Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.

BACKGROUND: Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. METHODS: A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). RESULTS: Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival. CONCLUSIONS: No significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.

Clinical characteristics of chronic lymphocytic leukemia occurring in chornobyl cleanup workers.

The recently demonstrated radiation-induction of chronic lymphocytic leukemia (CLL) raises the question as to whether the amount of radiation exposure influences any of the clinical characteristics of the disease. We evaluated the relationship between bone marrow radiation doses and clinical characteristics and survival of 79 CLL cases diagnosed during 1986-2006 in a cohort of 110 645 male workers who participated in the cleanup work of the Chornobyl nuclear accident in Ukraine in 1986. All diagnoses were confirmed by an independent International Hematology Panel. Patients were followed up to the date of death or end of follow-up on 31 October 2010. The median age at diagnosis was 57 years. Median bone marrow dose was 22.6 milligray (mGy) and was not associated with time between exposure and clinical diagnosis of CLL (latent period), age, peripheral blood lymphocyte count or clinical stage of disease in univariate and multivariate analyses. Latent period was significantly shorter among those older at first exposure, smokers and those with higher frequency of visits to the doctor prior to diagnosis. A significant increase in the risk of death with increasing radiation dose was observed (p = 0.03, hazard ratio = 2.38, 95% confidence interval: 1.11,5.08 comparing those with doses ≥22 mGy to doses <22 mGy). After adjustment for radiation dose, survival of CLL cases was significantly shorter among those with younger age at first exposure, higher peripheral blood lymphocyte count, more advanced clinical stage of disease and older age at diagnosis (all p < 0.05). This is the first study to examine association between bone marrow radiation doses from the Chornobyl accident and clinical manifestations of the CLL in Chornobyl cleanup workers. The current study provides new evidence on the association of radiation dose and younger age at first radiation exposure at Chornobyl with shorter survival after diagnosis. Future studies are necessary with more cases in order to improve the statistical power of these analyses and to determine their significance. Copyright © 2016 John Wiley & Sons, Ltd.

Radiation and the risk of chronic lymphocytic and other leukemias among chornobyl cleanup workers.

BACKGROUND: Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear. OBJECTIVES: We estimated relative risks of CLL and non-CLL from protracted exposures to low-dose ionizing radiation. METHODS: A nested case-control study was conducted in a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chornobyl nuclear power plant accident. Cases of incident leukemia diagnosed in 1986-2006 were confirmed by a panel of expert hematologists/hematopathologists. Controls were matched to cases on place of residence and year of birth. We estimated individual bone marrow radiation doses by the Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) method. We then used a conditional logistic regression model to estimate excess relative risk of leukemia per gray (ERR/Gy) of radiation dose. RESULTS: We found a significant linear dose response for all leukemia [137 cases, ERR/Gy = 1.26 (95% CI: 0.03, 3.58]. There were nonsignificant positive dose responses for both CLL and non-CLL (ERR/Gy = 0.76 and 1.87, respectively). In our primary analysis excluding 20 cases with direct in-person interviews < 2 years from start of chemotherapy with an anomalous finding of ERR/Gy = -0.47 (95% CI: < -0.47, 1.02), the ERR/Gy for the remaining 117 cases was 2.38 (95% CI: 0.49, 5.87). For CLL, the ERR/Gy was 2.58 (95% CI: 0.02, 8.43), and for non-CLL, ERR/Gy was 2.21 (95% CI: 0.05, 7.61). Altogether, 16% of leukemia cases (18% of CLL, 15% of non-CLL) were attributed to radiation exposure. CONCLUSIONS: Exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase in risk of leukemia, which was statistically consistent with estimates for the Japanese atomic bomb survivors. Based on the primary analysis, we conclude that CLL and non-CLL are both radiosensitive.

Rates of vaso-vagal reactions among first time teenaged whole blood, double red cell, and plateletpheresis donors.

