Cardiovascular and Oncologic Considerations in Adult Hodgkin Lymphoma: JACC: CardioOncology State-of the-Art Review.

Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm arising from B cells that represents approximately 10% to 15% of lymphomas. It is associated with a bimodal age distribution, with most patients diagnosed at 20 to 30 years and older than 55 years. 1 Up to 80% of patients with cHL can now be cured in the frontline setting, in part because of recent advances incorporating novel therapies and improved radiation techniques with a standard chemotherapy backbone. Given the young age of most patients at diagnosis, late treatment-related toxicities must be considered alongside therapeutic efficacy. Notably, cardiovascular (CV) complications related to cHL treatment are relatively common and remain a leading cause of death in cHL survivors. 2 Older patients diagnosed with cHL are particularly at risk given the increased prevalence of pre-existing heart failure (HF) and other cardiac comorbidities. As such, all cHL patients benefit from careful pretreatment evaluation, therapy selection, and post-treatment monitoring, often in a multidisciplinary setting, to limit these toxicities. Here we review the important cardio-oncologic considerations and strategies to mitigate CV complications in the context of the modern treatment paradigm for adult patients with cHL.

Case Presentation

A 26-year-old man with mild cerebral palsy presented to his primary care physician with a persistent cough lasting longer than 1 month with drenching night sweats that were increasing in frequency. Chest computed tomography (CT) revealed a large lobulated mass in the right perihilar region >10 cm in size along the transverse axis. Biopsy revealed cHL, nodular sclerosis subtype. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET)/CT revealed fluorodeoxyglucose-avid disease in the mediastinum and bilateral axillary lymphadenopathy with no other sites of disease. Laboratory studies were notable for an erythrocyte sedimentation rate of 60 mm/h and mild lymphopenia. In the setting of his bulky mediastinal involvement, B symptoms, and elevated erythrocyte sedimentation rate, the patient was diagnosed with Lugano classification stage IIB disease 3 with an unfavorable prognosis on the basis of both the German Hodgkin Study Group and the European Organization for Research and Therapy in Cancer classification criteria. 4 The patient’s Eastern Cooperative Oncology Group performance status was 0.

Standard Frontline Treatment Options for cHL

The standard approach to curative treatment for adults with cHL is determined by the extent of disease involvement, prognostic clinical characteristics, and underlying comorbidities. The primary consideration in therapy selection is the presence of early-stage (stages I and II; lymph nodes localized to one side of the diaphragm) or advanced-stage (stages III and IV) disease as determined using the Lugano staging system. 3 The commonly used frontline treatment regimens are outlined in Table 1 and discussed in further detail as follows. Table 1 Frontline Treatment Regimens for Hodgkin Lymphoma Study Stage Systemic Therapy Radiation Efficacy Cardiac Events HD10 9 Early favorable ABVD × 2 20 Gy 10-y PFS 87.2% 1% cardiac-related mortality H10F 18 Early favorable ABVD × 3 30 Gy 10-y PFS 98.8% 4.6% long-term toxicity H10U 18 Early unfavorable ABVD × 4 30 Gy 10-y PFS 91.4% 12.7% long-term toxicity RATHL 129 Early unfavorable AVD or ABVD × 6 None 7-y PFS 84.7% 1% cardiac-related mortality ECHELON-1 26 Advanced BV-AVD × 6 None 7-y PFS 82.3% None reported S1826 29 Advanced N-AVD × 6 None 2-y PFS 92% 2.4% any cardiac events HD21 28 Advanced BrECADD × 4-6 None 4-y PFS 94.3% 1% grade ≥3 cardiac events All listed regimens are included in current National Comprehensive Cancer Network guidelines. ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; AVD = doxorubicin, vinblastine, and dacarbazine; BV = brentuximab-vedotin; BrECADD = brentuximab-vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone; ECHELON-1 = A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma; PFS = progression-free survival; RATHL = Risk-Adapted Therapy in Hodgkin Lymphoma.

Early-stage disease

Outcomes in early-stage cHL are generally excellent, and clinical and laboratory characteristics are used to risk stratify patients with favorable and unfavorable disease. Although there are multiple risk stratification systems for early-stage cHL, all incorporate the presence of bulky mediastinal disease, B symptoms, elevated erythrocyte sedimentation rate, and number of nodal groups. 5 , 6 Therapeutic options for patients with early-stage cHL require balancing long-term disease control with possible treatment-related complications, including but not limited to cardiotoxicity, pulmonary disease, and secondary malignancies. 1 , 7

Historically, combined modality treatment (CMT) with both radiation therapy (RT) and chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has been the preferred approach for early-stage cHL, with 5-year event-free survival rates >90%. 8 , 9 Although CMT is highly effective in treating patients with cHL, late treatment effects related to radiation remain a key consideration in treatment selection. 1 , 10 The decision to omit RT is nuanced and often influenced by several patient-specific factors. Generally, RT is avoided in young patients and those with CV risk factors who have disease in the chest given the increased risk for late cardiac toxicity. 11 In addition, RT is associated with increased risk for secondary malignancies including breast cancers in women treated younger than 30 to 35 years. 7 , 12 Although CMT yields superior progression-free survival (PFS) compared with ABVD alone, studies have not yet demonstrated a difference in overall survival, in part because of these late toxicities. 7

Encouragingly, RT techniques have significantly evolved since the era of mantle-field radiation, which exposed cardiac and chest wall tissue to high doses, with mean heart doses (MHDs) that could be >30 Gy ( Figure 1 ). 13 Improvements in radiation targeting through involved node/site RT, daily image guidance, and breath-hold and respiratory gating techniques in conjunction with newer modalities such as 3-dimensional conformal therapy, intensity-modulated RT, and/or proton therapy have shown promise in sparing normal tissue while maintaining therapeutic doses to target regions. 14 , 15 Indeed, in the modern era, the estimated MHD during CMT therapy has fallen to <10 Gy. 13 , 14 However, although newer radiation techniques offer greater precision and reduce exposure to normal tissues, their long-term toxicity remains unclear. 16 Figure 1 Evolution of RT in HL (A) Schematic representation of field design, radiation therapy (RT) doses, and radiation techniques for adult Hodgkin lymphoma (HL) as they have evolved over time. (B,C) RT plan comparison of an HL patient treated with involved-site RT to the mediastinum including color wash dose distribution. Recreated historical mantle field (B), anterior-posterior technique, treated to a dose of 40 Gy, vs involved-site RT using intensity-modulated radiation therapy (IMRT) (C), with deep-inspiration breath hold (note expansion of lungs and elongation of mediastinal structures, displacing lungs and heart away from target volume) with arms down on inclined board (further displacement of heart inferiorly), treated to 30 Gy with a 6-Gy boost to a level 5 node. (D) Dosimetric comparison of plans in (B) and (C). CT = computed tomography; LAD = left anterior descending coronary artery; LV = left ventricular; PET = positron emission tomography. Adapted with permission from Bergom et al. 14

In patients who are not ideal candidates for CMT, the incorporation of interim PET/CT allows the identification of patients who are likely to experience long-term remission with chemotherapy alone. Recent clinical trials have tested these response adapted strategies using PET/CT after 2 cycles of therapy, assigning patients with negative findings to chemotherapy alone and including radiation with or without intensified systemic therapy in those with positive results. 17 , 18 , 19 , 20 However, without RT, the RAPID (PET Scan in Planning Treatment in Patients Undergoing Combination Chemotherapy For Stage IA or Stage IIA Hodgkin Lymphoma) trial demonstrated that an abridged chemotherapy course led to inferior PFS compared with CMT, underscoring the need to consider additional chemotherapy even after negative results on interim PET/CT after 2 cycles of therapy. 20

Advances in the understanding of the unique biology of cHL have spurred investigation of targeted systemic therapies in combination with conventional chemotherapy to improve outcomes and further reduce the likelihood of therapy-related toxicity. The characteristic CD30 expression on Hodgkin and Reed-Sternberg cells led to the development of brentuximab-vedotin (BV), an anti-CD30 antibody-drug conjugate. Additionally, Hodgkin and Reed-Sternberg cells frequently express PD-L1 through genomic amplification of the 9p24.1 locus and constitutive JAK-STAT activation, providing therapeutic rationale for the incorporation of checkpoint inhibition in cHL. 21 These novel targeted therapies, which are discussed in further detail later, have not yet fully supplanted ABVD in frontline treatment of early-stage cHL; however, there are several ongoing trials examining their efficacy in this space, with preliminary data leading to the inclusion of these agents in national guidelines ahead of U.S. Food and Drug Administration approval. 22 , 23 , 24 Of note, the ongoing AHOD2131 (A Study to Compare Standard Therapy to Treat Hodgkin Lymphoma to the Use of Two Drugs, Brentuximab Vedotin and Nivolumab) phase III trial investigating the addition of BV and PD-1 blockade compared with standard chemotherapy in early PET-negative patients and CMT in PET-positive patients will likely provide further clarity on the role of targeted therapies in early-stage cHL. 22

Advanced-stage disease

In contrast to early-stage disease, radiation is typically not used in advanced-stage cHL given the extent of disease involvement with the rare exception of localized residual disease after the completion of systemic therapy. Although treatment with ABVD for 6 cycles was the gold standard for more than 2 decades in North America, 25 the relatively recent incorporation of novel therapeutic agents has supplanted this regimen in the frontline setting. The addition of BV to doxorubicin, vinblastine, and dacarbazine (AVD) in patients with advanced-stage cHL improved 6-year overall survival from 89% to 93% compared with ABVD in the ECHELON-1 (A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma) trial. 26 Although the German Hodgkin Study Group had previously established the efficacy of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, 27 a regimen used in patients younger than 60 years in Europe, the HD21 trial demonstrated an improvement in efficacy and a reduction in toxicity with the addition of BV to etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) in comparison with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, with 4-year PFS of 94%. 28 Recently, the Southwest Oncology Group S1826 trial compared the substitution of BV with nivolumab, an anti-PD-1 checkpoint inhibitor, in combination with AVD (N-AVD) in patients with advanced-stage disease and demonstrated 2-year PFS of 92% compared with the 83% in the BV plus AVD arm. 29 As BrECADD and N-AVD have not yet been directly compared, the comparative efficacy and toxicity of these 2 regimens remains unknown. 30 Currently, both N-AVD (in North America) and BrECADD are the preferred frontline treatment approaches for eligible patients with advanced-stage cHL.

