De novo acute myeloid leukemia risk factors: A Texas case-control study

BACKGROUND:

Acute myeloid leukemia (AML) is comprised of several bone marrow‐based cancers and is the most common type of leukemia in the United States. The etiology of AML is not well understood. A case‐control study was conducted at The University of Texas M. D. Anderson Cancer Center to investigate associations between lifestyle characteristics and the risk of AML in Texas.

METHODS:

This study included 638 adult patients with de novo AML (cases) and a group of 636 matched controls. Interviewer‐administered questionnaires were used to collect demographic and occupational data. The distribution of cases by World Health Organization (WHO) subtype was 71 patients (11%) with recurrent cytogenetic abnormalities (AML‐RCA), 134 patients (21%) with multilineage dysplasia (AML‐MD), and 389 patients (61%) with AML not otherwise categorized (AML‐NOC). Multivariate logistic regression analyses were performed among all AML cases and among both sexes and each WHO subgroup.

RESULTS:

Among men, heavy smoking (≥30 pack‐years; odds ratio [OR], 1.86) and occupational solvent exposure at low levels (OR, 2.87) or moderate/high levels (OR, 4.13) statistically significantly increased the risk of AML. Among women, obesity (OR, 1.62) and solvent exposure to low levels (OR, 2.73) or moderate/high levels (OR, 3.90) increased the risk of AML. Across WHO subtypes, obesity was associated with a statistically significantly increased risk of AML‐RCA (OR, 3.15), whereas solvent exposure increased the risk in all subtypes at low levels (AML‐RCA: OR, 4.11; AML‐MD: OR, 2.54) and moderate/high levels (AML‐RCA: OR, 5.13; AML‐MD: OR, 3.02). A joint effect between smoking and solvent exposure was observed, and the highest risk was observed among smokers who had solvent exposure (OR, 4.51).

CONCLUSIONS:

The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype. Cancer 2012. © 2012 American Cancer Society.     

Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study

Background:Optimal adherence to imatinib therapy is of paramount importance to maximise treatment effectiveness in patients with chronic myeloid leukaemia (CML). The main objective of this study was to investigate patient-reported personal factors associated with adherence behaviour.Methods:Analysis was conducted on 413 CML patients receiving long-term therapy with imatinib. Adherence behaviour was measured with the Morisky Medication Adherence Scale and personal factors investigated included: quality of life, perceived social support, fatigue, symptom burden, psychological wellbeing and desire for additional information. Key socio-demographic and treatment-related factors were also taken into account. Univariate and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence to therapy.Results:In all, 53% of patients reported an optimal adherence behaviour. The final multivariate model retained the following variables as independent predictors of optimal adherence to therapy: desire for more information (ref. no), odds ratio (OR)=0.43 (95% confidence interval (CI), 0.29-0.66; P<0.001), social support (higher score representing greater support), OR=1.29 (95% CI, 1.11-1.49; P<0.001) and concomitant drug burden (ref. no), OR=1.82 (95% CI, 1.18-2.80; P=0.006).Conclusion:This study suggests that a higher level of social support, satisfaction with information received and concomitant drug burden are the main factors associated with greater adherence to long-term imatinib therapy.     

Acute myeloid leukemia in adults: a case-control study in Yorkshire

This paper reports the results of a case-control analysis of 161 cases of acute myeloid leukemia and 310 matched hospital controls. The patients were interviewed between 1982 and 1986. The study shows a weak association for cases with previous malignant disease. Furnace workers show excess risks. Urticaria and vertigo are in excess, as well as some aspects of family medical histories, including multiple sclerosis and cases of leukemia/lymphoma in blood relations.     

Medical and drug risk factors associated with neuroblastoma: a case-control study

A matched case-control study of prenatal risk factors for neuroblastoma was conducted, including 104 cases diagnosed over the period 1970-79 in the Greater Delaware Valley. Significantly elevated odds ratios (ORs) were associated with maternal use of a neurally active drug during pregnancy (OR = 2.83), sex hormone exposure 3 months prior to or during pregnancy (OR = 2.25), frequent alcohol consumption during pregnancy (OR = 9.0), and maternal use of diuretic drugs during pregnancy (OR = 5.75). Significantly more case mothers than control mothers reported use of hair coloring products during pregnancy (OR = 3.0). No association was found between cigarette smoking, coffee consumption, or medical irradiation and case-control status.     

