Macrophage Activation Syndrome Following Atezolizumab in Advanced Non-Small-Cell Lung Cancer: A Case Report

Simple Summary

Immunotherapy has changed the treatment of several neoplasms, including advanced non-small-cell lung cancer; despite being described as more tolerable than classic chemotherapy, immune-related adverse events may be severe and difficult to recognize. In this case, we describe a rare syndrome linked to immunotherapy, the macrophage activation syndrome.

Abstract

Immunotherapy with immune checkpoint inhibitors (ICIs) has profoundly transformed the therapeutic landscape of lung cancer. Although ICIs are generally associated with a more favorable toxicity profile compared with traditional chemotherapy, rare and potentially severe immune-related adverse events (irAEs) may occur, sometimes posing significant diagnostic challenges. We report a case of macrophage activation syndrome (MAS) following a single administration of the anti-PD-L1 antibody atezolizumab in a patient with advanced non-small-cell lung cancer (NSCLC). A 62-year-old woman was diagnosed in February 2024 with stage IIIB NSCLC according to the 8th TNM classification. The patient was deemed ineligible for radiotherapy because of previous thoracic irradiation for breast cancer. First-line therapy with carboplatin plus pemetrexed was administered from March to June 2024, resulting in stable disease; this was followed by pemetrexed maintenance from July to October 2024, at which time thoracic disease progression was documented. Second-line treatment with atezolizumab was initiated in November 2024. Ten days after the first infusion, the patient was admitted to the emergency department for fever and confusion. Laboratory investigations revealed markedly elevated C-reactive protein and hyperferritinemia. Despite empirical antibiotic therapy, fever and thrombocytopenia persisted. Bone marrow biopsy demonstrated findings consistent with MAS. Corticosteroid therapy with prednisone at 1 mg/kg was promptly initiated under rheumatologic supervision, leading to a rapid clinical and biochemical improvement. During tapering, inflammatory markers relapsed when prednisone was reduced to below 12.5 mg/day. Given the occurrence of a grade 4 (CTCAE v5.0) immune-related adverse event, atezolizumab was permanently discontinued. The patient remains in follow-up without radiological evidence of disease progression. This case highlights the diagnostic challenge of MAS secondary to ICIs, which may initially present with nonspecific symptoms such as fever, confusion, and elevated inflammatory markers. Early recognition and timely initiation of high-dose corticosteroids were essential for effective management and full recovery. Clinicians should maintain a high index of suspicion for MAS among rare but severe hematologic irAEs during immunotherapy.

1. Introduction

The introduction of immune checkpoint inhibitors (ICIs) has profoundly transformed the therapeutic landscape of several malignancies, including non-small-cell lung cancer (NSCLC); by targeting inhibitory pathways involved in immune regulation, in fact, ICIs restore antitumor immune responses and enable cytotoxic T lymphocytes to recognize and eliminate malignant cells more effectively. Over the past decade, monoclonal antibodies directed against programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have demonstrated significant survival benefit in both early, as adjuvant treatment, and advanced stages, as monotherapy and also in combination with chemotherapy based on PD-L1 expression [1,2].

Despite these therapeutic advances, immune checkpoint blockade is associated with a unique spectrum of toxicities known as immune-related adverse events (irAEs), caused by a nonspecific activation of the immune system and the disruption of physiological immune tolerance mechanisms. Unlike traditional chemotherapeutic agents, irAEs may involve virtually any organ system and range from mild inflammatory manifestations to severe and potentially life-threatening complications: systematic analyses estimate that immune-related toxicities occur in approximately 30–40% of patients receiving ICI monotherapy, while severe events may develop in up to 20% of treated patients [2,3,4].

The most frequently reported irAEs involve skin, gastrointestinal tract, endocrine organs, liver, and lungs; however, rare systemic hyperinflammatory syndromes have also been described and may represent significant diagnostic challenges due to their nonspecific presentation and rapid clinical progression. Among these uncommon complications, one of the rarest is macrophage activation syndrome (MAS), a severe inflammatory condition characterized by uncontrolled immune activation and excessive cytokine release.