Cardiotoxicity Considerations With Frontline Hodgkin Lymphoma Treatments

In devising a treatment plan and a long-term management plan for patients with Hodgkin lymphoma (HL), it is crucial to understand the CV risks of treatment ( Table 2 , Central Illustration ). CV disease is a significant cause of morbidity and mortality in patients with HL and is the leading cause of death in long-term survivors of stage I and stage II cHL. 2 Anthracyclines and radiation are the major contributors to cardiotoxicity, with both early and late treatment effects, although there are also important considerations for immunotherapy and other cancer agents. Table 2 Summary of Cardiovascular Effects of Hodgkin Lymphoma Therapies Agent Cardiovascular Effects Estimated Incidence Risk Modifiers Anthracyclines Heart failure a 1%-10% Patient factors: older age, LVEF < 55%, CAD, valve disease (moderate or greater), HTN, DM, obesity Therapy factors: lifetime cumulative dose and combination with thoracic radiation Atrial/ventricular arrhythmias 1%-5% Immune checkpoint inhibitors Myocarditis ∼1% Combination therapy with CTLA-4 and PD-1/PD-L1 Heart failure 1%-5% Atrial/ventricular arrhythmias 1%-5% Pericarditis <1% Accelerated CAD Unknown Vasculitis <1% Thoracic radiation Atrial arrhythmias 5%-10% Patient factors: tobacco use, HTN, DM Therapy factors: radiation doses to the heart and cardiac substructures Combination anthracycline and thoracic radiation Heart failure a 1%-10% Pericarditis/pericardial effusion 1%-5% Coronary artery disease a 1%-10% Valvular disease a 1%-10% Autologous SCT Heart failure a 5%-10% Patient factors: HTN, DM, CHIP Therapy factors: prior anthracycline dose Arrhythmias 1%-10% Allogenic SCT Heart failure a 5%-10% Patient factors: HTN, DM, tobacco use, age Therapy factors: prior anthracycline dose, prior thoracic radiation, GVHD Coronary artery disease a 5%-10% Arrhythmias 10%-15% CAD = coronary artery disease; CHIP = clonal hematopoiesis of indeterminate potential; DM = diabetes mellitus; GVHD = graft-vs-host disease; HTN = hypertension; LVEF = left ventricular ejection fraction; SCT = stem cell transplantation. a Risk varies strongly according to known patient- and therapy-related risk factors, and predicted risk is much higher in some subgroups of patients. Central Illustration Treatment and Long-Term Cardio-Oncology Considerations in Hodgkin Lymphoma Arrows indicate relationships. Therapy selection in classical Hodgkin lymphoma requires careful consideration of efficacy and toxicity. Anthracyclines, immune checkpoint inhibitors, and radiation therapy all pose unique cardiac risks. Pre- and post-treatment cardiac evaluation along with the strategies illustrated may mitigate treatment-related cardiac toxicities. LVEF = left ventricular ejection fraction; MHD = mean heart dose.

Anthracyclines

Anthracyclines are most strongly linked to myocardial toxicity, with HF from anthracycline chemotherapy being first described in 1973, shortly after this class of highly effective cancer therapies was discovered. In addition to left ventricular systolic dysfunction, anthracyclines are also associated with increased risk for diastolic dysfunction, arrhythmias, and QT interval prolongation ( Table 2 ). Doxorubicin leads to cardiotoxicity in a dose-dependent manner through multiple mechanisms that include oxidative stress, mitochondrial damage, and calcium dysregulation. The risk for doxorubicin cardiotoxicity is significantly increased in patients who also receive radiation as well as patients with hypertension or other CV risk factors. 31

Over the past 5 decades, HF risk has been reduced by efforts to decrease cumulative anthracycline dose, substantially reduce radiation dose to the heart, improve monitoring, and manage cardiac risk factors such as hypertension and diabetes. In addition, dexrazoxane, a cardioprotectant given with anthracycline infusions, is used more commonly by pediatric providers and is associated with favorable echocardiographic and cardiac biomarker profiles, which likely translates into reduced long-term risk for clinical HF. 32 With current frontline cHL therapy, most patients receive approximately 200 to 300 mg/m 2 doxorubicin for early-stage disease and 300 mg/m 2 doxorubicin for advanced-stage disease. 24 Even with these changes, population-based estimates suggest that cHL survivors continue to have higher cardiac-related mortality than age- and sex-matched noncancer control subjects. 33 Although estimates of absolute HF risk vary widely according to the presence of other CV risk factors, age at the time of treatment, and use of dexrazoxane, the 30-year risk for severe or fatal cardiac disease for a teenager treated with doxorubicin 300 mg/m 2 without RT is estimated to be 6.2% (95% CI: 2.7%-10.9%) on the basis of simulation studies using S1826 treatment (N-AVD) and estimates of cardiac late effects from these treatments in the CCSS (Childhood Cancer Survivor Study). 34

RT

RT causes microvascular endothelial damage, capillary loss, inflammation, and fibrosis and can affect all structures of the heart. 35 The late CV effects of RT are diverse and can include coronary artery disease, valvular stenosis or regurgitation, arrhythmias, constrictive pericarditis, restrictive cardiomyopathy, and HF with preserved or reduced ejection fraction. 36 , 37 , 38 , 39 MHD and doses to cardiac substructures (left ventricle, coronary arteries, heart valves) are predictive of CV risk. 36 , 38 , 39 , 40 , 41 , 42 , 43 As mentioned earlier, the use of RT in cHL treatment is decreasing overall, and improvements in technology and techniques are associated with much lower radiation doses to normal structures including the heart 44 , 45 , 46 ( Figure 1 ). Although extended mantle RT has not been used for more than 25 years, given the long latency prior to clinically evident heart disease coupled with the high cure rates of cHL, it is important that clinicians be cognizant of the late effects of more extended RT fields.

Immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) are best known for the risk for associated myocarditis, a rare but serious complication occurring in <1% of patients receiving PD-1 inhibitors, with a high fatality rate of 27.6%. 47 , 48 , 49 Other CV complications associated with checkpoint inhibitors include acute coronary syndrome (1.73%), stroke (2.17%), tachyarrhythmia (3.15%), HF (3.4%), pericardial effusions (3.98%), and CV death (0.67%). 49 Observational and preclinical studies also suggest that PD-1 inhibition may be associated with accelerated atherosclerosis. 50 , 51 The risks of these toxicities from ICI-containing HL regimens have not been quantified, and the impact of short-term PD-1 inhibition as part of N-AVD is uncertain. In the N-AVD trial, immune-mediated adverse events were infrequent, and no cases of myocarditis were reported, though longer term follow-up to monitor the incidence of delayed cardiac toxicities on immunotherapy-based cHL regimens is needed. 52

Absolute risk estimates after cHL treatment

Estimating CV risk with current HL therapies is challenging because of the long latency period and young age at the time of cHL diagnosis (often <40 years). However, multivariable risk calculators based on longitudinal cohort studies of patients treated many decades ago can help estimate the long-term risk for HF, ischemic heart disease, and stroke. 40 , 41 , 53 , 54 The CCSS models were derived from longitudinal follow-up of patients diagnosed before 21 years of age, treated from 1970 to 1986, and surviving at least 5 years postdiagnosis. Of the CCSS cohort, 13% had HL. The models estimate risk for HF, ischemic heart disease, and stroke through 50 years of age, with good discrimination in independent validation cohorts, on the basis of age at diagnosis, sex, and cancer treatment data, including cumulative anthracycline and RT doses. 40 , 41 The CCSS models have since been updated to include hypertension, diabetes, and hyperlipemia, on the basis of self-reported medication use, performing well with internal CCSS validation. External validation has not yet been reported for the updated models. 53 The CCSS risk calculators are available online at https://ccss.stjude.org/resources/calculators/cardiovascular-risk-calculator.html .

Another prediction model specific to patients 18 to 50 years of age at time of cHL diagnosis was developed using a cohort of 1,433 5-year HL survivors treated between 1965 and 2000 in the Netherlands. This model includes age at HL diagnosis, sex, smoking status at the time of HL diagnosis, RT, and anthracycline dose and predicts 20- and 30-year risks for coronary heart disease and HF on the basis of Common Terminology Criteria for Adverse Events 3 to 5 (severe or fatal) definitions and medical record review with good discrimination of the coronary heart disease model in external validation. An online calculator is available at evidencio.com. 54

Pretreatment evaluation and considerations for patients with prevalent cardiac disease or multiple cardiac risk factors

The aforementioned risk models were developed among 5-year survivors of cHL and do not include baseline echocardiographic results or pre-existing CV disease. Although most patients with cHL are young, with a low likelihood of pre-existing CV disease, approximately 20% are older than 65 years and have more prevalent cardiac comorbidities. 55 The 2022 European Society of Cardiology guidelines on cardio-oncology recommend the use of cancer therapy–specific risk stratification schemas that account for patient and therapy risk factors with specific criteria for categorizing patients as “very high risk,” “high risk,” “moderate risk,” or “low risk” prior to the initiation of cancer therapy. 56 For example, patients receiving anthracycline chemotherapy would be categorized as “very high risk” in the setting of pre-existing HF or cardiomyopathy or as “high risk” with any 1 high-risk factor (severe valvular heart disease, coronary artery disease, angina, age ≥ 80 years, chest RT) or >5 moderate risk factors. 56

