BMJ Open. Pattern of Cardiac Surveillance Among Lymphoma Patients Receiving Anthracycline-Based Chemotherapy

Transcription

1 Pattern of Cardiac Surveillance Among Lymphoma Patients Receiving Anthracycline-Based Chemotherapy Journal: BMJ Open Manuscript ID: bmjopen Article Type: Research Date Submitted by the Author: 0-Mar-0 Complete List of Authors: Hung, Olivia; Emory University School of Medicine, Medicine Brown, Jennifer; Emory University, Medicine Dai, Tian; Emory University, Biostatistics & Bioinformatics Easley, Kirk; Emory University, Biostatistics & Bioinformatics Flowers, Christopher; Emory University, Medicine Parashar, Susmita; Emory University, Medicine <b>primary Subject Heading</b>: Cardiovascular medicine Secondary Subject Heading: Oncology Keywords: Heart failure < CARDIOLOGY, Adult cardiology < CARDIOLOGY, Cardiomyopathy < CARDIOLOGY, Cardiology < INTERNAL MEDICINE, Adult oncology < ONCOLOGY, Lymphoma < ONCOLOGY

2 Page of BMJ Open Pattern of Cardiac Surveillance Among Lymphoma Patients Receiving Anthracycline- Based Chemotherapy Olivia Y. Hung, MD, PhD ; Jennifer R. Brown MD, MS ; Tian Dai BS ; Kirk A. Easley, MS, MApStat ; Christopher R. Flowers MD, MS ; Susmita Parashar MD, MPH, MS Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Department of Biostatistics & Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA Division of Hematology & Medical Oncology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Key Words: anthracycline-based chemotherapy, cardiotoxicity, anthracycline-induced cardiomyopathy Total Word count:, (excluding title page, abstract, summary, references, figures and tables) Contributorship Statement: OYH, JRB, CRF and SP were critically involved in the study design, collection and analysis as well as the preparation and editing of this manuscript. TD and KAE performed all statistical analyses in this study, provided substantial insight into data analysis and helped with manuscript preparation and editing. Data Sharing Statement: No additional data available. Disclosure Statement: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. None of the authors have any disclosures or competing interests relevant to this study to report.

3 Page of Address for correspondence: Susmita Parashar MD, MPH, MS Associate Professor of Medicine Emory University School of Medicine Clifton Road NE, Suite 0 Atlanta, GA 0 Phone: 0-- Fax: susmita.parashar@emory.edu Abbreviations: AC: anthracycline-based chemotherapy B-NHL: B-cell non-hodgkin's lymphoma CMP: cardiomyopathy LVD: left ventricular dysfunction LVEF: left ventricular ejection fraction MCL: mantle cell lymphoma MUGA: multigated acquisition scan NHL: non-hodgkin's lymphoma TTE: transthoracic echocardiography

4 Page of BMJ Open ABSTRACT Objective: Anthracyclines are potent anti-neoplastic agents in the treatment of lymphoid malignancies but their therapeutic benefit is limited by cardiotoxicity. The American Heart Association (AHA) recommends routine surveillance, early diagnosis and treatment of anthracycline-based chemotherapy (AC) induced cardiomyopathy (AC-CMP). We aimed to assess the prevalence of AC-CMP in lymphoma patients, surveillance patterns of left ventricular ejection fraction (LVEF) in those receiving AC and management of AC-CMP patients at an academic medical center prior to the development of a comprehensive cardio-oncology program. Methods: We performed a retrospective cohort study examining patients with aggressive B- cell Non-Hodgkin lymphomas (B-NHL) who received AC -0 and had serial follow-up. AC-CMP was defined as LVEF decrease 0% with final LVEF 0% or LVEF reduction % regardless of final LVEF. Results: Of patients treated with AC, (%) had LVEF assessment both prior to and after receiving AC. Of these patients, developed AC-CMP and had higher cumulative all-cause mortality than those without AC-CMP (HR., p=0.0). Coronary artery disease (CAD) was an independent predictor of AC-CMP (p=0.0). Mean post-ac LVEF was lower in CAD patients compared to those without CAD when their baseline LVEF was % (p=0.000) or % (p=0.00) but was similar at % (p=0.). Less than half of AC-CMP patients received recommended heart failure medication therapy. Conclusions: Historically, one third of B-NHL patients treated with AC underwent surveillance according to AHA guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of lymphoma patients receiving AC.

5 Page of ARTICLE SUMMARY Strengths and limitations of this study The benefits of anthracycline-based chemotherapy (AC) are limited by cumulative-dose related cardiotoxicity. The 00 AHA/ACC/ASE guidelines advised all patients undergoing treatment with anthracyclines to monitor left ventricular ejection fraction (LVEF) prior to and after AC administration. This study examines real-world surveillance and management practices of lymphoma patients with anthracycline-induced cardiomyopathy (AC-CMP) and represents a comprehensive single institution approach of using evidence-based guidelines to evaluate practice patterns. We observed that only one third of patients who underwent AC for B-cell non-hodgkin lymphomas (B-NHL) prior to the establishment of a comprehensive cardio-oncology program had documentation of undergoing the recommended LVEF assessments for AC- CMP monitoring. Less than half of patients who developed AC-CMP received serial non-invasive cardiac monitoring or were prescribed standard heart failure medications. As a small retrospective study at a single institution, the generalizability of our results is limited to a subset of the targeted population that received the expected surveillance and treatment according to AHA guidelines; however, the investigation represents a first step towards overcoming barriers to effective AC-CMP management by documenting the scope of the problem and suggesting specific areas of improvement.