Ph-Chromosome-positive chronic myeloid leukemia with associated bone marrow mastocytosis

The concurrent development of chronic myeloid (CML) or myelomonocytic (CMML) leukemia in patients with systemic mastocytosis (SM) is a well recognized phenomenon. Although the leukemia often resembles CML in morphological and in clinical terms, a Ph-Chromosome-positive variant has not been reported in SM so far. We here describe a 43-year-old female patient with typical Ph-Chromosome-positive CML in whom a co-existing bone marrow mastocytosis, a special subvariant of SM, was diagnosed. RT-PCR analysis revealed the typical p210 kDa form of BCR/ABL in leukemic cells. The diagnosis SM was based on the typical focal aggregates of spindle-shaped mast cells (MC) in the bone marrow, expression of CD25 in MC, and the c-kit mutation D816V, which was detectable in microdissected bone marrow MC, but not in microdissected leukemic cells, suggesting the presence of two different (sub)clones of neoplastic cells. Therapy with the BCR/ABL-targeting drug Imatinib (STI571) resulted in complete cytogenetic remission of CML. Together, our case provides further evidence for the biologic diversity of leukemias that may occur in patients with SM. The exact knowledge of the pathology and target-profile of the associated leukemias in SM have important therapeutic implications.     

Rectal cancer and occupational risk factors: a hypothesis-generating, exposure-based case-control study

In 1979, a hypothesis-generating, population-based case-control study was undertaken in Montreal, Canada, to explore the association between occupational exposure to 294 substances, 130 occupations and industries, and various cancers. Interviews were carried out with 3, 630 histologically confirmed cancer cases, of whom 257 had rectal cancer, and with 533 population controls, to obtain detailed job history and data on potential confounders. The job history of each subject was evaluated by a team of chemists and hygienists and translated into occupational exposures. Logistic regression analyses adjusted for age, education, cigarette smoking, beer consumption, body mass index, and respondent status were performed using population controls and cancer controls, e.g., 1,295 subjects with cancers at sites other than the rectum, lung, colon, rectosigmoid junction, small intestine, and peritoneum. We present here the results based on cancer controls. The following substances showed some association with rectal cancer: rubber dust, rubber pyrolysis products, cotton dust, wool fibers, rayon fibers, a group of solvents (carbon tetrachloride, methylene chloride, trichloroethylene, acetone, aliphatic ketones, aliphatic esters, toluene, styrene), polychloroprene, glass fibers, formaldehyde, extenders, and ionizing radiation. The independent effect of many of these substances could not be disentangled as many were highly correlated with each other.     

Factors associated with prolonged survival in chronic myeloid leukemia.

Four patients who demonstrated unusually prolonged survival with Philadelphia chromosome positive Ph' (+) chronic myeloid leukemia (CML) were analyzed for factors associated with survival. Survival duration from initial diagnosis ranged from 120 to 222 months, with a mean of 170 months. At diagnosis, age, symptoms, liver or spleen size, hematocrit, white blood cell count, absolute peripheral myeloblast plus promyelocyte count, and uric acid did not have unique prognostic significance. At diagnosis all four patients had normal or low-normal platelet counts, (range: 170,000 to 248,000/mm3). Thrombocytopenia occurred during treatment in three patients. None of the four patients, however, developed severe marrow hypoplasia or leukopenia during treatment for the chronic phase. Cytogenic studies performed from 103 to 156 months after diagnosis did not reveal a large subpopulation of marrow cells with a normal karyotype or cells with the XO genotype in the male patients. These observations suggest that prolonged survival in CML 1) is not contingent upon intensive treatment resulting in marrow hypoplasia, and 2) does not require the persistence of a clone of karyotypically-normal bone marrow cells or a clone of marrow cells in males which has lost the Y chromosome. A normal or low-normal platelet count at diagnosis may be a favorable prognostic indicator.     

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.     