The 2017 American Society of Clinical Oncology guideline for the prevention and monitoring of cardiac dysfunction in adult cancers define combinations of patient and therapy risk factors that categorize patients as “increased risk for cardiac dysfunction” including cumulative anthracycline dose, radiation dose, cardiac risk factors, and baseline echocardiography. 57 Both the 2022 European Society of Cardiology guidelines and the 2017 American Society of Clinical Oncology guidelines include recommendations for cardio-oncologic evaluation, multidisciplinary discussion about the benefits and harms of different cancer treatment strategies, optimization of CV risk factors, consideration of cardioprotective strategies and monitoring in patients at higher risk for cardiac events, especially in patients with pre-existing HF or cardiomyopathy. The recommendations for CV monitoring in patients undergoing treatment with potentially cardiotoxic therapies are shown in Table 3 . Most recommendations stem from expert consensus informed by nonrandomized retrospective studies and registry data. This summary presents guidance from leading oncologic and cardio-oncology societies to support readers in selecting an appropriate surveillance strategy. Table 3 Cardiovascular Monitoring Recommendations for Patients With Anthracycline Exposure Exposure Timing ASCO 57 ESC 56 NCCN 130 , 131 NCCN 24 /COG 132 Anthracyclines Baseline (pretreatment) • TTE with LVEF ± GLS • TTE with LVEF + GLS • Troponin/NT-proBNP as adjuncts • TTE with LVEF ± GLS • TTE with LVEF During treatment • TTE in symptomatic patients or in asymptomatic patients based on clinical judgement • TTE every 2 cycles in high-risk/very high-risk patients • Troponin/NT-proBNP as adjuncts • TTE in symptomatic patients • TTE with LVEF After treatment • TTE within 6-12 mo in high-risk patients • TTE within 12 mo in all patients • TTE after doxorubicin dose a ≥250 mg/m 2 in moderate-risk patients • TTE within 3 mo in high-risk patients • Troponin/NT-proBNP as adjuncts • TTE within 12 mo in high-risk patients • TTE with LVEF at completion Long-term follow-up • Annual CV assessment in high-risk patients with imaging as clinically indicated • Life-long follow-up in high-risk survivors • TTE every 1-5 y based on risk • Prepregnancy or first-trimester cardiac evaluation • Annual CV assessment in high-risk patients with imaging as clinically indicated • Lifelong follow-up in moderate- to high-risk survivors • TTE every 2 y in high-risk and every 5 y in moderate-risk patients • Prepregnancy or first-trimester cardiac evaluation in high-risk survivors High-risk definition • Doxorubicin dose ≥250 mg/m 2 , doxorubicin dose <250 mg/m 2 + cardiac RT, any doxorubicin dose + any of the following: age ≥60 y, LVEF 50%-55%, MI, moderate or greater valvular heart disease, or ≥2 CV risk factors • Doxorubicin dose a ≥250 mg/m 2 , doxorubicin dose a ≥100 mg/m 2 + RT with MHD ≥5 Gy, any doxorubicin + any of the following: history ofHF/cardiomyopathy, severe valvular heart disease, symptomatic CAD/revascularization, age ≥80 y, multiple moderate risk factors (score ≥5) • Doxorubicin dose a ≥250 mg/m 2 , any doxorubicin dose a + any of the following: age >65 y, LVEF 50%-54%, pre-existing CVD, or CV risk factors • Doxorubicin dose a ≥250 mg/m 2 , doxorubicin dose a ≥100 mg/m 2 + chest RT ≥15 Gy, any doxorubicin + chest RT ≥30 Gy Thoracic radiation Baseline (pretreatment) • TTE with LVEF ± GLS • Baseline estimate of 10-y CVD risk • Consider baseline TTE Not addressed in these guidelines Not addressed in these guidelines During treatment • TTE in symptomatic patients or in asymptomatic patients based on clinical judgement No recommendations Not addressed in these guidelines After treatment • TTE within 6-12 mo in high-risk patients • TTE within 12 mo in all patients Not addressed in these guidelines Long-term follow-up • Annual CV assessment in high-risk patients with imaging as clinically indicated • Lifelong follow-up in high-risk survivors • TTE every 1-5 y based on risk • Noninvasive screening for CAD every 5-10 y if MHD >15 Gy starting 5 y after RT • Carotid ultrasound every 5 y if neck RT starting 5 y after RT • Prepregnancy or first-trimester cardiac evaluation • Lifelong follow-up in moderate- to high-risk survivors • TTE every 2 y in high-risk and every 5 y in moderate-risk patients • CAD evaluation 5-10 y after RT • Carotid ultrasound 10 y after RT if RT >40 Gy to neck • Prepregnancy or first-trimester cardiac evaluation in high-risk survivors High-risk definition • RT ≥30 Gy if heart is in the treatment field • Any combination of anthracycline and cardiac radiation regardless of doses (as above) • Very high risk: MHD >25 Gy or MHD >15 Gy + doxorubicin dose a ≥100 mg/m 2 • High risk: MHD > 15 to 25 Gy or MHD 5-15 Gy + doxorubicin dose a ≥100 mg/m 2 • Chest RT ≥30 Gy • Chest RT ≥15 Gy + doxorubicin dose a ≥100 mg/m 2 Immune checkpoint inhibitors Baseline (pretreatment) Not addressed in these guidelines • Baseline clinical assessment, ECG, troponin, and NP in all patients • Baseline TTE in high-risk patients • Consider baseline ECG, troponin, and NP Not addressed in these guidelines During treatment • Can consider troponin and ECG during treatment based on risk and duration of ICI treatment • Consider periodic testing for those with abnormal baseline or those with symptoms After treatment No recommendations No recommendations Long-term follow-up No recommendations No recommendations High-risk definition Any of the following: dual ICI, combination ICI and cardiotoxic therapy, ICI-related non-CV adverse events, prior CTRCD or CVD No recommendations Stem cell transplantation Baseline (pretreatment) Not addressed in these guidelines • TTE, ECG, NP, comprehensive clinical assessment, CPET in select patients Not addressed in these guidelines Not addressed in these guidelines During treatment • No recommendations After treatment • TTE at 3 and 12 mo post-transplantation in high-risk patients Long-term follow-up • Annual lifelong follow-up with comprehensive clinical assessment, ECG, and NP in high-risk survivors • TTE in select patients High-risk definition Any of the following risk factors: allogenic (vs autologous), pre-existing CVD, multiple uncontrolled CV risk factors, prior mediastinal RT, doxorubicin dose a ≥250 mg/m 2 , alkylating agents, conditioning with TBI or alkylating agents, GVHD ASCO = American Society of Clinical Oncology; COG = Childhood Oncology Group; CPET = cardiopulmonary exercise testing; CTRCD = chemotherapy-related cardiac dysfunction; CV = cardiovascular; CVD = cardiovascular disease; ECG = electrocardiography; ESC = European Society of Cardiology; GLS = global longitudinal strain; HF = heart failure; ICI = immune checkpoint inhibitor; MHD = mean heart dose; MI = myocardial infarction; NCCN = National Comprehensive Cancer Network; NP = natriuretic peptide; RT = radiation therapy; TBI = total body irradiation; TTE = transthoracic echocardiography; other abbreviations as in Table 2 . a Doxorubicin equivalent. Multiply by 0.6 for daunorubicin and by 10.5 for mitoxantrone. No established conversion equivalents for epirubicin and idarubicin. 133

Summary

• Frontline treatment for cHL is highly dependent on disease involvement and typically includes anthracycline-based chemotherapy, with selective incorporation of novel therapies such as PD-1 inhibitors and targeted use of radiation. • Anthracyclines and RT are key contributors to CV toxicity, primarily presenting as cardiomyopathy, coronary artery disease, and valvular dysfunction, though modern dose limits and improved radiation precision have reduced these risks. • All patients receiving anthracyclines should undergo pretreatment echocardiography and cardiac risk stratification on the basis of history, physical examination, and echocardiographic results, with multidisciplinary input in those at high risk for cardiac dysfunction.

Strategies to Mitigate Cardiotoxicity

CV risk optimization

In all patients receiving potentially cardiotoxic therapies, CV risk factors should be identified and optimized before, during, and after cancer treatment ( Central Illustration ). 56 Risk factors can significantly potentiate the risk for cardiotoxicity. The onset of hypertension, specifically, increases the risk for developing HF 19-fold in childhood cancer survivors. 58

Prevention of anthracycline cardiotoxicity

Combined with efforts to minimize cumulative anthracycline doses and RT delivered to the mediastinum in modern treatment protocols, there are several additional cardioprotective strategies that may further reduce the risk for anthracycline cardiotoxicity.

Statins

In preclinical studies of anthracycline cardiotoxicity, atorvastatin reduced markers of oxidative stress and cell death and attenuated declines in left ventricular ejection fraction (LVEF). 59 , 60 The STOP-CA (Statins to Prevent the Cardiotoxicity From Anthracyclines) trial was a randomized, placebo-controlled trial of atorvastatin 40 mg/d or matching placebo in adult patients (≥18 years of age) with lymphoma and planned anthracycline treatment. 61 Of the 300 enrolled participants, 27% had cHL and 73% had non-Hodgkin lymphoma, with a median doxorubicin dose of 300 mg/m 2 . The primary endpoint, a reduction in LVEF of ≥10% from baseline to a value <55% by cardiac magnetic resonance imaging, occurred in 9% in the atorvastatin arm and 22% in the placebo group ( P = 0.002). Symptomatic HF events were numerically lower with atorvastatin, although this was not statistically significant, and the trial was not powered for this endpoint. Two smaller randomized trials of atorvastatin starting prior to anthracycline treatment had neutral primary outcome results and both enrolled a combination of patients with breast cancer and lymphoma, with the majority of patients having breast cancer and thus receiving a lower cumulative anthracycline dose. 62 , 63 All 3 studies demonstrated reassuring safety with no difference in liver function tests or myositis between the atorvastatin and placebo arms with atorvastatin 40 mg starting prior to multiagent chemotherapy. 61 , 62 , 63

