Association of Preexisting Heart Failure With Outcomes in Older Patients With Diffuse Large B-Cell Lymphoma

Jenica N Upshaw; Jason Nelson; Angie Mae Rodday; Anita J Kumar; Andreas K Klein; Marvin A Konstam; John B Wong; Iris Z Jaffe; Bonnie Ky; Jonathan W Friedberg; Matthew Maurer; David M Kent; Susan K Parsons

doi:10.1001/jamacardio.2023.0303

. 2023 Mar 29;8(5):453–461. doi: 10.1001/jamacardio.2023.0303

Association of Preexisting Heart Failure With Outcomes in Older Patients With Diffuse Large B-Cell Lymphoma

Jenica N Upshaw ^1,^2,^✉, Jason Nelson ², Angie Mae Rodday ², Anita J Kumar ^2,³, Andreas K Klein ³, Marvin A Konstam ¹, John B Wong ², Iris Z Jaffe ^1,⁴, Bonnie Ky ⁵, Jonathan W Friedberg ⁶, Matthew Maurer ⁷, David M Kent ², Susan K Parsons ^2,³

¹Division of Cardiology, Tufts Medical Center, Boston, Massachusetts

²Institute of Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts

³Division of Hematology-Oncology, Tufts Medical Center, Boston, Massachusetts

⁴Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts

⁵Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia

⁶Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York

⁷Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota

Accepted for Publication: December 22, 2022.

Published Online: March 29, 2023. doi:10.1001/jamacardio.2023.0303

^✉

Corresponding Author: Jenica N. Upshaw, MD, MS, Division of Cardiology, Tufts Medical Center, 800 Washington St, Boston, MA 02111 (jupshaw@tuftsmedicalcenter.org).

Author Contributions: Dr Upshaw had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Upshaw, Friedberg, Kent, Parsons.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Upshaw, Parsons.

Critical revision of the manuscript for important intellectual content: Nelson, Rodday, Kumar, Klein, Konstam, Wong, Jaffe, Ky, Friedberg, Maurer, Kent, Parsons.

Statistical analysis: Nelson, Rodday, Maurer.

Obtained funding: Upshaw.

Administrative, technical, or material support: Upshaw, Kumar, Klein, Konstam, Kent, Parsons.

Study supervision: Jaffe, Ky, Kent, Parsons.

Conflict of Interest Disclosures: Dr Upshaw has received grants from the National Institute of Health during the conduct of the study. Dr Klein has received personal fees from Takeda, Lilly, and Pfizer outside the submitted work. Dr Konstam has received grants from the National Institutes of Health during the conduct of the study. Dr Wong has received grants from the National Institutes of Health. Dr Jaffe has received grants from the National Institutes of Health outside the submitted work. Dr Ky has received grants from the National Institutes of Health and American Heart Association as well as consulting fees from Pfizer and Roche outside the submitted work. Dr Maurer has received grants from Bristol Myers Squibb, Roche/Genentech, GenMab, and Morphosys as well as personal fees from GenMab, Adaptive Biotechnologies, and Pfizer outside the submitted work. Dr Parsons has received consulting fees from Seagen. No other disclosures were reported.

Funding/Support: This study is supported by grants K08HL146959 (Dr Upshaw) and R01CA243542 (Drs Upshaw and Jaffe) from the National Institute of Health.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC10061311 PMID: 36988926

Key Points

Question

What is the association of preexisting heart failure (HF) and lymphoma treatment with anthracycline-based chemotherapy?

Findings

In this cohort study using longitudinal data of 30 728 patients from the Surveillance, Epidemiology, and End Results–Medicare registry, preexisting HF was present in 4266 patients (13.9%) with newly diagnosed lymphoma and was associated with less anthracycline use.

Meaning

Patients with preexisting HF in this study had lower use of anthracyclines and lower use of any chemotherapy, and future studies should focus on interventions to reduce mortality in this population.

This cohort study assesses the prevalence of preexisting heart failure in older patients with diffuse large B-cell lymphoma and its association with treatment patterns and outcomes using data from the Surveillance, Epidemiology, and End Results–Medicare registry.

Abstract

Importance

Anthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less likely to receive anthracyclines and may be at higher risk of lymphoma mortality.

Objective

To assess the prevalence of preexisting HF in older patients with DLBCL and its association with treatment patterns and outcomes.

Design, Setting, and Participants

This longitudinal cohort study used data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry from 1999 to 2016. The SEER registry is a system of population-based cancer registries, capturing more than 25% of the US population. Linkage to Medicare offers additional information from billing claims. This study included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 with Medicare Part A or B continuously in the year prior to lymphoma diagnosis. Data were analyzed from September 2020 to December 2022.