6 Page of BMJ Open INTRODUCTION The American Cancer Society estimates that in 0 there were approximately. million children and adults with a history of cancer including,0 male and,000 female survivors of non-hodgkin Lymphoma (NHL). While the development of effective diagnostic and chemotherapeutic strategies has resulted in a large population of long-term cancer survivors, the impact of chemotherapy on the long-term health of these survivors is substantial. Cardiac toxicity is a common complication of anthracycline-based chemotherapy (AC), with the clinical course ranging from transient asymptomatic left ventricular dysfunction (LVD) to chronic heart failure (HF) and even cardiac death. The most common clinical presentation of AC cardiotoxicity is a dose-dependent cardiomyopathy (CMP) that leads to HF. Symptomatic HF is the most serious form of AC-CMP, with an incidence of % to 0%, depending on the cumulative dose of AC received. - Asymptomatic CMP manifested by echocardiographic abnormalities is more common than symptomatic disease and, depending on the definitions applied, can be found in approximately 0% of all patients who received AC. Compared with other more frequent forms of CMP, AC-CMP has been associated with an especially poor prognosis, with a -year mortality rate up to 0%. Importantly, AC-CMP also limits the therapeutic choices for relapsed cancer patients to less intensive and potentially less effective cancer therapies. However, recent studies have indicated that in AC-CMP left ventricular ejection fraction (LVEF) recovery and adverse cardiac event reduction may be achieved when asymptomatic cardiac dysfunction is detected early and modern HF therapy is promptly initiated. Therefore, the American College of Cardiology/American Heart Association/American Society of Echocardiography (ACC/AHA/ASE) committee gives a class I recommendation for regular LVEF monitoring in patients exposed to cardiotoxic agents in order

7 Page of to facilitate decisions regarding further chemotherapy as well as provide early diagnosis and treatment of AC-CMP. Echocardiographic surveillance is also supported by the European Society for Medical Oncology (ESMO). 0 Despite these recommendations, there are limited data regarding surveillance patterns and cardiovascular treatment for lymphoma patients receiving AC. NHLs are characterized by abnormal tissue growth in the lymphatic system and is the sixth most common cancer in both men and women, with increasing incidence among all age groups. Aggressive subtypes of B- cell NHLs (B-NHLs) such as diffuse large B-cell lymphoma and Burkitt lymphoma are commonly cured with anthracycline chemoimmunotherapy while other subtypes such as follicular lymphoma and mantle cell lymphoma often require systemic AC. We therefore conducted a retrospective cohort study of patients with aggressive B-cell NHLs who were treated with AC to assess the cardiac surveillance and HF management of these patients at an academic medical center prior to the development of a comprehensive cardio-oncology program and to examine clinical characteristics that may impact AC-CMP development or mortality METHODS Participants and Data Collection We utilized the Emory University Lymphoma Enterprise Architecture Data-system (LEAD ), a database that integrates genetic, clinical, histological, epidemiological and clinical trial information from disparate medical systems for improved research, disease diagnosis, treatment and statistical outcomes measurements. The process for managing the LEAD registry and incorporating new patient data into LEAD is approved by the Emory Institutional

8 Page of BMJ Open Review Board (IRB) and data collection and extraction procedures have previously been described. Patients with NHL diagnoses who had received AC were identified through a series of search strategies including International Classification of Disease - Oncology (ICD-O) histology codes and free text searches of anatomical pathology reports and electronic medical records. An IRB waiver of consent was obtained for the data analysis required for this current study. The retrospective cohort for the current analysis was limited to patients with aggressive B- NHLs who received AC and evaluation during their care at an Emory Healthcare facility. Predictor Variables Comprehensive chart review was undertaken to identify patients who underwent LVEF evaluation both prior to and after AC and to collect sociodemographic data (e.g. age, sex, race), comorbid conditions (e.g. hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease), health status and treatment variables (e.g. mediastinal radiation, method of LVEF assessment). All available imaging data were reviewed by an independent researcher (JRB). Outcome Variables The primary outcome measures were ) documented pre- and post-ac LVEF evaluations and ) development of AC-CMP, among B-cell NHL patients treated with AC. Consistent with current guidelines, AC-CMP was defined as a LVEF reduction by 0% concomitant with an absolute post-ac LVEF 0%, or a LVEF reduction of % regardless of post-ac LVEF. Secondary outcome measures included vital status after the first post-ac LVEF evaluation as well as AC-CMP management. Mortality data were obtained using chart documentation and the Social Security Death Index. For patients referred to hospice but

