THYROID DISEASE IN THE LATE OBSERVATION PERIOD UPON CHEMO AND RADIOTHERAPY IN CHILDREN/SURVIVORS OF ACUTE LYMPHOBLASTIC LEUKEMIA. / KhVOROBY ShchYTOPODIBNOÏ ZALOZY PISLIa KhIMIO TA PROMENEVOÏ TERAPIÏ U DITEI, IaKI PERENESLY GOSTRU LIMFOBLASTNU LEIKEMIIu, U VIDDALENOMU PERIODI SPOSTEREZhENNIa.

OBJECTIVE: to assess the thyroid disease in the late observation period in children who had received chemo- andradiotherapy for the acute lymphoblastic leukemia (ALL) taking into account gender, age period and disease sub-type. MATERIALS AND METHODS: The incidence and nature of thyroid disease (hypothyroidism, thyroiditis, and thyroid can-cer) were studied in children-survivors of acute lymphoblastic leukemia (ALL) being in remission from 6 to 25 years.The distribution of patients by leukemia subtypes was as follows: «common¼ - 67.4 %, pre-B - 23.9 %, pro-B andT-cell - 4.3 %. Children had been receiving chemo- and radiotherapy according to the protocol. Regarding the ageof patients at the time of ALL diagnosis the prepubertal, pubertal and postpubertal periods were taken into account.The endocrine diseases in family history, body weight at birth, serum content of free thyroxine, pituitary thyroid-stimulating hormone, cortisol, iron, ferritin and thyroperoxidase antibodies were evaluated and assayed. RESULTS: Thyroid disease in children was emerging in the first 2-3 years after the ALL treatment with an incidenceof 22.8 % (hypothyroidism - 14.1 %, autoimmune thyroiditis - 7.6 %, papillary cancer - 1.1 %). Seven children inthis group had received radiotherapy (12-18 Gy doses) on the central nervous system (CNS). No correlation wasfound between the radiation exposure event itself, radiation dose to the CNS and thyroid disease in the long-termfollow-up period. Thyroid cancer had developed in a child 11 years upon chemo- and radiotherapy. Hypothyroidismwas more often diagnosed in the patients of prepubertal age (rs = 0.49). There were endocrine diseases in thefamily history in about a half of children, being significantly higher than in the general sample (р < 0.05). The bodyweight at birth of a child who had later developed hypothyroidism was less than in children having got thyroiditis(rs = 0.57). CONCLUSIONS: Disorders in endocrine regulation and of thyroid in particular can affect the prognosis of blood can-cer course in the long-term follow-up in children, especially in prepubertal age, which requires systematic supervi-sion by hematologist and endocrinologist.

Estimating the risk of developing secondary hematologic malignancies in patients with T1/T2 prostate cancer undergoing diverse treatment modalities: A large population-based study.

BACKGROUND: Patients with prostate cancer (PC) are at a high risk of developing secondary hematologic malignancies (SHMs) after radiation therapy (RT), while no study has assessed the relationship of different treatment modalities with the occurrence of SHMs after PC at early stage. This study aimed to investigate the risks of developing SHMs in patients with T1/T2 PC undergoing different treatment modalities. METHODS: Patients with T1/T2 PC were identified from the Surveillance, Epidemiology, and End Results database. Competing risk regression (CRR) model was performed to evaluate the hazard ratios (HRs) of developing SHMs. As SHMs scarcely occur, the relative risk (RR) analysis was employed to compare the risks of different treatment modalities associating with the development of SHMs. RESULTS: The CRR analysis showed that undergoing RT was associated with a higher risk of developing SHMs (external beam radiation therapy [EBRT]: HR = 1.21, 95% confidence interval [CI]: 1.10-1.34; radioactive implant [RI]: HR = 1.20, 95% CI: 1.06-1.36). As for different types of SHMs, EBRT, and RI were correlated with decreased risks of developing CLL (RR = 0.67, 0.72; 95% CI: 0.53-0.85, 0.54-0.96, respectively), but with the increased risks of developing NHL (RR = 1.18, 1.23; 95% CI: 1.02-1.35, 1.05-1.44, respectively); EBRT also showed increased risks of developing acute/ chronic myeloid leukemia (AML/CML, RR = 1.54, 1.56; 95% CI: 1.16-2.03,1.05-2.33, respectively); No increased risk of developing SHMs was detected in patients who only underwent prostatectomy. CONCLUSIONS: Although RT was found to be associated with the increased risks of developing SHMs in patients with T1/T2 PC, this finding cannot be extended to diverse types of SHMs. RT was correlated with the increased risks of the development of NHL, AML, and CML, but with the decreased risk of developing CLL. Prostatectomy did not increase the risk of developing SHMs.

