What are the cardiotoxicity risks associated with cyclophosphamide and bortezomib?

Cardiotoxicity Risks of Cyclophosphamide and Bortezomib

Both cyclophosphamide and bortezomib carry distinct cardiotoxicity risks that require careful monitoring, with cyclophosphamide primarily causing acute heart failure at high doses and bortezomib demonstrating variable cardiac effects ranging from minimal risk in patients without pre-existing cardiac disease to significant dysfunction in vulnerable populations.

Cyclophosphamide Cardiotoxicity

Risk Profile and Incidence

Cyclophosphamide cardiotoxicity is relatively rare but can be severe, occurring primarily in patients receiving high doses (>140 mg/kg) before bone marrow transplantation. 1 Heart failure typically develops within days of drug administration, distinguishing it from the delayed cardiotoxicity seen with anthracyclines. 1

Specific Cardiac Manifestations

The FDA label clearly delineates the cardiac complications: 2

• Myocarditis, myopericarditis, pericardial effusion (including cardiac tamponade), and congestive heart failure, which may be fatal 2
• Supraventricular arrhythmias (atrial fibrillation and flutter) and ventricular arrhythmias, including severe QT prolongation associated with ventricular tachyarrhythmia 2
• Myocardial scar formation has been documented in case reports 3

Risk Factors for Cyclophosphamide Cardiotoxicity

The risk of cardiotoxicity increases with: 1, 2

• High cumulative doses (>140 mg/kg) 1
• Advanced age 1, 2
• Combination therapy with other cardiotoxic agents (particularly anthracyclines) 1, 2
• Previous radiation treatment to the cardiac region 1, 2
• Pre-existing cardiac disease 2

Clinical Presentation

A documented case demonstrated that cyclophosphamide-induced cardiotoxicity can present acutely with: 3

• Dyspnea developing within 7 days of chemotherapy initiation 3
• Low voltage on ECG in limb and precordial leads 3
• Left ventricular ejection fraction dropping to 31% from normal baseline 3
• Diffusely increased myocardial echogenicity 3
• Pericardial and pleural effusions 3

Importantly, this cardiotoxicity can be partially reversible with prompt recognition and heart failure management, with LVEF recovering to 60% within one month in the reported case. 3

Bortezomib Cardiotoxicity

Divergent Evidence on Cardiac Risk

The evidence regarding bortezomib cardiotoxicity presents a nuanced picture with significant variation based on patient population and pre-existing cardiac conditions.

In Patients WITHOUT Pre-existing Cardiac Disease

A prospective study using intensive cardiac monitoring (echocardiography, cardiac MRI, and biomarkers) in patients aged 18-70 years without significant cardiovascular disease found NO evidence of cardiotoxicity from bortezomib-based chemotherapy. 4 This study specifically evaluated:

• Global longitudinal strain (GLS) showed no cumulative dysfunction (average change -1.17; P=0.064) 4
• No transient cardiotoxicity detected 4
• LVEF remained stable (ΔLVEF -2.17%; P=0.15) 4
• Cardiac MRI confirmed no structural or functional changes 4

In Patients WITH Cardiac Risk Factors or AL Amyloidosis

Bortezomib demonstrates cardiotoxicity in vulnerable populations, particularly those with cardiac amyloidosis. The 2021 Blood Cancer Journal guidelines specifically address this: 1

• Bortezomib can be cardiotoxic in patients with cardiac involvement from AL amyloidosis 1
• Initiating at lower doses (0.7-1.0 mg/m²) with uptitration as tolerable should be considered in patients with cardiac involvement 1
• Subcutaneous administration at weekly dosing is recommended; twice-weekly dosing increases toxicity risk 1
• Regular monitoring of cardiac biomarkers is essential, especially in high-risk disease 1

FDA-Documented Cardiac Effects

The FDA label for bortezomib states: 5

• Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred, including in patients with no risk factors 5
• Incidence of cardiac disorders was 8% in relapsed multiple myeloma studies 5
• Heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) occurred in ≤1% for each individual reaction 5
• Isolated cases of QT-interval prolongation reported, though causality not established 5

