Long-term Survivors Of Hodgkin Lymphoma Research Articles

Aerobic exercise training combined with local strength exercise restores muscle blood flow and maximal aerobic capacity in long-term Hodgkin lymphoma survivors.

It is unclear whether muscle blood flow (MBF) is altered in long-term Hodgkin lymphoma (HL) survivors. We tested the hypothesis that 1) MBF response during mental stress (MS) is impaired in long-term HL survivors and 2) aerobic exercise training combined with local strength exercise (ET) restores MBF responses during MS in these survivors. Eighteen 5-year HL survivors and 10 aged-paired healthy subjects (HC) were studied. Twenty HL survivors were randomly divided into two groups: exercise-trained (HLT, n = 10) and untrained (HLUT, n = 10). Maximal aerobic capacity was evaluated by a cardiopulmonary exercise test and forearm blood flow (FBF) by venous occlusion plethysmography. MS was elicited by Stroop color and word test. ET was conducted for 4 mo, 3/wk for 60 min each session. The aerobic exercise intensity corresponded to anaerobic threshold up to 10% below the respiratory compensation point. The strength exercises consisted of two to three sets of chest press, pulley and squat exercises, 12-15 repetitions each exercise at 30-50% of the maximal voluntary contraction. Baseline was similar in HL survivors and HC, except peak oxygen consumption (peak V̇o2, P = 0.013) and FBF (P = 0.006) that were lower in the HL survivors. FBF responses during MS were lower in HL survivors (P < 0.001). ET increased peak V̇o2 (11.59 ± 3.07%, P = 0.002) and FBF at rest (33.74 ± 5.13%, P < 0.001) and during MS (24 ± 5.31%, P = 0.001). Further analysis showed correlation between the changes in peak V̇o2 and the changes in FBF during MS (r = 0.711, P = 0.001). In conclusion, long-term HL survivors have impaired MBF responses during MS. ET restores MBF responses during MS.NEW & NOTEWORTHY Long-term Hodgkin lymphoma (HL) survivors have impaired muscle blood flow responses during mental stress and decreased maximal aerobic capacity. Supervised aerobic exercise training combined with local strength exercises restores muscle blood flow responses during mental stress and maximal aerobic capacity in these survivors. These findings provide evidence of safety and effectiveness of exercise training in HL survivors. Moreover, they highlight the importance of exercise training in the treatment of this set of patients.

Systemic Biological Mechanisms of Neurocognitive Dysfunction in Long-term Survivors of Childhood Hodgkin Lymphoma.

Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about underlying mechanisms. HL survivors (n=197) and age-, sex- and race/ethnicity-frequency-matched community controls (n=199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections. HL survivors (mean[SD] current age 36[8] years, 22[8] years post-diagnosis) demonstrated higher concentrations of interleukin-6 (IL-6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared to controls (p's<0.001). Among survivors, higher concentrations of IL-6 were associated with worse visuomotor processing speed (p=0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (p's<0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (p's<0.05). Homocysteine was associated with worse short-term recall (p=0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, while IL-6 partially mediated associations between pulmonary conditions and visuomotor processing speed. Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials.

Evaluation of late effects during a 21-year follow-up of pediatric Hodgkin lymphoma survivors: Experience of a pediatric cancer center in Turkey, as a developing country model.

Long-term survivors of Hodgkin lymphoma (HL) are at risk of developing a range of late effects, with a second malignant neoplasm and cardiovascular diseases being the leading causes of death in these patients. The present study aims to evaluate the late side effects in children with HL. Out of 53 HL patients, we assessed the long-term effects of childhood HL survivors (HLSs; n = 50) diagnosed between 1998 and 2019. Patient data related to chronic health conditions, and sociodemographic characteristics were compared with their siblings (n = 56). The cumulative overall survival (OS) at 1, 5, and 10 years from diagnosis was 98.1 ± 1.9%, 93.3 ± 3.8%, and 93.3 ± 3.8%, respectively. Groups of HLSs and their siblings were matched according to age and gender. Compared with siblings, survivors had will be changed as 'a higher frequency of nephrotoxicity (P = 0.02)', cardiotoxicity (P = 0.12), thyroid dysfunction (P = 0.001), health care service usage (P < 0.01), limitation of physical function (P = 0.01), and pulmonary disease (P = 0.01). The control group of siblings had a higher incidence of marital status (P < 0.01), parenthood (P = 0.01), and smoking habit (P = 0.03). Thyroid dysfunction was associated with neck radiotherapy (P < 0.01). No secondaryneoplasm was detected. In relapsed, refractory setting (n = 10), autologous transplantation (n = 9) is performed after a complete remission. Brentuximab vedotin with or without bendamustine and rituximab is also used in selected patients. Increased number of chronic health conditions and social problems point to the significance of long-term follow-up of HLSs. We are currently preparing a survivorship guideline appropriate for Turkey's conditions. Renal, heart, pulmonary impairment, thyroid dysfunction, limitation in physical functioning, and deterioration in social status (marriage, having children, education).