Exposures

Preexisting HF in the year prior to DLBCL diagnosis ascertained from billing codes required one of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis.

Main Outcomes and Measures

The primary outcome was anthracycline-based treatment. The secondary outcomes were (1) cardioprotective medications and (2) cause-specific mortality. The associations between preexisting HF and cancer treatment were estimated using multivariable logistic regression. The associations between preexisting HF and cause-specific mortality were evaluated using cause-specific Cox proportional hazards models with adjustment for comorbidities and cancer treatment.

Results

Of 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Preexisting HF at lymphoma diagnosis was present in 4266 patients (13.9%). Patients with preexisting HF were less likely to be treated with an anthracycline (odds ratio, 0.55; 95% CI, 0.49-0.61). Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%). One-year lymphoma mortality was 41.8% (95% CI, 40.5-43.2) with preexisting HF and 29.6% (95% CI, 29.0%-30.1%) without preexisting HF. Preexisting HF was associated with higher lymphoma mortality in models adjusting for baseline and time-varying treatment factors (hazard ratio, 1.24; 95% CI, 1.18-1.31).

Conclusions and Relevance

In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.

Introduction

Anthracycline-containing regimens are recommended as first-line treatment for diffuse large B-cell lymphoma (DLBCL).¹ While anthracycline chemotherapeutic agents are an effective treatment for lymphoma, they also may contribute to cardiac injury increasing the risk of clinical heart failure (HF).^2,3 Patients with existing cardiomyopathy, structural heart disease, older age, or multiple cardiac risk factors have an increased risk of HF with anthracyclines.^4,5,6,7 This is especially relevant for the population of patients with DLBCL, as the median age at diagnosis is 66 years, 75% of patients are older than 55 years at the time of diagnosis, and more than 50% are older than 65 years at the time of diagnosis.⁸ Comorbid cardiovascular disease is more common in older individuals; however, the prevalence of comorbid HF in those with newly diagnosed DLCBL and its association with cancer treatment and outcomes is not known.

Small randomized trials in predominately nonlymphoma populations have identified several potential strategies to prevent HF with reduced ejection fraction in patients receiving anthracyclines, including dexrazoxane,⁹ liposomal doxorubicin,^10,11 and neurohormonal antagonist therapy.^12,13 The National Comprehensive Cancer Network Guidelines for DLBCL include liposomal doxorubicin in combination with rituximab, cyclophosphamide, vincristine, and prednisone as an option for patients with poor ventricular function and also note dexrazoxane as a consideration in patients with prior anthracycline exposure.¹ However, neither dexrazoxane or liposomal doxorubicin are approved by the US Food and Drug Administration for the prevention of anthracycline-associated HF in newly diagnosed adults with DLBCL, and to our knowledge, no studies to date have explored the prevalence of off-label use of cardioprotective strategies in older patients with DLBCL.

Therefore, our aim was to assess the prevalence of HF at the time of DLBCL diagnosis and the association of preexisting HF with the use of anthracycline-based chemotherapy, cardioprotective agents, and cardiac and lymphoma mortality in a national population-based sample of older patients with newly diagnosed DLBCL.

Methods

Data Sources and Study Population

We used linked Surveillance, Epidemiology, and End Results (SEER)–Medicare data from 1999 to 2016. The National Cancer Institute SEER program is a system of population-based cancer registries that captures more than 25% of the US population diagnosed with cancer and includes patient demographic characteristics, date of cancer diagnosis, cancer characteristics, initial cancer treatments and follow-up of vital status, and cause of death. Linkage to Medicare offers additional information on outpatient therapies, diagnostic tests, procedures, and hospitalizations ascertained from billing claims by hospitals, outpatient facilities, and physicians, with 94% of those 65 years and older in SEER registries matched to Medicare enrollment records. For this study, we included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 who had fee-for-service Medicare Part A or B continuously in the year prior to lymphoma diagnosis and in whom lymphoma diagnosis did not first appear on a death certificate (see the eMethods in Supplement 1 for DLBCL diagnosis codes). For analyses that included neurohormonal antagonist and statin therapy, the population was additionally restricted to those with Medicare Part D (2007 to 2016). The Tufts Health Sciences Institutional Review Board determined that the current study was exempt from review (CFR 46.104[4]). Informed consent was waived due to the deidentified nature of the data. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies was followed.¹⁴