MAS belongs to the spectrum of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome resulting from dysregulated activation of macrophages and cytotoxic lymphocytes; more commonly observed in the context of autoimmune or autoinflammatory diseases, this pathological immune activation leads to massive cytokine release, often referred to as a “cytokine storm,” which may rapidly result in multiorgan dysfunction and fatal outcomes if not promptly recognized and treated [5,6,7]. The available evidence suggests that HLH or MAS associated with ICIs remains extremely uncommon, with reported incidence rates ranging from approximately 0.03% to 0.4% of treated patients [4].

Atezolizumab is a humanized monoclonal antibody targeting PD-L1 that blocks its interaction with PD-1 and B7.1 receptors, thereby restoring antitumor immune responses. The drug has been approved for the treatment of NSCLC in multiple clinical settings, including adjuvant setting, first-line therapy and subsequent lines following chemotherapy failure. The clinical efficacy of atezolizumab was demonstrated in the pivotal OAK trial, which showed a significant improvement in overall survival compared with docetaxel in previously treated metastatic NSCLC patients, regardless of PD-L1 expression [8].

Here, we report the case of a 62-year-old woman who developed macrophage activation syndrome shortly after a single administration of atezolizumab for advanced lung adenocarcinoma. Molecular profiling performed through next-generation sequencing did not reveal actionable mutations, and tumor PD-L1 expression was absent (0%). This case highlights the importance of maintaining a high index of suspicion for rare immune-related toxicities during immunotherapy and underscores the crucial role of early recognition and multidisciplinary management.

2. Case Presentation

The patient was a 62-year-old woman with a previous history of breast cancer who underwent radical right mastectomy in 2007, preceded by neoadjuvant chemotherapy with taxanes and anthracyclines, followed by postoperative chemotherapy with CMF. She subsequently received radiotherapy in 2008 to the right chest wall and supraclavicular fossae and completed five years of endocrine therapy with tamoxifen.

Her medical history was also notable for allergic diathesis, including a previous anaphylactic reaction to acetylsalicylic acid, food allergy to eggplant, and contact allergies to metals.

In February 2024, the patient was diagnosed with locally advanced non-small-cell lung cancer (clinical stage IIIB sec TNM 9th ed), which was not eligible for radiotherapy due to the previous thoracic irradiation received during breast cancer treatment.

First-line chemotherapy with carboplatin and pemetrexed was administered for four cycles between March and June 2024, achieving a partial response according to RECIST criteria. Maintenance therapy with pemetrexed was subsequently administered from July to October 2024 for four cycles.

During the initial staging PET scan performed in February 2024, in addition to the hypermetabolic pulmonary lesion located in the upper lobe of the right lung and lymph node involvement, a moderate focal hyperaccumulation was also detected in the ascending colon, corresponding to an area of intestinal wall thickening. Endoscopic evaluation was therefore recommended.

Colonoscopy revealed superficial fragments of adenomatous tissue with tubulo-villous architecture and high-grade dysplasia. Given the lesion characteristics and anatomical location, the patient underwent robotic right hemicolectomy after completion of four cycles of chemotherapy for lung cancer. Histological examination revealed infiltrating mucinous adenocarcinoma of the colon, staged as pT2 pN0, corresponding to stage I according to the 2017 pTNM classification (Stage B1 according to the modified Dukes classification), with preserved expression of mismatch repair proteins.

Restaging imaging performed in June 2024 revealed thoracic disease progression, likely attributable to the lung primary tumor, considering the early stage of the intestinal malignancy. Therefore, second-line systemic therapy with atezolizumab (1200 mg flat dose intravenously) was initiated on 22 November 2024.

Approximately ten days after the first administration, the patient presented to the emergency department with fever and altered mental status as the only symptoms, without clinical autoimmune disease.