Given the paucity of published data regarding reaction rates in younger teenaged donors, we evaluated the reaction rates in all of our first time teenaged donors after New York Blood Center lowered the minimum permissible age for blood donations from 17 to 16 yr in 2005. The overall rates of vaso-vagal reactions in donors aged 16 to 19, and those resulting in syncope, occurring in 72,769 consecutive first time whole blood, 3,822 double red cell, and 777 platelet apheresis donations were calculated. They were correlated with age and compared to those found in donors aged 20-29. Separate rates were calculated by gender, age in yr, and donation type, and then compared to each other. The overall reaction rate among first time teenaged whole blood donors was 8.2% and was significantly greater than among plateletpheresis donors (4.0%; p <0.0002). The rate in female whole blood donors (10.0%) was significantly higher than in males (6.4%; p <0.0002). In male double red cell donors the overall reaction rate of 3.5% was significantly lower than that found in male whole blood donors (p <0.002). Among both male and female whole blood donors a significant correlation with decreasing donor age between 19 and 16 yr was found (r(2) = 0.981; p = 0.01) and (r(2) = 0.988; p = 0.006), respectively. We conclude that teenaged donors have increased reaction rates when compared to adults and the reaction rates increase with decreasing age. In addition, females have higher reaction rates than males. Finally, reaction rates associated with apheresis donations are significantly lower than those associated with whole blood donations.

The Ukrainian-American study of leukemia and related disorders among Chornobyl cleanup workers from Ukraine: III. Radiation risks.

Leukemia is one of the cancers most susceptible to induction by ionizing radiation, but the effects of lower doses delivered over time have not been quantified adequately. After the Chornobyl (Chernobyl) accident in Ukraine in April 1986, several hundred thousand workers who were involved in cleaning up the site and its surroundings received fractionated exposure, primarily from external gamma radiation. To increase our understanding of the role of protracted low-dose radiation exposure in the etiology of leukemia, we conducted a nested case-control study of leukemia in a cohort of cleanup workers identified from the Chornobyl State Registry of Ukraine. The analysis is based on 71 cases of histologically confirmed leukemia diagnosed in 1986-2000 and 501 age- and residence-matched controls selected from the same cohort. Study subjects or their proxies were interviewed about their cleanup activities and other relevant factors. Individual bone marrow radiation doses were estimated by the RADRUE dose reconstruction method (mean dose = 76.4 mGy, SD = 213.4). We used conditional logistic regression to estimate leukemia risks. The excess relative risk (ERR) of total leukemia was 3.44 per Gy [95% confidence interval (CI) 0.47-9.78, P < 0.01]. The dose response was linear and did not differ significantly by calendar period of first work in the 30-km Chornobyl zone, duration or type of work. We found a similar dose-response relationship for chronic and non-chronic lymphocytic leukemia [ERR = 4.09 per Gy (95% CI < 0-14.41) and 2.73 per Gy (95% CI < 0-13.50), respectively]. To further clarify these issues, we are extending the case-control study to ascertain cases for another 6 years (2001-2006).

Histologic verification of leukemia, myelodysplasia, and multiple myeloma diagnoses in patients in Ukraine, 1987-1998.

In preparation for a possible large epidemiological study of radiation-related leukemia in Chernobyl clean-up workers of Ukraine, histologic evaluation of 62 cases of leukemia and related disorders was conducted by a panel of expert hematologists and hematopathologists from the United States, France, and Ukraine. All cases were randomly selected from a surrogate population of men in the general population of 6 regions of Ukraine who were between the ages of 20 and 60 years in 1986 and were reported to have developed leukemia, myelodysplasia, or multiple myeloma between the years 1987 and 1998. The hematologists and hematopathologists on the panel were in agreement with one another and with the previously reported diagnoses and classifications of about 90% of the cases of acute and chronic leukemia in the study. These results suggest that strong reliance can be placed on the clinical diagnoses of acute and chronic forms of leukemia and multiple myeloma that have occurred in Ukrainian Chernobyl clean-up workers providing that the diagnoses are supported by records of the patients having had adequate histologic bone marrow studies. The number of cases in this study with the diagnosis of myelodysplasia, however, was too small to draw firm conclusions.