The pathophysiology of secondary HLH is heterogeneous and depends on the triggering factor. As a diagnostic approach, HLH can be categorized into malignancy-associated and non-malignancy-associated subgroups [9]. Due to the rarity and often delayed diagnosis of malignancy-associated HLH, fewer than 50% of patients receive appropriate treatment in a timely fashion [10].

Among oncologic patients, HLH can be further subdivided into three groups: malignancy-associated HLH, HLH during chemotherapy, and HLH-like cytokine storm induced by novel immunotherapies. Malignancy- and chemotherapy-related HLH are most frequently observed in patients with hematologic malignancies and are often triggered by viral infections [7, 11, 12]. The increasing use of immune checkpoint inhibitors has led to reports of cytokine release syndrome (CRS) associated with these therapies. Patients have been treated with CTLA‑4 and PD-1/PD-L1 checkpoint inhibitors [3, 13,14,15,16]. Early recognition of this syndrome, cessation of immunotherapy, and prompt corticosteroid treatment often result in rapid and complete resolution. [7, 9].

Our patient developed early, uncommon adverse effects after administration of pembrolizumab, with initial improvement under corticosteroids. Upon readmission, persistent fever, cytopenia, and elevated inflammatory markers without evidence of infection prompted consideration of alternative diagnoses.

The key to diagnosing HLH lies in maintaining a high index of suspicion in patients presenting with unexpected hyperinflammatory syndromes, especially those with persistent fever, hyperferritinemia, and pancytopenia [7, 9]. The HLH-2004 criteria, although developed for pediatric populations, remain a useful tool in adults as well. Additionally, the H‑score (Table 1) provides a strong aid to quantifying the probability of an HLH diagnosis. Our patient met both criteria, with an H‑score of 251 (99% probability). Genetic testing is not routinely recommended in adults presenting with HLH due to low yield [7].

This syndrome has been most frequently reported in patients with hematologic malignancies undergoing CAR-T cell therapy [17]. With the expanding use of immune checkpoint inhibitors (ICIs) in various solid tumors—especially melanoma—there has been an increasing number of secondary HLH cases attributed to immunotherapy. [3, 7, 14, 15, 19].

Immune checkpoints maintain immune homeostasis by attenuating T cell responses. Their inhibition with ICIs eliminates this regulatory control, resulting in excessive T cell recruitment and hyperactivation, potentially causing HLH-like toxicities. This phenomenon has been observed with anti-CTLA‑4, anti-PD‑1, and anti-PD-L1 therapies, whether used as monotherapy or in combination [14,15,16].

A query of the WHO pharmacovigilance database identified 38 cases of HLH, showing low co-occurrence with other immune-related adverse events or infections. The median onset was 6.7 weeks after initiating ICIs, and in 7 cases, HLH was the primary or contributing cause of death [18].

The HLH-94 protocol can serve as a reference template, with appropriate dose and frequency adjustments based on the patient’s condition. Recommended therapies include corticosteroids, etoposide, cyclosporine, and methotrexate, aimed at controlling the hyperinflammatory response by killing immune cells, thereby terminating the pathologic immune response [2, 3, 7].

In suspected cases of immunotherapy-induced HLH, discontinuation of ICIs and administration of high-dose corticosteroids for 3–5 days may suffice. In our case, corticosteroid therapy was initiated with 100 mg of prednisolone i.v. per day, resulting in marked clinical improvement within 3 days [7, 19]. Leukocyte and neutrophil counts recovered, and C‑reactive protein levels gradually returned to normal (Fig. 2), allowing for discontinuation of antibiotics and supportive therapies. The corticosteroid treatment was gradually and completely discontinued over a period of 3 weeks.

Rechallenging oncologic patients after severe grade 3 or 4 immune-related adverse events (irAEs) after ICI administration harbors an increased risk for relapse of irAEs [20]. In concordance with the ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up of toxicities from immunotherapy [21], in this case, we did not rechallenge the patient, especially considering that several studies and reviews have shown that the occurrence of irAEs in patients treated with checkpoint inhibitors, such as pembrolizumab, may be associated with a better clinical response and longer overall survival [22].