Safety of immune checkpoint inhibitor rechallenge following immune-related takotsubo syndrome

Background

Immune checkpoint inhibitors (ICIs) are associated with immune-related cardiotoxicities, including Takotsubo syndrome (TTS). Whether ICI rechallenge after ICI-related TTS is safe remains unknown, and evidence to guide clinical decision-making is limited.

Purpose

To assess outcomes of ICI rechallenge after ICI-associated TTS through a review of the literature.

Methods

We reviewed all published cases of ICI-associated TTS with documented rechallenge identified through PubMed. Rechallenge was defined as re-exposure to the same ICI after clinical recovery from the initial TTS episode. Diagnostic certainty was assessed using the International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria), exclusion of obstructive coronary artery disease by coronary angiography and myocarditis by cardiac magnetic resonance imaging when available, and WHO–Uppsala Monitoring Centre causality categories. Cardiac recovery was defined as normalization or near-normalization of left ventricular systolic function on follow-up imaging.

Results

Five patients with immune checkpoint inhibitor–associated TTS who underwent rechallenge were identified (80% male; mean age 67.5 years). At rechallenge, three patients had complete cardiac recovery, one had partial recovery, and one had unspecified recovery status. Rechallenge was performed 14 days to 4 months after TTS onset.

Among the five rechallenged patients, only one (20%) experienced an early recurrence of TTS 4 days after rechallenge, followed by complete cardiac recovery and no further rechallenge. The remaining four patients had no recurrent cardiac events. During follow-up (4–13 months), all patients achieved complete cardiac recovery. All cases exhibited classical apical TTS with normal or non-obstructive coronary arteries.

Conclusion

These cases suggest that ICI rechallenge after TTS may be feasible following cardiac recovery. Early recurrence can occur, indicating that apparent recovery does not eliminate risk. The lack of standardized TTS diagnosis and reporting in cancer patients resulted in the small number of cases included in the present analysis, and the retrospective nature of the available data precludes definitive conclusions regarding rechallenge safety. These observations underscore the importance of individualized decision-making, balancing oncologic benefit against potential cardiovascular risk, and highlight the need for close cardiac monitoring when rechallenge is considered.