The absolute risk reduction by prophylaxis in chemotherapy-induced febrile neutropenia (FN) is largest in patients at highest underlying risk. Therefore, reliable predictive models are needed. Here, ...we develop and validate such a model for risk of FN during chemotherapy cycles 2-6. A prediction score for risk of FN during the first cycle has recently been published. Patients with solid cancers initiating first-line chemotherapy in 2010-2016 were included. Cycle-specific risk factors were assessed by Poisson regression using generalized estimating equations and random split sampling. The derivation cohort included 4,590 patients treated with 15,419 cycles, wherein 326 (2.1%) FN events occurred. Predictors of FN in multivariable analyses were: higher predicted risk of FN in the first cycle, platinum- or taxane-containing therapies, concurrent radiotherapy, treatment in cycle 2 compared to later cycles, previous FN or neutropenia and not receiving granulocyte colony-stimulating factors. Each predictor added between -2 and 8 points to each patient's score (median score 4; interquartile range, 1-6). The incidence rate ratios for developing FN in the intermediate (score 1-4), high (score 5-6) and very high risk groups (score ≥7) were 7.8 (95% CI, 2.4-24.9), 18.6 (95% CI, 5.9-58.8) and 51.7 (95% CI, 16.5-162.3) compared to the low risk group (score ≤0), respectively. The score had good discriminatory ability with a Harrell's C-statistic of 0.78 (95% CI, 0.76-0.80) in the derivation and 0.75 (95% CI, 0.72-0.78) in the validation cohort (patient n = 2,295, cycle n = 7,670). The Cycle-Specific Risk of FEbrile Neutropenia after ChEmotherapy score is the first published method to estimate cycle-specific risk of FN.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The absolute risk reduction by prophylaxis in chemotherapy‐induced febrile neutropenia (FN) is largest in patients at highest underlying risk. Therefore, reliable predictive models are needed. Here, ...we develop and validate such a model for risk of FN during chemotherapy cycles 2–6. A prediction score for risk of FN during the first cycle has recently been published. Patients with solid cancers initiating first‐line chemotherapy in 2010–2016 were included. Cycle‐specific risk factors were assessed by Poisson regression using generalized estimating equations and random split sampling. The derivation cohort included 4,590 patients treated with 15,419 cycles, wherein 326 (2.1%) FN events occurred. Predictors of FN in multivariable analyses were: higher predicted risk of FN in the first cycle, platinum‐ or taxane‐containing therapies, concurrent radiotherapy, treatment in cycle 2 compared to later cycles, previous FN or neutropenia and not receiving granulocyte colony‐stimulating factors. Each predictor added between −2 and 8 points to each patient's score (median score 4; interquartile range, 1–6). The incidence rate ratios for developing FN in the intermediate (score 1–4), high (score 5–6) and very high risk groups (score ≥7) were 7.8 (95% CI, 2.4–24.9), 18.6 (95% CI, 5.9–58.8) and 51.7 (95% CI, 16.5–162.3) compared to the low risk group (score ≤0), respectively. The score had good discriminatory ability with a Harrell's C‐statistic of 0.78 (95% CI, 0.76–0.80) in the derivation and 0.75 (95% CI, 0.72–0.78) in the validation cohort (patient n = 2,295, cycle n = 7,670). The Cycle‐Specific Risk of FEbrile Neutropenia after ChEmotherapy score is the first published method to estimate cycle‐specific risk of FN.
What's new?