2134P Self-reported late effects, need for information and follow-up in long-term Hodgkin lymphoma survivors

2134P Self-reported late effects, need for information and follow-up in long-term Hodgkin lymphoma survivors

Neurocognitive impairment associated with chronic morbidity in long-term survivors of Hodgkin Lymphoma

AbstractThoracic radiation is associated with significant cardiopulmonary morbidities in survivors of long-term Hodgkin lymphoma and may affect neurocognitive outcomes. Survivors (N = 204; 52.5% female; mean [standard deviation] age, 36.6 [8.01] years) treated with thoracic radiation and age-, sex-, and race/ethnicity-matched community controls (N = 205; 51.7% female; age, 36.7 [9.17] years) completed standardized neurocognitive testing, echocardiography, pulmonary function tests, and vascular studies during the same visit. Treatments were abstracted from medical records. Cardiac (ie, left ventricular ejection fraction [LVEF], global longitudinal strain [GLS]), vascular (ie, large and small artery elasticity [SAE]), pulmonary (ie, diffusing capacity of the lungs for carbon monoxide [DLCO] and forced expiratory volume [FEV1]), and chronic health conditions were evaluated for associations with age-adjusted neurocognitive performance using multivariable linear regression. Compared with controls, survivors had lower performance (P < 0.05) in visuomotor (0.11 vs 0.41), visual processing speed (0.25 vs 0.64), short-term recall (−0.24 vs 0.12), and flexibility (−0.04 vs 0.28). Survivors had lower pulmonary (FEV1, DLCOcorr), cardiac (LVEF, GLS), and vascular function (SAE) than controls (all P < 0.001). FEV1 was associated with visuomotor (P = .008) and visual processing speed (P = .05), and flexibility (P = .05). GLS was associated with short-term recall (P = .03). SAE was associated with flexibility (P = .007). Neurocognitive outcomes were also associated with moderate-to-severe neurologic chronic conditions (P < .05). Findings suggest a link between subclinical cardiopulmonary and vascular findings, neurologic morbidity, and neurocognitive impairments. Prevention of health morbidity may benefit neurocognitive outcomes.

Work ability and work status changes in long-term Hodgkin lymphoma survivors with focus on late adverse effects.

We studied work-related issues in long-term survivors of Hodgkin lymphoma [HLSs] who had undergone treatment according to contemporary stage risk-adapted approaches. At survey, work changes and problems since diagnosis, comparisons of HLSs with low/moderate versus high work ability, associations between work issues, and late adverse effects [LAEs] were examined. This cross-sectional questionnaire-based study included HLSs treated from 1997 to 2006 and alive at the end of 2016. They completed a mailed questionnaire including work and health-related issues. Among 518 invited HLSs, 297 (58%) completed the work-related issues, and 48% of them were females. Mean age at survey was 45.9 years, and mean time was 16.7 years since diagnosis. At follow-up, 71% of the HLSs held paid work and 19% were on disability pension. Only 3% of HLSs did not hold paid work at any time after diagnosis. In total, 43% HLSs had low/moderate and 57% high work ability at follow-up. Low/moderate work ability was significantly associated with older age, female sex, more LAEs, disability pension, lower household income, distressed personality, obesity, fatigue, and mental disorders. More LAEs were significantly associated with more work problems. Many HLSs manage to stay in the work force. Several health problems and LAEs amenable for interventions are significantly associated with low/moderate work ability and emphasize the importance of focus on these issues in long-term follow-up. HLSs in paid work at diagnosis can be optimistic as to their future participation in work life. Screening and treatment for health problems such as LAEs may improve work ability.

Work and education interruption in long-term Hodgkin lymphoma survivors: an analysis among patients from nine EORTC-LYSA trials

Background Disease-specific studies on the impact of Hodgkin lymphoma (HL) on education or work interruption and resumption are lacking. Material and methods In a cross-sectional study conducted among long-term HL survivors enrolled from 1964 to 2004 in nine randomised EORTC-LYSA trials, the interruption and resumption of education/work was investigated. Survivors alive 5–44 years after diagnosis who were studying or working at time of diagnosis were included (n = 1646). Patient and treatment characteristics were obtained from trial records. Education and work outcomes were collected using the Life Situation Questionnaire. Logistic regression was used to model education or work interruption; Cox regression was used to study resumption rates. Results Among survivors studying at time of diagnosis (n = 323), 52% (95% CI: 46–57%) interrupted their education; however, it was resumed within 24 months by 92% (95% CI: 87–96%). The probability of interruption decreased with time: the more recent the treatment era, the lower the risk (OR 0.70 per 10 years, 95% CI: 0.49–1.01). Treatment with radiotherapy (yes vs. no) was associated with a higher education resumption rate (HR 2.01, 95% CI 1.07–3.78) whereas age, sex, stage, radiotherapy field and chemotherapy were not. Among survivors working at time of diagnosis (n = 1323), 77% (95% CI: 75–79%) interrupted their work. However, it was resumed within 24 months by 86% (95% CI: 84%-88%). Women were more likely to interrupt their work as compared to men (OR 1.90, 95% CI: 1.44–2.51) and, when interrupted, less likely to resume work (HR 0.70, 95% CI: 0.61–0.80). Survivors with a higher educational level were less likely to interrupt their work (OR 0.68 for university vs. no high school, 95% CI: 0.46–1.03); and when interrupted, more likely to resume work (HR 1.50 for university vs. no high school, 95% CI: 1.21–1.86). Increasing age was also associated with lower resumption rates (HR 0.62 for age ≥50 vs. 18–29 years, 95% CI: 0.41–0.94). Conclusion An interruption in education/work was common among long-term HL survivors. However, most of the survivors who interrupted their studies or work had resumed their activities within 24 months. In this study, no associations between survivors’ characteristics and failure to resume education were observed. Female sex, age ≥50 years, and a lower level of education were found to be associated with not resuming work after treatment for HL.

