Rechallenge of immunotherapy after rituximab-induced Takotsubo syndrome: a case report and review of the literature

Abstract

Background

Rituximab, an anti-CD20 monoclonal antibody, is commonly used in the treatment of B-cell haematologic malignancies. Although caution is recommended in patients with underlying cardiovascular disease, its cardiotoxic potential—particularly in relation to Takotsubo syndrome (TS)—remains underrecognized compared to other agents such as trastuzumab. While rarely described in the literature, Takotsubo syndrome occurrence in association with rituximab administration may represent a serious adverse event that raises the question of safe chemotherapy rechallenge.

Case summary

We report the case of an 80-year-old woman with stage IV diffuse large B-cell lymphoma (DLBCL), who developed TS 48 h after her first rituximab-containing chemotherapy (R-mini-CHOP). She presented with acute heart failure symptoms, elevated cardiac biomarkers, and echocardiographic findings of mid-septal hypokinesis and apical akinesis. Coronary angiography showed no obstructive lesions, and ventriculography confirmed TS. The patient was managed conservatively with diuretics and beta-blockers and showed progressive improvement. Follow-up echocardiography at one month demonstrated normalization of left ventricular ejection fraction (LVEF 68%) and recovery of function. Given the absence of cytokine release syndrome and the patient's clinical stability, rituximab was cautiously reintroduced. Two subsequent cycles of R-mini-CHOP were well tolerated. Due to disease progression, the chemotherapy regimen was later changed to etoposide and ifosfamide.

Discussion

This case represents the fifth reported instance of rituximab-associated TS and the first to describe a successful rechallenge after recovery. With the increasing use of immunotherapies and recognition of their cardiovascular effects, clinicians must be aware of TS as a potential complication. When rechallenge is considered, individualized risk assessment and cardioprotective strategies are essential. This case also illustrates the importance of differentiating TS from other cardiotoxicities, such as anthracycline-induced cardiomyopathy, particularly in cancer patients with multiple cardiovascular risk factors.

Learning points.

• Takotsubo syndrome can occur as an uncommon cardiac complication of rituximab therapy, even in the absence of cytokine release.

• Rechallenge with immunotherapy may be safely considered after full cardiac recovery, under close multidisciplinary supervision.

Introduction

The contemporary cardio-oncologist faces the increasingly complex task of managing an expanding spectrum of cardiovascular toxicities arising from oncological therapies, with the overarching goal of preserving cardiovascular health without compromising antineoplastic efficacy. The concept of permissive cardiotoxicity is therefore central to the modern management of cardiovascular disease in cancer patients.¹

This challenge is further compounded by the high baseline prevalence of cardiovascular comorbidities in cancer populations² and by the frequent exposure of individual patients to multiple cardiotoxic agents, administered either concurrently or sequentially.

In instances where an acute cardiovascular event occurs during cancer therapy, a rigorous evaluation of its causal relationship with the oncological treatment is essential, both for appropriate management of the cardiovascular disease and for informing subsequent cancer treatment decisions.

Among patients with non-Hodgkin lymphoma, current treatment protocols integrate multiple potentially cardiotoxic modalities, ranging from conventional agents such as anthracyclines and cyclophosphamide to more recent targeted therapies, including Bruton tyrosine kinase inhibitors, and immune-based approaches such as the monoclonal antibody rituximab.³

Rituximab is widely used in the treatment of various haematologic malignancies. Although caution is recommended in patients with significant cardiorespiratory comorbidities—due to reported exacerbations of angina and arrhythmias—its cardiotoxic profile remains less well recognized than that of other monoclonal antibodies, such as trastuzumab.

We report the case of an 80-year-old woman who developed Takotsubo syndrome (TS) following her first rituximab infusion. To the best of our knowledge, this is the fifth reported case of TS temporally associated with rituximab administration and the first documentation of successful rituximab rechallenge in this setting. We review previously published cases and explore potential pathophysiological mechanisms linking rituximab and immunotherapy-related TS.

Summary figure

Case Report Timeline: Rechallenge of Immunotherapy After Rituximab-Induced Takotsubo Syndrome

Case report

An 80-year-old female patient was treated for stage IV diffuse large B-cell lymphoma (DLBCL) diagnosed in June 2024. She subsequently received a course of vincristine and corticosteroids, which was well-tolerated. A decision was made to initiate treatment with R-mini-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, prednisone), which commenced on 29 July 2024, and was initially well-tolerated. Her cardiovascular risk factors included arterial hypertension and hypercholesterolaemia. Her other past medical history included a bulbar ulcer with gastrointestinal haemorrhage and chronic constipation. Pre-treatment ECG showed a sinus rhythm with LBBB and cardiac echocardiography revealed an ejection fraction of 60% with moderate aortic regurgitation and moderate aortic stenosis.