9 Page of without a verified exact date of death, the last recorded date of patient contact in the electronic medical record was used as the date of death. Cardiomyopathy management was defined using standard guideline recommendations for patients with decreased LVEF, such as treatment with angiotensin converting enzyme inhibitors (ACEi), β-blocker therapy, serial imaging and/or cardiology referral. Statistical Analysis The prevalence of cardiomyopathy was estimated as a single-sample proportion. A % confidence interval based on Wilson s score method for a single sample proportion was calculated for the prevalence of cardiomyopathy. Odds ratio (ORs) were calculated to measure the degree of association between risk factors and AC-CMP. Only risk factors significant at P<0.0 in univariable analyses were included in the multivariable analyses. The OR and its % CI were calculated for each factor in the presence of others in the final multiple variable logistic regression model. Using linear regression, post-lvef was regressed on initial LVEF and compared in patients with and without specific risk factors for AC-CMP. History of CAD was the only independent predictor identified, so this factor and the interaction between initial LVEF and CAD history were included as covariates. Adjusted post-lvef means were estimated for patients with and without a history of CAD and defined as the predicted response values obtained by evaluating the regression equation for CAD at the mean initial LVEF. Results are provided as adjusted means with % confidence intervals. Cumulative survival was estimated with the Kaplan-Meier method. Log-rank tests were used to compare survival according to demographic and clinical characteristics. Age of the

10 Page of BMJ Open patient was evaluated as a categorical covariates (above or below the median age of 0, or per 0 year increase) and as a continuous covariate. Only risk factors that were significant at P<0.0 in univariable analyses were included in the multivariable analyses. The hazard ratio (HR) and its % CI were calculated for each factor in the presence of others in the final Cox proportionalhazards regression model. RESULTS Of 0 patients in the LEAD registry who received AC for aggressive B-cell NHL between and 0, patients completed AC and regular follow up within the Emory Healthcare system. Seventy three of patients (%) received imaging surveillance of LVEF with either transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA) both prior to and after receiving chemotherapy, whereas patients (0%) had imaging surveillance only prior to receiving chemotherapy, patients (%) received imaging surveillance only after receiving chemotherapy and (%) had no documentation of imaging surveillance within the electronic medical record (Figure ). Of the patients who underwent both baseline and follow up LVEF examinations, patients underwent MUGA, patients underwent echocardiography and patient underwent positron emission tomography prior to receiving AC. The same modality was used for serial LVEF examinations in % of patients. Follow up diastolic function was evaluated in patients. The prevalence of AC-CMP was estimated at % (% CI: %, %). Eleven of the patients who developed AC-CMP had mildly reduced LVEF (post-ac LVEF > %) and the remaining thirteen had moderately to severely reduced LVEF (post-ac LVEF %). Among patients receiving AC, patients with CAD were more likely to develop AC-CMP (Table ). As

11 Page 0 of CAD history was the only significant independent predictor (p=0.0), adjusted post-ac LVEF means were compared in patients with and without CAD using linear regression (Table ). Post-AC LVEF in these two groups differed significantly depending on the baseline LVEF (p=0.0, test for interaction between baseline LVEF and CAD). Mean post-ac LVEF was significantly lower in patients with CAD compared to patients without CAD when baseline LVEF was % (% vs %, p=0.000) and when baseline LVEF was % (% vs %, p=0.00). However, mean post-ac LVEF was similar in patients with CAD compared to patients without CAD when their baseline LVEF was % (0% vs %, p = 0.). Mean follow up was.0 ±. years. Cumulative all-cause mortality rates were higher in patients who developed AC-CMP compared to those who did not (Figure, Table ). This difference remained significant (p=0.0) even after adjusting for age, sex, hyperlipidemia and history of CAD (Table ). Interestingly, hyperlipidemia was an independent prognostic factor for survival after adjusting for age, sex and CAD history. Of the patients with AC-CMP, were referred to cardiology, received β-blocker therapy, received treatment with ACEi and underwent additional LVEF evaluation. Six patients were prescribed both β-blocker and ACEi therapy and only patients received β-blocker and ACEi therapy in addition to repeat TTE. DISCUSSION The benefits of AC are limited by cumulative-dose related cardiotoxicity. In this study, we observed that ) patients (%) who completed AC at a single academic medical center for aggressive B-cell NHL had imaging surveillance both prior to and after receiving chemotherapy, ) % of patients who underwent LVEF evaluation both prior to and after

12 Page of BMJ Open receiving AC developed cardiomyopathy, ) patients with CAD were more likely to develop AC- CMP and this was influenced by their baseline LVEF and ) a minority of patients who developed AC-CMP were referred to a cardiologist, started on heart failure medications such as β-blockers or ACEi or had repeat imaging for further LVEF evaluation. Anthracycline-induced cardiotoxicity ranges from asymptomatic mild LVD to severe HF that decreases patients quality of life and life expectancy. In our investigation, we observed that patients with AC-CMP were. times more likely to die than those without AC-CMP. Furthermore, patients who had CAD and LVD on their baseline LVEF assessment were more likely to develop further reduced LVEF and AC-CMP, thereby supporting the theory that if early LVD is not diagnosed or treated, additional AC may lead to irreversible HF. Many have proposed recommendations for early LVD detection in order to prevent transient LVD from becoming a debilitating complication of chemotherapy. For example, Schwartz et al. reported that patients at high risk of developing HF could still be treated with AC provided that serial studies were performed after delivering set amounts of chemotherapy and that doxorubicin was discontinued when indicated. The 00 AHA/ACC/ASE guidelines advised all patients undergoing treatment with anthracyclines to undergo baseline echocardiogram with assessment of both systolic and diastolic cardiac function and to monitor LVEF after administration of either half the planned dose or a cumulative dose of 00 mg/m of doxorubicin, as well as follow up imaging at least months after AC completion. This study found that only about one third of patients who underwent AC for aggressive B-cell NHLs prior to the establishment of a comprehensive cardio-oncology program had documentation of receiving the recommended LVEF assessments for AC-CMP monitoring. Of those who developed AC-CMP, less than half were referred to a cardiologist, received serial non-