Employment situation among long-term Hodgkin lymphoma survivors in Europe: an analysis of patients from nine consecutive EORTC-LYSA trials.

Little is known about the employment situation of long-term Hodgkin lymphoma (HL) survivors despite their young age at diagnosis and the favorable prognosis of the disease. In this cross-sectional study, we aim to describe the employment situation in a cohort of long-term HL survivors compared to the general population and investigate the associations with disease characteristics and treatment exposure. HL survivors > 25years (n = 1961) were matched 1:25 to controls (n = 49,025) from the European Union Labour Force Survey. Individual treatment information was obtained from trial records. Employment and socio-demographic characteristics were collected using the Life Situation Questionnaire. Logistic regression models were used to estimate associations between disease and treatment characteristics with employment status and work-related attitudes. At employment assessment, 69.7% of survivors (95% CI: 67.6-71.7%) were working; of these, 68.9% (95% CI: 66.3-71.3%) worked full-time, a figure comparable to that of controls (p value 0.17). The risk of not working was associated with increasing age at diagnosis, increasing age at survey, female sex, lower educational level, and relapse history. Of those who were at work during treatment, 16.8% (95% CI: 14.5-19.3%) stated their income had subsequently decreased, which was attributed to their HL by 65.4% (95% CI: 57.5-72.8). Among those not at work, 25.1% (95% CI: 20.7-29.8) survivors were disabled compared to only 14.5% (95% CI: 13.8-15.3%) of controls. In this cohort of HL survivors, employment status was comparable to that of the general population. However, increasing age at follow-up, female sex, lower educational level, and relapse history are risk factors for unemployment, a perceived decrease in income, and disability. To further improve follow-up care, special attention should be paid to these vulnerable subgroups.

P067: A pilot of lung cancer screening for survivors of Hodgkin lymphoma

Background: Alkylating agents and thoracic radiation put survivors of Hodgkin lymphoma (HL) at excess risk of lung cancer (30-year cumulative incidence 6.4%). Lung cancer screening (LCS) using low-dose CT thorax (LDCT) scans reduces lung cancer mortality in ever smokers in the general population by detecting early-stage lung cancers. We ran an LCS pilot in HL survivors, who are generally ineligible for LCS programmes aimed at the general population. Methods: 218 5+ year survivors of HL treated with mustine or procarbazine and/or thoracic radiation were identified from a follow-up database (ADAPT) hosted at The Christie NHS Foundation Trust and sent a letter of invitation. Participants underwent a baseline LDCT scan. Scans were reported as negative/indeterminate/positive in accordance with lung nodule guidelines. Indeterminate nodules required a further LDCT scan 3-months later. Participants with a positive scan were referred to lung cancer services. Results: Of the 218 invited to the study 54% were female, median age was 53 (range 25–80), median years since treatment 21 (6–45). 12 were ineligible. 127 (59%) expressed interest in participating. The uptake among eligible responders was 83% (102/123). Participation was not influenced by age or gender. Baseline LDCT scan results in 102 participants were: 90 (88.2%) negative, 10 (9.8%) indeterminate, 2 (2.0%) positive. 3-month surveillance LDCT scan results (n=9) were: positive (2), stable (5), with 2 pending. Among 4 participants with positive baseline or 3-month scans, 1 has been diagnosed with early-stage small-cell lung cancer and treated with curative intent, 1 is undergoing tests for presumed lung cancer and 2 are undergoing further surveillance. Coronary artery calcification was detected in 36.3%. Clinically significant incidental findings including emphysema, bronchiectasis, pulmonary inflammation/infection, metastatic breast cancer and vertebral insufficiency fractures were seen in 20 (19.6%). Notably, 3/35 participants who were ever smokers met the age and risk criteria for LCS through the programme aimed at the general population. Conclusion: LDCT scanning protocols tested in the general population are appropriate for use in the HL survivor population in a future targeted LCS programme. The feasibility of such a programme is contingent on developing methods to identify and contact long-term survivors of HL at risk of lung cancer and on investigating and addressing barriers to uptake.

Radiotherapy-Related Dose and Irradiated Volume Effects on Breast Cancer Risk Among Hodgkin Lymphoma Survivors.

BackgroundBreast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients.MethodsWe conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined.ResultsStatistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed.ConclusionMean breast dose predicts subsequent BC risk in long-term HL survivors.

Assessment of cognitive function in long-term Hodgkin lymphoma survivors, results based on data from a major treatment center in Hungary

IntroductionNowadays, more than 80% of newly diagnosed classical Hodgkin lymphoma (HL) patients can be cured and become long-term survivors due to risk and response-adapted treatment strategies. A well-known side effect is cognitive dysfunction that appears in HL patients after chemotherapy. In the present study, we aimed to measure cognitive dysfunction in our HL patients in this study and to find potential correlations between patient-related factors, the signs and symptoms of their diseases, or therapeutic factors.MethodsWe carried out a computer-assisted assessment (CANTAB) of cognitive dysfunction in 118 patients. We examined the domains of visual memory, attention, working memory, and planning.ResultsThe median age of 64 females and 54 males at diagnosis was 29 (13–74) and 41 (21–81) years at the completion of CANTAB. Fifty-two percent of all patients showed cognitive impairment. Attention was impaired in 35% of patients, the working memory and planning were impaired in 25%, while visual memory was affected in 22%. All the three functions showed a significant association with inactive employments status. A close correlation was found between visual memory/working memory and planning, higher age at HL diagnosis or the completion of CANTAB test, and disability pensioner status.DiscussionOur investigation suggests that patients with inactive employment status and older age require enhanced attention. Their cognitive function and quality of life can be improved if they return to work or, if it is not possible, they receive a cognitive training.

