Risk of Hematologic Malignancies in Elderly Patients With Ankylosing Spondylitis: A Cohort Study and Systematic Review.

OBJECTIVE: To examine the risk of hematologic malignancies in older adults with ankylosing spondylitis (AS). PATIENTS AND METHODS: We used US Medicare data from January 1, 1999, to December 31, 2010, to identify a population-based cohort of beneficiaries with AS. We also included beneficiaries with inflammatory bowel disease (IBD) as disease controls and beneficiaries without AS or IBD as unaffected controls. We excluded those treated with tumor necrosis factor inhibitors in this period. We followed up each group for new diagnosis claims for hematologic malignancies until September 30, 2015. RESULTS: We included 12,451 beneficiaries with AS, 234,905 with IBD, and 10,975,340 unaffected controls, with a mean follow-up of 9.9, 9.3, and 8.0 years, respectively. We identified 297 hematologic malignancies in the AS group, 4538 malignancies in the IBD group, and 128,239 malignancies in unaffected controls. The standardized incidence ratio in AS vs unaffected controls was 1.39 (95% CI, 1.05 to 1.61) for non-Hodgkin lymphoma, 1.50 (95% CI, 1.17 to 1.92) for chronic lymphocytic leukemia, and 1.52 (95% CI, 1.12 to 2.06) for multiple myeloma. Risks of acute myeloid leukemia and chronic myeloid leukemia were not elevated in AS, and there were too few cases of Hodgkin lymphoma to compute risks. Risks were comparable to those of beneficiaries with IBD. We also performed a systematic literature review of the risk of hematologic malignancy in AS, focusing on age associations, which have not been previously examined. We identified 21 studies in the systematic literature review, which included mainly young or middle-aged patients. Results suggested that AS was largely not associated with an increased risk of hematologic malignancies. Two cohort studies reported an increased risk of multiple myeloma in AS. CONCLUSION: The risks of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma are increased among elderly patients with AS.

Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients

Objective: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. Materials and Methods: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors' and ALL/NHL patients' peripheral blood mononuclear cells. Results: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice. Conclusion: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.

Serological Assessment of 18 Pathogens and Risk of AIDS-Associated Non-Hodgkin Lymphoma.

BACKGROUND: HIV infection is associated with increased susceptibility to common pathogens, which may trigger chronic antigenic stimulation and hyperactivation of B cells, events known to precede the development of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL). METHODS: To explore whether cumulative exposure to infectious agents contributes to AIDS-NHL risk, we tested sera from 199 AIDS-NHL patients (pre-NHL, average lead time 3.9 years) and 199 matched HIV-infected controls from the Multicenter AIDS Cohort Study, for anti-IgG responses to 18 pathogens using multiplex serology. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models. RESULTS: We found no association between cumulative exposure to infectious agents and AIDS-NHL risk (OR 1.01, 95% CI: 0.91 to 1.12). However, seropositivity for trichodysplasia spinulosa polyomavirus (TSPyV), defined as presence of antibodies to TSPyV capsid protein VP1, was significantly associated with a 1.6-fold increase in AIDS-NHL risk (OR 1.62, 95% CI: 1.02 to 2.57). High Epstein-Barr virus (EBV) anti-VCA p18 antibody levels closer to the time of AIDS-NHL diagnosis (<4 years) were associated with a 2.6-fold increase in AIDS-NHL risk (OR 2.59, 95% CI: 1.17 to 5.74). In addition, high EBV anti-EBNA-1 and anti-ZEBRA antibody levels were associated with 2.1-fold (OR 0.47, 95% CI: 0.26 to 0.85) and 1.6-fold (OR 0.57, 95% CI: 0.35 to 0.93) decreased risk of AIDS-NHL, respectively. CONCLUSIONS: Our results do not support the hypothesis that cumulative exposure to infectious agents contributes to AIDS-NHL development. However, the observed associations with respect to TSPyV seropositivity and EBV antigen antibody levels offer additional insights into the pathogenesis of AIDS-NHL.