Covariate Definitions

HF or cardiomyopathy required at least 1 of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis, as previously described.¹⁵ Individual sociodemographic variables, such as age, sex, race and ethnicity, marital status, and Medicaid dual eligibility, and Census tract–level information, such as income and educational status, were derived from the SEER registry. Race information is collected by the SEER registry, and the SEER race recode variable includes the following categories: Black, White, and other (including American Indian and Alaskan Native, Asian, and Native Hawaiian or Other Pacific Islander). Hispanic ethnicity is collected by SEER and is independent of race. Other baseline cardiac and noncardiac comorbidities were defined based on International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 diagnostic codes in the 365 days prior to lymphoma diagnosis from Medicare inpatient data (MedPAR), Medicare outpatient data (Outpatient Claims), and physician visit data (Carrier Claims), requiring at least 2 codes appearing on separate days. A full list of ICD-9 and ICD-10 codes is available in the eMethods in Supplement 1. Of note, this database does not contain echocardiographic data, such as left ventricular ejection fraction (LVEF), and thus we were unable to categorize HF according to LVEF. In addition, the claims-based diagnosis codes may include some patients with cardiomyopathy but without the clinical syndrome of HF. Frailty was defined using the claims-based frailty index, which includes 21 claims and has been cross-validated with other frailty measures.¹⁶ We excluded comorbidity diagnoses made in the same month as the lymphoma diagnosis to reduce misclassification biases since cancer diagnoses in the SEER registry include the month and year of diagnosis only. Hospital-level variables were determined from the SEER registry and included number of beds, medical school affiliation, teaching status, National Cancer Institute Cancer Center designation, Commission on Cancer accreditation, and cooperative group membership.

Cancer Treatment

Cancer treatment was determined using Healthcare Common Procedure Coding Systems (HCPCS) codes, ICD-9 and ICD-10 codes, diagnostic-related group codes, and revenue center codes (eMethods in Supplement 1). Chemotherapy was categorized as anthracycline containing if the patient received at least 1 infusion of doxorubicin or liposomal doxorubicin; as non–anthracycline containing if the patient received at least 1 intravenous chemotherapy or targeted therapy but no doxorubicin; and as no chemotherapy if no systemic chemotherapy or targeted therapy was given. In addition, patients treated with anthracycline were further subdivided into those receiving the first anthracycline dose in the first 3 months after lymphoma diagnosis (early anthracycline group) or those receiving their first anthracycline dose 3 months or more after lymphoma diagnosis (late anthracycline group). Radiation therapy in the year after diagnosis and hematopoietic cell transplant in the 3 years after diagnosis were collected.

Cardioprotective Medications

Dexrazoxane and liposomal doxorubicin use was determined using HCPCS codes (eMethods in Supplement 1). For the subset of patients with Medicare Part D, prescriptions for β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) were identified using National Drug Codes. Prevalent users were defined by at least 1 prescription filled in the 4 months prior to lymphoma diagnosis, and new users were defined if a prescription was filled in the 6 months after lymphoma diagnosis (not including the month of lymphoma diagnosis) among those without a prescription in the 4 months prior to lymphoma diagnosis.

Outcomes

Cause of death was defined using the SEER Cause of Death Recode and grouped into lymphoma mortality, cardiovascular mortality, non–lymphoma cancer mortality, and noncardiovascular and noncancer mortality (eMethods in Supplement 1).

Statistical Analysis

Baseline characteristics were summarized using means and SDs for normally distributed continuous variables, medians and IQRs for skewed continuous variables, and percentages for categorical variables. All analyses were conducted using SAS version 9.4 (SAS Institute).

Preexisting HF and Cancer Treatment

The associations between preexisting HF and the outcome of receiving anthracycline chemotherapy compared with nonanthracycline chemotherapy were modeled with multivariable logistic regression using 2 sequential models. Model A included patient-level covariates (age, sex, race and ethnicity, cancer stage, diabetes, coronary artery disease, atrial fibrillation, peripheral vascular disease, ischemic stroke, chronic obstructive pulmonary disease, dementia, chronic kidney disease, and any prior cancer diagnosis), and model B added geographic, social determinants of health (SDOH), and hospital-level variables to model A (SEER region, metropolitan/nonurban metropolitan/rural area, Medicaid dual eligibility, Census tract poverty indicator, National Cancer Institute cancer center, medical school affiliation, and number of beds). We repeated these sequential models with the outcomes of (1) any chemotherapy vs no chemotherapy, (2) early anthracycline chemotherapy (in the first 3 months after diagnosis) vs nonanthracycline chemotherapy in the first 3 months, and (3) early vs late anthracycline chemotherapy. We also used the same sequential models to understand the associations between preexisting HF and the use of cardioprotective medications (either dexrazoxane or liposomal doxorubicin) in the subcohort of patients who received early anthracycline therapy.