The effects of secondary iron overload and iron chelation on a radiation-induced acute myeloid leukemia mouse model.

BACKGROUND: Patients with myelodysplastic syndrome (MDS) require chronic red blood cell (RBC) transfusion due to anemia. Multiple RBC transfusions cause secondary iron overload and subsequent excessive generation of reactive oxygen species (ROS), which leads to mutations, cell death, organ failure, and inferior disease outcomes. We hypothesize that iron loading promotes AML development by increasing oxidative stress and disrupting important signaling pathways in the bone marrow cells (BMCs). Conversely, iron chelation therapy (ICT) may reduce AML risk by lowering iron burden in the iron-loaded animals. METHODS: We utilized a radiation-induced acute myeloid leukemia (RI-AML) animal model. Iron overload was introduced via intraperitoneal injection of iron dextran, and iron chelation via oral gavage of deferasirox. A total of 86 irradiated B6D2F1 mice with various levels of iron burden were monitored for leukemia development over a period of 70 weeks. The Kaplan-Meier estimator was utilized to assess AML free survival. In addition, a second cohort of 30 mice was assigned for early analysis at 5 and 7 months post-irradiation. The BMCs of the early cohort were assessed for alterations of signaling pathways, DNA damage response and gene expression. Statistical significance was established using Student's t-test or ANOVA. RESULTS: Iron loading in irradiated B6D2F1 mice accelerated RI-AML development. However, there was a progressive decrease in AML risk for irradiated mice with increase in iron burden from 7.5 to 15 to 30 mg. In addition, ICT decreased AML incidence in the 7.5 mg iron-loaded irradiated mice, while AML onset was earlier for the 30 mg iron-loaded irradiated mice that received ICT. Furthermore, analysis of BMCs from irradiated mice at earlier intervals revealed accelerated dysregulation of signaling pathways upon iron loading, while ICT partially mitigated the effects. CONCLUSIONS: We concluded that iron is a promoter of leukemogenesis in vivo up to a peak iron dose, but further iron loading decreases AML risk by increasing cell death. ICT can partially mitigate the adverse effects of iron overload, and to maximize its benefit this intervention should be undertaken prior to the development of extreme iron overload.

Domestic radon exposure and risk of childhood leukemia: A meta-analysis.

PURPOSE: This meta-analysis evaluated the potential influence of environmental radon exposure on childhood leukemia. METHODS: We searched comprehensive electronic databases from PubMed, EMBASE, and Cochrane Library to identify studies evaluating the association between radon and leukemia. RESULTS: Ten eligible studies published from 1995 to 2014 were enrolled. Of these 10 studies, 8 were case-control studies (involving 10803 cases and 16202 controls) and 2 were cohort studies (involving 1,428 cases). Overall results as odds ratio (OR) with the corresponding 95% confidence intervals (95%CI) for case-control studies and fully adjusted hazard ratio (HR) with corresponding 95%CI for cohort studies were identified. A positive but weak association was found between radon exposure and childhood leukemia in case-control studies (summary OR 1.22, 95%CI 1.01-1.42) rather than cohort studies (summary HR 0.97, 95%CI 0.81-1.15). Heterogeneity or publication bias was not observed. Moreover, overall ORs were not changed by removing any single study, suggesting the stability and reliability of conclusions. CONCLUSIONS: Future prospective studies with well-controlled confounders are needed to verify the conclusion.