Neurological examinations showed isochoric and reactive pupils, no nystagmus, and no cranial nerve deficits. Speech appeared slowly with occasional dysarthric and anomic episodes. No sensory or motor deficits were observed.

Laboratory tests revealed elevated C-reactive protein levels, abnormal liver function tests, and severe thrombocytopenia (<50,000/μL). Empirical antibiotic therapy with piperacillin/tazobactam at a dose of 4 g/0.5 g every 8 h was initiated and the patient was admitted to the internal medicine ward.

During hospitalization, persistent fever and the development of a diffuse cutaneous rash led to antibiotic modification, on suspicion of an allergic reaction, with replacement by daptomycin, antiviral therapy with acyclovir together with antihistamines and corticosteroid therapy (methylprednisolone 40 mg).

Persistent thrombocytopenia and fever (T 39.5 °C) prompted further investigations to exclude alternative causes such as thrombotic thrombocytopenic purpura or infections. The bone marrow biopsy revealed a pattern of mild erythroid hyperplasia with features of dyserythropoiesis, an increase in megakaryocytes (12–15 per HPF) with hypolobated nuclei tending to cluster, histiocytes, some of which contained erythrocytes, and free iron deposits in the matrix, a pattern compatible with macrophage activation syndrome (MAS).

The score for reactive hemophagocytic syndrome was calculated and resulted in over a 99% probability, due the presence of increased AST, hemophagocytosis features on bone marrow aspirate, elevated fibrinogen, elevated triglyceride and ferritin, splenomegaly, fever over 39.4 °C, thrombocytopenia and neutropenia; a rheumatological consultation was required, with indication to increase corticosteroid therapy to 1 mg/kg/day of prednisone and perform an autoimmune screening, with the finding of positivity for antinuclear antibodies (ANA), anti-SSA antibodies and rheumatoid factor [

Table 1. Laboratory values of our patient during steroid therapy with prednisone.

PCR (<5.0 mg/L)	Neutrophils (1.9–8.0 × 103/μL)	Platelets (150–400 × 109/L)	Ferritin (15–165 ng/mL)	Triglycerides (<180 mg/dL)	Gamma-Glutamyl Transferase (<35 U/L)	Alanine Aminotransferase (<40 U/L)	Aspartate Aminotransferase (<35 U/L)	Prednisone
99 mg/L	1.4 × 103/μL	46 × 109/L			173 U/L	31 U/L	135 U/L	0 mg
79.5 mg/L	2.45 × 103/μL	66 × 109/L	6576 ng/mL	159 mg/dL	1232 U/L	129 U/L	209 U/L	50 mg
	5.02 × 103/μL	181 × 109/L	3347 ng/mL					100 mg
	3.8 × 103/μL	185 × 109/L	1899 ng/mL	132 mg/dL	556 U/L	38 U/L	61 U/L	75.5 mg
	4 × 103/μL	307 × 109/L	1052 ng/mL					50 mg
3.03 mg/L	9.1 × 103/μL	379 × 109/L	495 ng/mL	182 mg/dL	261 U/L	30 U/L	22 U/L	37.5 mg
1.01 mg/L	9.88 × 103/μL	314 × 109/L	327 ng/mL	220 mg/dL	196 U/L	40 U/L	26 U/L	30 mg
2.02 mg/L	6.03 × 103/μL	232 × 109/L	305 ng/mL	157 mg/dL	145 U/L	37 U/L	28 U/L
2.08 mg/L	5.01 × 103/μL	262 × 109/L	272 ng/mL		114 U/L	28 U/L	21 U/L	20 mg
1.07 mg/L	4.02 × 103/μL	254 × 109/L	202 ng/mL	173 mg/dL	78 U/L	18 U/L	18 U/L	15 mg
2.04 mg/L	5.06 × 103/μL	237 × 109/L	201 ng/mL	139 mg/dL	57 U/L	16 U/L	20 U/L	10 mg
3.07 mg/L	2.79 × 103/μL	217 × 109/L	223 ng/mL	96 mg/dL	50 U/L	16 U/L	20 U/L	5 mg
2.07 mg/L	9.32 × 103/μL	265 × 109/L	120 ng/mL	126 mg/dL	46 U/L	22 U/L	22 U/L	12.5 mg

].

