RARE DISEASE
Primary hemophagocytic lymphohistiocytosis
Primary hemophagocytic lymphohistiocytosis
Primary hemophagocytic lymphohistiocytosis
Synonyms: Genetic HLH, Genetic hemophagocytic lymphohistiocytosis, Primary HLH
Synonyms: Genetic HLH, Genetic hemophagocytic lymphohistiocytosis, Primary HLH
Synonyms: Genetic HLH, Genetic hemophagocytic lymphohistiocytosis, Primary HLH
Drug discovery
2
drugs
With orphan designations
Overview
Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome caused by genetic defects in lymphocyte cytotoxicity (e.g., PRF1, UNC13D mutations) or X-linked lymphoproliferative disorders. Uncontrolled immune activation leads to cytokine storm, multiorgan damage, and mortality without prompt intervention. Diagnosis follows HLH-2004 criteria. Curative treatment requires immunosuppression (e.g., etoposide, dexamethasone) to stabilize inflammation, followed by hematopoietic stem cell transplantation (HSCT) [1][6][7].
Burden
Historical 5-year survival: 50–59%; contemporary HSCT achieves 77–82% 3-year survival [1][9].
Morbidity: Organ failure, neurotoxicity, and treatment-related infections or secondary malignancies [1][4].
Psychosocial impact: High caregiver stress due to prolonged hospitalization and treatment complexity [5][13].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
856 drug discovery papers about Primary hemophagocytic lymphohistiocytosis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
856 drug discovery papers about Primary hemophagocytic lymphohistiocytosis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Immune Checkpoint Inhibitor-Associated Hemophagocytic Lymphohistiocytosis: Clinical Presentation and Outcomes in Three Patients.
Immune checkpoint inhibitor therapy has become increasingly recognized as a trigger for hemophagocytic lymphohistiocytosis, a life-threatening hyperinflammatory syndrome that may lead to organ failure without timely interventions. Given the rarity of this entity, patients are often misdiagnosed with more common oncologic complications. In the present series, we describe 3 patients with diverse clinical pictures evaluated at hospital admissions, who were ultimately diagnosed with immune checkpoint inhibitor-associated hemophagocytic lymphohistiocytosis. Treatment consisted of dexamethasone combined with an immunosuppressive agent such as anakinra, ruxolitinib, or tocilizumab, with variable clinical responses among patients. These cases highlight the importance of maintaining a high index of suspicion for hemophagocytic lymphohistiocytosis in patients presenting with systemic inflammation during immune checkpoint inhibitor therapy.
2026-08-11 | Case Report: Transjugular liver biopsy-confirmed lymphoma presenting as hemophagocytic lymphohistiocytosis with severe thrombocytopenia: a case series of three patients.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that can obscure underlying malignancies, particularly aggressive B-cell lymphoma. Severe cytopenias and coagulopathy often preclude conventional biopsy, delaying diagnosis. To assess the diagnostic utility of transjugular liver biopsy (TJLB) in adult patients presenting with HLH, transfusion-refractory thrombocytopenia, and predominant hepatic involvement, and to explore mechanisms of thrombocytopenia. Three adult patients with HLH, hepatic lesions, and severe thrombocytopenia unresponsive to platelet transfusions were retrospectively analyzed. Conventional biopsy was contraindicated due to bleeding risk. TJLB was performed for histopathological confirmation, followed by lymphoma-directed therapy. Laboratory, imaging, and histopathological data were reviewed. TJLB established aggressive B-cell lymphoma in all patients, enabling timely chemophagocytic therapy. Platelet counts normalized within 2-4 weeks (case 1 and 2), and HLH-related hyperinflammation resolved. Thrombocytopenia was multifactorial, reflecting hemophagocytosis, immune-mediated platelet destruction, hepatic sequestration, and cytokine-mediated suppression of megakaryopoiesis. HLH may be the first manifestation of occult lymphoma. TJLB is a safe, effective diagnostic strategy in patients with hepatic involvement and high bleeding risk, facilitating early curative therapy. These cases highlight the value of a multidisciplinary, risk-adapted diagnostic approach and provide mechanistic insight into cytopenia in HLH-associated lymphoma.