慢性髓性白血病研究现状

 近年来对慢性髓性白血病（CML）发病的分子机制研究取得了较大进展,推动了临床治疗的发展。bcr-abl酪氨酸激酶活性异常是CML发病的主要分子机制,在DNA、mRNA、蛋白质、细胞水平不同层次上选择治疗药物,推动了分子靶向性药物治疗的开发,其中酪氨酸激酶抑制剂甲璜酸伊马替尼的出现成为CML药物治疗的里程碑。同时造血干细胞移植技术的完善以及其他治疗手段的应用,为CML的根治提供了更多的机会。现就有关CML发病的分子机制和治疗进展作一综述。     

慢性髓系白血病相关抗原的研究进展

 【摘要】　慢性髓系白血病（CML）是一种起源于造血干细胞的恶性增生性疾病，目前仍缺乏有效的根治方法。联合治疗以提高患者免疫功能状态以及免疫治疗以重建患者免疫功能，是CML比较理想的治疗方法。因此，寻找合适的CML相关性抗原，研究其特异性淋巴细胞，是CML免疫相关治疗的基础。     

New therapeutic approaches and prognostic factors in chronic myeloid leukemia

Imatinib mesylate is now the first-choice treatment for all newly diagnosed CML patients, but despite the impressive percentage of responding patients, some CML cases show primary resistance or relapse after an initial response. Although some clinical and biological findings have been found to be associated with a lower probability of response to imatinib, at present no precise markers allowing to predict outcome for individual patients exist. The most common mechanisms of resistance to imatinib include BCR-ABL kinase domain mutations, BCR-ABL amplification and overexpression, and clonal evolution with activation of additional transformation pathways. These mechanisms are caused by the genomic instability, which characterises the Ph-positive clone. Several approaches to overcome resistance have been proposed, including novel tyrosine kinase inhibitors (TKIs) that have now reached the clinical or pre-clinical phase of evaluation. Clinical trials with these novel TKIs have shown good rates of hematologic and cytogenetic responses that appear also durable in time, but still cases of resistance are also observed, supporting the notion that genomic instability represents the major determinant affecting the final outcome of the CML patients when treated with TKIs. Understanding exactly the mechanisms leading to genomic instability of the Ph-positive cells represents therefore the real challenge for the near future.     

A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia

Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations between circulatory albumin adducts and acute myeloid leukemia (AML), the most common adult myeloid leukemia that showed consistent associations with environmental exposures. We conducted a nested case-control study of 52 incident AML cases and 103 controls matched on age, sex and race within two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in prediagnostic samples using liquid chromatography-high-resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of the essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios [95% confidence intervals]) for the 1st, 2nd and 3rd tertiles were 1.0, 0.65 (0.31-1.36) and 0.31 (0.12-0.80), respectively (P-trend = .01). These associations were largely driven by effects present among cases diagnosed at or above the median follow-up time of 5.5 years. In conclusion, applying a novel approach to characterize exposures in the prediagnostic samples, we found evidence supporting the notion that oxidative stress may play a role in the pathogenesis of AML. Our findings offer insight into AML etiology and may be relevant in identifying novel therapeutic targets.     

Increased telomerase activity is associated with shorter survival in patients with chronic phase chronic myeloid leukemia

BACKGROUND: Significantly elevated telomerase activity (TA) has been found in samples from patients with many malignant hematologic diseases. However, the impact of elevated TA on the course of patients with chronic phase chronic myeloid leukemia (CP-CML) is unknown. METHODS: Using a modified polymerase chain reaction-based telomeric repeat amplification protocol assay, the authors measured TA in bone marrow samples from 93 patients with CP-CML and correlated it with patient characteristics and survival. TA also was measured in bone marrow samples from 29 patients with accelerated/blastic phase CML. RESULTS: Patients with accelerated/blastic phase CML were found to have somewhat higher levels of TA compared with patients with CP-CML (P = 0.07). Among patients with CP-CML, those with high TA progressed to advanced stages of disease sooner (P = 0.05) and had a significantly shorter survival (P = 0.04) than patients with low TA. No correlation was found between TA and patient age, hemoglobin, platelet and leukocyte counts, percentage of peripheral or bone marrow blasts or basophils, or bone marrow cellularity. On multivariate analysis, high TA retained its significance as a factor associated with shorter patient survival (P = 0.02). CONCLUSIONS: The current study data suggest that TA plays a role in the propagation of CP-CML and that the potential of telomerase inhibitors in patients with CML should be explored, even in those with early phase disease.     

BCR-ABL-negative chronic myeloid leukemia

Constitutive activation of protein tyrosine kinases plays a central role in the pathogenesis of myeloproliferative disorders, including BCR-ABL-negative chronic myeloid leukemia. Current research is focused on elucidating the full spectrum of causative mutations in this rare, heterogeneous disease. Activated tyrosine kinases are excellent targets for signal transduction therapy, and an accurate diagnosis including morphology, karyotyping, and molecular genetics will become increasingly important to direct individualized treatment. In addition, new molecular findings need to be incorporated into disease classification systems.     