13 Page of invasive cardiac monitoring or were treated with standard HF medications. These observations suggest that there is substantial opportunity for providers in Oncology and Cardiology to collaborate and improve upon the current delivery of care in patients with AC-CMP. This study does have several limitations as it is a small retrospective study at a single institution that focused on patients with B-NHL who received AC and regular follow-up. Patients who received care outside the Emory Healthcare system may have received the recommended surveillance and management but their Emory records may be missing this information. The generalizability of our results is therefore limited to a subset of the targeted population that received the expected surveillance and treatment according to AHA guidelines. Nevertheless, to our knowledge, this is the first study to examine real-world surveillance and management practices of patients with AC-CMP. It is thus a comprehensive single institution approach to use evidence-based guidelines to evaluate practice patterns, which could eventually lead to practice improvement and provide metrics for other academic centers and community practices. Barriers to improving AC-CMP surveillance patterns include unawareness of the scope of the problem, uncertainty regarding appropriate methods of diagnosis and management and lack of coordination between the two subspecialty fields. For example, the patients in this study were diagnosed with B-NHL during a period prior to the establishment of well-defined guidelines. The precise definition of cardiotoxicity and the recommendations for screening have not always been entirely clear; it has only been more recently that both the Annals of Oncology and AHA/ACC guidelines agreed on LVD monitoring and treatment of systolic heart failure with β-blockers and 0 ACEi unless contraindicated. Therefore, management of competing risks such as cancer relapse, treatment complications (e.g. development of treatment-related cancers, infections,

14 Page of BMJ Open hypothyroidism, depression and/or atherosclerosis) and psychosocial factors have historically been prioritized. In conclusion, this study showed that a minority of patients with aggressive B-cell NHL undergoing AC received guideline-based LVEF surveillance. Considering that reduced LV function is associated with worse morbidity and mortality, early identification of patients with LVD is essential to determine optimal oncological and cardiac management. Ideally, high risk patients could be identified prior to developing LV dysfunction and early identification and initiation of appropriate heart failure therapy could allow patients with mild cardiotoxicity to continue to receive AC under close observation and monitoring by a multidisciplinary team including both oncologists and cardiologists. This study represents a first step towards overcoming barriers to effective AC-CMP management by documenting the scope of the problem and suggesting specific areas of improvement. Systematically tackling these challenges could lead to improved diagnosis and management of AC-CMP in lymphoma patients.

15 Page of REFERENCES. American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 0-0. Atlanta: American Cancer Society, 0.. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents - Incidence, treatment and prevention. Drug Safety 000;():-0.. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 00;0():-.. Pinder MC, Duan Z, Goodwin JS, et al. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. Journal of Clinical Oncology 00;():0-.. Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: Cardiac and pulmonary late effects. Journal of Clinical Oncology 00;():-00.. Carver JR, Szalda D, Ky B. Asymptomatic cardiac toxicity in long-term cancer survivors: defining the population and recommendations for surveillance. Seminars in oncology 0;0():-.. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. New England Journal of Medicine 000;():0-.. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-Induced Cardiomyopathy Clinical Relevance and Response to Pharmacologic Therapy. Journal of the American College of Cardiology 00;():-0.. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 00 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the Guidelines for the Clinical Application of Echocardiography). Circulation 00;0():-. 0. Bovelli D, Plataniotis G, Roila F. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 00; Suppl :v-.. American Cancer Society. Cancer Facts & Figures 0. Atlanta: American Cancer Society, 0.. Flowers CR, Armitage JO. A decade of progress in lymphoma: advances and continuing challenges. Clinical lymphoma, myeloma & leukemia 00;0():-.. Huang T, Shenoy PJ, Sinha R, et al. Development of the Lymphoma Enterprise Architecture Database: a cabig Silver level compliant system. Cancer informatics 00;:-.. Muringampurath-John D, Jaye DL, Flowers CR, et al. Characteristics and outcomes of diffuse large B-cell lymphoma presenting in leukaemic phase. British journal of haematology 0;():0-.. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clinical cancer research : an official journal of the American Association for Cancer Research 00;():-.

16 Page of BMJ Open Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the Guidelines for the Evaluation and Management of Heart Failure). Circulation 00;0():-00.. Elliott P. Pathogenesis of cardiotoxicity induced by anthracyclines. Semin Oncol 00;( Suppl ):S-.. Schwartz RG, McKenzie WB, Alexander J, et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. The American journal of medicine ;():0-.. Hunt SA, Abraham WT, Chin MH, et al. 00 Focused Update Incorporated Into the ACC/AHA 00 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 00;():E-E.

