Pseudoprogression and Suspected Immune-Mediated Cardiotoxicity During Pembrolizumab Therapy in Relapsed/Refractory Classical Hodgkin Lymphoma

Immune checkpoint inhibitors have significantly improved outcomes in relapsed/refractory classical Hodgkin lymphoma (cHL), but atypical response patterns and immune-related adverse events may complicate treatment assessment and subsequent therapeutic decisions. We report a heavily pretreated patient who developed discordant PET-CT findings together with severe cardiac dysfunction during pembrolizumab therapy.

A 37-year-old woman was diagnosed in 2018, during pregnancy, with stage IVB nodular sclerosis cHL and high-risk prognostic features. She received three cycles of dose-adjusted ABVD, followed after delivery by three cycles of escalated BEACOPP, salvage IGEV, mediastinal radiotherapy, and 11 cycles of brentuximab vedotin. Autologous stem cell transplantation was initially declined. After relapse in 2024, biopsy confirmed recurrent cHL. Four cycles of brentuximab vedotin plus nivolumab achieved a partial response, allowing autologous transplantation. This treatment phase was complicated by invasive pulmonary aspergillosis requiring prolonged voriconazole therapy. Post-transplant PET-CT showed persistent metabolically active disease, with a Deauville score of 4. Pembrolizumab was started in January 2025 and administered every three weeks for 22 cycles. Baseline left ventricular ejection fraction (LVEF) was approximately 55%.

In February 2026, CT demonstrated regression of a previously involved right axillary lymph node but an increasing pericardial effusion, measuring up to 19 mm. PET-CT in March 2026 revealed newly developed bilateral metabolically active cervical lymph nodes, with a Deauville score of 5, while previously involved axillary and pulmonary lesions were regressing. According to LYRIC criteria, this discordant pattern was classified as an indeterminate response, IR(2), rather than definite progression, and repeat PET-CT was planned after 12 weeks.

Concurrently, the patient developed exertional dyspnea. Echocardiography showed diffuse left ventricular hypokinesia, LVEF reduction to approximately 25%, and a moderate circumferential pericardial effusion without overt tamponade. Electrocardiography showed sinus rhythm without specific repolarization abnormalities. Pembrolizumab was discontinued. Guideline-directed heart failure therapy was initiated, with minimal early clinical and echocardiographic benefit. Because immune-mediated myocarditis/pericarditis was suspected, dexamethasone was subsequently started. Follow-up echocardiography demonstrated a slight decrease in pericardial effusion and an absolute LVEF improvement of approximately 5-10 percentage points, although clinically significant systolic dysfunction persisted. The patient remains on corticosteroid and heart failure therapy under close cardiologic monitoring, and pembrolizumab has not been resumed.

In accordance with LYRIC recommendations, repeat PET-CT performed 12 weeks later demonstrated complete metabolic response. This evolution supported pseudoprogression or an immune-mediated inflammatory flare rather than true lymphoma progression. At latest follow-up, hematologic remission was maintained without further lymphoma-directed therapy.

This case highlights the simultaneous diagnostic and therapeutic challenges of anti-PD-1 therapy in cHL. New metabolically active lesions should not automatically be considered progression when previously involved sites are regressing. LYRIC-based reassessment prevented premature classification of treatment failure, while persistent cardiac dysfunction and partial improvement after corticosteroids supported a suspected immune-mediated component and precluded pembrolizumab rechallenge. Multidisciplinary hematology, nuclear medicine, cardiology, and cardio-oncology collaboration is essential when atypical imaging responses coexist with potentially severe immune-related toxicity.