Febrile neutropenia (FN), involving fever and abnormally low neutrophil count, is a severe complication of chemotherapy. Current guidelines suggest assessing FN risk at the start of each chemotherapy cycle in order to prevent or better manage the condition if it arises. Here, to improve FN prediction, the authors developed the Cycle‐Specific Risk of FEbrile Neutropenia after ChEmotherapy (CSRFENCE) score. Risk factors were analyzed by Poisson regression for 6,885 patients with solid cancers who received standard first‐line chemotherapy in cycles 2‐6. In derivation and validation cohorts, the CSRFENCE score was found to successfully predict FN risk at cycle initiation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Febrile neutropenia (FN) is a critical complication of chemotherapy associated with increased in‐hospital mortality. However, associations with increased mortality and intensive care unit (ICU) ...admissions during longer follow‐up are not established. Patients treated with standard first‐line chemotherapy for solid cancers at Rigshospitalet, Denmark in 2010‐2016 were included. Incidence rate ratios (IRR) of all‐cause, infectious and cardiovascular mortality, and ICU admissions after FN were analyzed by Poisson regression. Risk factors at the time of FN were analyzed in the subpopulation of patients with FN; all‐cause mortality was further stratified by the time periods 0‐30, 31‐365, and 366+ days after FN. We included 9018 patients with gastric (14.4%) and breast (13.1%) cancer being the most common, 51.2% had locally advanced or disseminated disease and the patients had a median Charlson Comorbidity Index score of 0 (interquartile range, 0‐0). During follow‐up, 845 (9.4%) experienced FN and 4483 (49.7%) died during 18 775 person‐years of follow‐up. After adjustment, FN was associated with increased risk of all‐cause mortality, infectious mortality, and ICU admissions with IRRs of 1.39 (95% CI, 1.24‐1.56), 1.94 (95% CI, 1.43‐2.62), and 2.28 (95% CI, 1.60‐3.24). Among those with FN, having a positive blood culture and low lymphocytes were associated with excess risk of death and ICU admissions (predominantly the first 30 days after FN), while elevated C‐reactive protein and low hemoglobin predicted mortality the first year after FN. The risk of death varied according to the time since FN; adjusted IRR per additional risk factor present for the time periods 0‐30, 31‐365, and 366+ days after FN were 2.00 (95% CI, 1.45‐2.75), 1.36 (95% CI, 1.17‐1.57), and 1.17 (95% CI, 0.98‐1.41). FN was associated with increased mortality and risk of ICU admissions. An objectively identifiable subgroup of patients among those with FN carried this excess risk.
Febrile neutropenia (FN) is a severe complication to chemotherapy. However, associations between FN and longer term clinical outcomes are poorly elucidated. Among 9018 patients with solid cancers followed for 18 775 person‐years after initiating first‐line chemotherapy FN was associated with increased risk of all‐cause and infectious mortality and risk of intensive care unit admissions. A range of risk factors at the time of FN were found that identified a subgroup of patients carrying a grave prognosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
Emerging EBV DNAemia in plasma is considered an early sign of post-transplant lymphoproliferative disorder (PTLD). The aim of this study was to quantify the extent of benefit from screening ...for EBV DNAemia to detect emerging PTLD among solid organ (SOT) or hematopoietic stem cell transplant recipients (HSCT).
Methods
We used receiver operating characteristic (ROC) curves for assessing ability of models to predict PTLD. Among 2642 recipients transplanted between January 2004 and December 2014, 79 (3%) developed PTLD.
Results
EBV DNAemia was observed in 331/1784 recipients (18.6%, 95% CI 16.8–20.4) with measured EBV DNA. The area under the curve (AUC) of the ROC of EBV DNAemia to identify persons with subsequent PTLD was 72% (95% CI, 64–79%) among SOT and 59% (51–68%) among HSCT. Including clinical predictors such as age, gender, transplant year and type, high-risk EBV serostatus, and routine biochemistry in addition to EBV DNAemia increased AUC to 83% (75–90%) among SOT and 84% (79–89%) among HSCT. Among HSCT, including additional factors such as T-cell-depleting treatment, acute graft vs. host disease and donor match increased AUC to 85% (78–91%).
Conclusions
We constructed a model to better predict PTLD compared to EBV DNA screening alone which could have clinical implications.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Cytomegalovirus (CMV) is a serious complication following Hematopoietic Stem Cell Transplant (HSCT) and can lead to serious organ disease and mortality. This study aimed to ...investigate the association between absolute lymphocyte count (ALC) and CMV to determine whether ALC could help to identify those at an increased risk of CMV infection and recurrence
Methods
Adults undergoing HSCT between 2011 and 2016 at Rigshospitalet, Denmark were included. Cox proportional hazards models investigated risk factors, including ALC, for CMV infection in the first year post-transplant and recurrent CMV infection 6 months after clearance and stopping CMV treatment for the first infection. For the primary outcome ALC was investigated as a time-updated risk factor lagged by 7 days, and for recurrent CMV, ALC measured at the time at the time of stopping treatment for the first CMV infection was investigated (+/- 7 days).
