Cause-specific Late Mortality Research Articles

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study

Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. American Lebanese Syrian Associated Charities and US National Institutes of Health.

Risky health behaviors and subsequent late mortality after blood or marrow transplantation: a BMTSS report

AbstractWe examined the association between risky health behaviors (smoking, heavy alcohol consumption, and lack of vigorous physical activity) and all-cause and cause-specific late mortality after blood or marrow transplantation (BMT) to understand the role played by potentially modifiable risk factors. Study participants were drawn from the BMT Survivor Study (BMTSS) and included patients who received transplantation between 1974 and 2014, had survived ≥2 years after BMT, and were aged ≥18 years at study entry. Survivors provided information on sociodemographic characteristics, chronic health conditions, and health behaviors. National Death Index was used to determine survival and cause of death. Multivariable regression analyses determined the association between risky health behaviors and all-cause mortality (Cox regression) and nonrecurrence-related mortality (NRM; subdistribution hazard regression), after adjusting for relevant sociodemographic, clinical variables and therapeutic exposures. Overall, 3866 participants completed the BMTSS survey and were followed for a median of 5 years to death or 31 December 2021; and 856 participants (22.1%) died after survey completion. Risky health behaviors were associated with increased hazard of all-cause mortality (adjusted hazard ratio [aHR] former smoker, 1.2; aHR current smoker, 1.7; reference, nonsmoker; aHR heavy drinker, 1.4; reference, nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity) and NRM (aHR former smoker, 1.3; aHR current smoker, 1.6; reference, nonsmoker; aHR heavy drinker, 1.4; reference: nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity). The association between potentially modifiable risky health behaviors and late mortality offers opportunities for development of interventions to improve both the quality and quantity of life after BMT.

Late Morbidity and Mortality after Autologous Blood or Marrow Transplantation (BMT) for Lymphoma in Children, Adolescents and Young Adults - a Report from the BMT Survivor Study (BMTSS)

Introduction: Autologous BMT is an integral part of consolidation and/or salvage therapy for children, adolescents and young adults with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). However, there is paucity of information regarding the long-term outcome after autologous BMT for lymphoma performed in this age group. We address this gap by leveraging the BMTSS to determine the magnitude of risk of chronic health conditions as well as cause-specific late mortality in patients undergoing autologous BMT for lymphoma between 1980 and 2014 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, patients had to have received a single or tandem autologous BMT before age 40y and survived ≥2y after transplantation. BMT recipients (n=583 [HL: 59.7%; NHL: 40.3%]) and a sibling comparison group (n=330) completed a 255-item survey, and self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Vital status and cause of death information was ascertained using the National Death Index (NDI), medical records and Accurint databases. Logistic regression estimated the odds of grade 3-4 conditions in BMT recipients alive at study participation compared to siblings. Fine-Gray regression estimated the hazard of grades 3-5 chronic health conditions among BMT recipients (alive and deceased), treating death as a competing risk. Results: Median age at BMT was 30.0y (range: 2.0-39.0); median length of follow-up was 9.6y (2.0-32.1) and median age at study participation was 41.1y (13.7-67.1). Severe/life-threatening chronic health conditions in BMT survivors compared with siblings: By age 45y, the cumulative incidence of a grade 3-4 chronic health condition was 31.2% (95%CI; 25.5-37.0) among the BMT survivors and 12.9% (95%CI; 8.8-17.7) among the siblings (p<0.0001) (Figure 1). BMT survivors were at a 3.2-fold greater odds of a grade 3-4 condition (aOR=3.2, 95%CI=2.2-4.8) compared to siblings. Greater odds were observed among BMT survivors vs. siblings for the following conditions: joint replacement (OR=4.9, 95%CI=1.7-13.7), cataract (OR=4.2; 95%CI=1.4-13.0), cardiovascular disease (OR=2.2, 95%CI=1.2-4.0), and multiple conditions (OR=4.9; 95%CI=2.6-9.5). Severe/life-threatening/fatal chronic health conditions among BMT recipients: The 20y cumulative incidence of grade 3-5 conditions for the entire cohort was 46.8% (95%CI=41.6-51.7%). The 20y cumulative incidence was 42.1% (95%CI=34.2-49.7%) for patients with NHL and 49.6% (95%CI=42.9-56.0%) for patients with HL, placing HL patients at a 1.4-fold higher adjusted hazard of grade 3-5 conditions (95%CI=1.0-1.8, p=0.0232). Late mortality in BMT survivors: Conditional on surviving the first 2y after BMT, the all-cause mortality rate was 54.3% (95%CI=48.8-59.4%) at 25y from BMT (HL: 62.6%; NHL: 42.3%). The adjusted hazards of all-cause mortality were higher in HL patients (HR=1.8, 95%CI, 1.3-2.4; reference: NHL), and among Black patients (HR=3.0, 95%CI, 1.9-4.6; reference: non-Hispanic white). Causes of death were available for 84% of the cohort, and included primary disease (35%), subsequent neoplasm (16%), infection (13%), cardiac disease (8%), pulmonary disease (3%), and homicide/suicide/accident (3%). As shown in Figure 2, relapse-related mortality (RRM) plateaued after 20y from BMT, whereas the non-relapse-related mortality (NRM) continued to climb, crossing RRM at 20y from BMT. The 25y cumulative incidence of RRM was 28% (95%CI=22-34%), while that for NRM was 37% (95%CI=31-44%). Patients with HL were at increased risk for RRM (HR=2.3, 95%CI=1.3-3.8, p=0.0029; reference: NHL). The hazard of NRM was greater among HL patients (HR=1.7, 95%CI=1.1-2.7), and Black patients (HR=3.1, 1.5-6.4; reference: non-Hispanic white). Conclusions: The burden of severe/life-threatening chronic health conditions was 3-fold higher in autologous BMT recipients for lymphoma when compared with a non-BMT sibling comparison group. Patients with HL were at increased risk of a severe/life-threatening/fatal conditions as well as late mortality, when compared to patients with NHL. Finally, Black patients were at a higher risk for non-relapse-related mortality. These findings suggest a need for long-term surveillance among the vulnerable sub-populations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trends in Late Mortality and Life Expectancy After Autologous Blood or Marrow Transplantation Over Three Decades: A BMTSS Report.

