Clinical guide to HLH/MAS

Secondary HLH/MAS: A multi-faceted syndrome

Hemophagocytic lymphohistiocytosis (HLH), also termed “HLH / macrophage activation syndrome (MAS)” (HLH/MAS), is a rare systemic hyperinflammatory syndrome with high risk for rapid progression, multi-organ failure, and death.^1,2

According to the 2022 European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) Delphi consensus, there are three categories of contributing factors for HLH/MAS in adult and pediatric patients, also shown in Figure 1:³

• Predisposing health conditions: Congenital immunodeficiency diseases (e.g., X-linked lymphoproliferative disorder, Chédiak–Higashi syndrome, Heřmanský–Pudlák syndrome), autoimmune rheumatic diseases (e.g., systemic juvenile idiopathic arthritis [sJIA], systemic lupus erythematosus, adult-onset Still’s disease [AOSD]), and hematologic malignancies^1,2,4
• Acute triggers: Infections (most commonly Epstein–Barr virus),^5,6 immunotherapies,^7,8 surgeries (e.g., cardiac),⁹ severe burns,¹⁰ and vaccinations^11,12
• Genetic factors: Homozygous or compound heterozygous loss-of-function mutations in genes that modulate cytolytic functions, lymphocyte survival, and inflammasome activation can be the main underlying cause of HLH/MAS in children, and occasionally in adults

Figure 1. The proportion of attributable secondary HLH/MAS cases by primary trigger, for pediatric and adult patient populations. Data based on individual cohort studies (N≥30 patients in each study) identified in a systematic literature review.³ Attributable cases are described as the median percentage; as such, the data for each pie chart totals >100%.

Although the precise level of risk associated with these factors is not fully known, patients with autoimmune rheumatologic diseases, hematologic malignancies, and those exposed to acute triggers have a notably high risk for developing HLH/MAS. For example, approximately 10% of people with sJIA and 15% of those with AOSD develop HLH/MAS.^13,14 Moreover, HLH/MAS is also a known serious adverse event in people who receive chimeric antigen receptor (CAR) T-cell therapy.¹⁵

Historically, HLH/MAS has been termed “primary HLH” when associated with underlying genetic factors and “secondary HLH” when linked to non-genetic triggers, such as autoimmune rheumatic diseases, malignancies, and acute triggers.^3,16 However, there has been notable variability in use of the term “MAS” within the literature.^3,16 It has been used interchangeably to refer to all forms of secondary disease, as well as specifically to secondary disease associated with autoimmune rheumatic diseases. Here, we will use “secondary HLH/MAS” to refer to all forms of HLH/MAS disease primarily driven by non-genetic contributors, regardless of etiology.

Clinical manifestations

People with secondary HLH/MAS often present with non-specific symptoms, including unexplained fever, hepatosplenomegaly, cytopenias (absolute or relative to baseline levels), coagulopathy, hyperferritinemia, and central nervous system involvement.^1,16,17 Distinguishing the clinical manifestations of secondary HLH/MAS from active autoimmune disease flares or sepsis can be challenging and is a common cause for diagnostic delay.¹⁸

These non-specific clinical manifestations, combined with the rare prevalence of the disease and a general lack of awareness among clinicians, likely contribute to high patient mortality rates.^14,19,20 There are sparse data on the mortality rate specifically in patients with secondary HLH/MAS; however, the mortality rate for HLH/MAS, regardless of the underlying etiology, is estimated to range from 18% to 57%.^17,21,22

People with secondary HLH/MAS have a high risk of death, with contributing factors being non-specific clinical signs and symptoms, and there is low awareness among healthcare professionals of this rare condition

Pathways to a cytokine storm

The exact pathogenic mechanisms underlying secondary HLH/MAS remain to be clearly defined; the current understandings of pathogenesis are mainly based on mouse models and samples from patients with primary HLH.²³ The pathogenic mechanism is thought to involve a complex combination of preexisting immunosuppression, inflammation (in the context of underlying autoinflammatory or rheumatic disorders), cytokine release triggered by infections or malignant diseases, and, in some patients, genetic predisposition.²⁴ This combination of triggers is believed to result in excessive macrophage and T-cell activation, leading to the continual production of cytokines such as interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, and macrophage colony-stimulating factor.²⁵ This eventually leads to a cytokine storm response.²

