasing A dose was associated with higher risk of AML (p&lt;0.05). Conclusions: There is a small but real increase in AML after adjuvant chemotherapy for breast cancer in older women. The risk appears to be highest from A-based regimens, most of which also contained cyclophosphamide, and may be dose-dependent. T do not appear to increase risk. The role of GCSF should be further explored. No significant financial relationships to disclose.

Birth characteristics, sibling patterns, and acute leukemia risk in childhood: a population-based cohort study.

The occurrence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) during childhood may be influenced by factors operating in fetal life. Furthermore, childhood ALL has been suggested to be linked to patterns of infection during infancy. To explore these hypotheses and other associations, we studied the impact of sibling patterns (e.g., birth order) and birth characteristics (e.g., birth weight) on the risk of childhood ALL and AML. By linkage of records of population-based registries, a cohort of all children whose mothers were born in Denmark from April 1935 through March 1978 was established. Children who developed ALL or AML during the period from April 1968 through December 1992 were identified by linkage with the Danish Cancer Registry. Birth weights were obtained for children born during the period from January 1973 through December 1992 by linkage with the Medical Birth Registry. The cohort of approximately 2.0 million children was followed for the diagnosis of ALL or AML for 20.9 million person-years. A total of 704 cases of childhood ALL were identified. Among 0-4 year olds, the relative risks (RRs) of ALL for birth order positions 1, 2, 3, and 4+ were 1.00 (reference), 0.85 (95% confidence interval [CI] = 0.68-1.07), 0.91 (95% CI = 0.66-1.25), and 0.57 (95% CI = 0.30-1.06), respectively (P for trend = .09). A decreasing trend was not observed among 5-14 year olds. A significant log-linear association between birth weight and the risk of ALL was observed for both age groups. Overall, the RR of ALL increased by a factor of 1.46 (95% CI = 1.18-1.81) (P = .0005) for each kilogram of increase in birth weight. A total of 114 cases of childhood AML were identified. Children born second or later in the birth order had an increased risk of AML (RR = 1.53; 95% CI = 1.01-2.32) compared with firstborns. A particularly high risk of AML at ages 2 (RR = 2.53; 95% CI = 1.46-4.40) and 3 years was associated with having siblings compared with being an only child at those ages. Similar to the findings for ALL risk, there was a significant association between birth weight and AML risk. The relative increase in AML risk per 1-kg increase in birth weight was 2.14 (95% CI = 1.19-3.85; P = .009). The association between birth weight and childhood leukemia suggests the importance of intrauterine factors. A plausible explanation may be that increasing birth weight is associated with a higher rate of cell proliferation and/or a larger number of precursor cells being at risk of malignant transformation. The inverse association between birth order and ALL risk among 0-4 year olds was weak, but it was compatible with the hypothesis that delayed exposure to infection may increase the risk of ALL in this age group. The association of childhood AML with birth order and sibship size at young ages deserves further attention in the search for environmental factors that affect childhood AML risk.