17 Page of Table and Figure Legends Figure : Surveillance pattern amongst patients with aggressive non-hodgkin s lymphoma who received anthracycline-based chemotherapy. Imaging surveillance of LVEF was performed with either transthoracic echocardiogram or multigated acquisition scan. * AC = anthracycline-based chemotherapy, AC-CMP = anthracycline-based chemotherapy induced cardiomyopathy, B-NHL = B-cell non-hodgkin's Lymphoma, LVEF = left ventricular ejection fraction. Figure : Cumulative survival among lymphoma patients with left ventricular ejection fraction assessment before and after receiving Anthracycline-based chemotherapy by the presence or absence of AC-CMP. Cumulative survival by presence or absence of cardiomyopathy. The median years on study for survivors were. years. * AC = anthracycline-based chemotherapy, CMP = cardiomyopathy

18 Page of BMJ Open Table. Univariable analysis of clinical characteristics potentially associated with AC- CMP among lymphoma patients with left ventricular ejection fraction assessment before and after receiving Anthracycline-based chemotherapy * AC-CMP=Anthracycline-based chemotherapy induced cardiomyopathy, CI=Confidence Interval. Table : Adjusted post-ac mean LVEF in lymphoma patients with and without CAD. The median years on study for survivors were. years. * CI=Confidence Interval, LVEF=left ventricular ejection fraction Table : Univariable analysis of clinical characteristics potentially associated with time to death among lymphoma patients with LVEF assessment before and after receiving Anthracycline * AC-CMP=Anthracycline-based chemotherapy induced cardiomyopathy, SE=Standard Error. Table. Multivariable analysis of clinical characteristics potentially associated with time to death among lymphoma patients with LVEF assessment before and after receiving Anthracycline. * AC-CMP=Anthracycline-based chemotherapy induced cardiomyopathy, CI=Confidence Interval.

19 Page of Table Characteristic Total (n=) AC-CMP (n=) No AC-CMP (n=) Odds Ratio (% CI) P value Mediastinal Radiation. (0.,.) 0. Yes No Age.0±. 0.0±..00 (0.,.0) 0. Sex 0. (0.,.00) 0. Female Male Race 0. (0.,.0) 0. Black Caucasian Unknown Smoking History. (0.,.) 0. Yes No Hypertension. (0.0,.) 0. Yes No Diabetes Mellitus. (0.,.) 0. Yes No Hyperlipidemia. (0.,.0) 0. Yes 0 No Coronary Artery Disease. (.0,.0) 0.0* Yes No

20 Page of BMJ Open Table Coronary Artery Disease Pre-LVEF Adjusted-Post LVEF mean % CI Yes (n=) All, mean = % % (%, %) % % (%, %) % % (%, %) % 0% (%, %) No (n=) All, mean = % % (%, %) % % (%, %) % % (%, 0%) % % (0%, %)

21 Page 0 of Table Characteristic Total Death -yr Survival -yr Survival (n=) (n=) (SE) (SE) P value AC-CMP 0.0* Yes 0. (0.0) 0. (0.) No 0.0 (0.0) 0. (0.0) Mediastinal Radiation 0. Yes 0. (0.) 0. (0.) No 0 0. (0.0) 0. (0.0) Age 0.0* <0 years 0. (0.0) 0. (0.0) 0 years 0. (0.0) 0. (0.0) Sex 0.* Female 0. (0.0) 0. (0.0) Male 0. (0.0) 0. (0.0) Race 0. Black 0. (0.0) 0.0 (0.) Caucasian 0. (0.0) 0. (0.0) Unknown Smoking History 0. Yes 0. (0.0) 0. (0.) No 0 0. (0.0) 0. (0.0) Hypertension 0. Yes 0. (0.0) 0. (0.0) No 0. (0.0) 0. (0.0) Diabetes Mellitus 0. Yes 0. (0.) 0. (0.) No 0. (0.0) 0.0 (0.0) Hyperlipidemia 0.* Yes 0. (0.0) 0. (0.) No 0.0 (0.0) 0. (0.0) Coronary Artery Disease 0.* Yes 0. (0.) 0. (0.) No 0. (0.0) 0. (0.0)

22 Page of BMJ Open Table Characteristic Hazard Ratio % CI P value AC-CMP Yes vs No. (.,.0) 0.0* Sex Female vs Male 0. (0.,.) 0. Hyperlipidemia Yes vs No 0. (0.0, 0.) 0.0* Coronary Artery Disease Yes vs No. (0.,.) 0. Age Per 0 year.0 (0.,.) 0.

23 Page of xmm (0 x 0 DPI)

24 Page of BMJ Open xmm ( x DPI)

25 Page of STROBE Statement checklist of items that should be included in reports of observational studies Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or Introduction the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was found Background/rationale Explain the scientific background and rationale for the investigation being reported Objectives State specific objectives, including any prespecified hypotheses Methods Study design Present key elements of study design early in the paper - Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection Participants (a) Cohort study Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Variables Clearly define all outcomes, exposures, predictors, potential confounders, Data sources/ measurement and effect modifiers. Give diagnostic criteria, if applicable * For each variable of interest, give sources of data and details of methods of assessment (measurement). Bias Describe any efforts to address potential sources of bias - Study size 0 Explain how the study size was arrived at - Quantitative variables Explain how quantitative variables were handled in the analyses. Statistical methods (a) Describe all statistical methods, including those used to control for Continued on next page confounding Page (b) Describe any methods used to examine subgroups and interactions - (c) Explain how missing data were addressed (d) Cohort study If applicable, explain how loss to follow-up was addressed (e) Describe any sensitivity analyses