Dexrazoxane

Dexrazoxane inhibits DNA topoisomerase IIb-anthracycline–mediated double-stranded DNA breaks and reduces oxygen free radical formation in cardiomyocytes. 64 Randomized studies in adult patients with metastatic breast cancer treated with high-dose anthracyclines showed that dexrazoxane significantly reduced the risk for HF (risk ratio: 0.22; 95% CI: 0.11-0.43), with no significant difference in oncologic outcomes and no signal for an increase in other adverse events. 65 The Food and Drug Administration indication for dexrazoxane reflects this evidence, and dexrazoxane is specifically approved for patients with metastatic breast cancer who have already received more than 300 mg/m 2 doxorubicin and who would benefit from ongoing doxorubicin therapy. 66 There are no randomized studies of dexrazoxane in adult patients with cHL. There were 2 randomized trials of dexrazoxane in children and adolescents with cHL up to 21 years of age, P9426 (n = 294, treated with doxorubicin, bleomycin, vincristine, and etoposide [ABVE] and radiation) and P9425 (n = 216; treated with ABVE with prednisone and cyclophosphamide and radiation). 67 , 68 In patients on ABVE with prednisone and cyclophosphamide, randomization to dexrazoxane was associated with higher rates of myelosuppression and infections, 67 while combined analysis of both pediatric HL trials showed concern for secondary malignancies with dexrazoxane, including secondary acute myeloid leukemia. 69 The higher rates of secondary malignancies were not seen in other studies of dexrazoxane in pediatric acute lymphoblastic leukemia, 70 , 71 with the possible difference being the inclusion in the HL trials of etoposide, an additional topoisomerase inhibitor. Long-term outcome analyses of randomized dexrazoxane studies, including these 2 HL studies, have not suggested increased long-term risks for mortality or secondary malignancies with dexrazoxane but have shown improvement in long-term cardiac outcomes. 32 , 72 , 73 In a median of 18-year follow-up of patients treated in 5 studies incorporating dexrazoxane, including the 2 cHL studies, patients who received dexrazoxane prior to anthracycline therapy had higher LVEFs and lower N-terminal pro–brain natriuretic peptide with lower odds of left ventricular systolic dysfunction, defined as LVEF <50% or fractional shortening <30%. 32 The cardiac benefit was observed primarily among patients receiving >250 mg/m 2 doxorubicin. 32 A more recent study using simulation models and data from 4 recent HL Children’s Oncology Group clinical trials has argued that both the use of dexrazoxane and decrease in mediastinal RT has significantly lowered the estimated 30-year cumulative incidence of severe or fatal cardiac disease in HL survivors, with an expected estimate of 6.2% for patients in the recent N-AVD trial (S1826), as mentioned previously. 34

Liposomal anthracyclines

Liposomal anthracycline formulations reduce drug delivery to tissues with tight capillary junctions, including the heart, and also reduce the risk for cardiotoxicity in patients with metastatic breast cancer receiving high-dose anthracyclines (OR: 0.46; 95% CI: 0.23-0.92). 74 Pegylated liposomal doxorubicin (Doxil/CAELYX, Janssen Pharmaceuticals) is currently Food and Drug Administration approved for ovarian cancer, Kaposi sarcoma, and multiple myeloma. 75 The combination of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) has been studied in the setting of relapsed HL after an initial course of doxorubicin containing regimens and is included in the National Comprehensive Cancer Network guidelines as an option for second-line therapy in relapsed or refractory (R/R) disease. 24 , 76 There are limited studies of the use of liposomal anthracyclines for first-line therapy in cHL.

Continuous doxorubicin infusion

Randomized trials of doxorubicin given as a continuous infusion instead of bolus dosing for adult patients with sarcoma, breast cancer, or ovarian cancer have demonstrated reduced cardiotoxicity. 77 , 78 However, continuous doxorubicin infusion was not found to improve echocardiographic measures of cardiotoxicity in children with acute lymphoblastic leukemia over a 10-year follow-up. 79 Notably, dexrazoxane cannot be given in conjunction with continuous anthracycline infusions. Continuous doxorubicin infusion is incorporated into the inpatient regimen of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin that is used in non-Hodgkin lymphoma; however, continuous doxorubicin infusion to limit cardiotoxicity has not been studied in cHL regimens and is not typically incorporated into standard cHL regimens.

Neurohormonal antagonist therapy

Randomized trials of neurohormonal antagonist therapy for the primary prevention of anthracycline cardiotoxicity have been mixed. 80 Some trials have demonstrated modest benefit 81 , 82 , 83 ; however, many studies have been neutral. 84 , 85 , 86 Most studies enrolled patients with breast cancer and excluded patients already taking these classes of medications for other indications such as hypertension, so the study cohorts tend to have lower risk for cardiotoxicity. Although there is insufficient evidence to recommend neurohormonal antagonist therapy for all patients, patients with low-normal LVEFs or with hypertension may benefit from consideration of these agents. In patients with reduced LVEFs or HF with preserved ejection fraction, standard HF therapies should be prescribed according to the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America HF guidelines. 87

Lifestyle interventions

The American Heart Association’s Life’s Essential 8 provides an approach to assessing and promoting CV health and includes recommendations for healthy diet, physical activity, nicotine avoidance, sleep health, healthy weight, blood lipids, blood glucose, and blood pressure. 88 Regular physical activity is associated with improved CV health and longevity in the general population. 88 , 89 , 90 Structured physical activity as part of cardiac rehabilitation improves outcomes in patients with coronary artery disease, atrial fibrillation, and HF. 91 , 92 , 93 Higher self-reported physical activity was associated with lower incident CV events in adult survivors of childhood HL. 94 Randomized trials of structured exercise interventions have shown improved functional capacity assessed by cardiopulmonary exercise stress testing and favorable effects on health related quality of life, symptoms, and measures of vascular function. 95 , 96 Ongoing studies are investigating novel strategies to increase physical activity in adolescent and young adult cancer survivors. 97

Minimizing radiation-related cardiotoxicity

Modern RT techniques are associated with much lower radiation doses to normal structures, including the heart ( Figure 1 ), and are expected to reduce long-term cardiotoxicity associated with RT. 44 , 45 , 46 Patients who received prior RT with MHDs >25 Gy or MHDs of 5 to 25 Gy plus cumulative doxorubicin exposure ≥100 mg/m 2 are considered very high risk for cardiotoxicity, while those who received MHDs of 15 to 25 Gy or MHDs of 5 to 15 Gy with doxorubicin exposure ≥100 mg/m 2 are considered high-risk patients. 56 Primary prevention strategies should focus on optimizing lifestyle and cardiac risk factors according to the American Heart Association’s Life’s Essential 8, as described previously. 88 When the MHD is not available, total radiation exposure is used as a surrogate when the heart may have been in the radiation treatment field. In these cases, higher risk patients are those treated with >35 Gy or with 15 to 34 Gy plus doxorubicin exposure ≥100 mg/m 2 . Statins and other lipid-lowering agents should be considered to reduce atherosclerotic CV disease risk, with shared decision-making discussions informed by risk models that include radiation dosimetry when this information is available. 41 , 54

Summary

• In addition to optimizing CV risk factors and promoting lifestyle changes before treatment, moderate dose atorvastatin and the use of dexrazoxane may limit the risk of HF, although long-term data in cHL remain limited. • Modified anthracycline delivery methods, such as liposomal formulations and continuous infusions, have demonstrated moderate reductions in cardiotoxicity in solid tumors but are not routinely used in frontline cHL treatment.

Case Presentation Continued

The patient initiated ABVD with plans to de-escalate to AVD if interim PET/CT after 2 cycles of ABVD demonstrated a complete metabolic response. CMT was not initially planned because of his young age and bulky mediastinal disease, in an effort to mitigate long-term cardiac and oncologic complications. At treatment start, atorvastatin 40 mg/d was initiated for cardioprotection. PET/CT after 2 cycles of ABVD demonstrated ongoing response, and treatment was de-escalated to AVD for the remaining 4 cycles. Shortly after completing his fifth cycle, the patient presented to the clinic with progressive shortness of breath, sinus tachycardia, and radiographic imaging consistent with pulmonary edema. Transthoracic echocardiography revealed newly reduced systolic function, with a decline in LVEF from a baseline of 50% to 37%. Cardio-oncology believed that the decrement in systolic function was probably related to anthracycline therapy. Following multidisciplinary discussion, weighing the risk for exacerbating cardiomyopathy while proceeding with curative intent, the plan was made to repeat imaging to assess disease status and to sequentially initiate guideline-directed medical therapy for HF to optimize cardiac function in order to maximize lymphoma-directed therapy. Subsequent PET/CT unfortunately showed a new fluorodeoxyglucose-avid mediastinal lesion consistent with refractory cHL.

Treatment of Patients With R/R cHL

Despite the efficacy of frontline regimens, 10% to 25% of cHL patients will experience primary R/R disease. 1 Nonetheless, second-line therapy in this population is approached with curative intent in patients who are eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).

Salvage therapy prior to ASCT

The general approach to second-line chemotherapy for most patients consists of a inhibitor in combination with chemotherapy or BV. In contrast to the frontline approach, there is no standard chemotherapy backbone for cHL in the R/R setting, as direct prospective comparisons of regimens have not been undertaken. Generally, second-line regimens have incorporated various chemotherapeutic agents, including but not limited to cytarabine, cisplatin, gemcitabine, ifosfamide, etoposide, vinorelbine, and bendamustine. 98 The combination of ifosfamide, carboplatin, and etoposide as well as GVD are commonly used second-line regimens prior to ASCT and have demonstrated tolerability and efficacy, with initial response rates ranging from 70% to 88%. 99 , 100 As both checkpoint inhibition and BV have considerable single-agent efficacy in the R/R setting, 101 , 102 there has been recent momentum to incorporate these novel agents as part of standard second-line therapy. The combinations of BV and bendamustine and of BV and nivolumab followed by ASCT in eligible patients have been highly effective, with rates of long-term PFS >70%. 103 , 104 A phase II study of pembrolizumab and GVD followed by ASCT consolidation demonstrated significant efficacy, further supporting the incorporation of novel agents in the R/R setting. 76

ASCT

The role of ASCT as consolidation in R/R cHL was established more than 20 years ago on the basis of 2 randomized European trials that showed a significant PFS benefit over chemotherapy alone. 105 , 106 Currently, ASCT is considered in patients who achieve a response by PET/CT to at least 2 cycles of chemotherapy. Determining eligibility for ASCT is a complex consideration, but ASCT is generally reserved for fit patients up to 70 to 75 years of age. 107 High-dose chemotherapy with carmustine, etoposide, cytarabine, and melphalan prior to stem cell rescue is the most common ASCT regimen given the relatively lower risk for treatment-related mortality compared with other conditioning regimens. 108 In the era of incorporating PD-1 inhibitors in second-line chemotherapy, outcomes after ASCT have improved significantly compared with chemotherapy alone with or without BV with 2-year PFS >90% for patients undergoing ASCT in a large multicenter retrospective analysis. 109 In patients in whom ASCT is contraindicated, maintenance with either checkpoint inhibitors or BV following initial salvage therapy has been shown to be effective for long-term disease control. 101 , 103 , 110

Allogeneic stem cell transplantation

The majority of patients with R/R disease are effectively treated in the second-line setting, however in multiply-relapsed patients, allogeneic stem cell transplantation (SCT) remains a potential option. In contrast to ASCT, allogeneic SCT offers the potential of long-term adoptive immunity with a graft-vs-lymphoma effect following engraftment. Careful selection of patients is essential, as there is significant risk for treatment-related complications due to the conditioning regimens as well as the risk for graft-vs-host disease (GVHD). 1 Randomized studies in this context are lacking, but relatively recent examination of allogeneic SCT in the era of novel cHL treatments (including PD-1 inhibition) has shown a 1-year PFS of 76% and treatment-related mortality of 11%. 111

RT

The role of RT in the R/R setting has primarily been as an adjunct to systemic therapy, particularly in patients with persistent foci of bulky disease that have not fully resolved on PET/CT during treatment. In the frontline setting, patients with bulky disease that has largely but not completely responded to systemic therapy may be candidates for subsequent involved-site RT with doses ≥30 Gy. 112 , 113

CV Considerations in R/R cHL

Patients with R/R cHL will have both intermediate- to long-term risk from their frontline therapy as well as potentially additive risks from their second-line treatment. Given these combined risks, extra care should be taken to maximize cardioprotective efforts when indicated. Patients undergoing stem cell transplantation (SCT) will be receiving high-dose cytotoxic therapy that can trigger an extensive inflammatory response and exacerbate underlying comorbidities. As the patient case highlights, some patients will have established CV disease that is best managed by a multidisciplinary team.