Preexisting HF and Mortality

The association between preexisting HF and cause-specific mortality was estimated using a stratified cause-specific Cox proportional hazards model with adjustment for baseline comorbidities and time-varying treatment covariates in sequential models.^17,18 The univariable model included the independent variable of preexisting HF and the dependent outcome of cause-specific mortality. Models A and B included the same covariates as above, and model C added time-varying treatment information (anthracycline treatment including number of claims, radiation therapy, and cardioprotective medications liposomal formulations and dexrazoxane) to model A.

Temporal Trends

Poisson regression models were used to assess temporal trends in preexisting HF, anthracycline, dexrazoxane, and liposomal doxorubicin by year from 2000 to 2016, with an offset for the total number of people per year.

Results

Study Population

A total of 64 350 patients with newly diagnosed DLBCL were identified in the SEER-Medicare database from 2000 to 2015. After exclusion of those younger than 65 years (n = 15 942) and those with a lack of continuous enrollment in Medicare Part A and B for the past 12 months (n = 17 680), the study cohort consisted of 30 728 patients (Figure 1). Of 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Baseline patient-level, Census tract–level, and hospital-level variables are shown stratified by treatment strategy for DLBCL in Table 1 and eTable 1 in Supplement 1 and by preexisting HF in eTable 2 in Supplement 1). Cardiovascular and noncardiovascular comorbidities were highly prevalent in the cohort, including HF, coronary artery disease, atrial fibrillation, peripheral vascular disease, hypertension, diabetes, and hyperlipidemia. HF was present at the time of lymphoma diagnosis in 4266 patients (13.9%) (Table 1). Patients with preexisting HF were older with a higher burden of comorbidities (eTable 2 in Supplement 1). In the first year after lymphoma diagnosis, 14 887 (48.4%) received anthracycline-based chemotherapy, 6311 (20.5%) received nonanthracycline chemotherapy, and 9530 (31.0%) received no chemotherapy. Radiation therapy was used in 7568 patients with DLBCL (24.6%), and fewer than 1% of patients (245 of 30 728) were treated with hematopoietic cell transplant.

Figure 1. — DLBCL indicates diffuse large B-cell lymphoma; SEER, Surveillance, Epidemiology, and End Results.

Table 1. Baseline Characteristics of the Cohort Stratified by Cancer Treatment.

Characteristic	No. (%)
	Total cohort (N = 30 728)	Anthracycline treatment		Nonanthracycline chemotherapy (n = 6311 [21%])	No chemotherapy (n = 9530 [31%])
	Total cohort (N = 30 728)	Early (n = 13 396 [44%])^a	Late (n = 1491 [5%])^b	Nonanthracycline chemotherapy (n = 6311 [21%])	No chemotherapy (n = 9530 [31%])
Age, mean (SD), y	77.8 (7.2)	75.4 (6.1)	75.8 (6.3)	79.3 (7.2)	80.4 (7.6)
Sex
Female	15 474 (50.4)	6553 (48.9)	766 (51.4)	3307 (52.4)	4848 (50.9)
Male	15 254 (49.6)	6842 (51.1)	725 (48.6)	3004 (47.6)	4682 (49.1)
Race^c
Black	1110 (3.6)	430 (3.2)	72 (4.8)	193 (3.1)	415 (4.4)
White	27832 (90.6)	12231 (91.3)	1330 (89.2)	5755 (91.2)	8516 (89.4)
Other race	1699 (5.5)	690 (5.2)	86 (5.8)	351 (5.6)	572 (6.0)
Unknown	87 (0.3)	45 (0.3)	<11^d	12 (0.2)	27 (0.3)
Ethnicity
Hispanic^e	2020 (6.6)	789 (5.9)	134 (9.0)	425 (6.7)	672 (7.1)
Non-Hispanic	28 708 (93.4)	12 607 (94.1)	1357 (9.1)	5886 (93.3)	8858 (92.9)
Cancer stage
I	8660 (28.2)	3541 (26.4)	404 (27.1)	1949 (30.9)	2766 (29.0)
II	5583 (18.2)	2767 (20.7)	272 (18.2)	1095 (17.4)	1449 (15.2)
III	4886 (15.9)	2484 (18.5)	228 (15.3)	996 (15.8)	1178 (12.4)
IV	9748 (31.7)	3977 (29.7)	501 (33.6)	1921 (30.4)	3349 (35.1)
Unknown	1851 (6.0)	627 (4.7)	86 (5.8)	350 (5.5)	788 (8.3)
B symptoms
Present	6558 (21.3)	2982 (22.3)	304 (20.4)	1245 (19.7)	2027 (21.3)
Absent	15649 (50.9)	6900 (51.5)	801 (53.7)	3360 (53.2)	4588 (48.1)
Unknown	8521 (27.7)	3514 (26.2)	386 (25.9)	1706 (27.0)	2915 (30.6)
HF/cardiomyopathy^f	4266 (13.9)	957 (7.1)	154 (10.3)	1228 (19.5)	1927 (20.2)
Hypertension	21079 (68.6)	8951 (66.8)	1013 (67.9)	4532 (71.8)	6583 (69.1)
Diabetes	9077 (29.5)	3687 (27.5)	483 (32.4)	1929 (30.6)	2978 (31.2)
Hyperlipidemia	18162 (59.1)	8485 (63.3)	902 (60.5)	3836 (60.8)	4939 (51.8)
Coronary artery disease	9383 (30.5)	3481 (26.0)	413 (27.7)	2305 (36.5)	3184 (33.4)
Prior myocardial infarction	1600 (5.2)	471 (3.5)	70 (4.7)	416 (6.6)	643 (6.7)
Atrial fibrillation/flutter	4662 (15.2)	1405 (10.5)	189 (12.7)	1214 (19.2)	1854 (19.5)
Valvular heart disease	4336 (14.1)	1593 (11.9)	195 (13.1)	1023 (16.2)	1525 (16.0)
Peripheral vascular disease and carotid artery disease	4741 (15.4)	1560 (11.6)	211 (14.2)	1111 (17.6)	1859 (19.5)
Ischemic stroke	2293 (7.5)	620 (4.6)	86 (5.8)	523 (8.3)	1064 (11.2)
Chronic bronchitis/emphysema	6396 (20.8)	2458 (18.3)	319 (21.4)	1348 (21.4)	2271 (23.8)
Dementia	797 (2.6)	138 (1.0)	12 (0.8)	135 (2.1)	512 (5.4)
Moderate or severe kidney disease	2752 (9.0)	833 (6.2)	105 (7.0)	666 (10.6)	1148 (12.0)
Any prior cancer diagnosis	5184 (16.9)	2096 (15.6)	247 (16.6)	1167 (18.5)	1674 (17.6)
CFI score, mean (SD)	0.21 (0.16)	0.14 (0.11)	0.16 (0.12)	0.23 (0.15)	0.28 (0.19)