We determined trends in life expectancy and cause-specific late mortality after autologous blood or marrow transplantation (BMT) performed over a 30-year period, using the BMT Survivor Study. We constructed a cohort of 4,702 individuals with hematologic neoplasms who lived ≥ 2 years after autologous BMT performed between 1981 and 2014 at three transplant centers. The end of follow-up was April 19, 2021. The primary exposure variable was autologous BMT performed in four eras: 1981-1999; 2000-2005; 2006-2010; and 2011-2014. Vital status and cause of death were obtained from National Death Index Plus program and Accurinct databases. The median age at BMT was 53 years (range, 0-78 years), 58.7% were male, 67.8% were non-Hispanic White, and 28.3% had undergone transplantation between 2011 and 2014. Autologous BMT recipients experienced a 7-year reduction in life expectancy. The adjusted hazard of 5-year all-cause mortality declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005 = 0.77; 95% CI, 0.62 to 0.94; HR2006-2010 = 0.64; 95% CI, 0.51 to 0.79; HR2011-2014 = 0.56; 95% CI, 0.45 to 0.71; Ptrend < .001), as did years of life lost (5.0 years to 1.6 years). The reduction in all-cause mortality was most pronounced among those transplanted for Hodgkin lymphoma or plasma cell dyscrasias, but was not observed among those transplanted for non-Hodgkin lymphoma or those conditioned with total-body irradiation. We also observed a decline in late deaths because of infection (Ptrend < .0001; primarily for BMTs before 2006) and subsequent neoplasms (Ptrend = .03; confined to decline in therapy-related myeloid neoplasm-related mortality) but not because of cardiovascular or renal disease. Late mortality among autologous BMT recipients has declined over a 30-year period. However, ongoing efforts are needed to mitigate development of infections, subsequent neoplasms, and cardiovascular and renal disease to further reduce late mortality.

Trends in Late Mortality and Life Expectancy after Autologous Blood or Marrow Transplantation (BMT) Performed over Three Decades - a BMT Survivor Study (BMTSS) Report

Background: Advances in therapeutic and supportive care strategies have led to increasing use of autologous BMT to ensure durable disease-free survival in patients with hematologic malignancies. However, autologous BMT recipients carry a high burden of morbidity. The cumulative effect of autologous BMT and the long-term morbidity on life expectancy remains unknown. Further, the impact of changes in transplant practice (older age at BMT, increasing proportion of patients undergoing autologous BMT for plasma cell dyscrasias [PCD], increasing use of peripheral blood stem cells [PBSCs] and decreasing use of total body irradiation [TBI]) on late mortality and life expectancy remains unknown. We determined trends in life expectancy and cause-specific late mortality after autologous BMT performed over a 33y period (1981-2014) using the resources offered by BMTSS - a multi-institutional collaborative designed to examine late morbidity and mortality after BMT.Methods: This retrospective cohort included 4,702 individuals who lived ≥2y after autologous BMT performed between 1981 and 2014 at three transplant centers. We examined trends in life expectancy and late mortality over four eras: 1981-1999; 2000-2005; 2006-2010; 2011-2014. Endpoints included all-cause, recurrence-related mortality (RRM) and non-recurrence-related mortality (NRM) and projected reduction in life expectancy. Information on vital status and cause of death was obtained from National Death Index (NDI) Plus program and Accurinct databases. End of follow-up was 04/19/2021.Results: Median age at BMT was 53y (range, 0-78); 58.7% were male, 67.8% non-Hispanic white. Median follow up after BMT was 9y (range, 2-36). PCD was the most common indication for autologous BMT (42.3%). PBSCs were used for 91.6% of the transplants and TBI was used for conditioning in 23.1% of the patients. Across the four eras, the median age at BMT increased (40y→58y), as did the proportion of patients receiving autologous BMT for PCD (13.7%→60.0%) and the proportion of patients receiving PBSCs as the stem cell source (66.6%→99.5%). There was a dramatic decline in the proportion of patients conditioned with TBI (56.4%→5.2%), and those transplanted for acute myeloid leukemia/ myelodysplastic syndrome (AML/MDS) (15.4%→0.2%). Conditional on surviving ≥2y after autologous BMT, patients experienced a 25.8% reduction in life expectancy, representing 7.0y of life lost. In an analysis adjusted for all relevant demographic and clinical predictors and restricted to 5y of follow-up, the years of life lost declined across the four eras from 5y to 1.6y (Fig 1) The adjusted hazard of all-cause mortality also declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005=0.77; 95%CI=0.7-0.9; HR 2006-2010=0.62; 95%CI=0.5-0.7; HR 2011-2014=0.5; 95%CI=0.4-0.6; P trend <0.0001) (Fig 2). Mediation analysis revealed that the reduction in late mortality was evident among those transplanted for Hodgkin lymphoma (HL) or PCD, and among those who did not receive TBI . The 30y cumulative incidence of NRM (29.2%) was higher than that RRM (23.8%) (Fig 3). The adjusted hazard of RRM declined over the four eras (reference: 1981-1999; HR 2011-2014=0.55; 95%CI=0.4-0.7, P trend: <0.0001). Cause-specific late mortality declined for mortality related to infection (P trend <0.0001), subsequent malignant neoplasms (P trend=0.01), cardiovascular disease (P trend=0.001), and renal disease (P trend=0.0002), but not for pulmonary disease (P trend=0.3).Conclusions and Relevance: Late mortality among autologous BMT recipients has declined over a 30y period, likely due to changes in transplant practice (reduction in use of TBI) and improvement in disease-specific therapeutic strategies (newer therapeutic options for PCD and reduction in dose/volume of radiation for HL). Continued efforts need to focus on mitigation strategies for disease recurrence, subsequent neoplasms, infections, and cardiovascular, renal and pulmonary disease in this population. [Display omitted] DisclosuresArora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