Diagnosing secondary HLH/MAS

References

1. Chinnici, 2023. Approaching hemophagocytic lymphohistiocytosis. https://www.doi.org/10.3389/fimmu.2023.1210041
2. Wu, 2024. Hemophagocytic lymphohistiocytosis: Current treatment advances, emerging targeted therapy and underlying mechanisms. https://www.doi.org/10.1186/s13045-024-01621-x
3. Shakoory, 2023. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). https://www.doi.org/10.1136/ard-2023-224123
4. Gioia, 2024. Pathogenesis of hemophagocytic lymphohistiocytosis/macrophage activation syndrome: A case report and review of the literature. https://www.doi.org/10.3390/ijms25115921
5. Marsh, 2017. Epstein-Barr virus and hemophagocytic lymphohistiocytosis. https://www.doi.org/10.3389/fimmu.2017.01902
6. Ramos-Casals, 2014. Adult haemophagocytic syndrome. https://www.doi.org/10.1016/s0140-6736(13)61048-x
7. Sadaat and Jang, 2018. Hemophagocytic lymphohistiocytosis with immunotherapy: Brief review and case report. https://www.doi.org/10.1186/s40425-018-0365-3
8. Leclercq, 2024. Late-onset hemophagocytic lymphohistiocytosis in a lung transplant patient: A case of T-cell post-transplant lymphoproliferative disorder. https://www.doi.org/10.12659/ajcr.944761
9. Linthorst, 2011. Unexpected hemophagocytic syndrome in a post-cardiac surgery patient. https://www.doi.org/10.1186/cc10288
10. Porter, 2013. Haemophagocytic lymphohistiocytosis in a patient with severe burns. https://www.doi.org/10.1111/anae.12062
11. Cory, 2021. Lessons of the month 3: Haemophagocytic lymphohistiocytosis following COVID-19 vaccination (ChAdOx1 nCoV-19). https://www.doi.org/10.7861/clinmed.2021-0564
12. Tang and Hu, 2021. Hemophagocytic lymphohistiocytosis after COVID-19 vaccination. https://www.doi.org/10.1186/s13045-021-01100-7
13. De Filippo, 2019. Gut microbiota in children and altered profiles in juvenile idiopathic arthritis. https://www.doi.org/10.1016/j.jaut.2019.01.001
14. Jordan, 2019. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). https://www.doi.org/10.1002/pbc.27929
15. Fugere, 2023. Immune effector cell-associated HLH-like syndrome: A review of the literature of an increasingly recognized entity. https://www.doi.org/10.3390/cancers15215149
16. Sztajnbok, 2024. Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: Two rare sides of the same devastating coin. https://www.doi.org/10.1186/s42358-024-00370-2
17. Bichon, 2021. High mortality of HLH in ICU regardless etiology or treatment. https://www.doi.org/10.3389/fmed.2021.735796
18. Lerkvaleekul and Vilaiyuk, 2018. Macrophage activation syndrome: Early diagnosis is key. https://www.doi.org/10.2147/oarrr.S151013
19. Cox, 2024. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 Hyperinflammation and HLH Across Speciality Collaboration (HiHASC) consensus guideline. https://www.doi.org/10.1016/s2665-9913(23)00273-4
20. Zhang, 2022. A study on early death prognosis model in adult patients with secondary hemophagocytic lymphohistiocytosis. https://www.doi.org/10.1155/2022/6704859
21. Abdelhay, 2023. Epidemiology, characteristics, and outcomes of adult haemophagocytic lymphohistiocytosis in the USA, 2006-19: A national, retrospective cohort study. https://www.doi.org/10.1016/j.eclinm.2023.102143
22. Tan, 2023. Treatment and mortality of hemophagocytic lymphohistiocytosis in critically ill children: A systematic review and meta-analysis. https://www.doi.org/10.1002/pbc.30122
23. Lee and Logan, 2023. Diagnosis and management of adult malignancy-associated hemophagocytic lymphohistiocytosis. https://www.doi.org/10.3390/cancers15061839
24. Knauft, 2024. Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH): A scoping review unveils clinical and diagnostic patterns of a lymphoma subgroup with poor prognosis. https://www.doi.org/10.1038/s41375-024-02135-8
25. Kim and Kim, 2021. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. https://www.doi.org/10.5045/br.2021.2020323

How is secondary HLH/MAS diagnosed?

