A case report of hemophagocytic lymphohistiocytosis secondary to tislelizumab and bevacizumab combination therapy for renal cell carcinoma

Introduction

Since 2014, immunotherapy, represented by programmed cell death protein 1/programmed cell death protein 1-ligand 1 (PD-1/PD-L1) inhibitors, has gradually become an important treatment option for advanced tumors such as non-small cell lung cancer, renal cell carcinoma (RCC), melanoma, and esophageal cancer (1). Despite their efficacy, immune checkpoint inhibitors (ICIs) disrupt the immune balance of the organism, reduce T-cell tolerance, and lead to a series of immune-related adverse events (irAEs), characterized by its wide coverage, complex clinical manifestations, difficulty of differential diagnosis, and difficulty in predicting its occurrence and severity (2), and thus pose significant challenges in clinical practice. Therefore, the early diagnosis and effective management of irAEs are crucial for improving patient prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a systemic inflammatory disease characterized by the abnormal activation of natural killer (NK) cells, cytotoxic T cells, and macrophages, which may result in multi-organ failure, coagulation dysfunction, pancytopenia, systemic immune response syndrome, and potentially death (3). HLH is classified as primary or secondary. The former may be related to susceptibility or pathogenic genes, such as defects in lymphocyte cytotoxicity and the aberrant activation of inflammasome, while the latter may be triggered by various factors, such as infections, tumors, autoimmune disorders, and iatrogenic factors (4). In recent years, ICI-induced HLH has been flagged as an issue in multiple countries. Despite an incidence of only 0.03–0.4%, the Society for Immunotherapy of Cancer still includes HLH as a lethal irAE, not only because of its high mortality rate, but also because HLH can facilitate the progression of the primary tumor and lead to adverse outcomes (5).

Current reports on ICI-related HLH remain largely limited to case reports. In RCC, most HLH cases associated with ICI-combined anti-angiogenic therapy involve ICI plus anti-angiogenic tyrosine kinase inhibitors (TKIs) (e.g., lenvatinib) (6), while data on HLH induced by ICI plus bevacizumab—a first-line regimen for advanced RCC with favorable efficacy and tolerability—are still lacking. Furthermore, the immunomodulatory mechanisms of anti-angiogenic TKIs differ from those of bevacizumab, but whether these differences translate to distinct HLH pathogenesis or clinical phenotypes remains unclear. Several studies have confirmed that bevacizumab combined with ICIs increases the risk of serious adverse effects, potentially due to vascular endothelial growth factor (VEGF) inhibition-mediated immune dysregulation (e.g., impaired T cell tolerance and enhanced inflammatory responses) (7,8). However, the lack of data on bevacizumab-ICI-associated HLH in RCC hinders clinicians from assessing risks and optimizing management for this specific patient population. In this article, we report the first case of HLH in a RCC patient treated with tislelizumab plus bevacizumab, focusing on its atypical clinical presentation and potential risk factors. We also discuss the mechanism differences between anti-angiogenic TKIs and bevacizumab in HLH induction, aiming to provide clinical guidance for early diagnosis and risk stratification. We present this article in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2376/rc).

Case presentation

A 64-year-old male was referred to Hubei Cancer Hospital in April 2021 after experiencing persistent bilateral iliac pain without apparent cause over the past two months. The patient had a history of allergy to radiographic contrast agents that prevented him from undergoing an enhanced computed tomography (CT) scan. Non-contrast CT scans of the chest, abdomen and pelvis showed a 47 mm by 40 mm space-occupying lesion in the right kidney (Figure 1), accompanied by bone destruction of bilateral shoulder joints, partial thoracic and lumbar vertebrae, ribs, and pelvis. A pathological examination of the right sacroiliac joint mass suggested metastatic clear cell carcinoma of renal origin, leading to a diagnosis of stage IV RCC with multiple bone metastases. The patient had a history of diabetes and had been undergoing treatment with oral metformin. He had no history of smoking or alcohol consumption, and no specific occupational exposures. After consultation with the patient and his family, the patient underwent cytoreduction surgery of the right kidney, and was started on systemic therapy of tislelizumab (200 mg per dose) combined with bevacizumab (7.5 mg per kilogram of body weight) every three weeks one month later.