Forty-eight hours after receiving chemotherapy, the patient presented to the hospital with acute cardiac decompensation. An initial echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 40%. An electrocardiogram (ECG) showed sinus rhythm with the pre-existent left bundle branch block (LBBB) that obscured any possible new abnormalities (Figure 1). Initial echocardiography revealed severe mid-septal hypokinesis and apical akinesis extending circumferentially to all myocardial territories with a ballooning aspect (see Supplementary material online, video  S1–S2). A cardiac MRI was performed a few days later, revealing oedema on the T2 mapping sequence and diffuse late enhancement at the apical level, which could correspond to stress-induced cardiomyopathy (Figure 2 and Supplementary material online, video  S3).

Figure 1.

Pre-treatment ECG: sinus rhythm with left bundle branch block.

Figure 2.

Cardiac MRI late gadolinium enhancement sequence demonstrating contrast in the apical segments.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) was elevated at 2578 pg/ml (normal < 125pg/mL) and high- sensitivity-troponin level was also increased at 237 ng/l (N < 14ng/L).

Coronary angiography revealed atheromatous coronary arteries with no significant stenosis. Ventriculography demonstrated predominantly apical hypokinesis, highly suggestive of Takotsubo Syndrome (TS). Aortography revealed dilatation of the ascending aorta to 40 mm with moderate aortic regurgitation. Therefore, chemotherapy-induced Takotsubo syndrome was considered the most probable diagnosis.

The patient's clinical course was favourable with diuretic therapy. Beta-blocker therapy was introduced 24 h after the presentation of acute heart failure.

ACE inhibitors were planned to be introduced subsequently, depending on blood pressure control. Follow-up cardiac echocardiography at 7 days showed an LVEF of 38% by automated measurement, good right ventricular function, and a pulmonary artery systolic pressure (PASP) of 30 mmHg.

One month after chemotherapy, the patient reported no symptoms of dyspnoea or chest pain. Cardiac echocardiography revealed an LVEF of 68% with a global longitudinal strain (GLS) of −12%, normal filling pressures, a thin and compliant inferior vena cava, moderate aortic regurgitation, and moderate aortic stenosis (see Supplementary material online, video  S4). Given the complete EF normalization, we interpreted the persistent alteration in GLS as a sequela of the Takotsubo syndrome⁴ rather than a reflection of subclinical myocardial dysfunction secondary to doxorubicin administration. The ECG showed sinus rhythm with a previously known LBBB. Following multidisciplinary discussion involving the cardio-oncology team, a decision was made to continue the chemotherapy regimen unchanged.

She subsequently received two additional cycles of R-mini-CHOP with good tolerance in the oncology unit. The chemotherapy regimen was subsequently changed to etoposide and ifosfamide due to disease progression. Subsequently, the patient was transferred to palliative care due to tumour progression. No clinical cardiac events since hospitalization.

The clinical presentations of our case and the described cases in the literature are summarized in Table 1.

Table 1.

Clinical characteristics of reported cases of Takotsubo syndrome associated with haematologic malignancies

Study	Year	Age	Sex	Hematologic malignancy and treatment	CV Risk factors	Delay to TS Onset	Initial LVEF (%)	Cardiac recovery
Our case	2025	80	F	B-cell lymphoma; R-CHOP	Hypertension, dyslipidaemia	Day 1	38%	Yes
Arkar Min et al.5	2022	52	M	Myeloid leukaemia; no treatment	None	Day 0	Not described	Not described
Monti et al.6	2022	80	F	Non-Hodgkin lymphoma; no treatment	None	Day 14	47%	Yes
Kien Hoe Ng et al.7	2015	66	M	CLL; Fludarabine, cyclophosphamide, rituximab	None	Day 0 (cycle 2)	Not described	Not described
Smith et al.8	2013	60	F	Gray-zone lymphoma; no treatment	None	Day 0	20–25%	Yes (LVEF 42% at 1 month)

Abbreviations: TS, Takotsubo syndrome; CV, cardiovascular; LVEF, left ventricular ejection fraction; CLL, chronic lymphocytic leukaemia; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.

Discussion

With the recent growth of the field of cardio-oncology, the association between cancer and Takotsubo Syndrome (TS) is increasingly recognized. A history of current or past malignancy was observed in 16.6% of TS patients in an international registry.⁸ Conversely, 12% of patients with active cancer admitted to US hospitals in 2016 had current or prior TS, as shown by a retrospective analysis⁹; of note, the specific oncologic treatment administered was not documented in this study.

To date, Takotsubo syndrome related to rituximab administration has been rarely reported. Among the five cases documented in the literature, only one patient had pre-existing cardiovascular disease (coronary artery disease),⁵ whereas our patient presented with chronic left bundle branch block and moderate aortic valve disease. Although evidence is limited, the available observations suggest that underlying cardiac morbidity may not constitute a major predisposing factor for rituximab-associated Takotsubo syndrome.

