ALBERT

Beschreibung: Abstract 2252 Poster Board II-229 Introduction: HCT is increasingly offered as a therapeutic option for hematological malignancies. Improvement in therapeutic and supportive care strategies has resulted in a growing population of long-term survivors. These survivors are at a substantial risk of morbidity, contributed to by therapeutic exposures, and development of comorbidities. For example, HCT survivors are potentially at increased risk of atherosclerotic disease of large and small vessels, due to the higher risk of dyslipidemia, diabetes, and hypertension in HCT survivors (Blood 2007;109:1765-72) as well as prior exposures to atherogenic therapeutic exposures (pre-HCT, during conditioning and post-HCT). However, cardiovascular disease (CVD) has not been well-characterized in HCT survivors, in part because of the long latency of clinically overt disease, requiring extended follow-up of large cohorts. The current report addresses this gap in literature by comprehensively evaluating the role of pre- and post-HCT therapeutic exposures (chemotherapy, radiation), transplant-related conditioning regimens, and comorbidities (pre- and post-HCT) in the development of late CVD after HCT. Methods: Utilizing a nested case-control design, individuals with late CVD (diagnosed ≥1 year after HCT) were identified from a cohort of 3,287 1+ year survivors who underwent HCT at a single institution. This cohort formed the sampling frame for selecting controls (without CVD) matched for age and year of HCT, donor source (allogeneic vs. autologous), and length of follow-up. All episodes of CVD (cases) were clinically validated, and included coronary artery disease (CAD) or cerebrovascular events (stroke). Results: Sixty-three patients with late CVD were identified; 44 (69.8%) had CAD and 19 (30.2%) had stroke. Median age at HCT was 49.0 years (range, 18.6 to 78.9 years); median time to CVD was 4.1 years (range, 1.15 to 19.45 years); 66.7% received autologous HCT. Compared to matched controls (N=183), patients with late CVD were more likely to be male (68.3% vs. 51.6%; p=0.02), had greater body mass index at HCT (28.5 vs. 26.6 kg/m2; p=0.03), and were more likely to have multiple comorbidities after HCT (47.6% vs. 13.4%; p

Beschreibung: Patients undergoing HCT are at an increased risk of developing primary and/or reactivated CMV infection, although the magnitude of risk of CMV disease has decreased with the widespread use of preemptive ganciclovir. Most episodes of reactivation occur within the first year post-HCT and are associated with risk factors such as CMV serostatus of donor and recipient, development of acute graft vs. host disease (GVHD): and the immunosuppressive therapy used for its management. Because of prolonged periods of immunosuppression post-HCT, patients may be at risk for delayed CMV infection one or more years after HCT. However, the magnitude of risk of delayed CMV infection and characteristics of those at increased risk has not been described. Given the high morbidity and mortality associated with post-HCT CMV infection, identifying patients at high risk of delayed CMV could be useful for effective management. This report includes 2700 consecutive patients who survived more than one year after undergoing HCT at COH between 1976 and 2003; these included 1404 autologous HCT recipients and 1296 allogeneic HCT recipients (1043 related donor; 253 unrelated donor recipients). Median age at HCT was 38 years (range, 0.6 to 79 years) and 59% of the cohort was males. Median follow-up time from HCT until delayed CMV infection/disease, death, or end of study period (12/31/2006), whichever occurred first, was 4.3 years (range:1–26.6 years). Medical records from COH and/or outside facilities were the main source of data for CMV occurrences. In total, 33 patients (1%) developed delayed CMV infection after surviving at least one year post-HCT (1 autologous and 32 allogeneic [20 related donor and 12 unrelated donor HCT]) developed a total of 40 episodes of delayed CMV that included pneumonia (n=16), gastrointestinal disease (n=8), retinitis (n=2), hepatitis (n=1), concurrent pneumonia and hepatitis (n=1), and asymptomatic reactivation (n=12). The overall cumulative incidence of delayed CMV infection was 1.3% (95% Confidence Interval [CI], 0.9–1.8%) at 5 years from HCT. For autologous HCT recipients, the incidence was 0.07% at 1 year based on 1 event. Among allogeneic HCT recipients, the cumulative incidence at 5 years post-HCT was 2.1% [95%CI, 1.2–3.0%] for related donor HCT recipients; and 5.0% [95%CI, 2.2–7.7%] for unrelated donor HCT recipients. Among allogeneic HCT recipients, the risk factors for the development of delayed CMV infection included unrelated donor HCT (hazard ratio [HR] = 2.5, 95% CI, 1.1–5.7) and CMV seropositive status of the recipient (HR=7.7, 95% CI 1.0–57.0) (Figure). Interestingly, donor CMV status was not associated with increased risk of delayed CMV. All 32 allogeneic HCT recipients experienced chronic GVHD, with prolonged exposures to corticosteroids (median=494 days), and cyclosporine (median=380 days). Thirty patients with delayed CMV infection (94% of the allogeneic HCT recipients with delayed CMV) were receiving immunosuppressive therapy for management of chronic GVHD at onset of delayed CMV. A total of eight patients with delayed CMV did not have a history of CMV infection in the first year, and were characterized by the following clinical and demographic features: 6 (75%) were male; median age at HCT was 35 years; one was an autologous HCT recipient, who relapsed 10 months post-HCT for non-Hodgkin lymphoma, received further chemotherapy and radiation, including Rituximab and then developed late CMV, just over one year post-HCT. The seven allogeneic HCT recipients had chronic GVHD, and were CMV serostatus positive prior to HCT, with 4 also having CMV seropositive donors. Of the 33 patients with delayed CMV in this study, 26 expired; median survival after the development of delayed CMV was 46 days. This study describes the magnitude of risk of delayed CMV infection in autologous and allogeneic HCT recipients and identifies at risk patients as those who are seropositive for CMV, undergoing unrelated HCT, and those with prolonged exposures to immunosuppressive therapy for cGVHD (Figure), suggesting the need for a close surveillance of these patients at high risk. Figure Figure