Multidisciplinary considerations

It is not uncommon to encounter patients with CV disease, including left ventricular dysfunction, at the time of relapse or progression or even at initial presentation. A multidisciplinary approach is key to maximizing cancer therapy while minimizing potential CV toxicity. 114 No absolute contraindications have been clearly defined for a given cancer therapy, but the overall risk/benefit ratio may shift toward an alternative regimen in certain conditions. As an example, patients with LVEFs <40% may very well benefit from an alternative to anthracyclines for their conditioning regimen. In some cases, though, a strategy of permissive cardiotoxicity can be pursued, whereby some level of left ventricular dysfunction or other CV toxicity may be tolerated if the benefit of the cancer therapy is clear. 115 In most cases, patients will be more likely to die of their lymphoma, and care should be taken prior to withholding potentially lifesaving cancer therapy. In all cases, patients should be optimized fully for both their CV disease and their CV risk factors regardless of treatment pursued. Patients with LVEFs <40% can potentially tolerate SCT but should be well compensated and on maximum tolerated guideline-directed medical therapy before initiating treatment. There may be some utility to cardiopulmonary exercise testing for further risk stratification in select patients in whom the benefit/risk ratio of SCT is less clear, though more research is needed. 116

Salvage therapy prior to ASCT

Although alternative regimens are increasingly used, patients may be re-exposed to anthracyclines, which carry a risk for dose-dependent toxicity, as previously mentioned. In the GVD regimen, the liposomal form of doxorubicin does help lower the cardiac risk for additional anthracycline exposure. With checkpoint inhibition, there is a theoretical concern for atherosclerotic progression, though a dose effect has not yet been identified.

Additional agents that may be encountered in salvage therapy include carboplatin (part of the combination of ifosfamide, carboplatin, and etoposide) and gemcitabine (part of the GVD combination) as well as bendamustine. Carboplatin is overall well tolerated but has been associated with a risk for hypertension and a low risk for myocardial ischemia, similar to vinca alkaloids. Neither gemcitabine nor bendamustine has significant cardiotoxicity. Gemcitabine can rarely lead to capillary leak syndrome, which can mimic HF with noncardiogenic pulmonary edema and extremity swelling. Treatment is traditionally with corticosteroids.

SCT

Both ASCT and allogeneic SCT have been strongly associated with short- and long-term CV effects. Because of the effects of their cumulative treatment regimen and potential for other CV risk factors, SCT survivors are at 2-fold risk for CV mortality and a 4-fold risk for developing CV disease compared with the general population over more than 10 years of follow-up. 117 , 118 In a single-center analysis of 1,930 patients undergoing SCT (56% autologous, 38% lymphoma), risk factors for developing CVD included age >30 years, anthracycline dose >250 mg/m 2 , chest radiation, and presence of any CV risk factor (hypertension, diabetes mellitus, and/or smoking). 117

During the initial SCT hospitalization, atrial fibrillation or flutter occurs in 4% to 10% of patients, with a similar rate in autologous and allogenic SCT. 119 , 120 Patients who develop atrial fibrillation are at a significantly increased risk for mortality (13-fold higher risk in a study of allogeneic SCT patients). 121 Other CV events such as HF and coronary events are less common acutely (<2%), 122 though management during SCT is significantly more complex given comorbid thrombocytopenia or infection, which is often present. Notably, GVHD prophylaxis with post-transplant cyclophosphamide is becoming widely adopted, particularly in the ICI-exposed setting, and has been independently associated with a 2.7-fold higher risk for cardiac toxicity within the first 100 days. 123

Over intermediate- to long-term follow-up, SCT survivors remain at increased risk for atrial fibrillation or aflutter while also having a 5% to 6% risk for HF and a 1.1% to 3.7% risk for myocardial infarction. 120 The CARE-BMT risk score helps assess the 1- and 5-year predicted incidence of CV risk in SCT survivors, incorporating age, race, transplantation type, anthracycline exposure, and comorbidities. 124 Allogeneic SCT patients have an overall higher risk for CV events relative to ASCT. 120 Patients undergoing allogeneic SCT are notably at risk for GVHD, which can rarely affect the myocardium directly or lead to coronary thrombosis. Treatments for GVHD are also known to contribute to hypertension and hyperlipidemia. Recommendations for CV monitoring in patients undergoing SCT are outlined in Table 3 .

Summary

• In the salvage setting, cHL remains curable, with treatment involving combination chemotherapy plus immunotherapy or BV, followed by consolidation with ASCT in eligible patients. • Because of cumulative cardiotoxic effects of therapy, patients with R/R cHL, especially those with underlying cardiac dysfunction, should undergo multidisciplinary evaluation, including cardiology consultation, prior to therapy selection. • SCT carries significant short- and long-term cardiac toxicity risks including atrial arrythmias and CV disease, with increased incidence in those with prior exposure to anthracyclines and chest radiation.

CV Monitoring

All guidelines advise annual CV assessment for high-risk cancer survivors, including CV risk factor management and counseling on heart healthy lifestyle habits.

Surveillance for anthracycline cardiotoxicity in HL patients is essential given the well-established risk for dose-dependent toxicity ( Table 3 ). All patients should undergo baseline echocardiography to assess LVEF, preferably with global longitudinal strain, before initiating anthracycline therapy. Monitoring during treatment is based on individual risk factors, including cumulative anthracycline dose, age, pre-existing CV risk factors or CV disease, and cardiac radiation dose. Troponin and N-terminal pro–brain natriuretic peptide levels may be measured to detect early myocardial injury. Depending on the patient’s risk level (low, medium, or high), the patient may require only post-treatment echocardiography as opposed to more regular assessment of left ventricular function and biomarkers as often as every 2 cycles of anthracyclines. 114

Although post-treatment surveillance guidelines vary by society, all recommend echocardiography within 1 year after the completion of anthracycline therapy in high-risk patients. This recommendation is based on data from a longitudinal, prospective study in 2,625 breast cancer patients demonstrating that the majority of cases (98%) with anthracycline cardiotoxicity present within the first year after completion of treatment. 125 Long-term monitoring is particularly important in childhood cancer survivors. An analysis from the DCOG-LATER (Dutch Childhood Oncology Group—Long-Term Effects After Childhood Cancer) cohort, which includes 6,165 5-year childhood cancer survivors diagnosed between 1963 and 2002, showed that the cumulative incidence of HF increased over time, reaching 4.4% at 40 years postdiagnosis, with no evidence of a plateau. 126 Accordingly, the Childhood Oncology Group long-term follow-up guidelines recommend lifelong echocardiographic monitoring, with the frequency based on underlying risk.

Long-term monitoring may be beneficial in patients with higher risk radiation exposures. Like anthracyclines, chest radiation causes dose-dependent cardiotoxicity that may not manifest until decades after treatment. In a nested case-control study of 2,617 5-year HL survivors, treated between 1965 and 1995, each 1-Gy increase in MHD was associated with a 7.4% increased risk for coronary artery disease, with a median onset of 19 years postradiation. 36 Given this prolonged latency, guidelines recommend comprehensive CV surveillance, including echocardiography, stress testing, assessment of coronary calcium, and carotid ultrasound (in survivors treated with neck radiation), starting 5 to 10 years after completion of RT and then every 5 years thereafter in patients at increased risk for cardiotoxicity ( Table 3 ). 58 , 127

Patients at increased risk for ICI cardiotoxicity include those receiving ICIs combined with other cardiotoxic therapies, those with pre-existing CV disease, and those with other immune-related adverse events. The 2022 European Society of Cardiology cardio-oncology guidelines recommend baseline electrocardiography and troponin for all patients starting ICI therapy, with baseline echocardiography advised for high-risk patients ( Table 3 ). 56 As most ICI myocarditis cases occur within the first 3 months of ICI exposure, 128 electrocardiography and troponin monitoring before cycles 2, 3, and 4 of ICI therapy can be considered. 56

Summary

• In addition to baseline CV risk assessment and echocardiography, all patients receiving anthracyclines should undergo repeat echocardiography 1 year following treatment, with more frequent echocardiographic evaluation in high-risk patients and lifelong surveillance in pediatric patients. • Patients receiving chest radiation are at risk for late-term cardiotoxicities and as such should have indefinite comprehensive cardiac evaluation, beginning 5 to 10 years after therapy completion. • Immune checkpoint cardiac toxicity, although rare, primarily presents shortly after exposure to therapy and prompt assessment should be undertaken in symptomatic patients to improve outcomes.

Case Presentation Follow-Up

Following biopsy confirmation of refractory mediastinal disease, the patient began second-line therapy with an anthracycline-free regimen of BV-nivolumab, with repeat imaging demonstrating ongoing response. His cardiac function has since recovered on guideline-directed medical therapy, and consolidation with ASCT is being considered.