Figure 1 Abdominal plain CT scans. (A) Imaging data in April 2021 suggested a space-occupying lesion measuring 47 mm by 40 mm in the right kidney. (B) Imaging data in November 2021. The mass in the right kidney was comparatively reduced in size, measuring 30 mm by 29 mm. CT, computed tomography.

One week after the 4th cycle, the patient was re-admitted to the hospital with fatigue and loss of appetite. The physical examination suggested that his bilateral tonsils were slightly congested but not obviously enlarged, and the breath sounds of both lungs were slightly coarse, with no obvious dry or wet rales. The imaging examination suggested mild splenomegaly despite the reduced size of the right kidney tumor. The patient also showed a few chronic inflammatory changes in both lungs, consolidated with pleural effusion on the left side. The laboratory tests showed that the patient’s leukocyte count and absolute neutrophil count were within normal limits, but his hemoglobin and platelets had decreased to 59 g/L (from 118 g/L before treatment) and 15 g/L (from 141 g/L before treatment), respectively. His triglyceride (3.8 mmol/L) and ferritin (1,784.32 ng/mL) levels were elevated, and his thyroid function test results were suggestive of hypothyroidism (Table 1).

After ruling out the possibility of autoimmune diseases and other infectious diseases, we came to the view that the patient had developed treatment-related HLH. Specific exclusionary tests included: (I) infectious disease screening: Epstein-Barr virus DNA (<500 copies/mL), cytomegalovirus (CMV) DNA (<500 copies/mL), CMV pp65 antigen (negative), bacterial blood culture (negative), fungal 1,3-β-D-glucan (G test, 12.3 pg/mL), Aspergillus galactomannan (GM test, negative), and serological tests for hepatitis B, hepatitis C, and human immunodeficiency virus (all negative); (II) autoimmune disease screening: antinuclear antibody (titer <1:100), anti-double-stranded DNA antibody (negative), anti-extractable nuclear antigen antibodies (all negative), rheumatoid factor (8.2 IU/mL), and anti-cyclic citrullinated peptide antibody (negative). The patient further underwent a bone marrow aspiration. Bone marrow morphology analysis showed 13.5% phagocyte cells, and engulfed red blood cells and platelets were observed (Figure 2). Other HLH-related markers included decreased NK cell activity (18.2%) and a soluble interleukin-2 receptor (sCD25) level of 250.47 U/mL. Notably, the sCD25 level was lower than the threshold (>2,400 U/mL) specified in the HLH-2004 diagnostic criteria. However, the patient met six other key diagnostic criteria for HLH (i.e., splenomegaly, bicytopenia, hypertriglyceridemia (3.8 mmol/L), elevated ferritin (1,784.32 ng/mL), decreased NK cell activity, and the presence of hemophagocytosis in the bone marrow). Therefore, a diagnosis of secondary HLH was ultimately made.

Figure 2 Hemophagocytosis was observed in the bone marrow cytology obtained at diagnosis. On microscopy, macrophages ingested erythrocytes, platelets, and nuclear cells (arrow). Giemsa staining, ×200.

The patient’s specialist oncology treatment was then immediately suspended, and he was treated with high-dose prednisone (1 mg/kg). One week later, the patient’s symptoms had improved significantly, and his blood indicators had begun to recover. On day 12, the blood tests of the patient showed that his hemoglobin and platelet levels had returned to normal ranges (Figure 3). The timeline of the medical history of this patient is shown in Figure 4. Ultimately, the patient refused further anti-tumor treatment due to financial constraints and was transferred to a local hospital for palliative care. We conducted standardized telephone follow-up for 6 months after HLH remission (until March 2022). During follow-up, the patient received only supportive care (including nutritional support and blood glucose control). Repeated imaging examinations at the local hospital showed that the right renal tumor and bone metastases remained stable without significant progression. However, the patient’s general condition gradually declined due to cancer-related cachexia and diabetic complications (recurrent urinary tract infections). At the last follow-up, the patient was alive but required assistance with daily living activities.

Figure 3 Clinical course. One week after the patient received prednisone treatment, his blood indicators gradually recovered. HLH, hemophagocytic lymphohistiocytosis; PLT, platelet; RBC, red blood cell; WBC, white blood cell.