26 Page of BMJ Open Results Page Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed (b) Give reasons for non-participation at each stage (c) Consider use of a flow diagram Fig Descriptive * (a) Give characteristics of study participants (eg demographic, clinical, social) and Table data information on exposures and potential confounders (b) Indicate number of participants with missing data for each variable of interest (c) Cohort study Summarise follow-up time (eg, average and total amount) 0 Outcome data * Cohort study Report numbers of outcome events or summary measures over time Fig Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and -0 their precision (eg, % confidence interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses Discussion Key results Summarise key results with reference to study objectives 0- Limitations Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, - multiplicity of analyses, results from similar studies, and other relevant evidence Generalisability Discuss the generalisability (external validity) of the study results Other information Funding Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at Annals of Internal Medicine at and Epidemiology at Information on the STROBE Initiative is available at

27 Pattern of Cardiac Surveillance Among Lymphoma Patients Receiving Anthracycline-Based Chemotherapy Journal: BMJ Open Manuscript ID: bmjopen r Article Type: Research Date Submitted by the Author: 0-Jul-0 Complete List of Authors: Hung, Olivia; Emory University School of Medicine, Medicine Brown, Jennifer; Emory University, Medicine Dai, Tian; Emory University, Biostatistics & Bioinformatics Easley, Kirk; Emory University, Biostatistics & Bioinformatics Flowers, Christopher; Emory University, Medicine Parashar, Susmita; Emory University, Medicine <b>primary Subject Heading</b>: Cardiovascular medicine Secondary Subject Heading: Oncology Keywords: Heart failure < CARDIOLOGY, Adult cardiology < CARDIOLOGY, Cardiomyopathy < CARDIOLOGY, Cardiology < INTERNAL MEDICINE, Adult oncology < ONCOLOGY, Lymphoma < ONCOLOGY

28 Page of BMJ Open Pattern of Cardiac Surveillance Among Lymphoma Patients Receiving Anthracycline- Based Chemotherapy Olivia Y. Hung, MD, PhD ; Jennifer R. Brown MD, MS ; Tian Dai BS ; Kirk A. Easley, MS, MApStat ; Christopher R. Flowers MD, MS ; Susmita Parashar MD, MPH, MS Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Department of Biostatistics & Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA Division of Hematology & Medical Oncology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Key Words: anthracycline-based chemotherapy, cardiotoxicity, anthracycline-induced cardiomyopathy Total Word count:, (excluding title page, abstract, references, figures and tables) Address for correspondence Susmita Parashar MD, MPH, MS Associate Professor of Medicine Emory University School of Medicine Clifton Road NE, Suite 0 Atlanta, GA 0 Phone: 0-- Fax: susmita.parashar@emory.edu

29 Page of Abbreviations AC: anthracycline-based chemotherapy B-NHL: B-cell non-hodgkin lymphoma CMP: cardiomyopathy LVD: left ventricular dysfunction LVEF: left ventricular ejection fraction MCL: mantle cell lymphoma MUGA: multigated acquisition scan NHL: non-hodgkin lymphoma TTE: transthoracic echocardiography

30 Page of BMJ Open ABSTRACT Objective: Anthracyclines are potent anti-neoplastic agents in the treatment of lymphoid malignancies but their therapeutic benefit is limited by cardiotoxicity. The American Heart Association (AHA) recommends routine surveillance, early diagnosis and treatment of anthracycline-based chemotherapy (AC) induced cardiomyopathy (AC-CMP). We aimed to assess the prevalence of AC-CMP in lymphoma patients, surveillance patterns of left ventricular ejection fraction (LVEF) in those receiving AC and management of AC-CMP patients at an academic medical center prior to the development of a comprehensive cardio-oncology program. Methods: We performed a retrospective cohort study examining patients with aggressive B- cell Non-Hodgkin lymphomas (B-NHL) who received AC -0 and had serial follow-up. AC-CMP was defined as LVEF decrease 0% with final LVEF 0% or LVEF reduction % regardless of final LVEF. Results: Of patients treated with AC, (%) had LVEF assessment both prior to and after receiving AC. Of these patients, developed AC-CMP and had higher cumulative all-cause mortality than those without AC-CMP (HR., p=0.0). Coronary artery disease (CAD) was an independent predictor of AC-CMP (p=0.0). Mean post-ac LVEF was lower in CAD patients compared to those without CAD when their baseline LVEF was % (p=0.000) or % (p=0.00) but was similar at % (p=0.). Less than half of AC-CMP patients received recommended heart failure medication therapy. Conclusions: Historically, one third of B-NHL patients treated with AC underwent surveillance according to AHA guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of lymphoma patients receiving AC.