2026-08-11 | Treating hematologic immune dysregulation in inborn errors of immunity: a real-life multicenter study.
Hematologic immune dysregulation (H-ID) - including autoimmune cytopenia (AIC), lymphoproliferation (LPD), and hemophagocytic lymphohistiocytosis (HLH) - is a potentially life-threatening manifestation of inborn errors of immunity (IEI). Despite the availability of targeted therapies, its management remains challenging, with no standardized treatment strategies established. To evaluate the efficacy and safety of the available treatments for H-ID, with a specific focus on the treatment indications and outcome differences between targeted versus non-targeted therapies. This multicentric retrospective study included 116 patients with IEI and H-ID across Italian tertiary care centers. Data included treatment indications, response rate, and incidence of adverse events (AEs). We included patients with autoimmune lymphoproliferative immunodeficiencies (ALPID, 37.1%), humoral immunodeficiencies (31%), syndromic IEI (8.6%), and combined immunodeficiencies (8.6%). H-ID consisted of AIC (67.2%), LPD (71.6%), and HLH (9.5%). 85.3% of patients received treatment, including on-demand therapies (37.9%), long-term treatments (LTT, 84.8%), and hematopoietic stem-cell transplantation (HSCT; 9.1%). LTT included sirolimus (42.9%), mycophenolate mofetil (34.5%), rituximab (29.8%), and targeted therapies (17.9%). Sirolimus showed a higher complete response (CR) rate (61.1%), especially in ALPID patients and those with lymphoproliferation (72%). CR rate was significantly higher in patients receiving targeted therapies (80% vs 43.4%, p < 0.05). AEs were reported in 13.3% of cases, leading to drug withdrawal in 3.6%. The indications for LTT and HSCT in H-ID are still heterogeneous. Response rates are variable and influenced by the underlying diagnosis. Targeted therapies are associated with an improved response, the suboptimal molecular diagnosis rate currently limits their use.
2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
2026-08-02 | Effective Multi-agent Therapy With Anakinra, Corticosteroids and Mycophenolate in Immunotherapy-Associated Haemophagocytic Lymphohistiocytosis (HLH).
Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening complication of immune checkpoint inhibitor (ICI) therapy. Clinical overlap with sepsis contributes to delayed diagnosis and high mortality, showing the need for prompt recognition and targeted immunosuppression. This case presents a successful treatment pathway for HLH with high-dose methylprednisolone, mycophenolate mofetil (MMF) and anakinra, as well as emphasising the importance of early detection and management of HLH. A man in his sixties with stage IV cutaneous melanoma presented six weeks after the first cycle of ipilimumab and nivolumab immunotherapy with persistent high-grade fever, rigours, myalgia, malaise, and weight loss. Initial investigations revealed no infectious source, but computed tomography (CT) scans showed splenomegaly, and laboratory findings, including high ferritin, hypertriglyceridemia, high aspartate aminotransferase (AST), and low cell counts in two lines (lymphopenia and thrombocytopenia), met the modified HLH-2009 diagnostic criteria within 72 hours. Absence of melanoma progression, infection, or genetic predisposition suggested immunotherapy as the trigger. Treatment commenced on day 1 with anakinra and high-dose intravenous methylprednisolone, with mycophenolate mofetil added on day 3 due to worsening transaminitis, indicative of concurrent immunotherapy-induced hepatitis. The patient became afebrile within 48 hours, with ferritin normalising by day 10 and haematological and biochemical markers returning to normal. Anakinra was discontinued after 14 days. Complications included steroid-induced hyperglycemia, herpes simplex infection, and insomnia, all managed medically. At one-month follow-up, the patient remained asymptomatic with no HLH recurrence during immunosuppression tapering. This case highlights that steroids remain the primary acute treatment for HLH and immune-mediated disorders, with anakinra effectively inhibiting Interleukin-1 driven cytokine overproduction and mycophenolate mofetil addressing immune-related hepatitis. The combination of anakinra, mycophenolate mofetil, and high-dose methylprednisolone achieved rapid clinical and biochemical remission within 10 days, consistent with adult HLH consensus guidelines advocating early, multi-agent immunosuppression to prevent relapse in hyperinflammatory syndromes. Close monitoring of HLH biomarkers and a low threshold for suspicion in febrile patients on immunotherapy is recommended to facilitate timely intervention.