Beschreibung: Background: Lymphoma patients exposed to chest RT during adolescence/young adulthood are at increased risk for BC; the cumulative incidence exceeds 20% by age 45 and the BC risk is comparable to that in women with BRCA1 mutations. These findings present an urgent yet unmet need to reduce the risk of BC in RT-exposed lymphoma survivors. The risk of BC is 50% lower in chest RT-exposed survivors who also receive ovarian radiation, suggesting a critical role of endogenous estrogens in RT-related breast carcinogenesis, making tamoxifen (a selective estrogen receptor modulator) an attractive risk-reducing option. Tamoxifen administered at 20 mg/d is effective in BC prevention in other high risk populations, but severe adverse events (SAE: venous thromboembolism, endometrial cancer) have limited its broad use. Previous biomarker trials in the general population have shown that LDTam (5mg/d) is not inferior to tamoxifen at 20 mg/d in reducing BC risk, and is associated with a safer AE profile. Mammographic breast density (MBD) is an established biomarker of BC risk; high MBD is associated with a 4-fold higher risk of BC. We hypothesized that LDTam would be effective in reducing BC risk (using MBD as a primary endpoint) in chest RT-exposed lymphoma survivors. We used an investigator-initiated, multi-institutional, randomized phase IIb, double blind, placebo controlled trial (FDA IND 107367) to test this hypothesis. Methods: Female patients from 13 sites were ≥25y at enrollment, with a history of exposure to chest RT at ≥12 Gy by age 40 for their primary cancer, and were off therapy for ≥6 mo. Subjects with a prior history of BC/DCIS, B/L mastectomy, or baseline MBD

Beschreibung: Introduction: Hematopoietic cell transplantation (HCT)-related factors, such as total body irradiation (TBI) used for conditioning, graft-versus-host disease (GvHD), and prolonged exposure to calcineurin-inhibitors, can result in high risk for subsequent skin cancers in long-term survivors. Previous studies examining skin cancers after HCT have largely focused on patients transplanted in earlier eras (