Alcohol consumption and risk of adult-onset acute myeloid leukemia: results from a Los Angeles County case-control study

Few studies have examined the role of alcohol consumption in risk of adult acute myeloid leukemia (AML). Two previous case-control studies resulted in inconsistent findings. We report data from a Los Angeles County population-based case-control study in which 164 matched case-control pairs were asked about lifetime history of alcohol consumption and 136 cases were subtyped according to the French-American-British (FAB) criteria. Estimated categorical odds ratios (OR) adjusted for smoking and education were suggestive of a possible protective effect but trend tests were non-significant. Analyses by FAB subtype did not reveal subtype-specific associations but generally suffered from lack of power. Larger studies are needed to more thoroughly investigate the relationship between alcohol consumption and AML risk.     

Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia

Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for chronic myeloid leukemia (CML). The majority of patients continue treatment for their lifespan because discontinuation generally results in relapse. Many patients treated with imatinib experience adverse events (AEs) at some time during their treatment. Commonly encountered AEs and their management are well known. However, in addition to the common AEs with imatinib, there is a significant number of patients who display either uncommon or delayed AEs. These events can involve cardiac, renal, or dermatologic problems, and fluid retention. Herein, we review these less-than-common side effects and the hazard of administering imatinib during pregnancy. While chronic treatment with imatinib has revolutionized CML prognosis, physicians should be aware of both the common and uncommon adverse reactions.     

Chronic lymphocytic leukemia associated with myelodysplastic syndrome and/or chronic myeloid leukemia: evidence for independent clonal chromosomal evolution

We describe the cytogenetic findings of three cases with simultaneous or sequential development of a B-chronic lymphocytic leukemia (B-CLL) and either a myelodysplastic syndrome (MDS) in 2 cases or a chronic myeloid leukemia (CML) in one case. The coexistence of these two hematologic malignancies leads to questions about their cell of origin. Through analysis of the cytogenetic abnormalities, we studied the derivation of both malignancies. The cytogenetic analyses of these three patients were simultaneously studied from both peripheral blood and bone marrow. Furthermore unstimulated short-time (USSTC) and long-time (72-96 hours) stimulated cultures (LTSC) were systematically performed. In all cases, we have demonstrated the independent bi-clonal evolution. This is the first report ever described for patients with CLPD and MDS and/or MPD shown to arise from distinct chromosomal abnormalities.     

Environmental risk factors for nasopharyngeal carcinoma: a case-control study in northeastern Thailand.

A case-control study of nasopharyngeal carcinoma was conducted in northeast Thailand, a region which shows an intermediate risk for this neoplasm. The study was conducted to investigate the importance of environmental exposures, particularly salted fish consumption, cigarette smoking, alcohol drinking, and occupational exposure to smoke or dust, as risk factors for the disease. Data from 120 nasopharyngeal cancer cases and the same number of hospital-matched controls indicated that consumption of sea-salted fish at least once a week was a significant risk factor (odds ratio, 2.5; 95% confidence interval, 1.2-5.2). Agricultural workers were also at significantly higher risk (odds ratio, 2.8; 95% confidence interval, 1.3-6.2), and working in agriculture or as a woodcutter was associated with an even higher risk (odds ratio, 8.0; 95% confidence interval, 2.3-28.2). There was no association between nasopharyngeal carcinoma and alcohol drinking or cigarette smoking.     

Therapy of chronic myeloid leukemia with interferon

Several modalities are used for treatment of the chronic phase of chronic myelogenous leukemia. Most patients are treated with single agent chemotherapy. However, patients are cured only by isogenic or allogeneic bone marrow transplantation; otherwise the disease regularly proceeds to fatal blastic crisis. Alpha-interferon has an antiproliferative activity against hematopoietic cells in vitro and in vivo. We have treated 10 patients with the chronic phase of Philadelphia--chromosome-positive chronic myelogenous leukemia with alpha-interferon. The median duration of the disease was 10 months. Five patients were previously untreated and five achieved hematologic remission. Patients with a disease duration of less than 1 year, who had had no or only minimal pretreatment, showed the best response rates. These experiences confirm published data on interferon therapy. It remains to be determined whether interferon treatment and the hereby induced suppression of the Philadelphia-chromosome-positive cell clone in some patients will improve survival.