cell therapies
2026-08-04 | Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing.
The UNC13D gene encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in lymphocytes and the protein responsible for familial hemophagocytic lymphohistiocytosis (FHL). As an essential mediator of perforin release from cytotoxic T and NK cells, Munc13-4 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed "perforinopathy" manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13-4 deficiency, its association with autoimmune neuropathy remains largely unrecognized. We report two patients with a unique disease trajectory, presenting initially with autoimmune neuropathy before developing progressive FHL several years later. Both patients met the HLH-2004 diagnostic criteria, including fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. Genetic analysis revealed heterozygous UNC13D mutations: in Case 1, a nonsense (c.3193C>T; p.Arg1065*) and a missense (c.1135G>A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447 + 1G>A) and a paternal missense mutation (c.1241G>T; p.Arg414Leu). Case 1 underwent hematopoietic stem cell transplantation (HSCT), with significant recovery of weakness and numbness, and no recurrence of fever or lymphadenopathy at one year. Case 2 succumbed to disease progression after no timely, suitable allogeneic hematopoietic stem cell donor could be found. Our findings identify autoimmune neuropathy as a potential harbinger of FHL in perforinopathy, suggesting these neurological manifestations may be the initial phenotype of an underlying cytotoxic dysfunction. This temporal association mandates heightened clinical vigilance for immunodeficiency in patients with refractory neuropathy, particularly when accompanied by axonal degeneration or systemic inflammation. Recognizing this novel disease continuum has immediate diagnostic and therapeutic implications, as early genetic identification creates a critical window for potentially curative intervention with HSCT before irreversible multi-organ damage occurs. These cases expand the clinical spectrum of perforinopathy and challenge current diagnostic paradigms, emphasizing the need for an integrated neurological and immunological evaluation for unexplained autoimmune neuropathy.
2026-05-22 | Hematopoietic stem cell transplantation as a curative treatment for Nck-associated protein 1-like (HEM1) deficiency: A first case report.
We report two siblings with hematopoietic protein 1 (HEM1), also named Nck-associated protein 1-like (NCKAP1L), deficiency and varying clinical phenotype and the first case of successful hematopoietic stem cell transplantation for recurrent infections and EBV-induced hemophagocytic lymphohistiocytosis, showing curative potential.
2026-02-12 | Successful reduced-intensity cord blood transplantation in infants with familial hemophagocytic lymphohistiocytosis type 2.
Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare congenital disorder caused by PRF1 mutations that leads to life-threatening hemophagocytic lymphohistiocytosis during infancy. Hematopoietic cell transplantation (HCT) is the only curative treatment, but optimal transplantation strategies remain unclear. We report two cases of infants with FHL2 successfully treated with cord blood transplantation (CBT) following reduced-intensity conditioning (RIC). Case 1: A 1 month-old boy presented with fever, pancytopenia, and multi-organ failure. Genetic testing identified compound heterozygous PRF1 mutations. After immunochemotherapy, he underwent RIC-CBT at 2 months of age. Engraftment occurred on day 16, complicated by grade II acute graft-versus-host disease (GVHD) and sinusoidal obstruction syndrome, both successfully managed. He remains alive and disease-free 10 years post-transplant with complete donor chimerism. Case 2: A 1 month-old girl presented with fever, respiratory failure, and pancytopenia. She was diagnosed with FHL2 due to a homozygous PRF1 mutation. Following immunochemotherapy, she underwent RIC-CBT at 3 months of age. Engraftment occurred on day 15, without GVHD. She developed remains alive and disease-free 2.5 years later, with stable donor-dominant mixed chimerism (approximately 90%). These cases highlight the feasibility and efficacy of immunochemotherapy followed by RIC-CBT in infants with FHL2.