Projected Cancer Incidence Rates and Burden of Incident Cancer Cases in HIV-Infected Adults in the United States Through 2030.

Background: Persons living with HIV (PLWH) have an elevated risk for certain types of cancer. With modern antiretroviral therapy, PLWH are aging and cancer rates are changing. Objective: To project cancer incidence rates and burden (number of new cancer diagnoses) among adult PLWH in the United States through 2030. Design: Descriptive. Setting: HIV/AIDS Cancer Match Study to project cancer rates and HIV Optimization and Prevention Economics model to project HIV prevalence. Participants: HIV-infected adults. Measurements: Projected cancer rates and burden among HIV-infected adults in the United States by age during 2006 to 2030 for AIDS-defining cancer (ADC)-that is, Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer-and certain types of non-AIDS-defining cancer (NADC). All other cancer types were combined. Results: The proportion of adult PLWH in the United States aged 65 years or older is projected to increase from 8.5% in 2010 to 21.4% in 2030. Age-specific rates are projected to decrease through 2030 across age groups for Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer, lung cancer, Hodgkin lymphoma, and other cancer types combined, and among those aged 65 years or older for colon cancer. Prostate cancer rates are projected to increase. The estimated total cancer burden in PLWH will decrease from 8150 cases in 2010 (2730 of ADC and 5420 of NADC) to 6690 cases in 2030 (720 of ADC and 5980 of NADC). In 2030, prostate cancer (n = 1590) and lung cancer (n = 1030) are projected to be the most common cancer types. Limitation: Projections assume that current trends in cancer incidence rates, HIV transmission, and survival will continue. Conclusion: The cancer burden among PLWH is projected to shift, with prostate and lung cancer expected to emerge as the most common types by 2030. Cancer will remain an important comorbid condition, and expanded access to HIV therapies and cancer prevention, screening, and treatment is needed. Primary Funding Source: National Cancer Institute.

Comprehensive Evaluation of Medical Conditions Associated with Risk of Non-Hodgkin Lymphoma using Medicare Claims ("MedWAS").

BACKGROUND: Certain medical conditions affect risk of non-Hodgkin lymphoma (NHL), but the full range of associations is unknown. We implemented a novel method ("medical condition-wide association study," MedWAS) to comprehensively evaluate medical risk factors for NHL documented in administrative health claims. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we conducted a case-control study comparing NHL cases [N = 52,691, age 66+ years, with five subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), T-cell lymphoma (TCL)] to controls (N = 200,000). We systematically screened for associations with 5,926 medical conditions documented in Medicare claims more than 1 year before selection. RESULTS: Fifty-five conditions were variously associated with NHL. Examples include well-established associations of human immunodeficiency virus, solid organ transplantation, and hepatitis C virus with increased DLBCL risk (ORs 3.83, 4.27, and 1.74, respectively), and autoimmune conditions with DLBCL and MZL (e.g., ORs of 2.10 and 4.74, respectively, for Sjögren syndrome). Risks for all NHL subtypes were increased after diagnoses of nonmelanoma skin cancer (ORs 1.19-1.55), actinic keratosis (1.12-1.25), or hemolytic anemia (1.64-4.07). Nine additional skin conditions increased only TCL risk (ORs 2.20-4.12). Diabetes mellitus was associated with increased DLBCL risk (OR 1.09). Associations varied significantly across NHL subtypes for 49 conditions (89%). CONCLUSION: Using an exploratory method, we found numerous medical conditions associated with NHL risk, and many associations varied across NHL subtypes. IMPACT: These results point to etiologic heterogeneity among NHL subtypes. MedWAS is a new method for assessing the etiology of cancer and other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1105-13. ©2016 AACR.

Assessment of BCL2/J(H) translocation in healthy individuals exposed to low-level radiation of 137CsCl in Goiânia, Goiás, Brazil.