Changes in Second Primary Malignancies (SPM) after Hodgkin Lymphoma over Time in the United States

Background Improved treatments for Hodgkin lymphoma (HL) have prolonged survival. However, the increased risk of second primary malignancies (SPMs) among HL survivors compared to the general population remains the leading cause of death among long-term HL survivors. Treatment has evolved to include improved radiation techniques and response adapted chemotherapy regimens with the goal of improving HL cure rates, limiting treatment-associated morbidity, and improving long-term overall survival. Few population-based studies in the United States have examined whether the incidence of SPMs has decreased over time with these attempts to limit treatment-related toxicities.Methods Data for 20,530 patients of all ages diagnosed with a first primary HL during 1992-2013 were obtained from 13 Surveillance, Epidemiology and End Results (SEER13) regions in the United States. The incidences of SPM that developed >1 year after the initial HL diagnosis were determined for two treatment eras (1992-2002 and 2003-2013). To balance follow up time, HL patients diagnosed in 1992-2002 were followed through 2002 and patients diagnosed in 2003-2013 were followed through 2013. In each treatment era, we calculated standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (CIs) comparing HL patient's subsequent cancer incidence with the expected number of first primary cancer incidence, based on the age (at 5-year intervals), sex, calendar year (at 5-year intervals), cancer site, and race/ethnicity, derived from the general SEER13 population. SIRs were calculated for all invasive cancers and by cancer categories (solid and hematologic tumors) as well as by HL stage at diagnosis (stage I/II vs stage III/IV) and initial treatment with radiation. The cumulative incidence of SPMs, accounting for the competing risk of death, were estimated, with Gray's K-sample test statistic used to determine whether the difference in cumulative incidence of SPMs by treatment era was statistically significant (P -values that were <0.05).Results The mean follow-up time was 4.9 (±3.3) years for 9,989 patients (n=275 SPMs) diagnosed in 1992-2002 and 4.8 (±3.3) years for 10,541 patients (n=285 SPMs) diagnosed in 2003-2013. The mean age was similar for patients in the two treatment eras (38.4 years, 1992-2002; 39.4 years, 2003-2013). There was a statistically significant increase in SPMs of all sites in both time-periods compared to the expected number of first primary tumors in the general population. More specifically, there was a considerably elevated risk of lymphatic and hematopoietic SPMs amongst all patients with primary HL (1992-2002 SIR: 6.53 (5.24-8.03); 2003-2013 SIR: 5.85 (4.77-7.11)) and a suggestion of elevated risk of solid tumors (1992-2002 SIR: 1.37 (1.17-1.58); 2003-2013 SIR: 1.11 (0.95-1.29)). For all those diagnosed with HL, there was an increased rate of acute myeloid leukemia compared to the general population (1992-2002 SIR: 15.43 (9.14-24.39); 2003-2013 SIR: 17.23 (11.35-25.06)). At 5-years, the cumulative incidence of all SPMs (1992-2002: 1.93%; 2003-2013: 2.12%; p=0.84), lymphatic and hematopoietic SPMs (1992-2002: 1.23%; 2003-2013: 1.25%; p=0.94) and solid SPMs (1992-2002 0.69%, 2003-2013 0.85%, p=0.59) were similar in the two treatment eras (Figure). Further, the cumulative incidence of SPMs did not differ by stage at diagnosis or initial treatment with radiation therapy.Conclusions Despite changes in radiation techniques and chemotherapy regimens for the treatment of HL, there continues to be increased risk of SPMs, specifically those of the lymphatic and hematopoietic systems, in survivors of HL compared to the general population. Additionally, there is no change in the cumulative incidences of SPMs in HL survivors over time. Other studies have shown that SPMs do not begin to peak until 10-15 years after cancer diagnosis. Therefore, it is important to continue to monitor whether changes in treatment regimens will result in fewer SPMs as additional follow-up time becomes available.Figure. Cumulative incidence of all subsequent primary malignancies 1 to 10 years after a first diagnosis of Hodgkin lymphoma, by treatment era. [Display omitted] DisclosuresWun:Janssen: Other: Steering Committee for Cassini Study and Callisto Program, Research Funding; Pfizer: Other: Steering Committee: RESET study, Research Funding.

Integration of Pediatric Hodgkin Lymphoma Treatment and Late Effects Guidelines: Seeing the Forest Beyond the Trees.