MYC copy number and mRNA expression in chronic lymphocytic leukemia patients exposed to ionizing radiation due to the Chornobyl NPP accident.

Some clinical and biological features indicating an unfavorable course of the disease were found in ionizing radiation (IR) - related chronic lymphocytic leukemia (CLL) patients. The MYC proto-oncogene is considered to contribute to CLL pathogenesis. Increased MYC copy number is associated with poor prognosis in CLL. AIM: To investigate the frequency of MYC gene copy number amplification in IR-exposed CLL patients and relate the findings to the MYC mRNA levels, the presence of unfavourable prognosis mutations (TP53, SF3B1, NOTCH1), and patient`s outcome. MATERIALS AND METHODS: The analysis of MYC copy number was carried out by real-time quantitative polymerase chain reaction (PCR) in 70 IR-exposed CLL patients. The MYC mRNA expression was measured by real-time quantitative reverse transcription PCR. RESULTS: Increased MYC gene copy number was present in 5.7% of cases. There was a statistically significant association between increased MYC copy number and increased MYC mRNA (p < 0.014). Additionally, somatic deletion in MYC locus was found in one patient. Most of patients (80%) with detected MYC aberrations were previously untreated, suggesting that these lesions might occur early in the course of the disease. The MYC aberrations were found mutually exclusive with high risk TP53 and SF3B1 mutations, while one case was identified, where MYC amplification and NOTCH1 mutation coincided simultaneously. Regarding clinical outcome, the MYC aberrations were associated with a shorter time to first treatment (3 vs 25 months, p = 0.008) as well as reduced overall survival (60 vs 139 months). CONCLUSION: Our data suggest that MYC aberrations might be an early event in IR-related CLL and contribute to aggressive disease development in the absence of high risk TP53 and SF3B1 mutations.

Risk of Leukemia Associated with Protracted Low-Dose Radiation Exposure: Updated Results from the National Registry for Radiation Workers Study.

While the link between risk of leukemia and acute radiation exposure is well established for large doses received acutely, uncertainty remains around the translation of these risk estimates to occupational exposure scenarios where the doses are low and accumulated over time, possibly over many years. We present leukemia incidence and mortality radiation risk estimates derived from the National Registry for Radiation Workers, which is a large cohort of occupationally exposed workers from the United Kingdom (UK). The cohort comprised 173,081 workers from the UK who were monitored for occupational exposure to radiation. The cohort was followed for a total of 5.3 million person-years and the incidence and mortality due to leukemia was identified through to the end of follow-up in 2011. Poisson regression was used to investigate the relationship between cumulative radiation dose and leukemia mortality and incidence rates using excess relative risk (ERR) and excess additive risk (EAR) models. The results of this work showed a collective dose of 4,414 person-Sv accumulated by the cohort with an average cumulative dose of 25.5 mSv. Among male workers both the ERR and EAR models showed evidence of increased leukemia risk (excluding chronic lymphatic leukemia) associated with increasing cumulative dose. The ERR was 1.38 per Sv (90% CI: 0.04; 3.24) and EAR was 1.33 per 10,000 person-year-Sv (90% CI: 0.04; 2.89) when a linear model was used. These excess risks were driven by increased risks for chronic myeloid leukemia [ERR/Sv = 6.77 (90% CI: 2.14; 15.44)]. In conclusion, this study provides further evidence that leukemia risks may be increased by low-dose and protracted external radiation exposure. The risks are generally consistent with those observed in the atomic bomb survivor studies, as well as with risk coefficients on which international radiation safety standards, including the dose limits and constraints used to control exposures, are based.

Influence of diet and metabolism on hematopoietic stem cells and leukemia development following ionizing radiation exposure.

