Occupational Exposure to Pesticides and Chronic Lymphocytic Leukaemia in the MCC-Spain Study.

We aimed to study the association between occupational exposure to pesticides and chronic lymphocytic leukemia (CLL) in Spain. Occupational exposure to pesticides (four insecticides, four herbicides and two fungicides) was evaluated using a job-exposure matrix for the Spanish population (MatEmESp) among 302 CLL cases and 1567 population controls in five regions of Spain, 2010-2013. Cumulative exposure scores (CES) were obtained by summing across the exposed jobs the product of prevalence, intensity and duration of exposure to each active substance. Principal components analysis (PCA) and logistic regression models adjusted for age, sex, region, education and occupational exposure to solvents were used. Around 20% of controls and 29% of cases were exposed to one or more pesticides. Compared to non-exposed, subjects in the highest tertile (3rd tertile) of CES of insecticides, herbicides, fungicides were more likely to have CLL [OR (95% CI), P-trend; 2.10 (1.38; 3.19), 0.002; 1.77 (1.12; 2.80), 0.12; and 1.67 (1.06; 2.64), 0.10, respectively). Following PCA, the first component (PC1, explaining 70% of the variation) equally led by seven active substances (the insecticide pyrethrin, all herbicides, all fungicides) was associated with a 26% higher odds of having CLL for 1-standard deviation increase in PC1 (95% CI: 1.14 to 1.40). These results confirm previous associations between CLL and exposure to pesticides and provide additional evidence by application groups and active substance. However, more research is needed to disentangle independent effects of individual active substances.

Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Adherence to the 2018 WCRF/AICR cancer prevention guidelines and chronic lymphocytic leukemia in the MCC-Spain study.

INTRODUCTION: Preventable risk factors for chronic lymphocytic leukemia (CLL) remain largely unknown. The aim of this study was to evaluate the association between adherence to nutrition-based guidelines for cancer prevention and CLL, in the MCC-Spain case-control study. METHODS: A total of 318 CLL cases and 1293 population-based controls were included in the present study. The World Cancer Research Fund/American Institute for Cancer Research (WCRC/AICR) score based on the 2018 recommendations for cancer prevention (on body fatness, physical activity, and diet) was constructed. We used logistic regression analysis adjusting for potential confounders. RESULTS: Individuals in the highest tertile of the WCRF/AICR score had an odds ratio for CLL of 1.25 (95 % CI 0.91; 1.73) compared with individuals with low adherence (p-trend = 0.172). Each point increment in the score was associated with an OR for CLL of 1.06 (95 % CI 0.91; 1.23). Analyses by severity of disease did not show significant heterogeneity of effects. CONCLUSION: Overall, our results do not support an association between the WCRF/AICR score and CLL, yet we might have been limited by statistical power and study design to detect modest associations. Further research, ideally with a prospective design, long follow-up, and including additional lymphoma subtypes, is warranted to confirm the impact of composite healthy lifestyle behaviors on lymphoma risk.

Anthracycline-induced cardiotoxicity in diffuse large B-cell lymphoma: NT-proBNP and cardiovascular score for risk stratification.

OBJECTIVE: To evaluate the role of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and a cardiovascular (CV) risk score named FRESCO for predicting anthracycline-induced cardiotoxicity (AIC) in diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 130 consecutive DLBCL patients treated in first-line with anthracycline-containing immunochemotherapy. Competitive risk between NT-proBNP, FRESCO, and time to AIC was considered. RESULTS: Cumulative incidence of AIC was 12.2% and 17.5% at 1 and 5 years, respectively. Median time to development cardiotoxicity was 6.4 months, with half of the cases showing heart failure and the other half silent AIC. Both NT-proBNP levels and FRESCO score were independently associated with higher risk of AIC (P = 0.001 and P = 0.03, respectively). Patients with NT-proBNP ≥600 pg/mL or those with FRESCO ≥4.5% had 3.97 or 2.54 times higher risk of AIC than those with lower values (P = 0.001 and P = 0.048, respectively). According to the previous cutoffs, three groups of patients with a significantly different risk of AIC could be identified (P < 0.0001). CONCLUSIONS: Doxorubicin-containing chemotherapy is associated with increased risk of silent and overt AIC. Baseline NT-proBNP levels and FRESCO CV risk score are accurate predictors of AIC and can identify groups of patients at different risk, in which personalized cardiologic evaluation should be offered.

Established and suggested exposures on CLL/SLL etiology: Results from the CLL-MCC-Spain study.

INTRODUCTION: Chronic Lymphocytic Leukemia (CLL/SLL) is the most common adult leukemia in Western countries. Although it is mostly an indolent disease it is still incurable and with limited knowledge in relation to its etiology. We aim to confirm and quantify established risk factors for CLL/SLL using a multi-center epidemiological population-based case-control study on CLL/SLL as well as to explore new exposures inconclusively associated with CLL/SLL METHODS: Using the framework provided by the large MCC-Spain case-control study, we explored established and suggested risk factors associated with CLL/SLL using data collected through a face-to-face interview. We estimated odds ratios (OR) and confidence intervals (CI) adjusted by basic confounders, in 1,845 controls from the general population and 560 CLL/SLL from 5 different Spanish regions. RESULTS: Among the established risk factors, CLL/SLL cases were 3 times more likely to report first degree relatives with an hematological cancer (OR = 3.11, 95% CI 2.10 to 4.61) and nearly twice likely to have ever worked in agriculture (OR = 1.70, 95% CI = 1.34 to 2.16). New findings suggest that women with CLL/SLL were more likely to have central obesity (OR = 1.67 95% CI = 1.12 to 2.48). An inverse association was found for current alcohol consumption (p-trend<0.016) and for type II diabetes. CONCLUSION: We confirmed previous established risk factors for CLL/SLL. Among the new findings, further research of central obesity as preventable exposure and the treatment for type II diabetes are warranted.

Night shift work and chronic lymphocytic leukemia in the MCC-Spain case-control study.

Chronic lymphocytic leukemia (CLL) has few known modifiable risk factors. Recently, circadian disruption has been proposed as a potential contributor to lymphoid neoplasms' etiology. Serum melatonin levels have been found to be significantly lower in CLL subjects compared with healthy controls, and also, CLL prognosis has been related to alterations in the circadian molecular signaling. We performed the first investigation of an association between night shift work and CLL in 321 incident CLL cases and 1728 population-based controls in five areas of Spain. Participants were interviewed face-to-face by trained interviewers to collect information on sociodemographic factors, familial, medical and occupational history, including work shifts and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). Seventy-nine cases (25%) and 339 controls (20%) had performed night work. Overall, working in night shifts was not associated with CLL (OR = 1.06; 95% CI = 0.78-1.45, compared with day work). However, long-term night shift (>20 years) was positively associated with CLL (OR(tertile 3 vs . day-work) = 1.77; 95% = 1.14-2.74), although no linear trend was observed (P trend = 0.18). This association was observed among those with rotating (OR(tertile 3 vs . day-work) = 2.29; 95% CI = 1.33-3.92; P trend = 0.07), but not permanent night shifts (OR(tertile 3 vs . day-work) = 1.16; 95% CI = 0.60-2.25; P trend = 0.86). The association between CLL and long-term rotating night shift warrants further investigation.