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Abbreviations: CFI, claims-based frailty index¹⁶; HF, heart failure; SEER, Surveillance, Epidemiology, and End Results.

^{^a}

Early anthracycline refers to those receiving the first anthracycline dose in the first 3 months after lymphoma diagnosis.

^{^b}

Late anthracycline refers to those receiving their first anthracycline dose 3 months or more after lymphoma diagnosis.

^{^c}

Individual sociodemographic variables, such as age, sex, race and ethnicity, marital status, and Medicaid dual eligibility, and Census tract–level information, such as income and educational status, were derived from the SEER registry. The other race category in the SEER race recode includes American Indian and Alaskan Native, Asian, and Native Hawaiian or Other Pacific Islander.

^{^d}

Cell counts with values less than 11 were suppressed to avoid reidentification of patients in accordance with SEER-Medicare policy.

^{^e}

Hispanic ethnicity defined by the SEER registry. Hispanic ethnicity coding is independent of race.

^{^f}

HF or cardiomyopathy was defined from International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes (eMethods in Supplement 1). The claims-based diagnosis codes may include some patients with cardiomyopathy but without the clinical syndrome of HF.

Associations Between Preexisting HF and Cancer Treatment

Preexisting HF was associated with lower odds of receiving any chemotherapy (odds ratio [OR], 0.89; 95% CI, 0.82-0.96) and lower odds of receiving anthracyclines in the first year after diagnosis (OR, 0.55; 95% CI, 0.49-0.61) in multivariable models adjusting for clinical, SDOH, and hospital-level variables (Table 2). Among those with preexisting HF, 1119 of 4266 patients (26.2%) received an anthracycline (either doxorubicin or liposomal doxorubicin) in the first year, while among those without preexisting HF, 13 618 of 26 462 (51.4%) were treated with an anthracycline in the first year (eTable 3 in Supplement 1). Among patients treated with an anthracycline in the first year, preexisting HF was associated with higher odds of cardioprotective medication use with liposomal doxorubicin formulations or dexrazoxane (OR, 1.56; 95% CI, 1.17-2.08); however, liposomal formulations or dexrazoxane were only used in 311 of 13 618 patients without preexisting HF (2.2%) and only 78 of 1119 patients with preexisting HF (7.0%) (Table 2; eTables 3 to 5 in Supplement 1). Among patients with HF at the time of lymphoma diagnosis, approximately half were prescribed a β-blocker and slightly more than half were prescribed angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers at the time of lymphoma diagnosis (eTables 6 to 8 in Supplement 1).