PURPOSE: The review aims to discuss the prominence of dietary and metabolic regulators in maintaining hematopoietic stem cell (HSC) function, long-term self-renewal, and differentiation. RESULTS: Most adult stem cells are preserved in a quiescent, nonmotile state in vivo which acts as a "protective state" for stem cells to reduce endogenous stress provoked by DNA replication and cellular respiration as well as exogenous environmental stress. The dynamic balance between quiescence, self-renewal and differentiation is critical for supporting a functional blood system throughout life of an organism. Stress-conditions, for example ionizing radiation exposure can trigger the blood forming HSCs to proliferate and migrate through extramedullary tissues to expand the number of HSCs and increase hematopoiesis. In addition, a wealth of investigation validated that deregulation of this balance plays a critical pathogenic role in various different hematopoietic diseases including the leukemia development. CONCLUSION: The review summarizes the current knowledge on how alterations in dietary and metabolic factors could alter the risk of leukemia development following ionizing radiation exposure by inhibiting or even reversing the leukemic progression. Understanding the influence of diet, metabolism, and epigenetics on radiation-induced leukemogenesis may lead to the development of practical interventions to reduce the risk in exposed populations.

Exposure of remote organs and associated cancer risks from tangential and multi-field breast cancer radiotherapy.

PURPOSE: With the ever-increasing cure rates in breast cancer, radiotherapy-induced cancers have become an important issue. This study aimed to estimate secondary cancer risks for different treatment techniques, taking into account organs throughout the body. MATERIAL AND METHODS: Organ doses were evaluated for a tangential three-dimensional conformal (3D-CRT) and a multi-field intensity-modulated radiotherapy (IMRT) plan using a validated, Monte Carlo-based treatment planning system. Effects of wedges and of forward versus inverse planning were systematically investigated on the basis of phantom measurements. Organ-specific cancer risks were estimated using risk coefficients derived from radiotherapy patients or from the atomic bomb survivors. RESULTS: In the 3D-CRT plan, mean organ doses could be kept below 1 Gy for more remote organs than the lung, heart, and contralateral breast, and decreased to a few cGy for organs in the lower torso. Multi-field IMRT led to considerably higher mean doses in organs at risk, the difference being higher than 50% for many organs. Likewise, the peripheral radiation burden was increased by external wedges. No difference was observed for forward versus inverse planning. Despite the lower doses, the total estimated secondary cancer risk in more remote organs was comparable to that in the lung or the contralateral breast. For multi-field IMRT it was 75% higher than for 3D-CRT without external wedges. CONCLUSION: Remote organs are important for assessment of radiation-induced cancer risk. Remote doses can be reduced effectively by application of a tangential field configuration and a linear accelerator set-up with low head scatter radiation.

Tracking preleukemic cells in vivo to reveal the sequence of molecular events in radiation leukemogenesis.

Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1 GFP/mCh mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2. Moreover, following isolation of preleukemic hematopoietic stem and progenitor cells irradiated in their native microenvironment, we identified the presence of Sfpi1 point mutations within a subpopulation of these preleukemic cells expanding rapidly (increasing from 6% to 55% in 21 days in peripheral blood in one case), hence identifying for the first time the presence of such cells within a living animal. Importantly, we also report a previously undescribed gender difference in the phenotype of the preleukemic cells and leukemia, suggesting a gender imbalance in the radiation-induced leukemic target cell. In conclusion, we provide novel insights into the sequence of molecular events occurring during the (radiation-induced) leukemic clonal evolution.

Childhood leukaemia near nuclear sites in Belgium, 2002-2008.