Impact of era of diagnosis on cause-specific late mortality among 77 423 five-year European survivors of childhood and adolescent cancer: The PanCareSurFup consortium.

Late mortality of European 5-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 and 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95% CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95% CI 6.32-6.62). At 60 to 68 years of attained age all-cause mortality was still higher than expected (SMR=2.41, 95% CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95% CI 16.5-20.4) to 7.3% (95% CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960 to 1969, the mortality hazard ratio declined for first neoplasms (P for trend <.0001) and for infections (P < .0001); declines in relative mortality from second neoplasms and cardiovascular causes were less pronounced (P=.1105 and P=.0829, respectively). PanCareSurFup is the largest study with the longest follow-up of late mortality among European childhood and adolescent cancer 5-year survivors, and documents significant mortality declines among European survivors into modern eras. However, continuing excess mortality highlights survivors' long-term care needs.

Late mortality among survivors of childhood acute lymphoblastic leukemia diagnosed during 1971-2008 in Denmark, Finland, and Sweden: A population-based cohort study.

Investigate all-cause and cause-specific late mortality after childhood acute lymphoblastic leukemia (ALL) in a population-based Nordic cohort. From the cancer registries of Denmark, Finland, and Sweden, we identified 3765 five-year survivors of ALL, diagnosed before age 20 during 1971-2008. For each survivor, up to five matched comparison subjects were randomly selected from the general population (n=18,323). Causes of death were classified as relapse related, health related, and external. Late mortality was evaluated by cumulative incidences of death from 5-year survival date. Mortality hazard ratios (HR) were evaluated with Cox proportional models. Among the survivors, 315 deaths occurred during a median follow-up of 16years from 5-year survival date (range 0-42). The majority were attributable to relapse (n=224), followed by second neoplasm (n=45). Cumulative incidence of all-cause late mortality at 15years from diagnosis decreased gradually over treatment decades, from 14.4% (95% confidence interval [CI]: 11.6-17.2) for survivors diagnosed during 1971-1981, to 2.5% (95% CI: 1.3-3.7) for those diagnosed during 2002-2008. This was mainly attributable to a reduction in relapse-related deaths decreasing from 13.4% (95% CI: 10.7-16.1) for survivors diagnosed during 1971-1981 to 1.9% (95% CI: 0.9-2.8) for those diagnosed during 2002-2008. Health-related late mortality was low and did not change substantially across treatment decades. Compared to comparison subjects, all-cause mortality HR was 40 (95% CI: 26-61) 5-9years from diagnosis, and 4.4 (95% CI: 3.4-5.6) ≥10years from diagnosis. Survivors of ALL have higher late mortality than population comparison subjects. Among the survivors, there was a temporal reduction in risk of death from relapse, without increments in health-related death.