Early diagnosis is key if healthcare professionals are to initiate treatment quickly and minimize the risk of irreversible organ damage and death.^1,2

No single test or set of classification criteria can accurately diagnose secondary HLH/MAS, so diagnosis requires a high index of clinical suspicion

However, diagnosis of secondary hemophagocytic lymphohistiocytosis / macrophage activation syndrome (HLH/MAS) can be complicated; its clinical presentation resembles that of other cytokine storm-derived diseases, such as non-hyperferritinemic sepsis or even systemic juvenile idiopathic arthritis (sJIA) flares, making early recognition a challenge.^3,4

Furthermore, there is no single diagnostic test or classification criteria with sufficient specificity and sensitivity to accurately diagnose secondary HLH/MAS. Diagnosis requires a high index of suspicion relying on clinical judgment, patient history, and several clinical and laboratory features that vary in specificity, including fever, hepatosplenomegaly, hemophagocytosis, cytopenia, and hypofibrinogenemia, as well as increased ferritin, triglycerides, soluble CD25, and liver enzyme levels.^1-3,5

Considering the wide range of clinical features, a multidisciplinary approach to managing secondary HLH/MAS is of particular importance, ideally involving representation from at least rheumatology, infectious diseases, and hematology.²

Spotting the signs

A patient with early signs of secondary HLH/MAS may present with any or multiple of the following:

• Cytopenia^1,6
• High fever^1,6
• Lymphadenopathy^1,6
• Organomegaly^1,6
• Rash¹
• Arthralgias¹

These symptoms may be mild at first but then progress with unexpected rapidity and severity, despite antimicrobial therapy.¹ Patients with severe disease who are developing organ failure have symptoms including edema, purpura, dyspnea, diarrhea, diffuse bleeding, icterus, and an overall sepsis-like appearance.¹

The liver and spleen are frequently involved, and patients often develop respiratory distress syndrome and renal failure. Some exhibit neurological abnormalities, such as decreased consciousness, convulsions, cranial nerve abnormalities, and ataxia.⁶

Diagnostic first steps

As shown in Figure 1, the triad of fever, falling blood counts, and elevated ferritin (referred to as “the three F’s”) is the initial indicator that a patient might have secondary HLH/MAS.² Signs of central nervous system (CNS) dysfunction, cardiac compromise, liver dysfunction, and a preexisting diagnosis of a hematologic malignancy or rheumatologic disease should add to clinical suspicion.⁷ Once initial suspicion is raised, the next step in the diagnostic process involves a quick screen test and assessment using the appropriate diagnostic criteria.

Figure 1. Flowchart of the diagnostic process for secondary HLH/MAS, in both pediatric and adult patients.^2,3,8-11 ACR, American College of Rheumatology; EULAR, European Alliance of Associations for Rheumatology; HLH/MAS, hemophagocytic lymphohistiocytosis / macrophage activation syndrome; LDH, lactate dehydrogenase; OHI optimized HLH inflammatory index; PRINTO, Paediatric Rheumatology INternational Trials Organisation; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus.

Here are typical clinical and laboratory features for patients with secondary HLH/MAS:

• Persistent fever¹²
• Raised or rising ferritin;^2,12 serial ferritin testing is recommended for patients who show normal ferritin levels but there is an ongoing suspicion of secondary HLH/MAS¹²
• High lactate dehydrogenase and high C-reactive protein¹²
• Cytopenias (hemoglobin, platelet counts, or white blood cells)^2,12
• Transaminitis²
• Low fibrinogen and raised D-dimer^2,12
• High triglycerides²
• Hyponatremia²
• Hypoalbuminemia²
• Hepatic dysfunction (increased alanine transaminase, aspartate aminotransferase, and bilirubin)¹²
• Splenomegaly¹²
• CNS dysfunction¹²

The assessment of more specialized inflammatory biomarkers where available, such as interleukin (IL)-18, CXCL9, and CD25, is also recommended because these can be more specific than the biomarkers listed above.¹² Because the clinical features of secondary HLH/MAS may be mistaken for signs of other cytokine storm-related diseases, differential diagnosis is crucial. In a study assessing the accuracy of various biomarkers to differentiate HLH/MAS from sepsis in 120 patients, ferritin, IL-18, and glycosylated ferritin were the best-performing biomarkers for differential diagnosis.¹³

Alongside the quick screen test and assessment of diagnostic criteria, a full systemic examination should look for hepatosplenomegaly and lymphadenopathy, rashes, bruising, edema, synovitis, signs of infection, and neurological abnormalities.²