Beschreibung: BACKGROUND: BMT recipients are vulnerable to accelerated atherosclerosis due to prior exposure to radiation with or without chemotherapy, and consequent long-term cardiovascular morbidity, such as stroke. A comprehensive evaluation of the risk of late-occurring stroke in adult BMT survivors and the associated risk factors has not been performed. We addressed this gap using the resources offered by the BMTSS. METHODS: BMTSS includes patients transplanted between 1974 and 2014 at 3 US sites who survived ≥2y after BMT, were alive and ≥18y at BMTSS survey completion. The survey asked participants to report if a healthcare provider had diagnosed specific chronic health conditions (including stroke), or relapse of primary cancer or development of new cancer, along with age at diagnosis. The participants provided information on sociodemographics, health behaviors and medication use. Medical record abstraction was used for information regarding primary cancer diagnosis, therapeutic exposures (pre-BMT chemotherapy/radiation, transplant preparative regimens), stem cell source (autologous, allogeneic), graft type (bone marrow, cord blood or peripheral blood stem cells), and history of chronic graft vs. host disease (GvHD). A cohort of 908 siblings also completed the BMTSS survey and served as a comparison group. Informed consent was obtained from all participants. RESULTS: The study included 3,479 BMT survivors; 50.3% had received an allogeneic BMT, 54.8% were males; 71.4% were non-Hispanic whites. Median age at study participation was 59y (range: 18-89y) for BMT survivors and 57y (range: 18-90y) for siblings. Patient characteristics are shown in Table 1. BMT survivors were followed for a median of 9y (range: 2-41 y) from BMT. Stroke was reported by 136 BMT survivors (67 allogeneic, 69 autologous); of these, 75 (55%) patients developed stroke ≥2y after BMT. Conditional on surviving ≥2y after BMT, the 10y cumulative incidence of stroke was 3.8% (Fig 1), and was comparable for allogeneic (3.4±0.5%) and autologous (4.2±0.6%) BMT recipients, p=0.3. Stroke in BMT recipients compared with siblings: Using logistic regression, and after adjusting for sociodemographics, physical activity and relevant comorbidities, we found that allogeneic BMT survivors were at a 2.1-fold higher odds of reporting stroke as compared to siblings (95%CI: 1.2-3.7, p=0.01), and autologous BMT recipients were at a 1.7-fold higher odds of reporting stroke compared to siblings (95%CI: 0.9-3.0, p=0.09). Stroke after Allogeneic BMT: History of hypertension (HR=2.2, 95%CI: 1.2-3.9, p=0.007), venous thromboembolism (HR=3.4, 95%CI: 1.6-7.1, p=0.002), diagnosis of acute lymphoblastic leukemia (HR=4.9, 95%CI: 1.6-15.0, p=0.006), acute myeloid leukemia/ myelodysplastic syndrome (HR=5.2, 95%CI: 1.4-19.0, p=0.013) (ref: non Hodgkin lymphoma), pre-BMT exposure to alkylating agents (HR=3.3, 95%CI: 1.3-8.5, p=0.01) and pre-BMT neck radiation (HR=5.4, 95%CI: 1.2-23.8, p=0.03) were associated with increased stroke risk. Exercise was associated with lower stroke risk (HR: 0.5, 95%CI: 0.3-0.9, p=0.01). Stroke after Autologous BMT: The risk factors for stroke in autologous BMT survivors included: increasing age at BMT (HR=1.02/y, 95%CI: 1.0-1.1, p=0.05), history of hypertension (HR=1.8, 95%CI: 1.1-3.2, p=0.03), coronary heart disease (HR=2.8, 95%CI: 1.3-6.4, p=0.01) and venous thromboembolism (HR=2.3, 95%CI: 1.1-4.7, p=0.02). Relapse of primary disease or development of new cancer were not associated with increased stroke risk in either autologous or allogeneic BMT recipients. CONCLUSION: In this large study, we found that the incidence of stroke was 4% among BMT survivors, and that they are at an increased risk of developing stroke when compared to an unaffected comparison group. The study also identified subgroups among BMT survivors at increased risk of stroke such as those who received neck radiation and those with cardiovascular comorbidity. These findings suggest a need for increased awareness of stroke as a late complication of BMT, such that aggressive management of cardiovascular risk factors can be instituted among those at highest risk. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