Trends in Late Mortality and Life Expectancy After Allogeneic Blood or Marrow Transplantation Over 4 Decades

The past 4 decades have seen substantial changes in allogeneic blood or marrow transplantation (BMT) practice, with the overarching goal of expanding the eligible patient pool while optimizing disease-free survival. To determine trends in life expectancy and cause-specific late mortality after allogeneic BMT performed over a 40-year period. A retrospective cohort study of 4741 individuals who lived 2 or more years after allogeneic BMT performed between January 1, 1974, and December 31, 2014, was conducted at City of Hope, University of Minnesota, or University of Alabama at Birmingham. The end of follow-up was March 23, 2020. Allogeneic BMT performed in 3 eras: 1974-1989, 1990-2004, and 2005-2014. All-cause, recurrence-related, and nonrecurrence-related mortality and projected reduction in life expectancy. Information regarding vital status and cause of death was obtained from the National Death Index Plus and Accurint databases. Of the 4741 individuals included in the study, 2735 (57.7%) were male; median age at BMT was 33 years (range, 0-75 years). The cumulative incidence of recurrence-related mortality plateaued at 10 years, reaching 12.2% (95% CI, 11.0%-13.4%) at 30 years from BMT. In contrast, the incidence of nonrecurrence-related mortality continued to increase and was 22.3% (95% CI, 20.4%-24.3%) at 30 years. Leading causes of nonrecurrence-related mortality included infection (30-year cumulative incidence, 10.7%; standardized mortality ratio [SMR], 52.0), subsequent malignant neoplasms (30-year cumulative incidence, 7.0%; SMR, 4.8), cardiovascular disease (30-year cumulative incidence, 4.6%; SMR, 4.1), and pulmonary disease (30-year cumulative incidence, 2.7%; SMR, 13.9). Compared with the general population, the relative mortality remained higher at 30 or more years after BMT (SMR, 5.4; 95% CI, 4.0-7.1). The cohort experienced a 20.8% reduction in life expectancy (8.7 years of life lost). Compared with 1974-1989 (reference), the adjusted 10-year hazard ratio (HR) of all-cause mortality declined over the 3 eras (1990-2004: HR, 0.67; 95% CI, 0.53-0.85; 2005-2014: HR, 0.52; 95% CI, 0.39-0.69; P < .001 for trend), as did years of life lost (1974-1989: 9.9 years [reference]; 1990-2004: 6.5 years; and 2005-2014: 4.2 years). The reduction in late mortality was most pronounced among individuals who underwent transplantation at ages younger than 18 years (1990-2004: HR, 0.62; 95% CI, 0.40-0.96; 2005-2014: HR, 0.30; 95% CI, 0.16-0.54; reference: 1974-1989; P < .001 for trend) and those who received bone marrow (1990-2004: HR, 0.70; 95% CI, 0.54-0.90; 2005-2014: HR, 0.45; 95% CI, 0.29-0.69; reference: 1974-1989; P < .001 for trend). This cohort study noted that late mortality among recipients of allogeneic BMT has decreased over the past 40 years; however, life expectancy was not restored to expected rates compared with the general US population. Furthermore, the reduction in risk of late mortality appeared to be confined to those who underwent transplantation at a younger age or those who received bone marrow. Further efforts to mitigate disease recurrence, infections, subsequent neoplasms, cardiovascular disease, and pulmonary disease may be useful in this population.

Late Mortality after Allogeneic Bone Marrow Transplantation in Childhood for Bone Marrow Failure Syndromes and Severe Aplastic Anemia

Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P < .0001). The elevated relative risk persisted at ≥15years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up.

Venous Thromboembolism in Blood or Marrow Transplant (BMT) Survivors: A Report from BMT Survivor Study (BMTSS)