Given its high prevalence in this population, TS should be considered in the differential diagnosis of acute cardiovascular events in cancer patients, including suspected cardiotoxicity from cancer therapy. In our case, the rapid recovery of left ventricular function and the characteristic wall motion abnormalities favoured a diagnosis of TS over anthracycline-induced cardiomyopathy. Notably, while the LVEF typically normalizes spontaneously within days to weeks in Takotsubo syndrome,¹⁰ a large prospective study reported a mean duration of LVEF recovery of 8 months, following timely instauration of guideline-directed medical therapy for anthracycline-induced cardiomyopathy.¹¹

Current evidence suggests that TS is triggered by an acute catecholamine surge originating from the sympathetic nervous system or adrenal medulla, particularly in individuals with heightened myocardial and coronary sensitivity to stress hormones.¹² In addition, myocardial inflammation has been documented in TS, further supporting a multifactorial pathophysiology. In this context, cancer therapies may create the ideal conditions for TS development, by combining emotional distress, physiological vulnerability, and direct pharmacologic effects on the myocardium:

1. Cancer itself is associated with systemic inflammation and sympathetic activation.

2. Chemotherapy administration may act as a physical trigger for TS.

3. Components of chemotherapy regimens may directly interfere with TS pathogenetic pathways, sensitizing the myocardium and coronary arteries to catecholamines. Fluoropyrimidines, which trigger coronary vasospasm, are frequently implicated in chemotherapy-related TS.

Other implicated therapies induce myocardial dysfunction (e.g. anti-HER2 agents), inflammation (e.g. immune checkpoint inhibitors), or coronary microvascular dysfunction (e.g. anti-VEGF agents).

When rechallenge is contemplated following an episode of recovered chemotherapy-related TS, a careful clinical analysis is required to estimate, for each component of the regimen, the probability of a direct pathogenetic effect. If a high probability is suspected, rechallenge should be approached with dose modification and/or the implementation of targeted cardioprotective strategies. In the other published cases, immunotherapy rechallenge was either not attempted or not addressed, suggesting that patients were likely transitioned to alternative therapeutic options (Table 1).

In our case, the absence of cytokine release syndrome during the initial rituximab infusion supported the decision to proceed with rechallenge using the same regimen, following optimization of heart failure therapy. It may be further speculated that the absence of recurrent Takotsubo syndrome during the subsequent chemotherapy cycles was attributable to a reduced lymphoma burden (as a result of effective therapy), leading to attenuated cancer-related sympathetic drive and systemic inflammation.

Recent evidence indicates that the occurrence of Takotsubo syndrome, even after normalization of left ventricular ejection fraction (LVEF), independently confers an increased risk of subsequent cardiovascular events.⁴ In the present case, this risk was evidenced by the persistent impairment of GLS (despite complete LVEF recovery), and was further exacerbated by the cumulative, dose-dependent cardiotoxicity of doxorubicin, an essential component of the chemotherapy regimen that was re-administered.

Accordingly, meticulous cardiologic surveillance is warranted following an episode of cancer therapy–related Takotsubo syndrome, particularly when ongoing exposure to potentially cardiotoxic agents is anticipated. Beyond optimization of cardioprotective therapy, periodic assessment of biomarkers of myocardial injury and dysfunction (including troponin, B-type natriuretic peptide, GLS, and LVEF) is recommended to enable early detection of recurrent or progressive cardiotoxicity.

Conclusion

We describe a case of Takotsubo syndrome related to the administration of a rituximab-containing chemotherapy regimen in an elderly woman with non-Hodgkin lymphoma. The event presented as acute heart failure shortly after the first exposure to chemotherapy and resolved promptly following guideline-directed medical therapy. After thorough evaluation of the cardiotoxic profiles of all agents within the regimen and multidisciplinary discussion involving the cardio-oncology team, the decision was made to rechallenge the patient with the same treatment protocol. No recurrence of cardiotoxicity was observed. This clinical course suggests that, in the absence of evidence indicating a direct pathogenic contribution from specific chemotherapeutic agents, the occurrence of chemotherapy-related Takotsubo syndrome should not automatically prompt modification of the oncological regimen. Nevertheless, this management approach warrants validation in larger studies.

Lead author biography

Minh Tam Bailly is a cardiologist at the Department of Cardiology, Kremlin Bicêtre Hospital, affiliated with Paris Saclay University, France. Her primary area of expertise includes cardiac imaging, heart failure, and cardiooncology. She is an active member of several professional organizations, including the French Society of cardiology, French Heart Failure Association, and French working group Cardio-Oncology and Council of Cardio-Oncology-ESC.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Consent: A consent for publication has been obtained in line with the COPE best practice guidelines, and that the individual who is being reported on was made aware of the possible consequences of that reporting.

Funding

None declared.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.