Steroid treatment resulted in rapid clinical improvement. The patient was discharged on tapering corticosteroid therapy after one month; however, prednisone could not be reduced below 12.5 mg/day due to recurrence of fever and elevation of inflammatory markers.

Atezolizumab therapy was discontinued. The patient had been off therapy for three months from the last administration, until the subsequent TC scan revealed a thoracic progression; due to the severity of the previous adverse event, the oncologist decided to not try a rechallenge with immunotherapy, and a new line of treatment with docetaxel was begun, which is currently ongoing with no sign of HLH flares while continuing with prednisone 12.5 mg/day.

3. Discussion

We report a rare case of macrophage activation syndrome occurring shortly after initiation of atezolizumab therapy for advanced NSCLC; although immune checkpoint inhibitors have revolutionized cancer treatment, their mechanism of action inherently predisposes patients to immune-mediated toxicities [8].

Despite improved tolerability compared with cytotoxic chemotherapy, ICIs are associated with a distinct spectrum of adverse events resulting from immune dysregulation. Most irAEs involve the skin, gastrointestinal tract, endocrine glands, and lungs, with manifestations such as dermatitis, colitis, thyroiditis, and pneumonitis [1,2]. Hematological toxicities are less common but may result in severe complications including immune-mediated cytopenias [9,10,11].

Among the rare but potentially fatal complications of immune checkpoint blockade is hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory syndrome characterized by uncontrolled activation of macrophages and cytotoxic lymphocytes, leading to excessive cytokine production and progressive organ damage [6].

Macrophage activation syndrome is considered a secondary form of HLH and is more frequently associated with autoimmune diseases, although the direct pathogenic association between the two is not entirely clear and there are few cases described in the literature. Clinical manifestations are often nonspecific and include fever, cytopenias, neurological symptoms, and elevated inflammatory markers, which may delay diagnosis [12,13].

Diagnostic criteria have been proposed to support the identification of HLH/MAS, including the HLH-2004 criteria and the HScore, which estimates the probability of reactive hemophagocytic syndrome [5,14]. The best cutoff for HSscore was 169, corresponding to a sensitivity of 93%, a specificity of 86%, and an accurate classification of 90% of the patients. Unfortunately, the diagnostic criteria for HLH/MAS associated with ICIs are not standardized, which makes the diagnostic process even more difficult. Nevertheless, treatment should not be delayed in the presence of strong clinical suspicion [15] [

Table 2. HSscore for reactive hemophagocytic syndrome. HScore 90: 1% probability; HScore 130: 10% probability; HScore 160: 30% probability; HScore 190: 60% probability; HScore 210: 80% probability; HScore 230: 90% probability; HScore 250: 95% probability.

Parameter	Score
Known underlying immunosuppression	No (0 points)|Yes (18 points)
Temperature (°C)	<38.4 °C (0 point)|38.4–39.4 °C (33 points)|>39.4 °C (49 points)
Organomegaly	No (0 points)|hepato- or splenomegaly (23 points)|hepatosplenomegaly (38 points)
Number of cytopenias Definited as hemoglobin ≤ 9.2 g/dL and/or leukocytes ≤ 5000/µL and/or plt ≤ 110,000/µL	1 lineages (0 points)|2 lineages (24 points)|3 lineages (34 points)
Ferritin	<2000 µg/L (0 points)|2000–6000 µg (35 points)|>6000 µg/L (50 points)
Triglycerides	<1.5 mM|1.5–4 mM|>4 mM
Fibrinogen	>2.5 g/L|≤2.5 g/L
AST	<30 U/L|≥30 U/L
Hemophagocytosis in bone marrow aspirate	No (0 points)|Yes (35 points)

].