Diagnostic criteria: HLH-2004 and the HScore

Quick screen test results of patients with secondary HLH/MAS are very similar to those seen in patients with primary HLH. This has led clinicians to use the HLH-2004 diagnostic criteria, which are only validated in pediatric primary HLH, to diagnose pediatric and adult secondary HLH/MAS.^1,4,8,14

The HLH-2004 criteria are validated only for diagnosis of pediatric primary HLH, and can be misleading in patients with secondary HLH/MAS

The HLH-2004 criteria comprise eight items, of which at least five must be met to confirm likelihood of disease:^1-3,7

• Fever
• Splenomegaly
• Cytopenias affecting two or more of the following cell lineages: hemoglobin, platelets, and neutrophils
• Hypertriglyceridemia with or without hypofibrinogenemia
• Hemophagocytosis in the bone marrow, spleen, or lymph nodes
• No evidence of malignancy (not relevant for suspected secondary HLH/MAS in patients with existing malignancy)
• Low or absent natural killer (NK) cell activity
• Hyperferritinemia and elevated soluble CD25 serum levels

There are clear limitations to the use of these criteria in the context of secondary HLH/MAS, in addition to not being validated for this form of the disease.^5,15,16 For example, relying on the HLH-2004 criteria may lead clinicians to overlook an underlying malignancy that has triggered secondary HLH/MAS.¹⁷ In addition, the criteria have poor sensitivity for secondary HLH/MAS as a complication of existing sJIA,¹⁶ and do not reliably differentiate between primary HLH and secondary HLH/MAS in intensive care settings.¹⁷

A better option for adults with suspected secondary HLH/MAS is the HScore tool, an online probability calculator that is validated for use in this specific demographic.¹⁸ Compared with the HLH-2004 criteria, it has shown better performance for differentiating secondary HLH/MAS from other potential diagnoses.¹⁹ Based on nine variables, it uses widely available laboratory markers; the total score must reach 168 or above to indicate a high probability of HLH/MAS.⁷ However, it is important to note that the HScore has not been validated in children with secondary HLH/MAS.⁵

Diagnosis in patients with autoimmune rheumatologic conditions

Distinguishing the clinical features of secondary HLH/MAS from overlapping manifestations of autoimmune rheumatologic disease can be challenging.⁸ Recommendations for diagnosing secondary HLH/MAS in children and adults with Still’s disease have been published, and diagnostic criteria for disease triggered by specific rheumatologic conditions have been developed for sJIA and juvenile systemic lupus erythematosus (SLE).^10,20,21

In 2016, a collaboration between the European Alliance of Associations for Rheumatology (EULAR), the American College of Rheumatology (ACR), and the Paediatric Rheumatology INternational Trials Organisation (PRINTO) resulted in the publication of criteria for diagnosing secondary HLH/MAS in patients with known or suspected sJIA.⁹

The 2016 EULAR/ACR/PRINTO criteria comprise ferritin levels >684 ng/mL plus any two of the below criteria (provided that laboratory abnormalities are not otherwise explained by concomitant immune-mediated thrombocytopenia, infectious hepatitis, visceral leishmaniasis, or familiar hyperlipidemia):⁹

• Platelet count ≤181 × 10⁹/L
• Aspartate aminotransferase >48 units/L
• Triglycerides >156 mg/dL
• Fibrinogen ≤360 mg/dL

It is important to note that these criteria were developed primarily for use in clinical trials and research, rather than for routine clinical settings.⁹ Moreover, they were developed using a control group of patients with systemic infection, which is likely to have inflated the value of laboratory abnormalities required to distinguish patients living with sJIA with secondary HLH/MAS from controls.⁸ Additionally, the criteria may fail to detect secondary HLH/MAS in patients with sJIA who are receiving anti IL-1 and IL-6 treatment, and those with a subtle onset or who present with only some of the typical signs and symptoms.⁹

In order to address these limitations, the MAS/sJIA (MS) score was developed to assist in identifying secondary HLH/MAS in patients with sJIA.⁸ The MS score ranges from −8.4 to 41.8 and is based on seven variables: CNS dysfunction, hemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase, and ferritin.⁸ A cutoff value ≥−2.1 is recommended for distinguishing secondary HLH/MAS from active sJIA.⁸

Diagnosing secondary HLH/MAS as a complication of known juvenile SLE requires simultaneous fulfillment of at least one clinical criterion and at least two laboratory criteria:²¹