Results
Of the 352 HSCT recipients included, 57% were male, 40% received myeloablative conditioning, 42% had high risk (D-R+) CMV IgG serostatus at transplant and the median age was 56 (IQR 43-63). 143 (40.6%) patients had an episode of CMV DNAemia a median of 47 days after transplant (IQR 35-62). A lower current ALC (≤ 0.3 x109/L) was associated with a higher risk of CMV infection in univariate analysis compared to a high current ALC (> 1 x109/L). However, this association was attenuated after adjustment, particularly for acute graft versus host disease (Figure). 102 HSCT recipients were investigated for risk of recurrent CMV of which 41 (40.2%) had a recurrent CMV episode a median of 27 days (IQR 16-50) after stopping CMV treatment for the first infection. A lower ALC (≤ 0.3 x109/L) at the time of stopping CMV treatment was associated with a significantly higher risk of recurrent CMV after adjustment (Figure). A higher peak viral load (> 1500 IU/ml) during the first episode of CMV infection was also associated with an increased risk of recurrent CMV (aHR 2.47, 95%CI 1.00-6.10 compared to < 750 IU/ml).
Association between absolute lymphocyte count (ALC) and risk of CMV infection and recurrent CMV within 6 months. **First CMV infection multivariable model also adjusted for sex, CMV serostatus, age, year of transplant, Charlson Comorbidity Index, Anti-thymocyte globulin (ATG) given, HLA donor-recipient matching, and acute graft versus host disease (time-updated) *Recurrent CMV infection multivariable model also adjusted for conditioning regimen, sex, CMV serostatus, age, year of transplant Anti-thymocyte globulin (ATG) given, HLA donor-recipient matching, and acute graft versus host disease and peak CMV viral load during the first CMV infection
Conclusion
A lower ALC at the time of stopping treatment for the first CMV infection was associated with an increased risk of recurrent CMV and could be used to help guide decisions for augmented CMV surveillance and clinical awareness of CMV disease symptoms in these patients.
Disclosures
All Authors: No reported disclosures
Purpose
Solid organ (SOT) and allogeneic haematopoietic stem cell (HSCT) transplant recipients have elevated risks of de novo or secondary cancer. We explored risk factors hereof.
Methods
Among SOT ...and HSCT between January 2004 and December 2014, standardised incidence ratio (SIR) of de novo/secondary cancer compared with the Danish population was determined and risk factors were identified using Poisson regression.
Results
During a median of 3.4 (IQR 1.3–6.4) and 2.6 (0.8–5.4) person-years (PY) after SOT and HSCT, a total of 212/1656 (13%) and 75/992 (8%) persons developed cancer; SIR 3.61 (3.0–4.3) and 2.2 (1.6–3.0), resp.). SIR correlated with younger age and was highest for skin and haematological cancers for both types of transplantation. Within the cohort, cancer was associated with older age (adjusted incidence rate ratio > 50 vs ≤ 19 years, among SOT and HSCT: 9.4 (3.4–25.7) and 25.4 (5.1–126.0), resp.) and current elevated C-reactive protein (CRP) (≥ 10 vs < 10 mg/L: 2.5 (1.8–3.4) and 2.3 (1.4–3.9), resp.), but neither with prior cancer nor type of immunosuppressants.
Conclusion
Rates of de novo or secondary cancers are elevated in both SOT and HSCT compared with the general population and mainly for skin and haematological cancers. Among transplant recipients, older age and current elevated CRP are risk factors.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Febrile neutropenia (FN) after chemotherapy causes a high burden of morbidity and mortality. We aimed to develop and validate a risk score to predict FN in the first cycle of ...chemotherapy.
Methods
We included patients with solid cancers and diffuse large B-cell lymphomas at Rigshospitalet, University of Copenhagen, 2010-2016. Predictors of FN were analyzed using Poisson regression and random split-sampling.
Results
Among 6294 patients in the derivation cohort, 360 developed FN. Female sex, older age, cancer type, disease stage, low albumin, elevated bilirubin, low creatinine clearance, infection before chemotherapy, and number of and type of chemotherapy drugs predicted FN. Compared with those at low risk (n = 2520, 40.0%), the incidence rate ratio of developing FN was 4.8 (95% confidence interval CI = 2.9 to 8.1), 8.7 (95% CI = 5.3 to 14.1) and 24.0 (95% CI = 15.2 to 38.0) in the intermediate (n = 1294, 20.6%), high (n = 1249, 19.8%) and very high (n = 1231, 19.6%) risk groups, respectively, corresponding to a number needed to treat with granulocyte colony-stimulating factors to avoid one FN event in the first cycle of 284, 60, 34 and 14. The discriminatory ability (Harrell’s C-statistic = 0.80, 95% CI = 0.78 to 0.82) was similar in the validation cohort (n = 3163) (0.79, 95% CI = 0.75 to 0.82).