The successful integration of clinical trials into pediatric oncology has led to steady improvement in the 5-year survival rate for children diagnosed with Hodgkin lymphoma (HL). It is estimated that >95% of children newly diagnosed with HL will become long-term survivors. Despite these successes, survival can come at a cost. Historically, long-term survivors of HL have a high risk of late-occurring adverse health effects and increased risk of nonrelapse mortality compared with the general population. The recognition of late-occurring events paired with the decades of life remaining for children cured of HL have made paramount the need to develop effective treatments that minimize the risk of late toxicity. Toward this goal, multiple, dose-intense, risk- and response-based regimens that use lower cumulative doses of chemotherapy and radiation have been developed. Appropriate frontline treatment selection requires a level of familiarity with the efficacy, acute toxicity, convenience, and late effects of treatments that may be impractical for providers who infrequently treat children with HL. There is an increasing need for guideline developers to begin to merge considerations from both frontline treatment and survivorship guidelines into practical documents that integrate potential long-term health risks. Herein, we take the first steps toward doing so by aligning cumulative treatment exposures, anticipated risks of late toxicity, and suggested surveillance recommendations for NCCN-endorsed Pediatric HL Guidelines. Future studies that integrate simulation modeling will strengthen this integrated approach and allow for opportunities to incorporate regimen-specific risks, health-related quality of life, and cost-effectiveness into decision tools to optimize HL therapy.

Vo2peak in Adult Survivors of Hodgkin Lymphoma: Rate of Decline, Sex Differences, and Cardiovascular Events

BackgroundAdult survivors of Hodgkin lymphoma (HL) are at increased risk of cardiovascular (CV) events secondary to mediastinal radiation therapy (RT). ObjectivesIn this group of patients, we assessed the association between cardiopulmonary exercise testing (CPET), as determined by percent-predicted peak Vo2 (ppVo2peak), and clinical outcomes, as well as the rate of ppVo2peak decline and sex differences. MethodsAll survivors of HL who were >10 years post chest RT and who underwent ≥1 CPET were enrolled from a single center. Traditional CV and treatment risk factors, along with CV events, were ascertained. ResultsA total of 64 patients (67% female; median age 51 years [range 26 to 70 years]) with a median follow-up time after RT of 23 years (range 11 to 41 years), and 141 CPET studies, were included. Median initial ppVo2peak was 91% (range 58% to 138%). ppVo2peak in survivors declined by 7.5 percentage points every 10-year period after RT, as compared with age- and sex-based norms (P = 0.001), even after adjusting for hypertension and history of anthracycline. Both male and female patients had a similar rate of ppVo2peak decline. However, women had a lower ppVo2peak at all times, and they developed abnormal ppVo2peak (≤85%) on average earlier than men (24.1 years vs 47.0 years after RT). Patients with abnormal ppVo2peak vs normal ppVo2peak (>85%), had an increased risk of CV events (59% vs 16%). Abnormal ppVo2peak was independently associated with the risk of CV events (adjusted HR: 6.37; 95% CI: 2.06-19.80; P = 0.001). ConclusionsPercent-predicted Vo2peak in long-term survivors of HL who were treated with chest RT progressively declined as compared with population- and sex-based norms. Importantly, women developed abnormal ppVo2peak more than 2 decades earlier than male survivors. Abnormal ppVo2peak was associated with an increased risk of CV events in this group of patients.

Abstract PS9-09: Web-based intervention to improve knowledge, intent to screen and uptake of breast cancer screening among long-term, high-risk Hodgkin lymphoma survivors who received chest radiation

Abstract Background Many cancer survivors experience late effects from their cancer treatment including second cancers. Breast cancer risk in Hodgkin lymphoma (HL) survivors is estimated at 35% by age 50 years1 with a 40-fold increase when treated with chest radiation prior to age 20 years2. For patients who received chest radiation between ages 10 and 30 years, NCCN recommends annual screening mammogram and breast MRI 10 years after chest wall radiation or after age 30 and 25 years respectively3. We designed a web-based intervention to improve knowledge, intent to screen and uptake of breast cancer screening among long-term, high-risk HL survivors.Methods We invited 263 long-term HL survivors treated with chest radiation, of which 60 women were enrolled. Participants were randomized 1:1 to web-based intervention or control groups. The web-based intervention consisted of daily, interactive, highly tailored learning modules over the course of one week. Both groups received handouts on potential complications from cancer treatment and screening recommendations. All participants were invited to a baseline survey, first follow-up survey 1-2 weeks post intervention, and a final survey 3 months post intervention. In total, 53 participants completed the baseline survey, and to-date 41 the first follow-up survey. The last 3-month follow-up surveys are due in fall 2020. We compared frequencies of who correctly answered questions regarding potential complications from prior treatment and breast cancer screening recommendations at baseline vs. first follow-up in the intervention and control groups using Chi-squared and Fisher’s exact tests. P value &amp;lt; 0.05 was considered significant.Results At baseline, participants were on average 49 years old, and 22.4 years out from their HL diagnosis. Baseline self-reported adherence to annual mammography and breast MRI screening was low: 55% of all participants reported receiving annual mammograms, and only 6% reported annual MRIs. At baseline, 79% of participants reported awareness of complications from previous treatments however, only 27% correctly identified national guidelines on breast cancer screening for HL survivors who received chest radiation. At one week after the intervention, individuals assigned to the intervention (compared with controls) more often 1) reported knowing how to reduce the risk from prior treatments (89.5% vs. 50%, p = 0.009), 2) correctly identified national guidelines on screening (63.2% vs. 27.3%, p=0.007) at first follow-up. Our preliminary data did not show an increase in intent to screen or uptake of screening shortly after intervention. Conclusions Adherence to breast cancer screening recommendations is low among long-term, high-risk HL survivors. Preliminary analysis of an RCT comparing a web-based intervention to paper handouts identified improved knowledge regarding current national guidelines on breast cancer screening and how to reduce the risk of complications from prior HL treatments. Further research should address barriers to screening and interventions to address them.