Beschreibung: Background: BMT is now an integral part of consolidation and/or salvage for patients with AML. With the growing population survivors, there is a need to understand the quality of survival. This would allow for appropriate resource allocation and implementation of risk-based screening for early detection of chronic health conditions over time. Yet, a comprehensive evaluation of the long-term burden of morbidity borne by AML patients treated with BMT remains unknown. We addressed this gap by evaluating long-term severe/life-threatening/fatal chronic health conditions (CHCs) in AML patients treated with BMT using the BMTSS. Methods: Patients were eligible if they had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for ≥2y after BMT, and were ≥21y of age at BMT. Of the 1,113 eligible subjects, 711 (64%) participated. BMT survivors identified a nearest-age sibling to constitute an unaffected comparison group (N=1,136). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHC diagnosis by their healthcare provider, including age at onset of CHC. Scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0) to determine the severity of CHCs. Using multivariable logistic regression, we determined the risk of any severe (CTCAE grade 3) or life-threatening (CTCAE grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information regarding therapeutic exposures (pre-BMT and transplant-related) was abstracted from medical records. Cumulative incidence of CHCs (including fatal [CTCAE grade 5] CHCs) were calculated for BMT survivors, treating relapse-related death as a competing risk. Results: Mean age at BMT was 48.6±13.8y and at survey was 58.2±11.5y. Mean interval between BMT and study participation was 9.7±6.8y; 53% were females, and 78% were non-Hispanic white; 86% received allogeneic BMT (48% from an unrelated donor). Conditioning was Fludarabine/Melphalan-based in 53% and TBI-based in 35%; stem cell source was peripheral blood (70.3%), bone marrow (19.3%), and cord (10.4%). For the siblings, the mean age at survey was 56.9+13.4y; 61% were females, and 88% were non-Hispanic white. BMT survivors vs. sibs: 53.3% of the BMT survivors and 30.4% of the sibs reported grades 3-4 CHCs, placing the survivors at a 3.0-fold higher odds of grades 3-4 CHC (95%CI, 2.4-3.7, p

Beschreibung: Abstract 808 The growing population of HCT survivors may be at risk for neuropsychological impairment due to exposure to neurotoxic agents. HCT survivors frequently report problems with memory and attention (Cancer 2002;95:183-192), and even though the patients are acutely aware of neuropsychological declines, these changes do not correlate well with impairment on standardized neuropsychological assessments (Bone Marrow Transplant 2005;36:695-702). This discrepancy suggests that the tests may not be sensitive enough to detect subtle changes that could nonetheless impact patients' societal reintegration, highlighting the importance of self-report instruments. The present study aims to assess the longitudinal trajectory of self-reported neuropsychological impairment in patients from pre-HCT to 1 year post-HCT; to evaluate the impact of demographic and clinical factors on self-reported neuropsychological impairment; to examine the relationship between self-reported neuropsychological impairment data and objective data collected using standardized assessments; and to understand the relationship between self-reported impairment and return to work. Participants were 182 adult patients undergoing HCT for hematological malignancies. Mean age at HCT was 50 years (range, 18-73); 60% were males; 68% were non-Hispanic whites; 62% received autologous HCT. Patients completed a 2-hour battery of standardized neuropsychological tests (domains: processing speed; immediate, general, and working memory; cognitive reserve; executive function) and a self-reported Neuropsychological Impairment Scale (NIS – scales: Global Measure of Impairment [GMI, an overall summary score], Cognitive Efficiency [COG], Attention [ATT], Memory [MEM], Learning-Verbal [L-V], Academic Skills [ACD]). Self-reported information on return to work was obtained at 6 months and 1 year after HCT. Demographic (sex, age, race/ethnicity, education, income, marital status) and clinical data (diagnosis, donor source, risk of relapse, conditioning exposures) were collected. Raw scores were converted to t-scores using normative data; individuals with t-scores above 1 SD of the normative distribution were classified as impaired. Generalized estimating equations were used to examine longitudinal trends. The prevalence of domain-specific impairment at specified time points is shown in the Table. After adjusting for significant covariates, GMI worsened at 6 months and plateaued thereafter (p=0.04) and ATT worsened at 6 months but returned to baseline at 1 year (p=0.006) (Figure). Multivariate analyses revealed the following risk factors: at pre-HCT: female gender and less than high school education (higher MEM impairment, p=0.03, p=0.05, respectively); at both 6 months and 1 year post-HCT: annual household income less than $20,000 (higher GMI impairment, p=0.02); exposure to total body irradiation (TBI: higher COG impairment, p=0.006, and higher ATT impairment, p=0.05); female gender (p=0.05) and 4-year college education (p=0.058) (higher MEM impairment). Correlations between NIS scores and standardized assessments were weak (range, r= -0.3 to 0.09). At 6 months, 57% of the patients had not returned to work. Patients with COG impairment were less likely to return to work (p=0.05), while patients with higher cognitive reserve were more likely to return to work (p=0.03). These results suggest that a significant proportion of patients undergoing HCT report neuropsychological impairment that may not be readily captured by standardized assessments. The present study identifies low household income, TBI, female gender, and college education as risk factors and describes the impact of self-reported neuropsychological impairment on the ability to return to work. This study therefore helps characterize a vulnerable population that needs to be followed closely for appropriate intervention to ensure appropriate societal reintegration after HCT.Table.Prevalence of neuropsychological impairment (t〉60) by time pointGMICOGATTMEML-VACD Pre-HCT29%33%25%25%24%22% 6 months (n=94)32%40%32%27%33%22% 1 year (n=69)32%29%23%29%25%23% Disclosures: Forman: City of Hope: Employment.