Healthy radio-exposed individuals who received low levels of Cesium-137 radiation during the accident that occurred in Goiânia in 1987, their families and controls were tested for the detection of t(14;18)-rearranged B cells in peripheral blood by using a highly sensitive, real-time quantitative PCR method. The chromosomal translocation t(14;18)(q32;q21) is characteristic of follicular lymphoma and is a frequent abnormality observed in other types of non-Hodgkin's lymphoma. This translocation leads to constitutive activation of the BCL2 oncogene by the enhancers of the immunoglobulin heavy-chain locus. In healthy individuals, the same translocation may also be found in a small fraction of peripheral blood lymphocytes, and positive cells might serve as an indicator for environmental exposure to carcinogens and possibly correlate with the cumulative risk of developing t(14;18)- positive non-Hodgkin's lymphoma. Twenty healthy radio-exposed individuals, 10 relatives and 10 non-exposed healthy individuals were tested for the detection of this translocation. Only 1 non-exposed individual was positive for the chromosomal translocation, and healthy radio-exposed individuals presented lower levels of cells bearing the BCL2/J(H) rearrangement when compared to the levels of the patients with follicular lymphoma before treatment. However, evaluation of more cells would be required to confirm the total absence of circulating cells bearing BCL2/J(H) rearrangement.

Pediatric kidney transplantation: analysis of donor age, HLA match, and posttransplant non-Hodgkin lymphoma: a collaborative transplant study report.

BACKGROUND: The impact and relationship of donor age, human leukocyte antigen (HLA) matching, and posttransplant non-Hodgkin lymphoma in pediatric kidney recipients are not completely understood. METHODS: We analyzed Collaborative Transplant Study data from 9209 pediatric kidney transplant recipients to examine the effects of donor age and HLA match on graft survival and the relationship between HLA match and occurrence of non-Hodgkin lymphoma. RESULTS: Survival rates using donors aged 11 to 17, 18 to 34, or 35 to 49 years were similar. Cox regression analysis showed that two HLA-DR mismatches were associated with lower graft survival in transplants performed during 1988 to 1997 (P<0.001) but not during the 1998 to 2007 period (P=0.95). A hierarchical relationship was observed for the effect of increasing numbers of combined HLA-A+B+DR mismatches on graft survival during the 1988 to 1997 (P<0.001) and the 1998 to 2007 period (P<0.001). An association between two HLA-DR mismatches and non-Hodgkin lymphoma was demonstrated by multivariate analysis (hazard ratio for 2 vs. 0-1 DR mismatches 2.04, P=0.021), and the result was consistent during both 10-year periods. CONCLUSION: We recommend that (1) kidneys from deceased donors up to 49 years be allocated to children, (2) an acceptable HLA-A+B+DR match be attempted in patients with relatively common HLA phenotypes, and (3) transplants with two HLA-DR mismatches be avoided to reduce the risk of posttransplant non-Hodgkin lymphoma.

Assessment of patients with primary Sjögren's syndrome--outcome over 10 years using the Sjögren's Syndrome Damage Index.

OBJECTIVE: To evaluate the long-term outcome in a cohort of patients with primary SS (PSS) using the recently proposed Sjogren's Syndrome Damage Index. METHODS: We reviewed the clinical records of 60 patients attending our Sjögren's clinic at University College London Hospital, who strictly fulfilled the American-European Consensus Group criteria and on whom we had a minimum of 10 years of follow-up (or until death) during this decade. However, we could not retrospectively identify damage in the oral domain as this had not been recorded reliably. RESULTS: Fifty-five per cent of patients in this study had no damage after 10 years of disease--a lower figure than our comparative group of patients with SLE (32.4%). Damage accrual was mostly in the ocular domain, parotid swelling and malignancy categories. There was a 6-fold increase in the 'malignancy damage' compared with the 2-fold increase in the total damage score in PSS. CONCLUSIONS: Unlike patients with SLE, it is clear that fewer patients with SS develop permanent damage, even after 10 years of follow-up. These data are thus encouraging but clearly larger numbers of patients need to be assessed.