BACKGROUNDPatients undergoing BMT are uniquely vulnerable to venous thromboembolism (VTE) due to high-intensity therapeutic exposures, prolonged hospitalizations (and attendant immobility), a high burden of comorbidities, and the pro-inflammatory state induced by graft-versus-host disease (GvHD) in allogeneic BMT recipients. An assessment of the long-term risk of VTE in BMT survivors and subsequent cause-specific late mortality remains unstudied. We used the BMTSS to address this gap. METHODSIn patients with hematologic malignancy treated with BMT at 3 sites in US, had survived ≥2y after BMT, were alive and ≥18yo at BMTSS survey completion, we examined: i) incidence/risk factors for VTE; ii) subsequent mortality by VTE status. The survey covered sociodemographics, tobacco use, diagnosis by a healthcare provider of specific chronic health conditions, including VTE, relapse, or development of new cancer and medication use. The outcome of interest (VTE) was defined as self-report of VTE diagnosed by a health care provider, supplemented by history of anticoagulant use. BMTSS survey was administered over two time periods: i) Survey completed between 2000 and 2004: 1,022 patients transplanted between 1974 and 1998 and survived ≥2y (original BMTSS cohort; participation rate: 63%). This cohort was followed for a median of 15.1y (range: 0.04-17.9) after survey completion, to determine the association between VTE and subsequent mortality using National Death Index; ii) Survey completed between 2014 and 2017: 1,711 patients transplanted between 1974 and 2010 and survived ≥2y (expanded BMTSS cohort; participation rate: 68%) - this cohort was used to determine demographic/clinical variables associated with VTE risk. A cohort of 644 siblings also completed the survey and served as a comparison group. Human Subjects Committee at participating sites approved the protocol. RESULTSRisk of VTE: Of the 1,711 participants, 891 (52.1%) had received an allogeneic BMT; 53.5% were males and 78.8% were non-Hispanic whites; median age at BMT was 48y. The cohort was followed for a median of 10.9y (3.8-40.6). BMT survivors were at a 2.8-fold higher risk of VTE as compared to siblings (95%CI:1.7-4.5, p<0.0001), after adjusting for sociodemographics. Conditional on surviving ≥2y after BMT, the cumulative incidence of VTE was 6.9±0.9% at 10y (Fig 1), with similar rates in autologous (6.1±1.1%) and allogeneic BMT recipients (7.5±1.5%%, p=0.5).Risk of VTE in allogeneicBMT recipients: History of chronic GvHD (HR=3.6, 95%CI:2.2-6.0, p<0.0001), primary diagnosis of acute myeloid leukemia/myelodysplasia (HR=1.9, 95%CI:1.0-3.7, p=0.05) or non-Hodgkin lymphoma (NHL) (HR=2.3, 95%CI:1.1-4.8, p=0.02) (ref: chronic myeloid leukemia), male sex (HR=1.6, 95%CI:1.0-2.6, p=0.05), and older age at BMT (HR=1.03/y, 95%CI:1.0-1.1, p=0.002), were associated with increased VTE risk.Risk of VTE in autologous BMT recipients: Diagnosis of a plasma cell disorder (HR=2.4, 95%CI: 1.3-4.2, p=0.004) (ref: NHL) and annual house hold income <$50,000 (HR=2.0, 95%CI 1.2-3.6, p=0.02) (ref: income >$50,000) were associated with increased VTE risk. Of note, relapse of primary disease or development of new cancer were not associated with increased VTE risk in either autologous or allogeneic BMT patients.Subsequent mortality: In this cohort of 1,022 BMT survivors, median age at BMT was 34.9y; 55% had received allogeneic BMT. The overall survival among patients with and without VTE was 50.4% vs. 72.3%, respectively at 15y from survey completion, p<0.0001 (Fig 2), yielding a higher risk of subsequent mortality in VTE patients when compared to those without VTE (HR=1.6, 95%CI:1.1-2.3, p=0.02) after adjusting for relevant clinical/demographic predictors, relapse of primary cancer and development of new cancer. The VTE-associated mortality risk was primarily due to non-relapse mortality (NRM: HR=1.7, 95%CI:1.1-2.5, p=0.02) and not due to relapse (HR=0.7, 95%CI, 0.2-1.8, p=0.5). Leading causes of NRM among those with VTE included infection (15.5%), cardiac (8.5%) and subsequent neoplasms (7%). CONCLUSIONBMT survivors are at a 2.8-fold increased risk of developing VTE when compared with a non-BMT sibling comparison group. Those with VTE are at an increased risk of subsequent NRM. Development of risk prediction models to identify BMT survivors at highest risk would facilitate targeted thromboprophylaxis. DisclosuresWeisdorf:Equillium: Consultancy; SL Behring: Consultancy; Seattle Genetics: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Late Mortality after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism: A Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2)

Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths.

Assessment of Late Mortality Risk After Allogeneic Blood or Marrow Transplantation Performed in Childhood

ImportanceAllogeneic blood or marrow transplantation (BMT) is a curative option for malignant and nonmalignant diseases of childhood. However, little is known about trends in cause-specific late mortality in this population during the past 3 decades.ObjectivesTo examine cause-specific late mortality among individuals who have lived 2 years or more after allogeneic BMT performed in childhood and whether rates of late mortality have changed over time.Design, Setting, and ParticipantsA retrospective cohort study was conducted of individuals who lived 2 years or more after undergoing allogeneic BMT performed in childhood between January 1, 1974, and December 31, 2010. The end of follow-up was December 31, 2016.ExposureAllogeneic BMT performed in childhood.Main Outcomes and MeasuresAll-cause mortality, relapse-related mortality, and non–relapse-related mortality. Data on vital status and causes of death were collected using medical records, the National Death Index Plus Program, and Accurint databases.ResultsAmong 1388 individuals (559 females and 829 males) who lived 2 years or more after allogeneic BMT performed in childhood, the median age at transplantation was 14.6 years (range, 0-21 years). In this cohort, there was a total of 295 deaths, yielding an overall survival rate of 79.3% at 20 years after BMT. The leading causes of death were infection and/or chronic graft-vs-host disease (121 of 244 [49.6%]), primary disease (60 of 244 [24.6%]), and subsequent malignant neoplasms (45 of 244 [18.4%]). Overall, the cohort had a 14.4-fold increased risk for death (95% CI, 12.8-16.1) compared with the general population (292 deaths observed; 20.3 deaths expected). Relative mortality remained elevated at 25 years or more after BMT (standardized mortality ratio, 2.9; 95% CI, 2.0-4.1). The absolute excess risk for death from any cause was 12.0 per 1000 person-years (95% CI, 10.5-13.5). The cumulative incidence of non–relapse-related mortality exceeded that of relapse-related mortality throughout follow-up. The 10-year cumulative incidence of late mortality decreased over time (before 1990, 18.9%; 1990-1999, 12.8%; 2000-2010, 10.9%; P = .002); this decrease remained statistically significant after adjusting for demographic and clinical factors (referent group: <1990; 1990-1999: hazard ratio, 0.64; 95% CI, 0.47-0.89; P = .007; 2000-2010: hazard ratio, 0.49; 95% CI, 0.31-0.76; P = .002; P < .001 for trend).Conclusions and RelevanceLate mortality among children undergoing allogeneic BMT has decreased during the past 3 decades. However, these patients remain at an elevated risk of late mortality even 25 years or more after transplantation when compared with the general population, necessitating lifelong follow-up.