2025-12-24 | Primary Hemophagocytic Lymphohistiocytosis: A Severe Immune Dysregulatory Disease with Various Genotypic Features and Outcomes: A Cross-Sectional Study from a Tertiary Pediatric Center.
Inborn errors of immunity (IEIs) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment, and hematopoietic stem cell transplantation (HSCT) as curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years. The study included 30 patients with primary HLH/IEI who were diagnosed and treated in the departments of pediatric hematology, immunology, and oncology of the Ankara University Faculty of Medicine Children’s Hospital and Bone Marrow Transplantation Unit from 2000 to 2025. Of the 30 patients, 18 were boys and 12 were girls. The median age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the median age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than 5 days, with a mean duration of 13.30±14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%) and hepatomegaly in 25 (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 (76.6%), and thrombocytopenia in 30 (100%). Genetic evaluation was performed for all patients and a causative gene was identified in 19 of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26.6%), followed by UNC13D defect (FHLH3) in 4 patients (13,3%). HSCT was performed for 17 patients (56.6%), with 6 receiving transplants from matched related donors, 4 from matched sibling donors, 5 from matched unrelated donors, and 2 from mismatched related donors. Thirteen patients remain alive, with mean survival of 119.89 months. Seventeen patients (56.6%) died, primarily due to multiorgan dysfunction syndrome, acute respiratory distress syndrome, HLH reactivation, septic shock, or heart failure. HSCT patients had a significantly longer survival (mean: 165.6 months) compared to patients who did not undergo HSCT (45.36 months; p<0.01). Admission to the pediatric intensive care unit, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p<0.05). Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with the results of national and international cohorts, confirm that HSCT remains the only curative option for familial HLH and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.
2025-11-20 | Hemophagocytic lymphohistiocytosis in the context of hepatitis-associated severe aplastic anemia: A case report.
Hemophagocytic lymphohistiocytosis (HLH) is a severe immune dysregulation syndrome. Hepatitis-associated severe aplastic anemia (SAA) is a specific subtype of acquired aplastic anemia characterized by concomitant hepatitis, leading to a challenging diagnosis and poor prognosis. Here, we present a rare case of HLH in the context of hepatitis-associated SAA, emphasizing the need for early recognition and individualized management. The patient, a 19-year-old male, presented with recurrent fever, jaundice, and cytopenias, indicative of hepatitis. Bone marrow aspiration and biopsy suggested SAA, while peripheral blood next-generation sequencing detected Candida tropicalis infection on 2 separate occasions. Despite combination antifungal therapy with amphotericin B and posaconazole, the bilirubin level continued to rise. Additional tests revealed an elevated soluble CD25 level of 3659 U/mL, decreased natural killer cell activity of 1.8%, and a serum ferritin level > 2000 μg/L. The final diagnosis was HLH. Dexamethasone and ruxolitinib were administered to control the fever. Subsequently, the patient underwent HLA-matched allogeneic bone marrow and peripheral blood hematopoietic stem cell transplantation for SAA. The patient's symptoms, including fever and fatigue, resolved. This case highlights that HLH should be considered in SAA patients with unexplained fever, poor response to anti-infectives, and elevated bilirubin. A treatment strategy addressing both bone marrow failure and hyperinflammation is essential. In this patient, allogeneic hematopoietic stem cell transplantation served as a successful curative intervention by targeting the shared pathophysiology of HLH and SAA. However, given the inherent limitations of a single case, the generalizability of our findings and the efficacy of allogeneic hematopoietic stem cell transplantation require validation through larger, controlled studies.
proteins
2026-06-12 | Cyclic Fevers in Pregnancy: A Case of Parvovirus-Related Hemophagocytic Lymphohistiocytosis.
