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The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients.

Recently, primary immune regulatory disorders have been described as a subset of inborn errors of immunity that are dominated by immune mediated pathology. As the pathophysiology of disease is elucidated, use of biologic modifiers have been increasingly used successfully to treat disease mediated clinical manifestations. Hematopoietic cell transplant (HCT) has also provided definitive therapy in several PIRDs. Although biologic modifiers have been largely successful at treating disease related manifestations, data are lacking regarding long term efficacy, safety, and their use as a bridge to HCT. This review highlights biologic modifiers in the treatment of several PIRDs and there use as a therapeutic bridge to HCT.

Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening, hyperinflammatory disorder, characterized by uncontrolled activation of the immune system. Mutations affecting several genes coding for proteins involved in the cytotoxicity machinery of both natural killer (NK) and T cells have been found to be responsible for the development of pHLH. So far, front-line treatment, established on the results of large international trials, is based on the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic hematopoietic stem cell transplantation (HSCT), the sole curative treatment for the genetic forms of the disease. However, despite major efforts to improve the outcome of pHLH, many patients still experience unfavorable outcomes, as well as severe toxicities; moreover, treatment-refractory or relapsing disease is a major challenge for pediatricians/hematologists. In this article, we review the epidemiology, etiology and pathophysiology of pHLH, with a particular focus on different cytokines at the origin of the disease. The central role of interferon-γ (IFNγ) in the development and maintenance of hyperinflammation is analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody is discussed. Available data support the use of emapalumab for treatment of pHLH patients with refractory, recurrent or progressive disease, or intolerance to conventional therapy, recently, leading to FDA approval of the drug for these indications. Additional data are needed to define the role of emapalumab in front-line treatment or in combination with other drugs.

Emapalumab, an interferon-γ (interferon-gamma)-blocking monoclonal antibody, has emerged as a targeted therapy for refractory hemophagocytic lymphohistiocytosis (HLH). This scoping review summarizes real-world evidence of its clinical use across HLH subtypes. A comprehensive search of PubMed, Scopus, and Web of Science through September 2025 identified studies reporting emapalumab use outside clinical trials. Case reports, series, and observational studies describing clinical outcomes were included. Thirty-one publications comprising 86 patients were analyzed. Disease contexts included familial/genetic HLH (n = 11), rheumatology-associated macrophage activation syndrome (MAS; n = 12), malignancy-associated HLH (n = 25), infection-associated HLH (n = 22), CAR-T/IEC-HS or cytokine-release-syndrome-related HLH (chimeric antigen receptor T-cell/immune effector cell-associated hemophagocytic syndrome; n = 11), and other secondary HLH (n = 5). Across all categories, emapalumab achieved rapid suppression of hyperinflammation, typically within 1-2 weeks. Clinical response rates were 100% in familial HLH, 91.7% in rheumatology-associated MAS, 72.7% in infection-associated HLH, 90.9% in CAR-T/IEC-HS-related HLH, and 80% in other secondary HLH. In contrast, only 6 of 25 patients with malignancy-associated HLH (24%) showed partial or complete responses, reflecting inferior outcomes due to underlying disease progression. Overall survival was highest in familial and infection-associated subgroups. The reported adverse events were generally infrequent and mild in the published cases, but causality cannot be reliably established given the complexity of the underlying disease and concurrent therapies. Real-world evidence demonstrates that emapalumab induces rapid and durable disease control across diverse HLH subtypes, with a favorable tolerability profile. However, outcomes remain markedly inferior in malignancy-associated HLH, where response rates are limited to approximately 24%, primarily due to the impact of underlying malignancy. Its role as rescue or bridging therapy to hematopoietic stem-cell transplantation (HSCT) is increasingly supported in both pediatric and adult populations.

Hemophagocytic lymphohistiocytosis (HLH), a severe, life-threatening hyperinflammatory syndrome driven by dysregulated immune activation, is characterized by rapid clinical deterioration and poor outcomes that pose critical challenges for clinical management. Here, we report on a female patient aged 10 years and 3 months who was diagnosed with systemic lupus erythematosus (SLE)-associated hemophagocytic lymphohistiocytosis with central nervous system (CNS) involvement. Treatment with the conventional HLH-94/2004 regimen failed to control disease progression. Subsequently, second-line salvage therapy, consisting of emapalumab in combination with teniposide and dexamethasone, was initiated to account for the CNS involvement. The patient achieved sustained, complete clinical response following use of this modified therapeutic approach. Our findings suggest that this combination regimen may offer a potentially feasible therapeutic alternative for managing patients with SLE-associated HLH accompanied by CNS involvement; however, given the single-case nature of this report, further validation in larger cohorts is needed.

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

Chimeric antigen receptor T (CAR-T) cell therapy significantly improves the prognosis of a variety of hematological malignancies; however, its broader application in clinical practice is hindered by adverse events, particularly cytokine release syndrome (CRS). Moreover, the selection of treatment strategies for patients with high-grade CRS must be meticulously tailored. Emapalumab, a fully human IgG1 monoclonal antibody targeting IFN-γ, has been proposed to have clinical benefit in CRS. In this retrospective study, we conducted a comprehensive analysis of clinical and laboratory parameters in 38 pediatric patients who failed low-dose glucocorticoids monotherapy, tocilizumab monotherapy or glucocorticoid-tocilizumab combination therapy, following treatment with investigational CAR-T products. Emapalumab significantly improved both clinical symptoms and laboratory parameters. The rapid decrease in mean temperature (39.61 vs. 38.38°C, < 0.001) and levels of inflammatory markers including IL-2 (32.35 vs. 11.94 pg/ml, < 0.001), IL-10 (222.29 vs. 86.09 pg/ml, = 0.018), TNF-α (4.17 vs. 2.94 pg/ml, = 0.032), and IFN-γ (21984.11 vs. 674.87 pg/ml, < 0.001) indicated the remarkable scavenging efficacy of emapalumab against cytokine storm following CAR-T therapy. Additionally, both mean CAR-T cell counts (549.95 vs. 8.16 cell/μl, < 0.001) and the ratio of CAR-T to CD3+ (11.3% vs. 36.54%, < 0.001) in peripheral blood increased significantly, demonstrating that the administration of emapalumab didn't seem to have a significant negative impact on the proliferation of CAR-T cells. The median EFS and OS were both not reached, with an EFS rate of 76.9% (95%CI, 63.8-92.6) and with an OS rate of 80.1% (95% CI, 67.7-94.6) at 6 months. Throughout the treatment course, no direct evidence of emapalumab-related safety risks was observed. Emapalumab seems to serve as an effective salvage therapy for patients experiencing high-grade CRS with inadequate response to low-dose glucocorticoids and/or tocilizumab following CAR-T therapy. These data supported the use of emapalumab in high-grade CRS as well as provide rationale for future prospective studies.