Figure 4 The timeline of the medical history of the patient. HLH, hemophagocytic lymphohistiocytosis; RCC, renal cell carcinoma.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

International Multidisciplinary Team (iMDT) discussion

Discussion among physicians from Hubei Cancer Hospital

Department of Thoracic Oncology

This is the first reported case of HLH due to the specific combination of tislelizumab and bevacizumab in RCC. Previously, two cases of HLH resulting from ICIs combined with anti-angiogenic therapy have been reported. A key distinction between this case and previous RCC-related HLH reports lies in the type of anti-angiogenic agent, and this difference may underlie unique HLH pathogenesis. Anti-angiogenic TKIs inhibit multiple kinases (e.g., VEGFR, FGFR, RET) in addition to VEGF, whereas bevacizumab specifically neutralizes VEGF without off-target kinase effects. Researchers have confirmed that VEGF inhibition alone can disrupt immune homeostasis by suppressing T cell function, inducing regulatory T cell infiltration, and impairing dendritic cell maturation (9). Compared with TKIs, bevacizumab may exert a more direct and specific effect on VEGF-mediated immune suppression, leading to uncontrolled T cell activation and HLH.

The pathophysiological basis of HLH in this case lies in the synergistic immune activation between anti-VEGF therapy and ICIs, rather than isolated effects of either agent. Anti-VEGF therapy enhances ICI-induced T cell activation by reshaping the tumor microenvironment (TME), ultimately triggering excessive inflammatory toxicity (10). Bevacizumab, as a highly specific VEGF-neutralizing antibody, exerts multifaceted effects on TME normalization. First, it alleviates the structural disorganization and hyperpermeability of tumor blood vessels, reducing the infiltration of immunosuppressive cells (e.g., regulatory T cells, M2-type macrophages) and decreasing the concentration of local immune-inhibitory cytokines (e.g., IL-10, transforming growth factor-β). Second, it enhances the recruitment and infiltration efficiency of effector T cells into tumor tissues, increasing the probability of T-cell receptor engagement with tumor antigens (11,12). Tislelizumab, a PD-1 inhibitor, further dismantles T-cell immune tolerance by blocking the PD-1/PD-L1 pathway, markedly amplifying T-cell proliferation and cytokine secretion (13). This synergy creates an “amplification loop”: TME normalization provides a permissive environment for ICI-mediated T-cell activation, while ICIs further unleash T-cell responses, leading to the excessive activation of cytotoxic T cells and NK cells. This overactivation triggers a “selective cytokine storm”.

Department of Lymphoma

A critical distinguishing feature of this case is the absence of fever and the unexpectedly low sCD25 level, which contradicts the HLH-2004 diagnostic criterion (14). This observation raises a key clinical question: what is the potential mechanism underlying these deviations? First, sCD25 is a soluble form of the IL-2 receptor α chain, and its massive elevation in classic HLH is driven by excessive T cell and NK cell activation and cytokine storm (15). However, emerging evidence suggests that ICIs-related HLH may exhibit distinct cytokine profiles compared to infection-induced or lymphoma-associated HLH. Unlike infection-induced HLH, ICIs-related HLH is driven by checkpoint blockade-mediated T cell overactivation without massive innate immune cell infiltration in the early stage (16). In our case, the patient’s sCD25 level was relatively low, which may reflect a “mild cytokine storm” induced by the combination of tislelizumab and bevacizumab—consistent with the absence of fever and mild splenomegaly. This suggests that sCD25 may not be a mandatory diagnostic marker for ICIs-related HLH. Second, fever in HLH is typically caused by the release of pro-inflammatory cytokines during immune cell hyperactivation (17). Additionally, bevacizumab’s anti-angiogenic activity may diminish vascular permeability and inhibit inflammatory cell infiltration into tissues, thereby further mitigating clinical systemic inflammatory manifestations such as fever (18).