Table 2. Association Between Preexisting Heart Failure (HF) and Cancer Therapy.

Comparison	Cancer treatment choices, OR (95% CI)
Comparison	Anthracycline vs nonanthracycline chemotherapy	Any chemotherapy vs no chemotherapy	Early vs late anthracycline	Early anthracycline vs nonanthracycline chemotherapy	Cardioprotective therapy (dexrazoxane or liposomal doxorubicin) among anthracycline-treated patients
Model A: preexisting HF (vs no preexisting HF) adjusted for clinical variables^a	0.55 (0.49-0.61)	0.87 (0.81-0.95)	0.82 (0.68-1.01)	0.53 (0.48-0.59)	1.51 (1.14-2.00)
Model B: preexisting HF (vs no preexisting HF) adjusted for clinical, SDOH, and hospital variables^b	0.55 (0.49-0.61)	0.89 (0.82-0.96)	0.82 (0.67-1.01)	0.54 (0.48-0.59)	1.56 (1.17-2.08)

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Abbreviations: OR, odds ratio; SDOH, social determinants of health.

^{^a}

Adjusted for age, sex, race, Hispanic ethnicity, advanced cancer stage (III/IV vs I/II), hypertension, diabetes, hyperlipidemia, coronary artery disease, atrial fibrillation, peripheral vascular disease, valvular heart disease, prior ischemic stroke, any prior cancer diagnosis, chronic bronchitis/emphysema, dementia, moderate/severe kidney dysfunction, dementia, and frailty.

^{^b}

Adjusted for model A variables as well as Surveillance, Epidemiology, and End Results region, metropolitan/nonurban metropolitan/rural area, Medicaid dual eligibility, marital status, UC Census tract poverty indicator, household income, percentage without high school diploma, National Cancer Institute Cancer Center designation, Commission on Cancer accreditation, hospital cooperative group membership (as of 2002), hospital classified as referral center, teaching hospital, hospital medical school affiliation, and number of beds.

Preexisting HF and Risk of Cardiovascular and Lymphoma Mortality

Preexisting HF (compared with no preexisting HF) was associated with higher lymphoma mortality in sequential models adjusting for clinical covariates (hazard ratio [HR], 1.36; 95% CI, 1.29-1.43), for clinical, SDOH, and hospital-level variables (HR, 1.35; 95% CI, 1.28-1.42), and for treatment variables (HR, 1.24; 95% CI, 1.18-1.31) (Table 3). Preexisting HF (compared with no preexisting HF) was also associated with higher cardiovascular mortality in models adjusted for clinical, SDOH, and hospital-level variables (HR, 1.82; 95% CI, 1.65-2.00). In those with preexisting HF, lymphoma-specific mortality was 41.8% (95% CI, 40.5-43.2) at 1 year and 51.6% (95% CI, 50.2-53.2) at 5 years (Figure 2; eTable 9 in Supplement 1). Cardiovascular mortality was 7.5% (95% CI, 6.9-8.1) at 1 year and 13.4% (95% CI, 12.5-14.4) at 5 years.

Table 3. Associations Between Preexisting Heart Failure (HF) and Cause-Specific Mortality.

Model	HR (95% CI)
Model	Lymphoma mortality	Cardiovascular mortality	Nonlymphoma cancer mortality	Noncardiovascular, noncancer mortality
Unadjusted^a	1.68 (1.61-1.76)	3.16 (2.90-3.45)	1.61 (1.44-1.81)	2.21 (2.01-2.43)
Model A (adjusted for clinical variables)^b	1.37 (1.30-1.44)	1.83 (1.66-2.02)	1.31 (1.16-1.48)	1.51 (1.36-1.67)
Model B (adjusted for clinical, SDOH, and hospital variables)^c	1.35 (1.29-1.42)	1.82 (1.65-2.00)	1.30 (1.15-1.46)	1.49 (1.35-1.66)
Model C (adjusted for clinical and treatment variables)^d	1.24 (1.18-1.31)	1.69 (1.52-1.86)	1.22 (1.07-1.38)	1.38 (1.24-1.54)

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Abbreviation: SDOH, social determinants of health.

^{^a}

Univariate includes preexisting heart failure as only independent variable.

^{^b}

^{^c}

^{^d}

Adjusted for model B variables as well as number of anthracycline claims (time-varying), radiation (time-varying), and cardioprotective medications (dexrazoxane/liposomal formulations; time-varying).