Conclusions

With modern HL treatment, many patients will be cured of their lymphoma but will remain at an increased risk for short- and long-term cardiotoxicity. Interventions such as reducing cardiac radiation exposure, optimization of CV risk factors, appropriate screening protocols, and incorporation of cardioprotectants help mitigate these CV risks. Ultimately, patients are best served by a multidisciplinary approach that maximizes cancer treatment while minimizing cardiac risks.

Funding Support and Author Disclosures

Dr Mitchell has received research support from Abbott Laboratories and Myocardial Solutions, unrelated to this work; and has served as a consultant or an advisor to Alnylam, AstraZeneca, BridgeBio, and Pfizer, unrelated to this work. Dr Nohria has received research support from Bristol Myers Squibb, unrelated to this work; and has served as a consultant to AstraZeneca and Takeda Oncology, unrelated to this work. Dr LaCasce has received consulting fees from Genmab, Kite Pharma, and Pierre Fabre, unrelated to this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

References

1 Brice P. de Kerviler E. Friedberg J.W. Classical Hodgkin lymphoma Lancet 398 2021 1518 1527 33493434 10.1016/S0140-6736(20)32207-8

2 Lu Z. Teng Y. Ning X. Wang H. Feng W. Ou C. Long-term risk of cardiovascular disease mortality among classic Hodgkin lymphoma survivors Cancer 128 2022 3330 3339 35872619 10.1002/cncr.34375

3 Kaplan H.S. Contiguity and progression in Hodgkin’s disease Cancer Res 31 1971 1811 1813 5121687

4 Eichenauer D.A. Aleman B.M.P. André M. Hodgkin lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 29 2018 iv19 iv29 29796651 10.1093/annonc/mdy080

5 Klimm B. Goergen H. Fuchs M. Impact of risk factors on outcomes in early-stage Hodgkin’s lymphoma: an analysis of international staging definitions Ann Oncol 24 2013 3070 3076 24148816 10.1093/annonc/mdt413

6 Noordijk E.M. Carde P. Dupouy N. Combined-modality therapy for clinical stage I or II Hodgkin’s lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials J Clin Oncol 24 2006 3128 3135 16754934 10.1200/JCO.2005.05.2746

7 Ng A.K. Bernardo M.P. Weller E. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger J Clin Oncol 20 2002 2101 2108 11956271 10.1200/JCO.2002.08.021

8 Loeffler M. Brosteanu O. Hasenclever D. Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin’s disease. International Database on Hodgkin’s Disease Overview Study Group J Clin Oncol 16 1998 818 829 9508162 10.1200/JCO.1998.16.3.818

9 Engert A. Plütschow A. Eich Hans T. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma N Engl J Med 363 2010 640 652 20818855 10.1056/NEJMoa1000067

10 Hay A.E. Klimm B. Chen B.E. An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma Ann Oncol 24 2013 3065 3069 24121121 10.1093/annonc/mdt389

11 Lee Chuy K. Nahhas O. Dominic P. Cardiovascular complications associated with mediastinal radiation Curr Treat Options Cardiovasc Med 21 2019 31 31161453 10.1007/s11936-019-0737-0

12 Swerdlow A.J. Higgins C.D. Smith P. Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study J Natl Cancer Inst 99 2007 206 214 17284715 10.1093/jnci/djk029

13 Campbell B.A. Voss N. Pickles T. Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin’s lymphoma: a question of field size J Clin Oncol 26 2008 5170 5174 18838714 10.1200/JCO.2007.15.1001

14 Bergom C. Bradley J.A. Ng A.K. Past, present, and future of radiation-induced cardiotoxicity: refinements in targeting, surveillance, and risk stratification JACC CardioOncol 3 2021 343 359 34604796 10.1016/j.jaccao.2021.06.007 PMC8463722

15 Bortfeld T. Jeraj R. The physical basis and future of radiation therapy Br J Radiol 84 2011 485 498 21606068 10.1259/bjr/86221320 PMC3473639

16 Hall M.D. Terezakis S.A. Lucas J.T. Radiation therapy across pediatric hodgkin lymphoma research group protocols: a report from the Staging, Evaluation, and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) group Int J Radiat Oncol Biol Phys 112 2022 317 334 34390770 10.1016/j.ijrobp.2021.07.1716 PMC8802654

17 André M.P.E. Girinsky T. Federico M. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial J Clin Oncol 35 2017 1786 1794 28291393 10.1200/JCO.2016.68.6394

18 Federico M. Fortpied C. Stepanishyna Y. Long-term follow-up of the response-adapted intergroup EORTC/LYSA/FIL H10 trial for localized Hodgkin lymphoma J Clin Oncol 42 2024 19 25 37967311 10.1200/JCO.23.01745 PMC10730029

19 LaCasce A.S. Dockter T. Ruppert A.S. Positron emission tomography-adapted therapy in bulky stage I/II classic Hodgkin lymphoma: CALGB 50801 (Alliance) J Clin Oncol 41 2023 1023 1034 36269899 10.1200/JCO.22.00947 PMC9928671

20 Radford J. Illidge T. Counsell N. Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma N Engl J Med 372 2015 1598 1607 25901426 10.1056/NEJMoa1408648

21 Mottok A. Steidl C. Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies Blood 131 2018 1654 1665 29500175 10.1182/blood-2017-09-772632

22 Henderson T.O. Hu B. Keller F. AHOD2131: a randomized phase 3 response-adapted trial comparing standard therapy with immuno-oncology therapy for children and adults with newly diagnosed stage I and II classic Hodgkin lymphoma Blood 142 2023 3084

23 Abramson J.S. Straus D.J. Bartlett N.L. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) for early-stage classical Hodgkin lymphoma (SGN35-027 Part C) Blood 142 2023 611

24 National Comprehensive Cancer Network NCCN guidelines: Hodgkin lymphoma (version 2.2025) https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439

25 Duggan D.B. Petroni G.R. Johnson J.L. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial J Clin Oncol 21 2003 607 614 12586796 10.1200/JCO.2003.12.086

26 Ansell S.M. Radford J. Connors J.M. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma N Engl J Med 387 2022 310 320 35830649 10.1056/NEJMoa2206125

27 Borchmann P. Goergen H. Kobe C. PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group Lancet 390 2017 2790 2802 29061295 10.1016/S0140-6736(17)32134-7

28 Borchmann P. Ferdinandus J. Schneider G. Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial Lancet 404 2024 341 352 38971175 10.1016/S0140-6736(24)01315-1

29 Herrera A.F. LeBlanc M. Castellino S.M. Nivolumab+AVD in advanced-stage classic Hodgkin’s lymphoma N Engl J Med 391 2024 1379 1389 39413375 10.1056/NEJMoa2405888 PMC11488644

30 Lehner B. Panny M. Advanced stage Hodgkin’s lymphoma 2024—update on first line treatment Magazine Eur Med Oncol 17 2024 172 174

31 Belger C. Abrahams C. Imamdin A. Lecour S. Doxorubicin-induced cardiotoxicity and risk factors Int J Cardiol Heart Vasc 50 2024 101332 10.1016/j.ijcha.2023.101332 PMC10784684 38222069

32 Chow E.J. Aggarwal S. Doody D.R. Dexrazoxane and long-term heart function in survivors of childhood cancer J Clin Oncol 41 2023 2248 2257 36669148 10.1200/JCO.22.02423 PMC10448941

33 Dores G.M. Curtis R.E. Dalal N.H. Linet M.S. Morton L.M. Cause-specific mortality following initial chemotherapy in a population-based cohort of patients with classical Hodgkin lymphoma, 2000-2016 J Clin Oncol 38 2020 4149 4162 32946352 10.1200/JCO.20.00264 PMC7723686

34 Lo A.C. Liu A. Liu Q. Late cardiac toxic effects associated with treatment protocols for Hodgkin lymphoma in children JAMA Netw Open 7 2024 e2351062 10.1001/jamanetworkopen.2023.51062 PMC10799264 38241048

35 Siaravas K.C. Katsouras C.S. Sioka C. Radiation treatment mechanisms of cardiotoxicity: a systematic review Int J Mol Sci 24 7 2023 6272 37047245 10.3390/ijms24076272 PMC10094086

36 van Nimwegen F.A. Schaapveld M. Cutter D.J. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma J Clin Oncol 34 2016 235 243 26573075 10.1200/JCO.2015.63.4444

37 van Nimwegen F.A. Schaapveld M. Janus C.P. Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk JAMA Intern Med 175 2015 1007 1017 25915855 10.1001/jamainternmed.2015.1180

38 Cutter D.J. Schaapveld M. Darby S.C. Risk of valvular heart disease after treatment for Hodgkin lymphoma J Natl Cancer Inst 107 4 2015 djv008 10.1093/jnci/djv008 PMC4394894 25713164

39 van Nimwegen F.A. Ntentas G. Darby S.C. Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines Blood 129 2017 2257 2265 28143884 10.1182/blood-2016-09-740332 PMC5418626

40 Chow E.J. Chen Y. Kremer L.C. Individual prediction of heart failure among childhood cancer survivors J Clin Oncol 33 2015 394 402 25287823 10.1200/JCO.2014.56.1373 PMC4314592

41 Chow E.J. Chen Y. Hudson M.M. Prediction of ischemic heart disease and stroke in survivors of childhood cancer J Clin Oncol 36 2018 44 52 29095680 10.1200/JCO.2017.74.8673 PMC5756324

42 Hahn E. Jiang H. Ng A. Late cardiac toxicity after mediastinal radiation therapy for Hodgkin lymphoma: contributions of coronary artery and whole heart dose-volume variables to risk prediction Int J Radiat Oncol Biol Phys 98 2017 1116 1123 28721895 10.1016/j.ijrobp.2017.03.026

43 Bates J.E. Shrestha S. Liu Q. Cardiac substructure radiation dose and risk of late cardiac disease in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study J Clin Oncol 41 2023 3826 3838 37307512 10.1200/JCO.22.02320 PMC10419575

44 Filippi A.R. Ragona R. Piva C. Optimized volumetric modulated arc therapy versus 3D-CRT for early stage mediastinal Hodgkin lymphoma without axillary involvement: a comparison of second cancers and heart disease risk Int J Radiat Oncol Biol Phys 92 2015 161 168 25863763 10.1016/j.ijrobp.2015.02.030