Parvovirus B19 typically causes mild symptoms in healthy adults, including fever, rash, and arthralgias. Certain immunocompromised adult populations, including those with immunodeficiencies or hematologic disease, are at risk of clinically significant complications, including transient aplastic crisis. Further, in pregnant patients, there is a risk of transplacental viral transmission, which may lead to severe fetal anemia, nonimmune hydrops fetalis, and intrauterine fetal demise. The clinical course of parvovirus B19 in pregnant patients with underlying hematologic disease has not been well reported. In this case report, we present a 27-year-old pregnant patient with sickle cell beta thalassemia who was infected with parvovirus B19 at 20 weeks of gestation. She experienced a prolonged hospitalization characterized by persistent maternal vaso-occlusive crisis with concomitant transient aplastic crisis. There was suspected vertical transmission of the virus, leading to concern for severe fetal anemia and termination of the pregnancy. The patient continued to have cyclic fevers, bicytopenia, and a constellation of laboratory findings leading to a diagnosis of postviral hemophagocytic lymphohistiocytosis (HLH). She was successfully treated with pulse dose corticosteroids and an Interleukin-1 receptor antagonist with subsequent improvement of her symptoms and laboratory markers. This report highlights the distinct diagnostic and management challenges of parvovirus B19 in pregnant patients with comorbid hematologic disease, including a rare but serious sequela of the infection, and the risk for severe maternal and fetal complications.
2026-05-04 | Severe Adult HLH/MAS With SPTCL-Like Panniculitis: A Phenotype-Guided, Resource-Adapted Therapeutic Strategy Without Cytotoxic Therapy.
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory conditions with heterogeneous triggers and overlapping clinical phenotypes. Diagnostic uncertainty is particularly challenging in resource-limited settings, where advanced molecular and immunophenotypic investigations are not readily available. A 31-year-old woman presented with recurrent febrile episodes, trilineage cytopenias, hyperferritinemia (peak 16,970 ng/mL [reference: < 200 ng/mL]), hypofibrinogenemia, and progressive necrotic panniculitis plaques involving both lower extremities. Histopathological evaluation revealed lobular panniculitis with adipocyte necrosis and absence of vasculitis. While these findings raised strong concern for subcutaneous panniculitis-like T-cell lymphoma (SPTCL), definitive diagnosis was precluded by the absence of immunophenotyping, T-cell receptor clonality studies, and HAVCR2 mutation testing-all unavailable in our setting. The HScore was 216 (> 99% probability of HLH/MAS). A striking feature was the persistent dissociation between markedly elevated ferritin and low C-reactive protein (CRP) values (ratio < 0.002), consistent with a non-IL-6-dominant, interferon-γ-driven hyperinflammatory state. Based on this phenotype, a sequential treatment strategy combining therapeutic plasma exchange (TPE), intravenous immunoglobulin (IVIG), and cyclosporine A (CyA) was implemented without cytotoxic chemotherapy. The patient demonstrated significant clinical and biochemical improvement, with resolution of cytopenias and progressive decline in ferritin. This case highlights the diagnostic overlap between autoimmune panniculitis, SPTCL, and HLH/MAS, and underscores the importance of phenotype-guided management in complex hyperinflammatory syndromes. It further illustrates that effective treatment can be achieved without cytotoxic therapy in selected patients, even in the absence of definitive molecular diagnosis.
2026-05-01 | Novel perspectives on the rare hemophagocytic lymphohistiocytosis: insights from a multi-center retrospective cohort.
Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a rare clinical disease that is highly challenging to diagnose, has a low long-term survival rate and a high mortality rate. Currently, due to the particularity of HLH and the lack of effective understanding of the severity and prognosis of the disease in clinical practice, HLH patients are often missed or misdiagnosed in clinical practice, causing them to miss the best opportunity for diagnosis and treatment. This study aimed to retrospectively summarize and analyze the clinical characteristics, diagnosis and treatment, and prognosis of HLH patients from four medical centers, aiming to explore the risk factors affecting the prognosis of HLH patients and further enhance the understanding of HLH. The clinical data of 162 patients with HLH diagnosed in four medical centers from May 2017 to May 2025 were collected. The general conditions, laboratory results, diagnosis and treatment processes, and prognosis of these patients were analyzed, and univariate and multivariate analyses of prognostic factors were conducted. A total of 162 HLH patients were included in this study, of whom 90 cases survived (55.56%), 72 cases died (44.44%), and there were 78 male patients (48.15%) and 84 female patients (51.85%), with a median age at onset of 52 years (range: 1-83 years). The most common etiological factor was Epstein-Barr virus (EBV) infection, and the primary presenting symptom was fever. First-line treatment primarily involved anti-infective therapy and symptomatic management, which was administered to 147 cases (90.74%). Prognostic analysis revealed that age, history of malignancy, infection history, presence of dermatological symptoms, APTT, INR, PCT, CRP, TG, TBIL, ferritin level, sCD25, lactate, SOFA score and time to treatment initiation, glucocorticoid monotherapy, gamma globulin treatment were significantly associated with patient outcomes in HLH. Tumor history, ferritin level, sCD25, lactate, SOFA score, time to treatment initiation, gamma globulin treatment were independent risk factors for mortality. Univariate Cox regression analysis identified that age, tumor history, history of rheumatic and autoimmune disorders, CRP, ferritin level, sCD25, lactate, SOFA score and time to treatment initiation, chemotherapy, glucocorticoid monotherapy, gamma globulin treatment were significant prognostic factors for OS in HLH patients. Multivariate analysis confirmed that tumor history, CRP, ferritin level, sCD25, lactate, SOFA score and time to treatment initiation, chemotherapy, glucocorticoid monotherapy, gamma globulin treatment were independent prognostic factors affecting OS in HLH patients. Age, APTT, INR, ferritin level, SOFA score, time to treatment initiation, glucocorticoid monotherapy, gamma globulin treatment were independent prognostic factors affecting OS in infection-triggered HLH patients. While age, INR, ferritin level, SOFA score, time to treatment initiation, chemotherapy were independent prognostic factors affecting OS in malignancy-associated HLH patients. Combined therapy regimens (especially chemotherapy combined with gamma globulin, glucocorticoid combined with gamma globulin) showed better clinical efficacy and survival benefits in the treatment of HLH. HLH is a rare clinical disease, EBV was the predominant trigger for HLH. Prognostic factors differed between infection- and malignancy-associated subgroups. Combined regimens, particularly those including gamma globulin, offered superior survival benefits, underscoring the need for etiology-specific treatment strategies.
2026-02-11 | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Bacillus Calmette-Guérin (BCG): A Steroid-Sparing Strategy in a Patient Awaiting Cardiac Surgery-A Case Report.
We report a case of hemophagocytic lymphohistiocytosis (HLH) secondary to disseminated Bacillus Calmette-Guérin (BCG) infection in an 80-year-old man treated with intravesical BCG for non-muscle-invasive bladder cancer. The patient presented with several weeks of constitutional symptoms including night sweats, fatigue, weight loss, confusion, and pancytopenia. Laboratory studies revealed profound inflammation, coagulopathy, and hepatocellular injury. HLH was suspected clinically and supported by a high H-score. Extensive infectious and autoimmune workup was negative. Mycobacterium bovis was subsequently isolated from urine and bone marrow cultures, which confirmed a diagnosis of disseminated BCG infection. The patient was treated with a combination of antimycobacterial therapy (isoniazid, rifampin, and ethambutol), intravenous immunoglobulin (IVIG), corticosteroids, and anakinra. Anakinra, an interleukin-1 receptor antagonist, was used both to minimize high-dose steroids, given the protracted inflammatory response anticipated with Mycobacterium infection, and to prevent steroid-related complications related to cardiac surgery. This therapeutic strategy was associated with improvement of cytopenias, normalization of inflammatory markers, and gradual clinical recovery. This case highlights the rare but serious complication of HLH triggered by disseminated BCG and suggests that targeted immunomodulation with anakinra may be a useful adjunct in selected, complex presentations of infection-associated HLH.