Socio-economic deprivation and survival of non-Hodgkin lymphoma in Scotland.

Socio-economic deprivation is known to be associated with poorer survival from non-Hodgkin lymphoma (NHL) but routine data have not been able to determine whether this can be explained by differences in disease severity at presentation. We examined survival in all patients diagnosed with NHL in Scotland between 1979 and 1996 and between 1994 and 1996 used Scotland and Newcastle Lymphoma Group data, which include detailed clinical staging information. Compared with individuals from the most affluent areas, survival is 10% poorer in intermediate, and 19% poorer in patients living in the most deprived areas. Deprivation is associated with more B symptoms and poorer performance status but not with other indicators of more advanced disease, suggesting that the disease may be more aggressive or immunocompetence poorer among more deprived populations. We also noted improvements in relative survival from NHL over time.

Assessment of ecological regression in the study of colon, breast, ovary, non-Hodgkin's lymphoma, or prostate cancer and residential UV.

Recent ecological studies have suggested a possible association between exposure to ultraviolet-B (UVB) radiation and reduction in the risk of various cancers; however, ecological studies are known to be subject to bias. The objective of this study was to demonstrate difficulties with the ecological approach. We conducted a multicountry ecological study using cancer incidence rates, residential UV levels, dietary intake, and different sociodemographic variables for 38 locations spanning 33 countries worldwide. The effect of residential UV exposure on cancer incidence was assessed using multiple linear regression models. The results of our multivariate analyses show no indication of an inverse association between residential UV levels and the risk of colon, non-Hodgkin's lymphoma (NHL), ovarian, prostate, or breast cancer in women. For colon cancer and NHL, a significant positive association was calculated. The rates of melanoma, which were used to examine the methods of this study, showed a strong and significant (P<0.01) association with solar radiation. Our results provide no evidence to support previous ecological results that UV exposure may reduce the risk of NHL, colon, breast, ovary, or prostate cancer. The study demonstrates the high sensitivity of ecological studies to adjustments for various confounders, and casts doubts on results of ecological analyses in this field.

Screening for celiac disease in asymptomatic children with Down syndrome: cost-effectiveness of preventing lymphoma.

BACKGROUND: Studies demonstrate an increased prevalence of celiac disease in persons with Down syndrome, leading some organizations and authors to recommend universal screening of children with Down syndrome. However, many children with Down syndrome are asymptomatic, and the long-term implications of screening are unknown. The complication of celiac disease that leads to mortality in the general population is non-Hodgkin's lymphomas. OBJECTIVES: The purpose of this research in asymptomatic children with Down syndrome was to (1) calculate the number needed to screen to prevent a single case of lymphoma and (2) present a cost-effectiveness study of screening. METHODS: We constructed a decision tree using probabilities derived from the published literature for Down syndrome or from the general population where Down syndrome-specific data were not available. Celiac disease was determined by serologic screening and confirmation with intestinal biopsy. Sensitivity analysis was used to alter probability estimates affecting the cost of preventing lymphoma. RESULTS: Using our baseline values, the no-screen strategy is dominant; that is, screening not only costs more but also results in fewer quality-adjusted life-years. A screening strategy costs more than $500,000 per life-year gained. Screening all asymptomatic children with Down syndrome for celiac disease costs almost $5 million to prevent a single case of lymphoma. CONCLUSION: These analyses do not support the cost-effectiveness of screening, and more data are needed before recommendations to screen asymptomatic children with Down syndrome for celiac disease can be made.

Non-Hodgkin's lymphoma: in a class all its own.

Non-Hodgkin's lymphoma (NHL) incidence rates have increased more than 50% over the past 15 years, making it the sixth leading cause of death from cancer in the United States and the fourth most significant malignancy in terms of economic impact. Comparable trends are noted worldwide. Improved diagnostic techniques have resulted in reclassifying some tumors that in the past would have been classified as Hodgkin's disease. In this article, the latest diagnostic, prognostic, and treatment options for NHL are reviewed and a cross-reference chart for these evolving class systems provided.