45 Paumier A. Ghalibafian M. Gilmore J. Dosimetric benefits of intensity-modulated radiotherapy combined with the deep-inspiration breath-hold technique in patients with mediastinal Hodgkin’s lymphoma Int J Radiat Oncol Biol Phys 82 2012 1522 1527 21705151 10.1016/j.ijrobp.2011.05.015

46 Hoppe B.S. Hill-Kayser C.E. Tseng Y.D. Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma Ann Oncol 28 2017 2179 2184 28911093 10.1093/annonc/mdx287 PMC5834068

47 Gougis P. Jochum F. Abbar B. Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade—a worldwide perspective EClinicalMedicine 70 2024 102536 10.1016/j.eclinm.2024.102536 PMC10981010 38560659

48 Wang D.Y. Salem J.E. Cohen J.V. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis JAMA Oncol 4 2018 1721 1728 30242316 10.1001/jamaoncol.2018.3923 PMC6440712

49 Li H. Zheng Y. Li B. Association among major adverse cardiovascular events with immune checkpoint inhibitors: a systematic review and meta-analysis J Intern Med 297 2025 36 46 39537368 10.1111/joim.20028

50 Gotsman I. Grabie N. Dacosta R. Sukhova G. Sharpe A. Lichtman A.H. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice J Clin Invest 117 2007 2974 2982 17853943 10.1172/JCI31344 PMC1974866

51 Drobni Z.D. Alvi R.M. Taron J. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque Circulation 142 2020 2299 2311 33003973 10.1161/CIRCULATIONAHA.120.049981 PMC7736526

52 Kuczmarski T.M. Ujjani C.S. Poh C. Potential delayed immune-related adverse events in patients treated with frontline pembrolizumab + AVD for classic Hodgkin lymphoma Blood 144 2024 1667-1667

53 Chen Y. Chow E.J. Oeffinger K.C. Traditional cardiovascular risk factors and individual prediction of cardiovascular events in childhood cancer survivors J Natl Cancer Inst 112 2020 256 265 31161223 10.1093/jnci/djz108 PMC7073918

54 de Vries S. Haaksma M.L. Jozwiak K. Development and validation of risk prediction models for coronary heart disease and heart failure after treatment for Hodgkin lymphoma J Clin Oncol 41 1 2023 86 95 35947813 10.1200/JCO.21.02613

55 Upshaw J.N. Nelson J. Sweigart B. Impact of preexisting heart failure on treatment and outcomes in older patients with Hodgkin lymphoma JACC CardioOncol 6 2024 200 213 38774008 10.1016/j.jaccao.2024.02.003 PMC11103040

56 Lyon A.R. Lopez-Fernandez T. Couch L.S. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) Eur Heart J Cardiovasc Imaging 23 2022 e333 e465 36017575 10.1093/ehjci/jeac106

57 Armenian S.H. Lacchetti C. Lenihan D. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline summary J Oncol Pract 13 2017 270 275 27922796 10.1200/JOP.2016.018770

58 Armstrong G.T. Oeffinger K.C. Chen Y. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer J Clin Oncol 31 2013 3673 24002505 10.1200/JCO.2013.49.3205 PMC3804290

59 Riad A. Bien S. Westermann D. Pretreatment with statin attenuates the cardiotoxicity of doxorubicin in mice Cancer Res 69 2009 695 699 19147586 10.1158/0008-5472.CAN-08-3076

60 Ramanjaneyulu S.V. Trivedi P.P. Kushwaha S. Vikram A. Jena G.B. Protective role of atorvastatin against doxorubicin-induced cardiotoxicity and testicular toxicity in mice J Physiol Biochem 69 2013 513 525 23385671 10.1007/s13105-013-0240-0

61 Neilan T.G. Quinaglia T. Onoue T. Atorvastatin for anthracycline-associated cardiac dysfunction: the STOP-CA randomized clinical trial JAMA 330 2023 528 536 37552303 10.1001/jama.2023.11887 PMC10410476

62 Hundley W.G. D’Agostino R. Jr. Crotts T. Statins and left ventricular ejection fraction following doxorubicin treatment NEJM Evid 1 9 2022 10.1056/evidoa2200097 PMC9997095 36908314

63 Thavendiranathan P. Houbois C. Marwick T.H. Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines Eur Heart J Cardiovasc Pharmacother 9 2023 515 525 37120736 10.1093/ehjcvp/pvad031 PMC10509566

64 Deng S. Yan T. Jendrny C. Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms BMC Cancer 14 2014 842 25406834 10.1186/1471-2407-14-842 PMC4242484

65 de Baat E.C. Mulder R.L. Armenian S. Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines Cochrane Database Syst Rev 9 2022 CD014638 10.1002/14651858.CD014638.pub2 PMC9512638 36162822

66 U.S. Food and Drug Administration ZINECARD (dexrazoxane) [package insert] Revised April 2014. Accessed November 2019. https://www.accessdata.fda.gov

67 Schwartz C.L. Constine L.S. Villaluna D. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425 Blood 114 2009 2051 2059 19584400 10.1182/blood-2008-10-184143 PMC2744567

68 Tebbi C.K. Mendenhall N.P. London W.B. Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children’s Oncology Group Pediatr Blood Cancer 59 2012 1259 1265 22911615 10.1002/pbc.24279 PMC3468662

69 Tebbi C.K. London W.B. Friedman D. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease J Clin Oncol 25 2007 493 500 17290056 10.1200/JCO.2005.02.3879

70 Vrooman L.M. Neuberg D.S. Stevenson K.E. The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium Eur J Cancer 47 2011 1373 1379 21514146 10.1016/j.ejca.2011.03.022 PMC3736806

71 Asselin B.L. Devidas M. Chen L. Cardioprotection and safety of dexrazoxane in patients treated for newly diagnosed T-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic non-Hodgkin lymphoma: a report of the Children’s Oncology Group Randomized Trial Pediatric Oncology Group 9404 J Clin Oncol 34 2016 854 862 26700126 10.1200/JCO.2015.60.8851 PMC4872007

72 Chow E.J. Aplenc R. Vrooman L.M. Late health outcomes after dexrazoxane treatment: a report from the Children’s Oncology Group Cancer 128 2022 788 796 34644414 10.1002/cncr.33974 PMC8792306

73 Chow E.J. Asselin B.L. Schwartz C.L. Late mortality after dexrazoxane treatment: a report from the Children’s Oncology Group J Clin Oncol 33 2015 2639 2645 26014292 10.1200/JCO.2014.59.4473 PMC4534526

74 Xing M. Yan F. Yu S. Shen P. Efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized controlled trials PLoS One 10 2015 e0133569 10.1371/journal.pone.0133569 PMC4512701 26204517

75 U.S. Food and Drug Administration DOXIL (doxorubicin HCl liposome injection) [package insert] Revised May 2007. Accessed November 2019. https://www.accessdata.fda.gov

76 Moskowitz A.J. Shah G. Schöder H. Phase II trial of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin as second-line therapy for relapsed or refractory classical Hodgkin lymphoma J Clin Oncol 39 2021 3109 3117 34170745 10.1200/JCO.21.01056 PMC9851707

77 Casper E.S. Gaynor J.J. Hajdu S.I. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors Cancer 68 1991 1221 1229 1873773 10.1002/1097-0142(19910915)68:6<1221::aid-cncr2820680607>3.0.co;2-r

78 Shapira J. Gotfried M. Lishner M. Ravid M. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation Cancer 65 1990 870 873 2297656 10.1002/1097-0142(19900215)65:4<870::aid-cncr2820650407>3.0.co;2-d

79 Lipshultz S.E. Miller T.L. Lipsitz S.R. Continuous versus bolus infusion of doxorubicin in children with ALL: long-term cardiac outcomes Pediatrics 130 2012 1003 1011 23166343 10.1542/peds.2012-0727 PMC3507254

80 Ganatra S. Nohria A. Shah S. Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series Cardiooncology 5 2019 1 32154008 10.1186/s40959-019-0036-7 PMC7048095

81 Gulati G. Heck S.L. Ree A.H. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol Eur Heart J 37 2016 1671 1680 26903532 10.1093/eurheartj/ehw022 PMC4887703

82 Bosch X. Rovira M. Sitges M. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies) J Am Coll Cardiol 61 2013 2355 2362 23583763 10.1016/j.jacc.2013.02.072

83 Nabati M. Janbabai G. Baghyari S. Esmaili K. Yazdani J. Cardioprotective effects of carvedilol in inhibiting doxorubicin-induced cardiotoxicity J Cardiovasc Pharmacol 69 2017 279 285 28141699 10.1097/FJC.0000000000000470

84 Boekhout A.H. Gietema J.A. Milojkovic Kerklaan B. Angiotensin II-receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer: a randomized clinical trial JAMA Oncol 2 2016 1030 1037 27348762 10.1001/jamaoncol.2016.1726

85 Avila M.S. Ayub-Ferreira S.M. de Barros Wanderley M.R. Jr. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial J Am Coll Cardiol 71 2018 2281 2290 29540327 10.1016/j.jacc.2018.02.049

86 Heck S.L. Mecinaj A. Ree A.H. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): extended follow-up of a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol Circulation 143 2021 2431 2440 33993702 10.1161/CIRCULATIONAHA.121.054698 PMC8212877

87 Heidenreich P.A. Bozkurt B. Aguilar D. 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America guideline for the management of heart failure: executive summary J Card Fail 28 2022 810 830 35378259 10.1016/j.cardfail.2022.02.009

88 Lloyd-Jones D.M. Allen N.B. Anderson C.A.M. Life’s Essential 8: updating and enhancing the American Heart Association’s construct of cardiovascular health: a presidential advisory from the American Heart Association Circulation 146 2022 e18 e43 35766027 10.1161/CIR.0000000000001078 PMC10503546

89 Eijsvogels T.M. Molossi S. Lee D.C. Emery M.S. Thompson P.D. Exercise at the extremes: the amount of exercise to reduce cardiovascular events J Am Coll Cardiol 67 2016 316 329 26796398 10.1016/j.jacc.2015.11.034