• Clinical criteria comprising fever, hepatomegaly and splenomegaly (≥3 cm below the coastal arch), hemorrhagic manifestations, and CNS dysfunction
• Laboratory criteria comprising cytopenia affecting two or more lineages (white blood cell count ≤4.0 × 10⁹/L; hemoglobin ≤90 gm/L or platelet count ≤150 × 10⁹/L), increased aspartate aminotransferase (>40 units/L), and lactate dehydrogenase (>567 units/L), hypofibrinogenemia (fibrinogen ≤1.5 gm/L), hypertriglyceridemia (triglycerides >178 mg/dl), and hyperferritinemia (ferritin >500 µg/L)

Bone marrow aspiration to provide evidence of macrophage hemophagocytosis may be necessary in cases of diagnostic uncertainty.²⁰

Secondary HLH/MAS is the main potentially fatal complication of adult-onset Still’s disease (AOSD), and can present at onset, during treatment, or during its course.²⁰ Recommendations from EULAR and the Paediatric Rheumatology European Society highlight the importance of monitoring patients for secondary HLH/MAS, particularly during treatment withdrawal from glucocorticoids and IL-6 or IL-1 inhibitors.²⁰ The recommendations also suggest to consider secondary HLH/MAS in patients who present with the following: persistent fever, splenomegaly, elevated or rising serum ferritin, inappropriately low cell counts, abnormal liver function tests, intravascular activation of coagulation, and elevated or rising serum triglycerides.²⁰

Furthermore, there is evidence supporting the use of the 2016 EULAR/ACR/PRINTO criteria in febrile patients with AOSD, to help identify those who have secondary HLH/MAS and are therefore at high risk of a poor outcome.¹⁰

Diagnosis of disease associated with malignancies

Malignancies associated with secondary HLH/MAS include high-grade lymphomas, B-cell lymphoma, Hodgkin lymphoma, and acute leukemia.²² Lymphoma is particularly difficult to distinguish from primary HLH and secondary HLH/MAS associated with rheumatologic conditions; for this reason, thorough imaging and aggressive biopsy, often guided by positron emission tomography–computed tomography (PET-CT), are recommended as part of the diagnostic procedure.²³

There is one set of diagnostic criteria for secondary HLH/MAS in patients with malignancy: the optimized HLH inflammatory (OHI) index, which comprises just two criteria – soluble CD25 >3,900 U/mL and ferritin >1,000 ng/mL.¹¹

Diagnosing drug-induced secondary HLH/MAS

Secondary HLH/MAS can also arise in patients who have received immunotherapy, such as chimeric antigen receptor (CAR) T-cell therapy.²⁴ The criteria for diagnosing CAR T-cell therapy-associated disease are a peak ferritin of more than 10,000 µg/L during the cytokine release syndrome phase of illness, as well as two of the following: organ toxicities greater than grade 3 involving the liver, kidney, or lung; or hemophagocytosis in the bone marrow or other organs.²

Completing the picture

For patients with a suspected case of HLH/MAS who do not have a preexisting disease diagnosis, it is important to identify the underlying trigger(s), which involves screening for:

• Predisposing conditions, including malignancies
• Testing for autoimmune antibodies
• Etiologic examination for potential infectious agents; it is recommended to include investigation of herpes virus infections, which are reported in two-thirds of secondary HLH/MAS cases²⁵
• A detailed patient history (including malignancy, inherited and autoimmune disorders, as well as travel and sexual history to assess for risks of infection).²
  
  