Beschreibung: Introduction: Frailty is a state of increased vulnerability resulting in a decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is compromised. We previously reported that BMT recipients with frailty were at a 2.8-fold higher risk of subsequent mortality (JAMA Oncol. 2016;2:1277-86) when compared with non-frail survivors. However, longitudinal trends in frailty several years after BMT are not known, and could possibly help in identifying the vulnerable sub-populations at highest risk of subsequent adverse events. We used BMTSS to report transitions in the frailty state over time. Methods: We included 484 patients who were i) transplanted for a hematologic malignancy between 1974 and 1998 at 2 sites and had survived ≥2y post-BMT; ii) were ≥18y of age at study participation; and iii) were alive both at completion of the baseline survey (t1: median of 7.3 y after BMT) and at follow-up survey (t2: median of 20.6y after BMT); median interval between t1 and t2 was 13.2y. Frailty phenotype used the previous definition (JAMA Oncol. 2016;2:1277-86), and included the presence of ≥3 of the following indices: 1) clinically underweight (body mass index [BMI]

Beschreibung: Background: Therapy-related heart failure (HF) is a leading cause of morbidity and mortality in patients who undergo successful HCT for hematological malignancies. To eventually help improve management of HF, timely and accurate diagnosis of HF is crucial. Currently, no established method for diagnosis of HF exist. One approach to help improve diagnosis and management of HF is to use predictive modeling to assess the likelihood of HF, using key predictors known to be associated with HF. Such models can, in turn, be used for bedside management, including implementation of early screening approaches. That said, many techniques for predictive modeling exist. Currently, it is not known if Artificial Intelligence machine learning (ML) approaches are superior to standard statistical techniques for the development of predictive models for clinical practice. Here we present a comparative analysis of traditional multivariable models with ML learning predictive modeling in an attempt to identify the best predictive model for diagnosis of HF after HCT. Methods: At City of Hope, we have established a large prospective cohort (〉12,000 patients) of HCT survivors (HCT survivorship registry). This registry is dynamic, and interfaces with other registries and databases (e.g., electronically indexed inpatient and outpatient medical records, national death index [NDI]). We utilized natural language processing (NLP) to extract 13 key demographics and clinical data that are known to be associated with HF. For the purposes of this project, we extracted data from 1,834 patients (~15% sample) who underwent HCT between 1994 to 2004 to allow adequate follow-up for the development of HF. We fit and compared 6 models [standard logistic regression (glm), FFT (fast-and-frugal tree) decision model and four ML models: CART (classification and regression trees), SVM (support vector machine), NN (neural network) and RF (random forest)]. Data were randomly split (50:50) into training and validation samples; the ultimate assessment of the best algorithm was based on its performance (in terms of calibration and discrimination) in the validation sample. DeLong test was used to test for statistical differences in discrimination [i.e. area under the curve (AUC)] among the models. Results: The accuracy of NLP was consistently 〉95%. Only the standard logistic regression model LR (glm) resulted in a well-calibrated model (Hosmer-Lemeshow goodness of fitness test: p=0.104); all other models were miscalibrated. The standard glm model also had best discrimination properties (AUC=0.704 in training and 0.619 in validation set). CART performed the worst (AUC=0.5). Other ML models (RF, NN, and SVM) also showed modest discriminatory characteristics (AUCs of 0.547, 0.573, and 0.619, respectively). DeLong test indicated that all models outperformed CART model (at nominal p

Beschreibung: Abstract 605 Background: Centers for Disease Control estimate that 26,000 cancers diagnosed each year in the general population are attributable to HPV; oropharyngeal and female genital cancers account for 75% of these. We hypothesized that HCT recipients are at an especially increased risk of HPV-attributable SNs, because of exposure to high-intensity therapy, coupled with immune dysregulation. However, the magnitude of this risk and sub-populations at highest risk are not known. Clinically this information is important because of the ability to institute primary prevention (HPV vaccine) for the young (