31 Page of ARTICLE SUMMARY Strengths and limitations of this study Comprehensive single institution approach of using evidence-based guidelines to evaluate real-world surveillance and management patterns of lymphoma patients with anthracyclineinduced cardiomyopathy (AC-CMP). Retrospective study of patients at a single institution with information on demographics, medical co-morbidities, left ventricular ejection fraction, and survival data. Generalizability of the results is limited to a subset of the targeted population that received the expected surveillance and treatment according to the American Heart Association guidelines 0

32 Page of BMJ Open INTRODUCTION The American Cancer Society estimates that in 0 there were approximately. million children and adults with a history of cancer including,0 male and,000 female survivors of non-hodgkin Lymphoma (NHL). While the development of effective diagnostic and chemotherapeutic strategies has resulted in a large population of long-term cancer survivors, the impact of chemotherapy on the long-term health of these survivors is substantial. Cardiac toxicity is a common complication of anthracycline-based chemotherapy (AC), with the clinical course ranging from transient asymptomatic left ventricular dysfunction (LVD) to chronic heart failure (HF) and even cardiac death. The most common clinical presentation of AC cardiotoxicity is a dose-dependent cardiomyopathy (CMP) that leads to HF. - Symptomatic HF is the most serious form of AC-CMP, with an incidence of % to 0%, depending on the cumulative dose of AC received. - Asymptomatic CMP manifested by echocardiographic abnormalities is more common than symptomatic disease and, depending on the definitions applied, can be found in approximately 0% of all patients who received AC. Compared with other more frequent forms of CMP, AC-CMP has been associated with an especially poor prognosis, with a -year mortality rate up to 0%. 0 Importantly, AC-CMP also limits the therapeutic choices for relapsed cancer patients to less intensive and potentially less effective cancer therapies. However, recent studies have indicated that in AC-CMP left ventricular ejection fraction (LVEF) recovery and adverse cardiac event reduction may be achieved when asymptomatic cardiac dysfunction is detected early and modern HF therapy is promptly initiated. Therefore, the American College of Cardiology/American Heart Association/American Society of Echocardiography (ACC/AHA/ASE) committee gives a class I recommendation for regular LVEF monitoring in patients exposed to cardiotoxic agents in order

33 Page of to facilitate decisions regarding further chemotherapy as well as provide early diagnosis and treatment of AC-CMP. - Echocardiographic surveillance is also supported by the European Society for Medical Oncology (ESMO). Despite these recommendations, there are limited data regarding surveillance patterns and cardiovascular treatment for lymphoma patients receiving AC. NHLs are characterized by abnormal tissue growth in the lymphatic system and is the sixth most common cancer in both men and women, with increasing incidence among all age groups. Aggressive subtypes of B- cell NHLs (B-NHLs) such as diffuse large B-cell lymphoma and Burkitt lymphoma are commonly cured with anthracycline chemoimmunotherapy while other subtypes such as follicular lymphoma and mantle cell lymphoma often require systemic AC. We therefore conducted a retrospective cohort study of patients with aggressive B-cell NHLs who were treated with AC to assess the cardiac surveillance and HF management of these patients at an academic medical center prior to the development of a comprehensive cardio-oncology program and to examine clinical characteristics that may impact AC-CMP development or mortality METHODS Participants and Data Collection We utilized the Emory University Lymphoma Enterprise Architecture Data-system (LEAD ), a database that integrates genetic, clinical, histological, epidemiological and clinical trial information from disparate medical systems for improved research, disease diagnosis, treatment and statistical outcomes measurements. The process for managing the LEAD

34 Page of BMJ Open registry and incorporating new patient data into LEAD is approved by the Emory Institutional Review Board (IRB) and data collection and extraction procedures have previously been described. Patients with NHL diagnoses who had received AC were identified through a series of search strategies including International Classification of Disease - Oncology (ICD-O) histology codes and free text searches of anatomical pathology reports and electronic medical records. An IRB waiver of consent was obtained for the data analysis required for this current study. The retrospective cohort for the current analysis was limited to patients with aggressive B- NHLs who received AC and evaluation during their care at an Emory Healthcare facility. Predictor Variables Comprehensive chart review was undertaken to identify patients who underwent LVEF evaluation both prior to and after AC and to collect sociodemographic data (e.g. age, sex, race), comorbid conditions (e.g. hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease), health status and treatment variables (e.g. mediastinal radiation, method of LVEF assessment). All available imaging data were reviewed by an independent researcher (JRB). Any disagreements between the reader and the original report (difference in LVEF > absolute points) was solved by consensus reached with subsequent joint evaluation (JRB and SP). Independent reports have suggested -dimensional transthoracic echocardiography test re-test 0 variability of around -%. Outcome Variables The primary outcome measures were ) documented pre- and post-ac LVEF evaluations and ) development of AC-CMP, among B-cell NHL patients treated with AC. Consistent with

35 Page of current guidelines, AC-CMP was defined as a LVEF reduction by 0% concomitant with an absolute post-ac LVEF 0%, or a LVEF reduction of % regardless of post-ac LVEF. Secondary outcome measures included vital status after the first post-ac LVEF evaluation as well as AC-CMP management. Mortality data were obtained using chart documentation and the Social Security Death Index. For patients referred to hospice but without a verified exact date of death, the last recorded date of patient contact in the electronic medical record was used as the date of death. Follow up time period was defined from the patient s first anthracycline-based chemotherapy at our institution to the date of their last known clinic visit or date of death. Cardiomyopathy management was defined using standard guideline recommendations for patients with decreased LVEF, such as treatment with angiotensin converting enzyme inhibitors (ACEi), β-blocker therapy, serial imaging and/or cardiology referral. Statistical Analysis The prevalence of cardiomyopathy was estimated as a single-sample proportion. A % confidence interval based on Wilson s score method for a single sample proportion was calculated for the prevalence of cardiomyopathy. Odds ratio (ORs) were calculated to measure the degree of association between risk factors and AC-CMP. Only risk factors that were significant at P < 0.0 in the univariable analyses were included in the multivariable analyses (Cox proportional-hazards regression analysis). A P value of 0.0 was used as a significance level to help ensure that all potentially important covariates were included in the final multivariable Cox model. The hazard ratio (HR) and its % CI were calculated for each factor in the presence of others in the final Cox proportional-hazards regression model.