The management of secondary HLH requires an individualized approach based on underlying etiology, disease severity, and risk of progression, with a core goal of rapidly controlling excessive inflammation while preserving organ function. In our case, the patient presented with grade 4 hematologic toxicity but lacked fever, severe organ dysfunction (e.g., normal liver and kidney function, no coagulopathy), and had a notably low sCD25 level—all indicative of a milder inflammatory phenotype dominated by T-cell activation rather than a full-blown cytokine storm. Thus, we opted for high-dose prednisone monotherapy (1 mg/kg/day), which resulted in significant symptomatic improvement and hematologic recovery within one week. This outcome aligns with clinical observations that mild ICI-related HLH may respond to glucocorticoid monotherapy. Further, several studies have suggested that patients who recover from secondary HLH may exhibit favorable short-term tumor responses (19,20). In this case, the patient’s tumor size was reduced during the combination therapy phase prior to HLH onset, and short-term follow-up showed no tumor progression after HLH remission. However, due to the patient’s premature discontinuation of anti-tumor therapy and limited follow-up duration, this case cannot corroborate the potential association between HLH recovery and long-term tumor control.

Intensive Care Unit

In this case, the patient’s chronic hyperglycemic state may have contributed to the atypical presentation: chronic hyperglycemia induces low-grade systemic inflammation and impairs immune cell function, including reduced TNF-α and IL-6 secretion by macrophages, which may blunt the febrile response (21). Additionally, diabetic complications (e.g., recurrent urinary tract infections) may further perturb immune homeostasis, increasing susceptibility to immune dysregulation induced by combination therapy.

Opinions from international experts on key diagnostic and therapeutic questions

Question 1: Secondary HLH is a disease with high demands for individualized treatment. So how to identify different initial treatment regimens based on the patient’s underlying etiology, disease severity, and risk of death and relapse?

Taigo Kato: HLH is characterized by excessive immune activation, which results in systemic inflammation, leading to multiorgan dysfunction, pancytopenia, and coagulopathy. Given its rapidly progressive and potentially fatal nature, the timely initiation of therapy following diagnosis—typically confirmed by bone marrow biopsy—is imperative. Standard treatment is based on the HLH-2004 protocol, a chemoimmunotherapy regimen comprising dexamethasone, etoposide, cyclosporine A, and intrathecal methotrexate. When patients reveal renal dysfunction, cyclosporine A should be avoided.

Question 2: Some patients with secondary HLH may have heterozygous alterations or polymorphisms in genes associated with primary HLH, which may increase an individual’s risk of developing the disease in response to a “second strike” such as infections or immune abnormality. In clinical practice, is it necessary to identify such patients? And does the therapy strategies, disease progression, and prognosis differ from those without a genetic alteration?

Taigo Kato: Considering that the primary form of HLH is generally familial, these patients usually showed phenotypes related to HLH before initiating ICIs. To avoid life-threatening events with the deterioration of HLH, TKIs, instead of ICIs, is recommended in patients with metastatic RCC.

Question 3: In clinical practice, the treatment of HLH has to strike a balance between limiting excessive inflammation and anti-tumor effects. When do you think the specialized oncology treatment should be re-commenced after patient recovery from HLH? How to adjust the drug dosages, especially chemotherapy agents? How to reduce the risk of secondary infections?

Taigo Kato: Basically, resuming of ICIs was risky after the recovery from HLH. Although there is no recommended treatment for the patients with metastatic RCC after they experience irAEs, TKIs may be the first option to avoid the possible relapse of HLH. Generally, the subsequent treatment will be started after the steroid dose was tapered to ≤10 mg/day of prednisone or equivalent. Of course, during the continuous immunosuppressive therapies including steroid, it is important to monitor secondary infections such as Epstein -Barr virus or CMV infections.

Conclusions

HLH is a syndrome characterized by an uncontrolled inflammatory response with rapid progression and high lethality. The early detection of this disease and the implementation of timely interventions are essential, especially in patients who may present with atypical manifestations. Clinicians should be highly vigilant of such atypical HLH and adopt a comprehensive diagnostic approach combining multiple key indicators and systematic exclusion of infections and autoimmune diseases, rather than over-relying on single markers. The treatment strategy for HLH should be individualized and standardized, and the presence of comorbidities as potential modifiers of clinical phenotypes should also be noted to improve the survival and quality of life of patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2376/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2376/prf

Funding: This work was supported by Bethune Wisdom Research and Science Foundation for Public Welfare Development Project (No. 2024-YJ-226-J-025).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2376/coif). J.T. reports funding support from Bethune Wisdom Research and Science Foundation for Public Welfare Development Project (No. 2024-YJ-226-J-025). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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