90 Nagata J.M. Vittinghoff E. Gabriel K.P. Physical activity from young adulthood to middle age and premature cardiovascular disease events: a 30-year population-based cohort study Int J Behav Nutr Phys Act 19 2022 123 36127703 10.1186/s12966-022-01357-2 PMC9487136

91 Dibben G.O. Faulkner J. Oldridge N. Exercise-based cardiac rehabilitation for coronary heart disease: a meta-analysis Eur Heart J 44 2023 452 469 36746187 10.1093/eurheartj/ehac747 PMC9902155

92 O’Connor C.M. Whellan D.J. Lee K.L. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial JAMA 301 2009 1439 1450 19351941 10.1001/jama.2009.454 PMC2916661

93 Buckley B.J.R. Harrison S.L. Fazio-Eynullayeva E. Exercise-based cardiac rehabilitation and all-cause mortality among patients with atrial fibrillation J Am Heart Assoc 10 2021 e020804 10.1161/JAHA.121.020804 PMC8477861 34096332

94 Jones L.W. Liu Q. Armstrong G.T. Exercise and risk of major cardiovascular events in adult survivors of childhood Hodgkin lymphoma: a report from the childhood cancer survivor study J Clin Oncol 32 2014 3643 3650 25311213 10.1200/JCO.2014.56.7511 PMC4220043

95 Santos L.S. Rehder M. Negrao M.V. Aerobic exercise training combined with local strength exercise restores muscle blood flow and maximal aerobic capacity in long-term Hodgkin lymphoma survivors Am J Physiol Heart Circ Physiol 326 2024 H1462 H1468 38639741 10.1152/ajpheart.00132.2024 PMC11380951

96 Courneya K.S. Sellar C.M. Stevinson C. Randomized controlled trial of the effects of aerobic exercise on physical functioning and quality of life in lymphoma patients J Clin Oncol 27 2009 4605 4612 19687337 10.1200/JCO.2008.20.0634

97 Beight L.J. Mendoza J.A. Leisenring W.M. Design and methods of the StepByStep randomized trial of a mobile health and social media physical activity intervention among adolescent and young adult survivors of childhood cancer: a report from the Children’s Oncology Group Contemp Clin Trials 145 2024 107645 10.1016/j.cct.2024.107645 PMC11473175 39079612

98 von Tresckow B. Moskowitz C.H. Treatment of relapsed and refractory Hodgkin lymphoma Semin Hematol 53 3 2016 180 185 27496309 10.1053/j.seminhematol.2016.05.010 PMC5637390

99 Bartlett N.L. Niedzwiecki D. Johnson J.L. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804 Ann Oncol 18 2007 1071 1079 17426059 10.1093/annonc/mdm090

100 Moskowitz C.H. Nimer S.D. Zelenetz A.D. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model Blood 97 2001 616 623 11157476 10.1182/blood.v97.3.616

101 Armand P. Zinzani P.L. Lee H.J. Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma Blood 142 2023 878 886 37319435 10.1182/blood.2022019386 PMC10624931

102 Moskowitz A.J. Hamlin P.A. Perales M.-A. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma J Clin Oncol 31 2012 456 460 23248254 10.1200/JCO.2012.45.3308 PMC3862960

103 LaCasce A.S. Bociek R.G. Sawas A. Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma Blood 132 2018 40 48 29703778 10.1182/blood-2017-11-815183 PMC6073588

104 Advani R.H. Moskowitz A.J. Bartlett N.L. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results Blood 138 2021 427 438 33827139 10.1182/blood.2020009178 PMC12684812

105 Schmitz N. Haverkamp H. Josting A. Long term follow up in relapsed Hodgkin’s disease (HD): updated results of the HD-R1 study comparing conventional chemotherapy (cCT) to high-dose chemotherapy (HDCT) with autologous haemopoetic stem cell transplantation (ASCT) of the German Hodgkin Study Group (GHSG) and the Working Party Lymphoma of the European Group for Blood and Marrow Transplantation (EBMT) J Clin Oncol 23 2005 6508

106 Linch D.C. Goldstone A.H. McMillan A. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial Lancet 341 1993 1051 1054 8096958 10.1016/0140-6736(93)92411-l

107 Tay J. Daly A. Jamani K. Patient eligibility for hematopoietic stem cell transplantation: a review of patient-associated variables Bone Marrow Transplant 54 2019 368 382 29988063 10.1038/s41409-018-0265-7

108 Chen Y.B. Lane A.A. Logan B. Impact of conditioning regimen on outcomes for patients with lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation Biol Blood Marrow Transplant 21 2015 1046 1053 25687795 10.1016/j.bbmt.2015.02.005 PMC4426014

109 Desai S.H. Merryman R.W. Shah H. PD-1 blockade before autologous stem cell transplantation improves outcomes in relapsed/refractory classic Hodgkin lymphoma: results from a multicenter cohort Blood 142 2023 182

110 Moskowitz A. Shah G.L. Ganesan N. Pembrolizumab maintenance instead of autologous hematopoietic cell transplantation for patients with relapsed or refractory Hodgkin lymphoma in complete response after pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin Blood 144 2024 569-569

111 Merryman R.W. Kim H.T. Zinzani P.L. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma Blood 129 2017 1380 1388 28073785 10.1182/blood-2016-09-738385 PMC5345733

112 Lockney N.A. Yang J.C. Radiation therapy for advanced-stage Hodgkin lymphoma Adv Radiat Oncol 5 2020 809 816 33083642 10.1016/j.adro.2020.06.001 PMC7557128

113 Borchmann P. Haverkamp H. Diehl V. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group J Clin Oncol 29 2011 4234 4242 21990399 10.1200/JCO.2010.33.9549

114 Celutkiene J. Pudil R. Lopez-Fernandez T. Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC) Eur J Heart Fail 22 2020 1504 1524 32621569 10.1002/ejhf.1957

115 Porter C. Azam T.U. Mohananey D. Permissive cardiotoxicity: the clinical crucible of cardio-oncology JACC CardioOncol 4 2022 302 312 36213359 10.1016/j.jaccao.2022.07.005 PMC9537074

116 Wood W.A. Deal A.M. Reeve B.B. Cardiopulmonary fitness in patients undergoing hematopoietic SCT: a pilot study Bone Marrow Transplant 48 2013 1342 1349 23584437 10.1038/bmt.2013.58

117 Armenian S.H. Yang D. Teh J.B. Prediction of cardiovascular disease among hematopoietic cell transplantation survivors Blood Adv 2 2018 1756 1764 30037802 10.1182/bloodadvances.2018019117 PMC6058239

118 Chow E.J. Mueller B.A. Baker K.S. Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation Ann Intern Med 155 2011 21 32 21727290 10.7326/0003-4819-155-1-201107050-00004

119 Krishan S. Asad Z.U.A. Quiroga D. Comparison of atrial fibrillation prevalence and in-hospital cardiovascular outcomes between patients undergoing allogeneic versus autologous hematopoietic stem cell transplantation: insights from the national inpatient sample Sci Rep 14 2024 16829 10.1038/s41598-024-65294-9 PMC11263704 39039091

120 Vasbinder A. Hoeger C.W. Catalan T. Cardiovascular events after hematopoietic stem cell transplant: incidence and risk factors JACC CardioOncol 5 2023 821 832 38205002 10.1016/j.jaccao.2023.07.007 PMC10774793

121 Chang E.K. Chanson D. Teh J.B. Atrial fibrillation in patients undergoing allogeneic hematopoietic cell transplantation J Clin Oncol 39 2021 902 910 33417479 10.1200/JCO.20.02401 PMC8078261

122 Hayek S.S. Zaha V.G. Bogle C. Cardiovascular management of patients undergoing hematopoietic stem cell transplantation: from pretransplantation to survivorship: a scientific statement from the American Heart Association Circulation 149 2024 e1113 e1127 38465648 10.1161/CIR.0000000000001220

123 Duléry R. Mohty R. Labopin M. Early cardiac toxicity associated with post-transplant cyclophosphamide in allogeneic stem cell transplantation JACC CardioOncol 3 2021 250 259 34396331 10.1016/j.jaccao.2021.02.011 PMC8352028

124 Vasbinder A. Catalan T. Anderson E. Cardiovascular risk stratification of patients undergoing hematopoietic stem cell transplantation: the CARE-BMT risk score J Am Heart Assoc 13 2024 e033599 10.1161/JAHA.123.033599 PMC10863830 38158222

125 Cardinale D. Colombo A. Bacchiani G. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy Circulation 131 2015 1981 1988 25948538 10.1161/CIRCULATIONAHA.114.013777

126 Feijen E. Font-Gonzalez A. Van der Pal H.J.H. Risk and temporal changes of heart failure among 5-year childhood cancer survivors: a DCOG-LATER study J Am Heart Assoc 8 2019 e009122 10.1161/JAHA.118.009122 PMC6405698 30595059

127 Mitchell J.D. Cehic D.A. Morgia M. Cardiovascular manifestations from therapeutic radiation: a multidisciplinary expert consensus statement from the International Cardio-Oncology Society JACC CardioOncol 3 2021 360 380 34604797 10.1016/j.jaccao.2021.06.003 PMC8463721

128 Mahmood S.S. Fradley M.G. Cohen J.V. Myocarditis in patients treated with immune checkpoint inhibitors J Am Coll Cardiol 71 2018 1755 1764 29567210 10.1016/j.jacc.2018.02.037 PMC6196725

129 Johnson P. Federico M. Kirkwood A. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma N Engl J Med 374 2016 2419 2429 27332902 10.1056/NEJMoa1510093 PMC4961236

130 Sanft T. Day A.T. Ansbaugh S.M. NCCN Guidelines® insights: survivorship, version 2.2025: featured updates to the NCCN Guidelines® J Natl Compr Canc Netw 23 2025 208 217 40499584 10.6004/jnccn.2025.0028

131 National Comprehensive Cancer Network NCCN guidelines: management of immunotherapy-related toxicities https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1486

132 Group CsO Long-term follow-up guidelines v6.0 2023

133 Kouwenberg T.W. van Dalen E.C. Mulder R.L. IGHG recommendations for anthracycline and anthraquinone cardiac dysfunction equivalence ratios after childhood cancer: JACC: CardioOncology expert panel JACC CardioOncol 7 6 2025 683 690 10.1016/j.jaccao.2025.05.009 40542813 PMC12790036

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center .