Prompt immunosuppressive therapy remains the cornerstone of management. Corticosteroids represent the first-line treatment and may be combined with immunosuppressive or targeted biological therapies in severe cases [16]. Recent consensus recommendations highlight the potential role of targeted therapies against inflammatory cytokines, particularly interleukin-1 inhibitors, in rapidly progressive cases of MAS [6,13].

HLH associated with immune checkpoint inhibitors remains extremely rare: a pharmacovigilance analysis identified 38 cases among nearly 50,000 reported adverse events related to immunotherapy [4]. Another case of atezolizumab-associated MAS has been described in a patient with metastatic lung adenocarcinoma and a previous history of immune thrombocytopenic purpura; despite high-dose corticosteroid therapy, the patient developed progressive clinical deterioration and died [16].

In fact, cancer itself has been recognized as a risk factor for MAS [17]: in this case, the causal association between the administration of atezolizumab and the syndrome was evaluated with Naranjo’s algorithm [18] with a score of five, which indicates a probable ADR.

Elevated autoantibodies in cancer patients have been well-documented over recent decades, potentially predicting treatment response and irAEs, but with divergent results [19].

Currently, there are no recommended biomarkers that preemptively identify patients who will experience severe irAEs [20]: in particular, results about the predictive value of autoantibodies (such as antinuclear) at baseline in predicting irAES are controversial, with some studies describing a higher risk in patients positive at baseline while others have not found any correlation [21].

In particular, despite it being known that patients with pre-existing autoimmune disease have an increased risk of flare-ups during treatment, little is known about patients with “subclinical autoimmunity”, which defined as seropositivity for autoantibodies without clinical signs or symptoms of autoimmune disease, in which ICIs may act as a “second hit” and arouse autoimmune disease [22].

The European League Against Rheumatism (EULAR) recommend testing for autoantibodies in patients receiving ICIs only if the patient has rheumatologic disease or “systemic symptoms of unclear etiology” [23].

In this case, the patient has a history of several allergies but no symptoms of rheumatic disease at baseline.

Despite being considered opposite conditions for years, growing evidence suggests that allergies and autoimmune disease have a common origin in dysregulation of the immune system [24]; in fact, a higher incidence of autoimmune disorders has been demonstrated in patients with allergic disease [25].

This evidence may suggest including allergic history during patient evaluation and eventually performing a panel to screen for autoantibodies at baseline to select patients who require close follow-up for irAEs and a prompt referral to a rheumatologist in case of appearance of suspicious symptoms for rheumatic disease; these can also be applied to patients with known positive autoantibodies at baseline.

While these patients, like patients with autoimmune disease but inactive or controlled symptoms, must not delay the start of cancer treatment with ICIs, a strict follow-up, based on autoantibodies (i.e., strict thyroid function monitoring in patients with Ab anti-TPO) and a prompt referral to specialists may be considered.

4. Conclusions

The increasing use of immune checkpoint inhibitors in oncology has led to growing recognition of immune-related adverse events, which may involve multiple organ systems and present with heterogeneous clinical manifestations.

In this case, the initial clinical presentation was highly nonspecific and mimicked infectious or paraneoplastic conditions, highlighting the diagnostic complexity of macrophage activation syndrome.

The presence of autoantibody positivity may suggest a possible predisposing autoimmune background; however, routine screening for autoimmune markers prior to immunotherapy is currently not recommended in the absence of clinical suspicion [26,27,28].

Although rare, MAS represents a potentially life-threatening complication of immunotherapy. Early recognition, multidisciplinary collaboration, and prompt immunosuppressive treatment are essential to improve patient outcomes.

Given the rarity of this syndrome, reporting individual cases remains essential to improve clinical awareness and understanding of this condition: a multidisciplinary approach involving oncologists, rheumatologists, hematologists and internists is crucial for timely diagnosis and optimal management.