Long-term Hodgkin Lymphoma Survivors: A Glimpse of What Happens 10 Years After Treatment

IntroductionThis retrospective study was focused on 96 patients (median age at diagnosis, 35 years) with newly diagnosed Hodgkin lymphoma (HL) treated at the University Hospital of Bari (Italy) between 2005 and 2008, to evaluate the outcome and the long-term toxicity. Patients and MethodsFirst-line chemotherapy was ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in all patients; 49 (51%) patients had undergone radiotherapy. At the end of treatment, 75 (78%) patients were in complete remission (CR); 18 (24%) of 75 patients relapsed after first-line treatment; 20 (21%) underwent autologous hematopoietic stem cell transplantation, and 3 (3%) underwent allogeneic stem cell transplantation. ResultsAfter a median follow-up of 12 years, 85 (88%) patients are alive in CR, and 11 (14%) have died (2 of a second neoplasia, 1 of infection, and 8 of the disease). The 140-month Kaplan-Meier survival estimates were 86%. Three women became pregnant and each gave birth to a healthy child. The most prevalent chronic conditions at last follow-up were: a reduction in lung transfer factor for carbon monoxide (40%), fatigue (31%), hypothyroidism (30%), and infertility (16%). ConclusionsResults of this study offer indications about how long after the initial treatment excess deaths from causes other than HL begin to occur. However, challenges remain, namely establishing the optimal time to begin screening for potential late complications and developing better surveillance guidelines. Further work is needed to identify risk factors that may predict specific late effects.

Associations between Persistent Inflammation and Oxidative Stress with Neurocognitive Impairment in Long-Term Hodgkin Lymphoma Survivors and Community Controls

Background: Long-term survivors of Hodgkin lymphoma (HL) experience neurocognitive impairment despite receiving no CNS-directed therapy, though little is known about the biologic mechanisms underlying this impairment. This study aimed to examine associations between pro-inflammatory and oxidative stress biomarkers with neurocognitive impairment in long-term HL survivors. Methods: 197 HL survivors (mean[SD] current age 36[8] years, 22[8] years post-diagnosis) and 199 age-, sex- and race/ethnicity-frequency-matched community controls completed neurocognitive testing (intelligence, attention, processing speed, memory) and systemic biomarker assessment. Neurocognitive scores were converted into age-adjusted Z-scores (μ=0, σ=1.0) using national normative data. Pro-inflammatory cytokines (IL-6, TNF-α) and markers of oxidative stress (malondialdehyde [MDA], oxidized low density lipoprotein, glutathione peroxidase [GPx]) were measured using multiplex assays on a Luminex platform. Biomarkers with undetectable concentrations were set at the lower limits of detection. Tertiles of each biomarker were created based on distributions in controls. Generalized linear models (GLM) compared survivors and controls on neurocognitive Z-scores adjusting for sex and on biomarker concentrations adjusting for sex and age. Sex-adjusted GLM compared the neurocognitive Z-scores across tertiles of each biomarker separately in HL survivors and controls. The analysis was limited to neurocognitive tests where survivors performed worse than controls after adjustment for the false discovery rate. Results: HL survivors demonstrated worse verbal reasoning (mean Z-score -0.3 vs. 0.1, p&amp;lt;0.001), focused (0.3 vs.0.6 p=0.034) and sustained attention (-0.1 vs. 0.2 p=0.005), short-term (-0.2 vs. 0.1 p=0.003) and long-term memory (-0.3 vs. 0.04 p=0.005), and fine motor (-0.4 vs 0.0 p&amp;lt;0.001), visual (0.3 vs 0.6 p&amp;lt;0.001), and visuomotor processing speed (0.1 vs 0.4 p=0.004) compared to controls. HL survivors, when compared to controls, demonstrated higher concentrations of TNF-α (β=0.9 95%CI 0.2, 1.6, p=0.012), IL-6 (β=0.8 95%CI 0.2, 1.5, p=0.013), oxidized low density lipoprotein (β=22.1 95%CI 14.1, 30.0, p&amp;lt;0.001), and GPx (β=54.5 95%CI 27.8, 81.2, p&amp;lt;0.001). Mean difference in neurocognitive tests scores across tertiles of MDA and GPx are presented in Table 1. Among HL survivors, higher concentrations of MDA were associated with worse verbal reasoning (β =-0.5 95%CI -0.9, -0.1), visual processing speed (β =-0.4 95%CI -0.8, -0.1), verbal learning (β =-0.4, 95%CI -0.8, -0.02), and short- (β =-0.5 95%CI -0.9, -0.1) and long-term memory (β =-0.5 95%CI -0.9, -0.04). Higher concentrations of GPx were associated with better verbal reasoning (β =0.51 95%CI 0.05, 0.97), visual processing speed (β =0.45 95%CI 0.02, 0.88) and focused attention (β =0.32 95%CI 0.01, 0.64) in HL survivors. No associations between neurocognitive function and MDA or GPx were found among community controls, suggesting HL survivors may be particularly susceptible to oxidative stress. No statistically significant associations with oxidized LDL were noted among survivors or controls. Among HL survivors, higher concentrations of IL-6 were associated with worse sustained attention (β=-1.1 95%CI -2.2, -0.02), and visuomotor (β=-0.4 95%CI -0.7, -0.01) and visual processing speed (β=-0.4 95% CI -0.7, -0.01). Among controls, these associations were less pronounced (β =-0.39 95%CI -0.69, -0.10, β =-0.41 95%CI -0.74, -0.09, and β =-0.10 95%CI -0.45, 0.24 respectively). Higher concentrations of IL-6 were associated with worse verbal learning and long-term memory in controls but not in HL survivors, suggesting the mechanisms by which IL-6 is associated with cognitive impairment may differ in survivors. Higher concentrations of TNF-α were associated with better long-term memory in survivors (β=0.6 95% CI 0.1, 1.0) but not controls. Conclusion: HL survivors have persistent neurocognitive impairment, inflammation, and oxidative stress up to 20 years after treatment. Associations between oxidative stress and intelligence, processing speed and memory deficits were unique to HL survivors, identifying potential causal pathways that warrant further research to understand the pathophysiology of neurocognitive impairment in HL. Disclosures No relevant conflicts of interest to declare.