Longitudinal Trends in Preexisting HF and Cancer Treatment

There was no significant change in the percentage of patients with preexisting HF at the time of lymphoma diagnosis when assessed by year from 2000 to 2016 (eFigure 1 in Supplement 1). There was no significant change in the use of anthracyclines or cardioprotective medications (dexrazoxane or liposomal doxorubicin) over the study period (eFigure 1 in Supplement 1) and similar trends in those with or without preexisting HF (eFigure 2 in Supplement 1).

Discussion

Our principal findings are as follows: (1) preexisting HF is common in older patients with DLBCL, (2) preexisting HF is associated with lower use of anthracyclines and lower use of any chemotherapy, (3) the cardioprotective agents dexrazoxane and liposomal doxorubicin were used infrequently, and (4) preexisting HF was associated with elevated risk of lymphoma and cardiovascular mortality, and this association remained significant after adjusting for clinical, SDOH, hospital, and treatment variables.

Cardiovascular comorbidities were highly prevalent at the time of lymphoma diagnosis in this cohort of patients 65 years and older, including HF or cardiomyopathy in 4266 (13.9%), coronary artery disease in 9383 (30.5%), atrial fibrillation in 4662 (15.2%), and valvular heart disease in 4336 (14.1%). A prior study of older patients with DLBCL using SEER-Medicare data from 1991 to 2002¹⁹ reported HF or cardiomyopathy in 22% of the cohort; however, this study included diagnoses both prior to DLBCL diagnosis and in the 6 months after DLBCL diagnosis. In the general population, estimated HF prevalence at age 60 to 79 years is 7.5% in men and 3.9% in women and at 80 years and older is 9.5% in men and 11% in women using National Health and Nutrition Examination Survey data from 2015 to 2018.²⁰ Therefore, preexisting HF at the time of lymphoma diagnosis is higher than the general population, possibly related to shared risk factors for heart disease and cancer as well as the possible link between HF and increased cancer incidence.^21,22,23 Patients with preexisting HF were 11% less likely to be treated with any chemotherapy and half as likely to be treated with an anthracycline compared with patients without preexisting HF.

Small randomized trials in predominately nonlymphoma populations have identified several potential strategies to prevent HF in patients receiving anthracyclines, including the iron chelator dexrazoxane,⁹ liposomal anthracycline formulations,¹⁰ and neurohormonal antagonist therapy.^12,13 Dexrazoxane inhibits DNA topoisomerase IIb–anthracycline mediated dsDNA breaks and reduces oxygen free radical formation in cardiomyocytes. Dexrazoxane was initially approved by the Food and Drug Administration in 1995 for patients with metastatic breast cancer who have already received more than 300 mg/m² of doxorubicin and who would benefit from ongoing doxorubicin therapy.^24,25,26 A 2019 meta-analysis of randomized and observational studies in breast cancer showed significant reductions in the risk of HF or cardiac events with no significant difference in oncologic outcomes.²⁷ In a case series of 5 patients (2 with DLBCL) with a low LVEF prior to lymphoma diagnosis, treatment with dexrazoxane with doxorubicin allowed patients to receive planned doses of doxorubicin without a change in LVEF, cardiac biomarkers, or clinical HF events.²⁸ Liposomal anthracycline formulations reduce drug delivery to tissues with tight capillary junctions, including the heart. Pegylated liposomal doxorubicin (Doxil/Caelyx) was the first liposomal formulation to be approved by the Food and Drug Administration in 1995 after studies showed benefit in ovarian cancer and AIDS-related Kaposi sarcoma and an indication for multiple myeloma subsequently added.²⁹ A phase 3 trial, which was powered for LVEF changes, randomized 88 individuals with diffuse large B-cell lymphoma to conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) or the same regimen with liposomal doxorubicin instead of conventional doxorubicin (R-COMP), finding no difference in LVEF but less elevation of natriuretic peptides with liposomal doxorubicin and no difference in progression-free survival or overall survival between the groups.¹¹ Of note, this study did not enrich for patients with cardiac comorbidities, and 98% of patients in the study had an LVEF of 50% or greater at baseline. Our current findings suggest that despite this evidence for benefit in reducing HF events, dexrazoxane and liposomal doxorubicin are rarely used off label for patients with DLBCL.