Treating secondary HLH/MAS

References

1. La Rosée, 2019. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. https://www.doi.org/10.1182/blood.2018894618
2. Cox, 2024. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 Hyperinflammation and HLH Across Speciality Collaboration (HiHASC) consensus guideline. https://www.doi.org/10.1016/s2665-9913(23)00273-4
3. Sztajnbok, 2024. Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: Two rare sides of the same devastating coin. https://www.doi.org/10.1186/s42358-024-00370-2
4. Carcillo, 2018. Secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and hyperferritinemic sepsis-induced multiple-organ dysfunction syndrome in the pediatric ICU. https://www.doi.org/10.1007/978-3-319-96499-7_14
5. Debaugnies, 2016. Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. https://www.doi.org/10.1093/ajcp/aqw076
6. Kim and Kim, 2021. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. https://www.doi.org/10.5045/br.2021.2020323
7. NHS England, 2024. Haemophagocytic lymphohistiocytosis (HLH). Guidance on the diagnosis, treatment, management and governance. https://gettingitrightfirsttime.co.uk/wp-content/uploads/2024/07/HLH-Guide-final-version-v1.1-July-2024.pdf
8. Minoia, 2019. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. https://www.doi.org/10.1136/annrheumdis-2019-215211
9. Ravelli, 2016. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation collaborative initiative. https://www.doi.org/10.1002/art.39332
10. Ahn, 2017. Application of the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome in patients with adult-onset Still disease. https://www.doi.org/10.3899/jrheum.161286
11. Zoref-Lorenz, 2022. An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis. https://www.doi.org/10.1182/blood.2021012764
12. Shakoory, 2023. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). https://www.doi.org/10.1136/ard-2023-224123
13. Debaugnies, 2021. Biomarkers for early diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients. https://www.doi.org/10.1007/s10875-020-00950-z
14. Hines, 2022. Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. https://www.doi.org/10.1097/ccm.0000000000005361
15. Naymagon, 2021. Can we truly diagnose adult secondary hemophagocytic lymphohistiocytosis (HLH)? A critical review of current paradigms. https://www.doi.org/10.1016/j.prp.2020.153321
16. Davì, 2014. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. https://www.doi.org/10.1002/art.38769
17. Gurunathan, 2018. Limitations of HLH-2004 criteria in distinguishing malignancy-associated hemophagocytic lymphohistiocytosis. https://www.doi.org/10.1002/pbc.27400
18. Fardet, 2014. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. https://www.doi.org/10.1002/art.38690
19. Fatma, 2024. Performances of the H-score and the HLH-2004 score in the positive diagnosis of secondary hemophagocytic lymphohistiocytosis. https://www.doi.org/10.1016/j.retram.2023.103430
20. Fautrel, 2024. EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease. https://www.doi.org/10.1136/ard-2024-225851
21. Parodi, 2009. Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty-eight patients. https://www.doi.org/10.1002/art.24883
22. Setiadi, 2022. Malignancy-associated haemophagocytic lymphohistiocytosis. https://www.doi.org/10.1016/S2352-3026(21)00366-5
23. Jordan, 2019. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). https://www.doi.org/10.1002/pbc.27929
24. Sandler, 2020. Diagnosis and management of secondary HLH/MAS following HSCT and CAR-T cell therapy in adults: A review of the literature and a survey of practice within EBMT centres on behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP). https://www.doi.org/10.3389/fimmu.2020.00524
25. Ramos-Casals, 2014. Adult haemophagocytic syndrome. https://www.doi.org/10.1016/s0140-6736(13)61048-x

Secondary HLH/MAS: Treatment pathways

Early and intensive intervention in patients with secondary hemophagocytic lymphohistiocytosis / macrophage activation syndrome (HLH/MAS) is crucial to achieve stabilization, prevent rapid progression to multi-organ failure, and enable specific treatment of the underlying disease triggers. Regardless of the underlying etiology, first-line treatment typically involves immunosuppressive and anti-inflammatory therapy.^1,2

Early and intensive initial treatment is critical to achieve stabilization and prevent rapid progression to multi-organ failure

First-line treatment: The initial step

Historically, the standard first-line treatment approach has been the HLH-94 protocol, which was later revised and amended to HLH-2004.¹

Large doses of corticosteroids, as per the HLH-2004 protocol, can mask underlying malignancy

However, this treatment protocol was developed specifically for pediatric patients with primary HLH, and in cases of secondary HLH/MAS may be inappropriate. For example, the large doses of corticosteroids prescribed in the protocol may lead to significant risk of secondary infection and can temporarily obscure underlying malignancies.³

Although there are no definitive treatment guidelines specifically for secondary HLH/MAS,³ a number of general recommendations have emerged from consensus groups. The 2022 European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) Delphi consensus emphasizes the importance of initiating immunomodulatory treatment without delaying until diagnostic tests are complete, due to the rapidly progressing and severe nature of the disease.^4,5

The group advises initial immunomodulatory treatment for patients with secondary HLH/MAS, regardless of its underlying triggers, using one or a combination of the below agents:⁴

• Corticosteroids (prednisone, prednisolone, or intravenous methylprednisolone; intravenous dexamethasone; or high-dose intravenous methylprednisolone)
• The interleukin (IL)-1 receptor antagonist anakinra, which at the time of writing is only approved in the UK, although off-label use is widespread in the USA⁶
• Intravenous immunoglobulin (IVIg)