Effect of new-onset atrial fibrillation on cause-specific late mortality after coronary artery bypass grafting surgery.

Postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting. Although transient, POAF is linked to increased late mortality. We hypothesized that POAF increases late cerebrovascular (CeV) and composite cerebrovascular/cardiovascular/vascular (CV* = CeV + CV + Other-V) but not non-cardiovascular (Non-CV) mortality. We analysed 8807 non-salvage coronary artery bypass grafting patients (1994-2011). Fifteen-year and time-segmented (early, 0-1 year; intermediate, 1-6 years and late, 6-15 years) all-cause and cause-specific mortality were compared for POAF versus No-POAF patients. Corresponding POAF versus No-POAF adjusted hazard ratios [AHRs (95% confidence interval, CI)] were derived using the competing risk Cox regression. POAF occurred in 1992 (23%) patients. Complications other than POAF occurred in 1875 (21%) patients but were more frequent among POAF patients (31% vs 18%; P < 0.001). Overall mean follow-up was 9 ± 4 years. POAF patients had a higher 15-year unadjusted mortality (53% vs 39%; P < 0.001) and were consequently associated with higher adjusted all-cause [AHR (95% CI) = 1.23 (1.14-1.33)] and composite cardiovascular [CV*: AHR (95% CI) = 1.15 (1.02-1.30)] mortality. The trends towards a higher 15-year CeV [AHR (95% CI) = 1.34 (0.94-1.91)] and Non-CV [AHR (95% CI) = 1.12 (0.99-1.26)] mortality were not significant. Time-segmented analyses showed that (i) POAF increased all-cause mortality early, and this persisted in the intermediate and late periods and (ii) CeV [AHR (95% CI) = 2.14 (1.14-4.04)] and CV* [AHR (95% CI) = 1.31 (1.06-1.62)] mortality rates were increased in the intermediate but not in the early or late periods. Non-CV mortality was similar in POAF and No-POAF for all time intervals. These findings were corroborated in propensity-matched sub-cohorts and in sensitivity analyses in patients free of any other complication. POAF is associated with worse long-term survival principally driven by increased intermediate-term cerebrovascular and cardiovascular mortality, while Non-CV mortality was similar.

Decline in Late Mortality after Allogeneic Blood or Marrow Transplantation (alloBMT) Performed in Childhood: a Report from the BMT Survivor Study-2 (BMTSS-2)

Background: AlloBMT is a curative option for children with malignant and non-malignant diseases. Nonetheless, the high intensity of therapeutic exposures at a young age increases the risk of organ compromise and may lead to premature death. However, there remains a gap in knowledge regarding cause-specific late mortality experienced by children undergoing alloBMT. Furthermore, it is not clear whether mortality rates have changed over the past 4 decades. We address these gaps by examining premature death (all-cause, relapse-related mortality [RRM] and non-relapse-related mortality [NRM]) in patients undergoing alloBMT between 1974 and 2010 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, the patients had to have received alloBMT before age 22, and survived for ≥2y after transplantation. Vital status information was ascertained as of Dec 31, 2016, using medical records, the National Death Index (NDI), and Accurint databases. Information on cause of death was obtained from the NDI Plus program and medical records. Using Kaplan-Meier techniques, we describe overall survival conditional on surviving 2+ and 20+y from alloBMT. We describe cumulative incidence of RRM and NRM using competing risk methods. We also describe all-cause late mortality for patients transplanted over 3 time periods: <1990; 1990-1999; 2000-2010. Standardized mortality ratio (SMR) was used to compare the mortality experienced by this cohort to the age- sex-, and calendar-specific mortality of the US general population. Proportional subdistribution hazards model (Fine-Gray) for competing risks was used for identifying predictors of late mortality, including demographics, primary disease, conditioning agents, disease status at alloBMT and GvHD prophylaxis. Results: In this cohort of 1,411 recipients of alloBMT performed in childhood and surviving ≥2y, the most common primary diagnoses were acute lymphoblastic leukemia (ALL: 25%), acute myeloid leukemia/myelodysplastic syndrome (AML/MDS: 24%), inborn errors of metabolism (IEM: 14%) and severe aplastic anemia (SAA: 11%). The distribution of the cohort over the 3 time periods was: <1990 (23%); 1990-1999 (29%); 2000-2010 (48%). After a median follow-up of 14.9y, we observed 295 deaths in this 2y survivor cohort, yielding an overall survival rate of 79.6% at 20y from alloBMT. The leading causes of premature death were infection (32.0%), primary disease (24.6%) and subsequent malignant neoplasms (18.4%). Overall, the cohort was at a 15-fold increased risk for premature death (SMR 15.3, 95% CI 13.6-17.2), when compared with the general population. Conditional on surviving 20y, the 5y overall survival was 96.0% for the entire cohort, and 98.4% for SAA, 96.0% for AML/MDS, 90.3% for ALL and 85.8% for IEM. Relative mortality declined with time from alloBMT, but remained significantly elevated at 25y after transplantation (SMR 1.9, 95% CI 1.1-2.9). The cumulative incidence of NRM exceeded that due to RRM (fig 1); the 20y cumulative incidence of NRM and RRM were 13.0% and 4.4%, respectively. The all-cause 10y cumulative mortality rate declined over the 3 eras (<1990: 18.9%, 1990-1999: 12.5%; >2000: 10.7%, p=0.001) (Fig 2). Adjusting for demographic and clinical variables, as well as conditioning, the hazard ratio (HR) of all-cause death decreased with more recent treatment eras (<1990: HR=1.0; 1990-1999: HR=0.7, 95%CI, 0.5-0.9, p=0.01; 2000-2010: HR=0.6, 95%CI, 0.4-0.8, p=0.004). Conclusions: This study demonstrates that compared with the general population, 2y survivors of alloBMT performed in childhood remain at an elevated risk of premature death, even after 25y from alloBMT. While the risk of relapse-related mortality plateaus with time, non-relapse-related mortality continues to increase and remains the major cause of late death in this population. However, we make an encouraging observation i.e., there has been a significant decline in all-cause mortality experienced by children undergoing alloBMT over the past 4 decades. [Display omitted] DisclosuresArora:Takeda Oncology: Consultancy.