36 Page of BMJ Open Using linear regression, post-lvef was regressed on initial LVEF and compared in patients with and without specific risk factors for AC-CMP. History of CAD was the only independent predictor identified, so this factor and the interaction between initial LVEF and CAD history were included as covariates. Adjusted post-lvef means were estimated for patients with and without a history of CAD and defined as the predicted response values obtained by evaluating the regression equation for CAD at the mean initial LVEF. Results are provided as adjusted means with % confidence intervals. Cumulative survival was estimated with the Kaplan-Meier method. Log-rank tests were used to compare survival according to demographic and clinical characteristics. Age of the patient was evaluated as a categorical covariates (above or below the median age of 0, or per 0 year increase) and as a continuous covariate. Only risk factors that were significant at P<0.0 in univariable analyses were included in the multivariable analyses. The hazard ratio (HR) and its % CI were calculated for each factor in the presence of others in the final Cox proportionalhazards regression model. RESULTS Of 0 patients in the LEAD registry who received AC for aggressive B-cell NHL between and 0, patients completed AC and regular follow up within the Emory Healthcare system. Seventy three of patients (%) received imaging surveillance of LVEF with either transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA) both prior to and after receiving chemotherapy, whereas patients (0%) had imaging surveillance only prior to receiving chemotherapy, patients (%) received imaging surveillance only after receiving chemotherapy and (%) had no documentation of imaging surveillance within the

37 Page 0 of electronic medical record (Figure ). Of the patients who underwent both baseline and follow up LVEF examinations, patients underwent MUGA, patients underwent echocardiography and patient underwent positron emission tomography prior to receiving AC. The same modality was used for serial LVEF examinations in % of patients. Follow up diastolic function was evaluated in patients. The prevalence of AC-CMP was estimated at % (% CI: %, %). Eleven of the patients who developed AC-CMP had mildly reduced LVEF (post-ac LVEF > %) and the remaining thirteen had moderately to severely reduced LVEF (post-ac LVEF %). Among patients receiving AC, patients with CAD were more likely to develop AC-CMP (Table ). As CAD history was the only significant independent predictor (p=0.0), adjusted post-ac LVEF means were compared in patients with and without CAD using linear regression (Table ). Post-AC LVEF in these two groups differed significantly depending on the baseline LVEF (p=0.0, test for interaction between baseline LVEF and CAD). Mean post-ac LVEF was significantly lower in patients with CAD compared to patients without CAD when baseline LVEF was % (% vs %, p=0.000) and when baseline LVEF was % (% vs %, p=0.00). However, mean post-ac LVEF was similar in patients with CAD compared to patients without CAD when their baseline LVEF was % (0% vs %, p = 0.). Median follow up was. years. Cumulative all-cause mortality rates were higher in patients who developed AC-CMP compared to those who did not (Figure, Table ). This difference remained significant (p=0.0) even after adjusting for age, sex, hyperlipidemia and history of CAD (Table ). Interestingly, hyperlipidemia was an independent prognostic factor for survival after adjusting for age, sex and CAD history.

38 Page of BMJ Open Of the patients with AC-CMP, were referred to cardiology, received β-blocker therapy, received treatment with ACEi and underwent additional LVEF evaluation. Six patients were prescribed both β-blocker and ACEi therapy and only patients received β-blocker and ACEi therapy in addition to repeat TTE (Figure ). DISCUSSION The benefits of AC are limited by cumulative-dose related cardiotoxicity. In this study, we observed that ) patients (%) who completed AC at a single academic medical center for aggressive B-cell NHL had imaging surveillance both prior to and after receiving chemotherapy, ) % of patients who underwent LVEF evaluation both prior to and after receiving AC developed cardiomyopathy, ) patients with CAD were more likely to develop AC- CMP and this was influenced by their baseline LVEF and ) a minority of patients who developed AC-CMP were referred to a cardiologist, started on heart failure medications such as β-blockers or ACEi or had repeat imaging for further LVEF evaluation. Anthracycline-induced cardiotoxicity ranges from asymptomatic mild LVD to severe HF that decreases patients quality of life and life expectancy. In our investigation, we observed that patients with AC-CMP were. times more likely to die than those without AC-CMP. Furthermore, patients who had CAD and LVD on their baseline LVEF assessment were more likely to develop further reduced LVEF and AC-CMP, thereby supporting the theory that if early LVD is not diagnosed or treated, additional AC may lead to irreversible HF. Many have proposed recommendations for early LVD detection in order to prevent transient LVD from becoming a debilitating complication of chemotherapy. For example, Schwartz et al. reported that patients at high risk of developing HF could still be treated with AC provided that serial