There are also several single-arm phase 2 studies of non–anthracycline-containing regimens in patients with DLBCL with established cardiomyopathy or cardiac risk factors.^30,31 In a single-arm phase 2 study of patients with DLBCL who were considered unfit for anthracycline because of cardiac comorbidity, rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) led to a disease response in 63% (95% CI, 49.2-73.4) and 2-year progression-free survival of 49.8% (95% CI, 37.3-62.3).³⁰ In another single-arm study of patients 70 and older and patients 60 and older with a poor performance status, the combination of rituximab, gemcitabine, and oxaliplatin was associated with a complete response in 47%.³¹ Observational studies have explored the substitution of doxorubicin with etoposide in the R-CHOP regimen (R-CEOP) in patients unable to receive doxorubicin with a 10-year time to progression of 53% and disease-specific survival of 58%.³² Dose-reduced CHOP with standard rituximab (R-mini-CHOP) has been evaluated in a single-arm prospective study of 150 patients 80 years and older with DLBCL with a 2-year progression-free survival of 47% (95% CI, 38-56); however, the safety and efficacy in patients with preexisting cardiomyopathy or HF is not known.³³

We demonstrated that preexisting HF among older patients was associated with higher lymphoma mortality compared with patients without HF. In models adjusting for potential confounding clinical, SDOH, and hospital-level variables, cardiomyopathy or HF at the time of lymphoma diagnosis was associated with a 35% increased risk of lymphoma mortality. Sequential models that included time-varying treatment in addition to clinical, SDOH, and hospital variables led to attenuation of the association between HF and lymphoma mortality, suggesting that decreased anthracycline use in DLBCL is one potential mediator of the association between preexisting HF and lymphoma mortality. However, even after adjusting for treatment, preexisting HF was still associated with a 24% increase in lymphoma mortality. Recent preclinical and epidemiological studies have suggested that HF itself may increase the risk of incident cancer and cancer mortality, potentially due to inflammatory or other circulating factors.^22,23,34

Limitations

There are several limitations of this study. First, HF, comorbidities, and cancer treatments were ascertained using claims data, and therefore, we do not have access to clinical data, such as LVEF, symptom burden, or biomarkers such as natriuretic peptides. We were therefore unable to categorize HF according to HF with reduced ejection fraction, HF with mildly reduced ejection fraction, or HF with preserved ejection fraction.³⁵ Second, claims for doxorubicin allow for the determination of the number of cycles of doxorubicin; however, we were unable to determine if there were dose reductions of chemotherapy or if the doxorubicin was given as a continuous infusion. Third, this study only applies to patients 65 years and older, and further research is needed to understand the effect of preexisting HF on lymphoma treatment and outcomes in younger populations. Fourth, there have been additional medications shown to reduce morbidity and mortality in patients with HF since the study period, including the angiotensin receptor–neprilysin inhibitor sacubitril-valsartan and sodium-glucose cotransporter 2 inhibitors. There are now 4 foundational medications recommended for the treatment of HF with reduced ejection fraction,³⁶ and future studies are needed to assess whether these medications improve cardiovascular and oncologic outcomes in patient with established HF and lymphoma.

Conclusions

In this study, HF or cardiomyopathy was present in 13.9% of patients 65 years and older with DLBCL at the time of lymphoma diagnosis, and preexisting HF was associated with less anthracycline use and with excess lymphoma mortality. Cardioprotective strategies, such as dexrazoxane and liposomal doxorubicin, were used infrequently. Our findings underscore the need for close collaboration between cardiology and oncology to ensure optimal guideline-directed medical therapy of all cardiac comorbidities and cardiac risk factors to improve lymphoma and cardiovascular outcomes.^{36,37,38,39,40,41} Cardio-oncology programs have been established at many hospitals with the goal of providing cardiology care that is informed by the patient’s oncologic treatment with multidisciplinary collaboration to optimize oncologic and cardiovascular outcomes.^42,43,44 Future randomized trials are needed to understand whether targeted cardioprotection with dexrazoxane or liposomal formulation in addition to optimized guideline-directed HF therapy can reduce lymphoma and cardiovascular mortality in this high-risk patient population.

Supplement 1.

eMethods.

eTable 1. Full Baseline Characteristics of the Cohort

eTable 2. Baseline Characteristics Stratified by Preexisting HF

eTable 3. Liposomal Anthracyclines and Dexrazoxane Use Stratified by Preexisting HF

eTable 4. Baseline Characteristics Stratified by Receipt of Dexrazoxane

eTable 5. Baseline Characteristics Stratified by Receipt of Liposomal Doxorubicin

eTable 6. Neurohormonal Antagonist and Statin Prescriptions in the Subset With Medicare Part D

eTable 7. Baseline Characteristics Stratified by Prevalent Neurohormonal Antagonists

eTable 8. Baseline Characteristics Stratified by Any Neurohormonal Antagonists

eTable 9. One-Year and 5 Year Cause-Specific Mortality Estimates by Preexisting HF

eFigure 1. Temporal Trends in Preexisting HF, Anthracycline, and Cardioprotective Use

eFigure 2. Temporal Trends in Anthracycline and Cardioprotective Medication Use Stratified by HF

Click here for additional data file.^{(308.3KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(16KB, pdf)}

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