Fertility Rates in Young Hodgkin Lymphoma Survivors: A Danish Nationwide Cohort Study of 769 Patients

Introduction: The vast majority of young adults with Hodgkin lymphoma (HL) are cured by contemporary first line treatments. Treatment-related long-term toxicities can have a negative impact on survivorship and the risk of infertility may be particularly pertinent to young HL survivors. This study aimed to investigate the fertility rate (rate of first child after index date) over time in patients with HL compared to the matched controls. Methods: All Danish patients with HL, including classical and lymphocyte predominant HL, diagnosed in the period 2000-2015 were identified in the Danish Lymphoma Registry. Patients aged 18-40 years at diagnosis with documented complete remission after first line therapy were included. Patient data were merged with the Danish Fertility Database and the Medical Register of Births and Deaths. For each HL patient, five random Danish citizens alive at the index date of the HL patient were matched on birth date, sex, and parenthood status (categorical; with children vs without children at the index date). Follow-up was measured from 9 months post diagnosis (index date) until the time of first child, relapse, death, or censoring, whichever came first. Patients with progression/relapse within the first 9 months after diagnosis were excluded. Cumulative incidences of first living child after the index date were computed for the entire cohort and stratified on sex using the Aalen-Johansen estimator with death or relapse before first child after index date as competing events. Cox regression was used to compare the rates of first child of HL patients and matched controls by clinical subgroups and estimated for males and females separately. Results: A total of 769 HL patients were included (male:female ratio 1.2, median age 30 years) and median follow-up was 9.9 years. The mean numbers of children per person at start of follow-up were similar in patients and matched controls (female HL patients 0.64 vs matched controls 0.63 children per individual; male HL patients 0.56 vs matched controls 0.54 children per individual). At the end of follow-up, average numbers of children were higher in male and female HL patients (female HL patients 1.22 children per individual; matched control 1.14 children per individual) and males (HL patients 1.00 children per individual; matched controls 0.92 children per individual). The cumulative incidence of first child after index date in female HL patients was lower during the first three years of follow-up compared to the matched controls. However, beyond three years of follow-up the cumulative incidences of first child after index date were similar (Figure 1A). Among male HL patients the cumulative incidence of first child after index date was higher than that of the matched controls throughout the entire follow-up (Figure 1B). Overall, fertility rates were higher in HL patients (males, 36.7 per 1,000 person years; females, 41.7 per 1,000 person years) as compared to the matched controls (males, 24.2 per 1,000 person years; females, 33.0 per 1,000 person years). The Cox regression showed that both male and female patients with HL had higher fertility rates as compared to matched controls (males, HR 1.5, p-value &lt; 0.001; females, HR 1.2, p-value = 0.012; Table 1). This was also observed in specific clinical subgroups, i.e. ages 18-30 years, CCI 0, no children prior to diagnosis, and limited stage disease. Moreover, among patients receiving 6+ cycles of chemotherapy, fertility rates were not lower than expected (Table 1). Conclusion: The fertility rates for long-term HL survivors without progression/relapse were higher than in matched controls, in particular for male HL patients. Elevated fertility rates as compared to the matched controls were observed for lower age (&lt;30 years), limited stage disease, and for patients without children at the time of diagnosis. No clinical subgroup did significantly decrease the fertility rates. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding. Frederiksen:Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Glimelius:Janssen Pharmaceuticals: Honoraria. Ekstroem Smedby:Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

Accelerated atherosclerosis, hyperlipoproteinemia and insulin resistance in long-term survivors of Hodgkin lymphoma during childhood and adolescence.