This paper describes an ecological study investigating whether there is an excess incidence of acute leukaemia among children aged 0-14 years living in the vicinity of the nuclear sites in Belgium. Poisson regression modelling was carried out for proximity areas of varying sizes. In addition, the hypothesis of a gradient in leukaemia incidence with increasing levels of surrogate exposures was explored by means of focused hypothesis tests and generalized additive models. For the surrogate exposures, three proxies were used, that is, residential proximity to the nuclear site, prevailing winds and simulated radioactive discharges, on the basis of mathematical dispersion modelling. No excess incidence of acute leukaemia was observed around the nuclear power plants of Doel or Tihange nor around the nuclear site of Fleurus, which is a major manufacturer of radioactive isotopes in Europe. Around the site of Mol-Dessel, however, two- to three-fold increased leukaemia incidence rates were found in children aged 0-14 years living in the 0-5, 0-10 and the 0-15 km proximity areas. For this site, there was evidence for a gradient in leukaemia incidence with increased proximity, prevailing winds and simulated radioactive discharges, suggesting a potential link with the site that needs further investigation. An increased incidence of acute leukaemia in children aged 0-14 years was observed around one nuclear site that hosted reprocessing activities in the past and where nuclear research activities and radioactive waste treatment are ongoing.

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.

Myelodysplastic Syndromes and Acute Myeloid Leukemia After Radiotherapy for Prostate Cancer: A Population-Based Study.

BACKGROUND: To understand the impact of radiotherapy on the development of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) among elderly prostate cancer patients. METHODS: We performed a retrospective cohort study of elderly prostate cancer patients diagnosed during 1999-2011 by using the National Cancer Institute's Surveillance, Epidemiology and End Results-Medicare linked database. Competing risk analyses adjusting for patient characteristics were conducted to assess the impact of radiotherapy on the development of subsequent MDS/AML, compared with surgery. RESULTS: Of 32,112 prostate cancer patients, 14,672 underwent radiotherapy, and 17,440 received surgery only. The median follow-up was 4.68 years. A total of 157 (0.47%) prostate cancer patients developed subsequent MDS or AML, and the median time to develop MDS/AML was 3.30 (range: 0.16-9.48) years. Compared with prostate cancer patients who received surgery only, patients who underwent radiotherapy had a significantly increased risk of developing MDS/AML (hazard ratio [HR] =1.51, 95% confidence interval [CI]: 1.07-2.13). When radiotherapy was further categorized by modalities (brachytherapy, conventional conformal radiotherapy, and intensity-modulated radiotherapy [IMRT]), increased risk of second MDS/AML was only observed in the IMRT group (HR = 1.66, 95% CI: 1.09-2.54). CONCLUSIONS: Our findings suggest that radiotherapy for prostate cancer increases the risk of MDS/AML, and the impact may differ by modality. Additional studies with longer follow-up are needed to further clarify the role of radiotherapy in the development of subsequent myeloid malignancies. A better understanding may help patients, physicians, and other stakeholders make more informed treatment decisions. Prostate 77:437-445, 2017. © 2016 Wiley Periodicals, Inc.

External radiation dose and cancer mortality among French nuclear workers: considering potential confounding by internal radiation exposure.

OBJECTIVES: French nuclear workers have detailed records of their occupational exposure to external radiation that have been used to examine associations with subsequent cancer mortality. However, some workers were also exposed to internal contamination by radionuclides. This study aims to assess the potential for bias due to confounding by internal contamination of estimates of associations between external radiation exposure and cancer mortality. METHODS: A cohort of 59,004 workers employed for at least 1 year between 1950 and 1994 by CEA (Commissariat à l'Energie Atomique), AREVA NC, or EDF (Electricité de France) and badge-monitored for external radiation exposure were followed through 2004 to assess vital status and cause of death. A flag based on a workstation-exposure matrix defined four levels of potential for internal contamination. Standardized mortality ratios were assessed for each level of the internal contamination indicator. Poisson regression was used to quantify associations between external radiation exposure and cancer mortality, adjusting for potential internal contamination. RESULTS: For solid cancer, the mortality deficit tended to decrease as the levels of potential for internal contamination increased. For solid cancer and leukemia excluding chronic lymphocytic leukemia, adjusting the dose-response analysis on the internal contamination indicator did not markedly change the excess relative risk per Sievert of external radiation dose. CONCLUSIONS: This study suggests that in this cohort, neglecting information on internal dosimetry while studying the association between external dose and cancer mortality does not generate a substantial bias. To investigate more specifically the health effects of internal contamination, an effort is underway to estimate organ doses due to internal contamination.