Postoperative atrial fibrillation predicts cause-specific late mortality after coronary surgery

Objectives. To investigate the association between postoperative atrial fibrillation (POAF) and cause-specific death after coronary artery bypass grafting (CABG) over time. Design. The cohort included 6821 patients undergoing primary isolated CABG between 1996 and 2009. Survival analyses using Cox proportional hazards determined the association between POAF and late mortality and cause of death. Four categories of mortality were examined: cardiac mortality; and death related to arrhythmia, cerebrovascular disease, and heart failure. Results. Median follow-up was 9.8 years and 2152 of 6821 patients (32%) developed POAF. During follow-up, 2302 of 6821 patients (34%) died. For all mortality categories, lower survival rates were found among POAF patients. After adjustment for baseline characteristics, medical history, and preoperative status, POAF was related to increased mortality in all four categories: cardiac mortality (HR 1.4; 95% CI 1.3–1.5); death related to arrhythmia (HR 1.8; 95% CI 1.6–2.0); cerebrovascular disease (HR 1.4; 95% CI 1.2–1.6); and heart failure (HR 1.4; 95% CI 1.3–1.6). The effect remained more than 8 years after surgery. Conclusions. POAF predicts cause-specific late mortality after CABG, with a sustained effect many years postoperatively. This suggests that POAF-episodes are not merely an indication of more advanced disease at surgery, but predicts a persistent negative effect on cause-specific survival.

Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer

Five-year survival rates for childhood cancer have improved over the past four decades. However, it is unknown whether changes in primary cancer therapy have improved rates of long-term (> 5 years from diagnosis) durable remissions and reduced treatment-related deaths. We investigated changes in patterns of late mortality over time and cause-specific attribution of late-mortality among 5-year survivors. Using data from the Surveillance, Epidemiology and End Results (SEER) population-based registry, we assessed all-cause and cause-specific (recurrence/progression of primary disease, external cause, and nonrecurrence/nonexternal cause) late mortality during four consecutive time periods from 1974 through 2000 among 26,643 5-year survivors of childhood cancer. All-cause late mortality improved during more recent eras, dropping from 7.1% (95% CI, 6.4% to 7.8%) among children diagnosed during 1974 to 1980 to 3.9% (95% CI, 3.3% to 4.4%) among children diagnosed during 1995 to 2000 (P < .001), largely because of reduced mortality from recurrence or progression. While there was no significant reduction in mortality attributable to other health conditions (including treatment-related health conditions), analysis controlling for demographic characteristics identified a trend toward reduced risk during more recent eras (P = .007). Disparity by race/ethnicity was identified, with higher mortality among non-Hispanic blacks than among non-Hispanic whites for all-cause and nonrecurrence/nonexternal -cause late mortality. While overall patterns of mortality from other health conditions do not differ over time, adjustment for demographic characteristics provides evidence that risk of treatment-related mortality may be lower in more recent eras. Disparities in health care utilization among survivors should be explored.

Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer

Temporal Trends in Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer

Temporal trends in cause-specific late mortality among five-year survivors of childhood cancer

10004 Background: Five-year survival rates for childhood cancer have increased over the past 4 decades, increasing the number of long-term survivors. Among 5-yr survivors, the impact of changes in therapy on cause-specific late mortality has not been thoroughly assessed. Methods: Late mortality was evaluated over 3 eras (1974–81, 1982–90, 1991–2000) in 26,643 5-year survivors diagnosed &lt;21 years of age from the SEER population-based registry. Cause-specific mortality was categorized as death from recurrence/progression of primary disease, external causes, and non-recurrence/non-external causes (Non-Recur/Ext) (i.e., deaths from health conditions including sequelae of cancer therapy). Results: All-cause and Recurrence mortality was significantly lower in more recent eras ( Table ). No significant improvement in late mortality attributable to Non-Recur/Ext causes was seen. Additionally, all-cause mortality was significantly lower in more recent eras for 5-year survivors of ALL, AML, Hodgkin, NHL, and CNS tumors, but not neuroblastoma and Ewing's Sarcoma where an increase in cumulative incidence of late mortality was seen in more recent eras. Significant improvement in late mortality from Recurrence by era was seen in most diagnostic groups. Conclusions: All-cause late mortality has improved with more recent eras, attributable to reduced rates of mortality from progression of primary disease (i.e., durable remission). Importantly, however, efforts to reduce the toxicity of more recent therapies have not produced detectable reduction in mortality attributable to other health conditions including sequelae of cancer therapy (non-Recur/Ext causes of death), which would include death from second malignancy, cardiac and pulmonary conditions. Worsening late mortality for 5-year survivors of neuroblastoma and Ewing's sarcoma may be due to improved use of salvage therapies that delay, but do not ultimately prevent death. [Table: see text] No significant financial relationships to disclose.

Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study

The proportion of pediatric and adolescent cancer patients surviving 5 years has increased during the past four decades. This growing population of survivors remains at risk for disease- and treatment-associated late mortality. A total of 20 483 five-year survivors of childhood and adolescent cancer diagnosed between January 1, 1970, and December 31, 1986, and enrolled in the Childhood Cancer Survivor Study (CCSS) were included in a National Death Index search for deaths occurring between January 1, 1979, and December 31, 2002. Treatment information was abstracted from primary medical records. Survival probabilities, standardized mortality ratios (SMRs), and absolute excess risks were calculated for overall and cause-specific deaths. Diagnosis- and sex-specific survival probabilities were estimated by the product-limit method. All statistical tests were two-sided. Among the CCSS cohort, 2821 (13.8%) 5-year survivors had died by the end of the follow-up period. The cause of death was obtained for 2534 individuals, with 57.5% of deaths attributed to recurrent disease. Estimated probability of survival 30 years from diagnosis was 82%. When compared with the US population, the absolute excess risk of death from any cause was 7.36 deaths per 1000 person-years. The overall SMR was 8.4 (95% confidence interval [CI] = 8.0 to 8.7). Increases in cause-specific mortality were seen for deaths due to subsequent malignancy (SMR = 15.2, 95% CI = 13.9 to 16.6) and cardiac (SMR = 7.0, 95% CI = 5.9 to 8.2), pulmonary (SMR = 8.8, 95% CI = 6.8 to 11.2), and other medical (SMR = 2.6, 95% CI = 2.3 to 3.0) causes. At 20 years of follow-up (25 years after first cancer diagnosis), the death rate due to a subsequent malignancy exceeded that due to all other causes. Our extended follow-up of 5-year survivors of pediatric and adolescent cancer indicates that excess mortality persists long after diagnosis. Continued observation is needed to further define lifetime risk and to determine the potential contribution of chronic health conditions and modifiable health behaviors.

Late mortality in two-year survivors of hematopoietic cell transplantation (HCT) performed in children and adolescents: Report from the BMT-Survivor Study

8507 Background: We assessed overall and cause-specific late mortality [death occurring 2 or more years (yrs) after HCT] in a retrospective cohort of 862 patients (pts), unedrgoing HCT between 1974 and 1998, before the age of 21 yrs, and surviving at least 2 yrs. Methods: Vital status information was obtained from medical records, National Death Index, and Social Security Death Index. Age- and sex-standardized mortality ratios (SMR) were calculated using US population mortality data. Results: Primary diagnoses included ALL (n=212), AML (n=205), SAA (n=113), HD/NHL (n=67), inborn errors of metabolism (IEM: n=81), and other diagnoses (n=184). Types of HCT included related donor (RD: n=496), unrelated donor (URD: n=186), and autologous (A-HCT: n=180). Median age at HCT was 9.3 yrs (0.1–20.9) and length of follow-up 10.1 yrs (2.0–28.4). A total of 182 (21%) late deaths were observed. The cohort was at a 20-fold increased risk of late death when compared with the general population. Leading causes of deaths included recurrence of original cancer (61%) and chronic graft vs. host disease (cGVHD) (12%). Excess mortality rates were also seen due to pulmonary complications (SMR=41.5, 95%CI,18.8–73.1) and SMs (SMR=24.0, 95%CI,13.1–38.2). The probability of living 10 or more yrs was 79.5±1.9%. Multivariate analysis for RD/URD-HCT revealed the risk of late death to be significantly higher in pts receiving TBI (RR=4.4,p<0.001), busulfan (RR=2.8,p=0.03), and those with cGVHD (RR=1.9,p<0.001). Use of cyclosporine (RR=0.5,p<0.001) and methotrexate (RR=0.6,p=0.03) were associated with decreased risk. Among pts receiving A-HCT, the risk of late death was significantly higher in females (RR=1.9,p=0.02). Conclusions: Late mortality rates remain elevated 15 yrs after HCT. Leading causes of death include relapse, pulmonary complications and SMs. No significant financial relationships to disclose.