Preclinical and Case Report Evidence

Animal studies demonstrated concerning findings: 6

• Left ventricular contractile dysfunction with significant drop in ejection fraction 6
• Dramatic ultrastructural abnormalities of cardiomyocytes, especially mitochondria 6
• Decreased ATP synthesis and cardiomyocyte contractility 6

Case reports document: 7, 8

• Acute left ventricular dysfunction developing hours after bortezomib administration 7
• Complete heart block requiring permanent pacemaker placement 8
• Myocardial scar formation 8
• Persistent asymptomatic elevations of cardiac biomarkers preceding clinical events 8

Comparison to Carfilzomib

Bortezomib appears significantly less cardiotoxic than the second-generation proteasome inhibitor carfilzomib. 1 The European Myeloma Network notes that carfilzomib's irreversible and highly potent proteasome inhibition may differentiate its safety profile from bortezomib. 1 Carfilzomib demonstrates: 1

• All-grade cardiovascular adverse events in 18.1% vs 2-5% with bortezomib 1
• Grade ≥3 cardiovascular events in 8.2% 1
• Heart failure in 4.1% (all grades) and 2.5% (grade ≥3) 1

Monitoring Recommendations

For Cyclophosphamide

Monitor patients with risk factors for cardiotoxicity and those with pre-existing cardiac disease closely. 2 The FDA label emphasizes particular caution in: 2

• Patients with advanced age 2
• Those receiving high doses 2
• Patients with previous cardiac radiation 2
• Those receiving concomitant cardiotoxic agents 2

For Bortezomib

In AL amyloidosis patients with cardiac involvement, implement regular cardiac biomarker monitoring and consider dose reduction strategies. 1 The 2023 ACC Expert Consensus specifically notes: 1

• Grade 3 heart failure occurs in 6.4% of bortezomib-treated patients 1
• >10% decrease in LVEF occurs in 23% of patients 1
• Patients with EF <40% should be carefully evaluated before stem cell transplantation 1

For patients without pre-existing cardiac disease, routine intensive cardiac monitoring may not be necessary based on prospective data showing no cardiotoxicity. 4 However, the FDA recommends frequent monitoring in patients with risk factors for or existing heart disease. 5

Role of Cardiac Biomarkers

Persistent asymptomatic elevations in cardiac biomarkers may predict subsequent clinical cardiotoxicity with bortezomib and warrant close surveillance. 8 This suggests a potential role for biomarker-guided monitoring, though prospective validation is needed. 8

Clinical Management Algorithm

When Using Cyclophosphamide:

1. Avoid high doses (>140 mg/kg) when possible 1
2. In patients requiring high doses, maintain aggressive hydration and consider prophylactic heart failure monitoring 1
3. If cardiac symptoms develop, immediately interrupt therapy and initiate heart failure management 2, 3
4. Recognize that cardiotoxicity can be partially reversible with prompt intervention 3

When Using Bortezomib:

1. In patients WITHOUT cardiac disease or risk factors: standard dosing with clinical monitoring is appropriate 4
2. In patients WITH cardiac involvement (especially AL amyloidosis): initiate at reduced dose (0.7-1.0 mg/m²), use subcutaneous weekly administration, and monitor cardiac biomarkers regularly 1
3. In patients with pre-existing cardiac disease: frequent cardiac monitoring is warranted despite lower overall risk compared to other proteasome inhibitors 5
4. If cardiac biomarkers persistently elevate or cardiac symptoms develop, reduce dose or discontinue therapy 1, 8

Critical Pitfalls to Avoid

Do not assume bortezomib is completely cardiac-safe in all populations—the risk varies dramatically based on underlying cardiac status. 1, 5, 4 While prospective data in healthy patients is reassuring, vulnerable populations (AL amyloidosis, pre-existing cardiac disease) require vigilant monitoring. 1, 5

Do not overlook the acute nature of cyclophosphamide cardiotoxicity—it develops within days, not months, requiring immediate recognition and intervention. 1, 3

When combining these agents with anthracyclines or other cardiotoxic drugs, the risk substantially increases and attribution of cardiotoxicity to individual agents becomes difficult. 1, 3 Close communication between hematologists and cardiologists is essential in these scenarios. 3