Treatment escalation, if required, involves higher doses of corticosteroids with or without additional agents, potentially including etoposide, emapalumab (an interferon-gamma [IFNγ] inhibitor approved in the USA for primary HLH) ruxolitinib (a Janus kinase [JAK] inhibitor), rituximab (which targets B cells), and cyclosporin A.⁴

Causes and triggers: Personalizing treatment

Once the hyperinflammation caused by secondary HLH/MAS has been controlled and the patient is stabilized with first-line therapy, the next step is to select a treatment approach specifically for managing the underlying cause(s).² Corticosteroids are the main therapeutic agent, combined with a treatment specifically targeting the underlying trigger or disease.^1,4

The Working Group “HLH in Adults” of the Histiocyte Society has developed a treatment algorithm to aid in treatment decision-making for secondary HLH/MAS, as shown in Figure 1.¹

Figure 1. Flowchart of the treatment algorithm for secondary HLH/MAS, as recommended by guidelines.^1,4,7,8 CAR-T, chimeric antigen receptor T-cell therapy; CNS, central nervous system; CS, corticosteroids; EBV, Epstein–Barr virus; HLH/MAS, hemophagocytic lymphohistiocytosis / macrophage activation syndrome; IL, interleukin; IVIg, intravenous immunoglobulin; MRI magnetic resonance imaging.

Infection-associated disease

The recommended approach for secondary HLH/MAS induced by infectious agents is corticosteroids, with the addition of disease-specific treatment.¹

Epstein–Barr virus (EBV) is a common infectious trigger.¹ Treatment in this case ranges from a short course of corticosteroids for patients with mild disease to allogeneic hematopoietic stem cell transplant (alloSCT) for those with increasing or sustained high levels of EBV DNA.^1,9 Other recommended treatments include ruxolitinib and rituximab – the latter specifically targets CD20, a protein expressed by B cells, in which EBV replicates.^1,4,10

Malignancy-associated disease

The treatment approach in patients who have malignancy-driven HLH/MAS needs to balance HLH/MAS-specific and tumor-specific treatment needs. Antineoplastic therapy should be given as soon as possible, but patients at imminent risk of severe organ damage should receive dose-adjusted etoposide prior to tumor-specific treatment.^1,11

Patients with aggressive lymphomas should be considered for evaluation of CNS system involvement.^1,11 Those whose cancer is in remission and who require treatment intensification for secondary HLH/MAS may also be eligible for autologous SCT, using high-dose etoposide-containing chemotherapy as primary consolidation.¹¹

Autoimmune rheumatologic disease-associated disease

For patients with autoimmune rheumatologic disease-driven HLH/MAS, the recommended initial treatment is high-dose corticosteroids (e.g., methylprednisolone, or dexamethasone in cases of central nervous system [CNS] involvement), with the addition of cyclosporin A and anakinra in case of insufficient immediate response.¹

IFNγ inhibition is also recommended in the EULAR / Paediatric Rheumatology European Society (PReS) guidance, with the caveat that no such medication is yet approved in secondary HLH/MAS.¹² Recent data suggest that emapalumab, which is approved in the USA for use in primary HLH, has therapeutic potential for patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) who show insufficient response to high-dose corticosteroids.^13,14

If, despite these treatments, a patient has severe active disease or CNS involvement, they may benefit from a reduced dose of etoposide.¹

Drug-induced disease

Patients who develop secondary HLH/MAS in response to immunotherapies (e.g., chimeric antigen receptor [CAR] T-cell therapy, blinatumomab, CTLA4- and PD-1/PD-L1–directed checkpoint antibodies) may benefit from interruption of these treatments or use of corticosteroids alone.¹

If patients have organ toxicities of grade 3 or above, expert recommendations advise initial treatment with anti-IL-6 therapy (tocilizumab) and corticosteroids, with the addition of etoposide if there is no clinical or serological improvement within 48 hours.¹⁵

Keeping watch: Monitoring and salvage therapy

Around 25–50% of patients do not achieve a complete response to initial treatment for secondary HLH/MAS

During and following on from treatment, longitudinal assessment of both routine and specialized secondary HLH/MAS biomarkers is essential for monitoring for progression or resolution.⁴ Deterioration of liver function and blood counts, as well as increases in serum ferritin, soluble CD25, and soluble CD163 levels are all correlated with increased disease severity and relapse.¹⁶

Longitudinal assessment of HLH/MAS biomarkers is essential for monitoring for progression or resolution⁴