Long-term survivors of Hodgkin lymphoma during childhood or adolescence (HL survivors) are at high risk of developing treatment-related late cardiovascular sequelae. In our study we evaluated the presence of modifiable cardiovascular risk factors (hypertension, hyperlipoproteinemia, hyperinsulinemia, obesity), endothelial and inflammatory markers (E-selectin, PAI-1, hs-CRP) and atherosclerotic changes in the common carotid arteries. Assessment was performed in 80 young adult Hodgkin lymphoma long-term survivors at more than 10 years after the potentially cardiovascular toxic anticancer treatment (median age at evaluation 34.7 years; range 24.1-40.9 years). The HL survivors were compared with 83 age- and gender-matched healthy volunteers. The HL survivors showed unfavorable lipid profiles compared to those of healthy controls: triglycerides (p=0.01), total cholesterol (p=0.0004), low density lipoprotein cholesterol (p=0.005). In HL survivors, we found a higher prevalence of hypertension (p=0.004) and insulin resistance - HOMA-IR (p=0.0002). Ultrasonographic examination of both common carotid arteries revealed a higher prevalence of atherosclerotic plaques (p=0.0009) and higher carotid intima-media thickness (p<0.0001) in HL survivors. Markers of oxidative stress (advanced oxidation protein products, oxidized low-density lipoprotein), inflammation (hs-CRP) and endothelial dysfunction (E-selectin, PAI-1) were also higher in HL survivors (p<0.0001, p=0.0002, p=0.0031, p=0.0087, p=0.004, respectively). Adult survivors of Hodgkin lymphoma during childhood and adolescence need closer follow-up with screening of metabolic syndrome components, unfavorable lifestyle factors and early management of these risk factors.

Increased Risk of Diabetes Mellitus Among Adult Survivors of B-Cell Non-Hodgkin Lymphoma

▪IntroductionImprovements in multi-modal therapies have increased survival rates for older adults diagnosed with B-cell Non-Hodgkin Lymphoma (B-NHL). Despite this success, B-NHL survivors are at an increased risk for developing long-term and late complications of these therapies thereby compromising survival. Several studies have reported an increased risk in diabetes mellitus (DM) among long-term survivors of Hodgkin lymphoma and pediatric cancers. However, there are limited data on the risk of DM and its risk factors in older adults following treatment for B-NHL. Using data from the Utah Population Database, we evaluated the association between treatment for B-NHL and DM risk and furthermore compared this risk to a matched Utah general population. We hypothesized that the risk of DM among B-NHL survivors would be significantly increased compared to the general population.MethodsAdult (age >18 years at diagnosis) survivors of primary B-NHL living in Utah at the time of diagnosis between 1997-2013, without a previous diagnosis of DM, and matched (1:4) to individuals without a prior history of DM from the Utah general population for birth year, birth state, and sex were included. New DM diagnoses were identified for all-time, 0-1, 1-5, and 5-10 years following a diagnosis of B-NHL. Adjusting for sex, race, baseline body mass index (BMI), and Charlson Comorbidity Index (CCI) scores, multivariate Cox proportional hazard analysis was performed to estimate the adjusted hazard ratio (aHR) of DM in B-NHL survivors compared with that in matched non-B-NHL individuals. Risk factors for DM were evaluated, including age at diagnosis, race, sex, BMI at baseline, family history of DM, cancer stage at diagnosis, and treatment modality. The risk of developing DM during all-time, 0 to 1, 1 to 5, and 5 to 10 years follow-up after adjusting for demographic variables was analyzed by age (< 40, 40-65, and >65 years) at diagnosis of B-NHL.ResultsThe study population included 3,970 B-NHL survivors and 19,821 matched individuals from the general population. At the time of diagnosis, the majority of B-NHL patients were age 60 or greater (61.4%), had diffuse large B-cell lymphoma (46%) or follicular lymphoma (26.4%), distant cancer stage (50.1%), and received chemotherapy (27.5%). DM was diagnosed in 897 (22.6%) B-NHL survivors and 3,253 (16.4%) non-B-NHL adults. The majority in both groups were male (B-NHL: 55.5%; controls: 55.5%), white (B-NHL: 97.4%; controls: 93.8%), overweight [BMI 25-29.9 kg/m2 (B-NHL: 40.7%; controls: 40.6%)] or obese [BMI ≥30 kg/m2 (B-NHL: 21.8%; controls: 18.5%)]. The risk of developing DM among B-NHL survivors compared to the control group was significantly increased over all time (HR, 1.34; 95% CI 1.24 - 1.44) and the 0 to 1 year follow-up period (HR, 1.28; 95% CI 1.15 - 1.43)(Table 1). Multivariable analysis for DM risk showed that age 40-65 years and BMI ≥25 were factors independently associated with developing DM at all-time, 0 to 1, 1 to 5, and 5 to 10 years after diagnosis of B-NHL. Male sex and a family history of DM were significantly associated with development of DM during all time, 1 to 5, and 5 to 10 year follow-up periods. Distant cancer stage at diagnosis was a significant risk factor for DM at all time and 1 to 5 years while receipt of chemotherapy only or chemotherapy with radiation were significantly associated with development of DM at 5 to 10 years after diagnosis of B-NHL (estimated aHR and CIs are shown in Table 2). There was no significant association between race and the development of DM.ConclusionAdult survivors of B-NHL have an overall significantly higher risk of developing DM in the first year and over all time following a diagnosis of B-NHL compared to the general population. Age 40 to 65 years and BMI ≥25 were significant risk factors for DM across all follow-up periods while treatment with chemotherapy only or chemotherapy with radiation significantly increased the risk of DM 5-10 years after diagnosis of B-NHL. Race did not appear to be a risk factor for DM but this result may reflect the homogeneity of our study population. These findings contribute important information to the existing literature regarding the risk of developing DM in adult B-NHL survivors and provide foundation for the development of screening and management guidelines for DM in the B-NHL survivor population. DisclosuresNo relevant conflicts of interest to declare.