Case-control assessment of the association between non-Hodgkin's lymphoma and occupational radiation with doses assessed using a job exposure matrix.

BACKGROUND: Epidemiologic data for an association between radiation exposure and non-Hodgkin's lymphoma (NHL) have been inconclusive though the strongest evidence has been provided by studies of patients treated with radiotherapy. METHODS: We evaluated the association between occupational radiation exposure and non-Hodgkin's lymphoma in men using a population-based case-control study with 1,056 case and 1,860 control subjects sampled from eight geographic areas in the United States. Because dosimetry data were not available, doses were estimated for individuals who reported occupational radiation exposure using a radiation job exposure matrix developed for this purpose. Conditional logistic regression was used to model the association between reported occupational radiation exposure and NHL incidence. RESULTS: We found that most men (> 90%) did not report exposure to occupational sources of radiation. Among those who reported exposure, estimated cumulative doses were low, with an estimated mean of less than 0.02 Gray and a maximum of 0.12 Gray. The risk for NHL was not associated with ever having reported an occupational radiation exposure (OR = 0.90, 95% CI = 0.74-1.10) nor was there evidence of a dose-response relationship between risk and either the estimated cumulative doses or duration of exposure. CONCLUSIONS: The findings in this study are consistent with results from most current research on occupational radiation and NHL risk that have found no increased risk of NHL at low levels of occupational radiation exposure. While it should be noted that exposure misclassification likely biased our results toward the null, this large population-based case-control study adds to existing evidence which suggests that there is little to no increased risk for NHL associated with exposure to low levels of radiation such as that commonly found in many occupational settings.

Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group.

We describe the anatomic and histologic presentation and prognosis of non-Hodgkin's lymphoma (NHL) among people with AIDS (PWA) and determine their contribution to the NHL burden. We linked AIDS and cancer registries in selected areas of the United States and compared NHL sites and histologies in PWA and non-PWA, after adjusting for age, sex and ethnicity. Among 51,033 PWA, we found 2,156 cases of NHL (4.3%). Half of NHL cases occurring post-AIDS were not reported to AIDS registries. NHL was part of an AIDS-defining condition for 3.2% of all PWA; the relative risk of NHL with 3.5 years of another AIDS diagnosis was 165-fold compared to non-PWA within the cancer surveillance system. Of NHLs, 39% were high grade (vs. 12% among non-PWA), 60% were nodal (vs. 74% among non-PWA) and 15% had brain primaries (vs. 1% among non-PWA). Excluding brain sites, extranodal sites were still 20% more common than expected. Relative risk was elevated for all histologic types, with the risk ranging from 652-fold for high-grade diffuse immunoblastic tumors and 261-fold for Burkitt's lymphomas to 113 for intermediate-grade lymphoma to 14-fold for low-grade lymphoma. Survival among PWA with NHL was poor, and tumor grade had little impact. In high-risk AIDS areas, AIDS-related NHLs constitute a major share of the NHL burden. We conclude that NHL risk is considerably under-estimated in AIDS registry data. The major differences between PWA and non-PWA were the high frequency of brain lymphoma and the increase in high-grade lymphomas in PWA. However, the grade of NHL did not influence the prognosis among PWA with lymphoma. The increasing risk of NHL in PWA has contributed substantially to the general increase in NHL rates in the United States since 1981.

Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma.

Exposure to diagnostic x-rays and the risk of leukemia, non-Hodgkin's lymphoma (NHL), and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565), NHL (n = 318), and multiple myeloma (n = 208) were matched to controls (n = 1390), and over 25,000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia, one of the few malignant conditions never linked to radiation (relative risk [RR], 0.66). For all other forms of leukemia combined (n = 358), there was a slight elevation in risk (RR, 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly, patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR, 1.32), but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma, overall risk was not significantly high (RR, 1.14), but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma, however, was increased among those patients who were frequently exposed to x-rays.