It is estimated that approximately 25–50% of patients do not achieve complete response to initial therapy; furthermore, patients who show initial response to therapy may experience a relapse.¹⁷ Depending on the underlying trigger, salvage options may include chemotherapy plus corticosteroids, and low-dose etoposide.^12,18,19

Other options for patients with refractory disease include ruxolitinib,^1,20-22 tocilizumab for patients with AOSD,²³ plasma exchange as a supportive measure for secondary HLH/MAS triggered by AOSD and systemic lupus erythematosus, and cytokine adsorption therapy for malignancy-induced disease.^1,19,24 For some patients, however, alloSCT may be the only recourse.^1,11

References

1. La Rosée, 2019. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. https://www.doi.org/10.1182/blood.2018894618
2. Wu, 2024. Hemophagocytic lymphohistiocytosis: Current treatment advances, emerging targeted therapy and underlying mechanisms. https://www.doi.org/10.1186/s13045-024-01621-x
3. Baverez, 2022. Anakinra for the treatment of hemophagocytic lymphohistiocytosis: 21 cases. https://www.doi.org/10.3390/jcm11195799
4. Shakoory, 2023. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). https://www.doi.org/10.1136/ard-2023-224123
5. Sztajnbok, 2024. Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: Two rare sides of the same devastating coin. https://www.doi.org/10.1186/s42358-024-00370-2
6. Yang, 2023. Use of intravenous anakinra for management of pediatric cytokine storm syndromes at an academic medical center. https://www.doi.org/10.1177/00185787221142470
7. Carter, 2019. Macrophage activation syndrome in adults: Recent advances in pathophysiology, diagnosis and treatment. https://www.doi.org/10.1093/rheumatology/key006
8. Hines, 2022. Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. https://www.doi.org/10.1097/ccm.0000000000005361
9. Arca, 2015. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: Impact of triggering disease and early treatment with etoposide. https://www.doi.org/10.1111/bjh.13102
10. Salles, 2017. Rituximab in B-cell hematologic malignancies: A review of 20 years of clinical experience. https://www.doi.org/10.1007/s12325-017-0612-x
11. Zoref-Lorenz, 2023. Inpatient recognition and management of HLH. https://www.doi.org/10.1182/hematology.2023000509
12. Fautrel, 2024. EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease. https://www.doi.org/10.1136/ard-2024-225851
13. De Benedetti, 2019. Op0204 Emapalumab, an interferongGamma (IFN-Y)-blocking monoclonal antibody, in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). https://www.doi.org/10.1136/annrheumdis-2019-eular.3341
14. De Benedetti, 2023. Efficacy and safety of emapalumab in macrophage activation syndrome. https://www.doi.org/10.1136/ard-2022-223739
15. Neelapu, 2018. Chimeric antigen receptor T-cell therapy - Assessment and management of toxicities. https://www.doi.org/10.1038/nrclinonc.2017.148
16. Kleynberg and Schiller, 2012. Secondary hemophagocytic lymphohistiocytosis in adults: An update on diagnosis and therapy. https://www.ncbi.nlm.nih.gov/pubmed/23271259
17. Salunke, 2019. Hemophagocytic syndrome - An approach to the management. https://www.doi.org/10.5005/jp-journals-10071-23251
18. Wang, 2015. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. https://www.doi.org/10.1182/blood-2015-05-644914
19. Lorenz, 2020. Adult macrophage activation syndrome–haemophagocytic lymphohistiocytosis: 'Of plasma exchange and immunosuppressive escalation strategies' – a single centre reflection. https://www.doi.org/10.1177/0961203320901594
20. Sin and Zangardi, 2019. Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: First case report. https://www.doi.org/10.1016/j.hemonc.2017.07.002
21. Marsh, 2013. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. https://www.doi.org/10.1002/pbc.24188
22. Yildiz, 2021. Clinical management of relapsed/refractory hemophagocytic lymphohistiocytosis in adult patients: A review of current strategies and emerging therapies. https://www.doi.org/10.2147/tcrm.S195538
23. Zhou, 2018. Biological therapy of traditional therapy-resistant adult-onset Still's disease: An evidence-based review. https://www.doi.org/10.2147/tcrm.S155488
24. Rademacher, 2021. Cytokine adsorption therapy in lymphoma-associated hemophagocytic lymphohistiocytosis and allogeneic stem cell transplantation. https://www.doi.org/10.1007/s10047-020-01244-2