Epidemiological study of power lines and childhood cancer in the UK: further analyses.

We report further analyses from an epidemiological study of childhood cancer and residence at birth near high-voltage power lines in the UK. These results suggest that the elevated risks for childhood leukaemia that we previously found for overhead power lines may be higher for older age at diagnosis and for myeloid rather than lymphoid leukaemia. There are differences across regions of birth but not forming any obvious pattern. Our results suggest the decline in risk we previously reported from the 1960s to the 2000s is linked to calendar year of birth or of cancer occurrence rather than the age of the power lines concerned. Finally, we update our previous analysis of magnetic fields to include later subjects.

Childhood CT scans and cancer risk: impact of predisposing factors for cancer on the risk estimates.

To investigate the role of cancer predisposing factors (PFs) on the associations between paediatric computed tomography (CT) scan exposures and subsequent risk of central nervous system (CNS) tumours and leukaemia. A cohort of children who underwent a CT scan in 2000-2010 in 23 French radiology departments was linked with the national childhood cancers registry and national vital status registry; information on PFs was retrieved through hospital discharge databases. In children without PF, hazard ratios of 1.07 (95% CI 0.99-1.10) for CNS tumours (15 cases) and 1.16 (95% CI 0.77-1.27) for leukaemia (12 cases) were estimated for each 10 mGy increment in CT x-rays organ doses. These estimates were similar to those obtained in the whole cohort. In children with PFs, no positive dose-risk association was observed, possibly related to earlier non-cancer mortality in this group. Our results suggest a modifying effect of PFs on CT-related cancer risks, but need to be confirmed by longer follow-up and other studies.

Deregulated Levels of the NF-κB1, NF-κB2, and Rel Genes in Ukrainian Patients with Leukemia and Lymphoma in the Post-Chernobyl Period.

OBJECTIVE: Nuclear factor kappa B (NF-κB) is an important transcription factor in cancer and NF-κB activation has been seen in angiogenesis, tumor progression, and metastasis. Relationships between specific NF-κB gene networks, leukemogenesis, and radiation exposure are still unknown. Our aim was to study the expression levels of the NF-κB1, NF-κB2, and Rel genes in hematological malignancies in the post-Chernobyl period. MATERIALS AND METHODS: We analyzed gene expression levels of NF-κB1, NF-κB2, and Rel in 49 B-cell chronic lymphocytic leukemia, 8 B-cell non-Hodgkin's lymphoma, 3 acute myeloid leukemia, 3 chronic myeloid leukemia, 2 hairy cell leukemia, 2 myelodysplastic syndrome, and 2 T-cell large granular lymphocytic leukemia patients using real-time polymerase chain reaction. RESULTS: Expression levels of NF-κB1, NF-κB2, and Rel genes were found to be deregulated. CONCLUSION: These results could be accepted as specific gene traces to radiation-induced leukemia or as potential candidates for new diagnostic biomarker studies. Larger experiments and non-exposed control malignant cell populations are needed to clarify these suggestions.

Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X-Irradiation.

Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described, which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min), resulting in an approximate LD10/60 (n = 5/59). Animals received medical management, and hematopoietic and immune cell recovery was assessed (n ≤ 14) through 370 d post exposure. A subset of animals (n ≤ 8) was examined through 700 d. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia, and thrombocytopenia resolved within 30 d. Total CD3+ cells µL required 60 d to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 d post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naïve subsets were markedly different. Memory populations were ≥ 100% of normal by day 60, whereas naïve populations were only 57% normal at 180 d and never fully recovered to baseline post irradiation. Total (CD20+) B cells µL were within normal levels by 77 d post exposure. This animal model elucidates the variable T- and B-cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion, and thymopoiesis.