Conclusion
We developed and internally validated a risk score for FN in the first cycle of chemotherapy. The FENCE score is available online and provides good differentiation of risk groups.
Abstract
Background
Persons with a compromised immune system are at increased risk of complications related to respiratory syncytial virus (RSV) but the risks are not well defined. We aimed to ...investigate the prevalence of RSV infection, associated risk factors and complications in a large population of people with immune dysfunction.
Methods
Persons with immune dysfunction, first seen at Copenhagen University Hospital, Rigshospitalet, between January 1, 2010 and February 21, 2017, aged ≥18 were included. RSV testing and positivity (positive PCR or antigen test) was determined through the Danish Microbiology Database. Generalized estimating equations logistic regression was used to investigate the risk factors for RSV positivity; Cox regression was used to assess the impact of RSV positivity (time-updated) on mortality in the first 12 months after first visit.
Results
The study included 42,567 persons, of which 3,356 (7.9%, 95% CI 7.6%-8.1%) were tested for RSV at least once during follow-up, with 2,374 (71%) tested in the first 12 months. Stem cell transplant (HSCT) and solid-organ transplant (SOT) recipients had the highest proportion of persons tested for RSV (66.0%, 95% CI 62.9%–69.1% and 31.6%, 95% CI 29.0%–34.2%, respectively). Of those tested, 256 (7.6%, 95% CI 6.7%–8.5%) had ≥1 positive RSV test (figure). After adjustment, HSCT and SOT recipients, as well as other hematologic and rheumatologic patient groups were more likely to have a positive RSV test compared with persons seen in the infectious disease department. Fifty-seven RSV-related complications were identified in 53/256 (20.7%, 95% CI 15.7%-25.7%) persons positive for RSV (table), of which 24 (45.3%) were HSCT recipients and 18 (34.0%) were other hematologic patients. In the 12 months after first department visit, 9,451 (22%) patients died; persons with RSV had an increased risk of short-term mortality (aHR 1.77, 95% CI 1.19–2.64), adjusting for sex, age, patient group and flu positivity.
Conclusion
Patients with a hematological or rheumatological condition and SOT recipients had the highest odds of contracting RSV, with hematological patients in particular at an excess risk of RSV-related complications. RSV was associated with an increased risk of death in the first 12 months of patient follow-up.
Disclosures
All authors: No reported disclosures.
Viral blips reflecting polymerase chain reaction (PCR) artefacts or transient low-level replication are well described in the human immunodeficiency virus setting. However, the epidemiology of such ...blips in transplant recipients screened for cytomegalovirus (CMV) with PCR remains uncertain and was investigated in a cohort of solid organ and hematopoietic stem cell recipients.
Eligible recipients had known donor/recipient CMV IgG serostatus, and 3 CMV PCRs ≥. The CMV PCR triplicates (3 consecutive CMV PCRs) were defined; the first CMV PCR was always negative, and the time between the second and third samples was 7 days ≤. A positive second but negative third sample represented a blip. Odds ratio (OR) for factors associated with a triplicate being a blip was estimated by binomial regression adjusted for repeated measurements. Whether blips affected the hazard ratio (HR) for subsequent CMV infection was determined with a Cox model.
851 recipients generated 3883 CMV PCR triplicates. The OR of a triplicate representing a blip decreased with increasing viral load of the second sample (vs 273 IU/mL; >273-910 IU/mL: odds ratio OR, 0.2; 95% confidence interval CI, 0.1-0.5; >910 IU/mL: OR, 0.08; 95% CI, 0.02-0.2;
≤ 0.0002) and increased with intermediary-/low-risk serostatus (vs high risk) (OR, 2.8; 95% CI, 1.2-5.5;
= 0.01). Cumulative exposure to DNAemia in the CMV blips greater than 910 IU/mL indicated increased HR of subsequent CMV infection (HR, 4.6; 95% CI, 1.2-17.2;
= 0.02).
Cytomegalovirus blips are frequent; particularly when the viral load of the first positive PCR is < 910 IU/mL, and serostatus risk is intermediary/low. Accumulating blips suggest intermittent low-level replication. If blips are suspected, confirmation of ongoing replication before initiation of treatment is prudent.
Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid ...organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 51% SOT and 192 49% HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.
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