2026-01-30 | Hemophagocytic lymphohistiocytosis associated with extranodal NK/T cell lymphoma, nasal type or aggressive NK cell leukemia: a retrospective multicenter study of Jiangsu Cooperative Lymphoma Group (JCLG).
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95% CI, 1.08-3.83; P = 0.029), platelet count < 20 × 10⁹/L (HR, 2.70; 95% CI, 1.46-4.99; P = 0.002), and Epstein-Barr virus DNA (whole blood) > 33,850 copies/mL (HR, 1.97; 95% CI, 1.01-3.81; P = 0.045). ECOG performance status ≥ 2 (HR, 2.00; 95% CI, 1.24-3.23; P = 0.004) and platelet count < 20 × 10⁹/L (HR, 7.61; 95% CI, 2.14-27.09; P = 0.002) were independent risk factors for poor OS. Therefore, we recommend asparaginase-based regimens as first-line therapy for treatment-naive adult patients with HLH related to NK-cell malignancies. Future multicenter prospective studies are warranted to optimize asparaginase-containing regimens, evaluate novel combination strategies, and establish precision risk-prediction models to guide clinical practice.
antibodies
2026-07-25 | Haemophagocytic lymphohistiocytosis: a life threatening complication of lymphoma.
Haemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome leading to organ damage and death, may arise as a complication of lymphomas (L-HLH). L-HLH diagnosis is challenging and optimal treatment strategies, influenced by factors such as timing of onset, lymphoma subtype and disease severity, remain ill-defined. This narrative review summarises recent evidence to support clinicians in navigating the competing priorities posed by L-HLH, including the urgent need to control inflammation, establish a diagnosis and initiate lymphoma-directed therapy, while minimising toxicity and avoiding unnecessary immunosuppression. While HLH-94 and H-score diagnostic criteria were not specifically designed for L-HLH, the optimised HLH inflammatory index (OHI) was developed in L-HLH patients and predicts the risk of multiorgan failure (MOF) but also benefit from etoposide. Recent evidence also highlights improved survival with early administration of lymphoma targeting drugs while, in critically unwell patients, non-myelosuppressive treatment with anakinra, ruxolitinib and intravenous immunoglobulins (IVIg) might offer a survival advantage. Finally, novel markers such as C-X-C motif chemokine ligand 9 (CXCL-9), recently shown to identify patients responding to interferon γ blockade, might become more widely available in the future. L-HLH encompasses a wide range of clinical presentations that force clinicians to balance competing priorities. Recent evidence improves patients stratification and supports early administration of lymphoma targeting drugs when feasible, etoposide in high risk patients and non-myelosuppressive regimens in critically unwell patients.
2026-07-09 | Advances in PD-1 monoclonal antibody therapy for hemophagocytic syndrome.
Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is a severe inflammatory condition, while the standard treatment still has limitations. With the conscious in-depth research on the pathogenesis, PD-1 (programmed cell death protein-1) monoclonal antibody has shown positive prospects in the treatment of HLH. This study retrospectively analyzed the clinical efficacy, and safety profile of PD-1 inhibitors in the treatment of HLH. A total of 15 studies was involved, covering with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and related malignancies. In pediatric patients with chronic active EBV infection (CAEBV) and refractory/relapsed EBV-HLH, sintilimab induced partial or complete clinical remission, and successfully served as a bridge therapy to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Retrospective studies on adult refractory/relapsed EBV-HLH showed that nivolumab treatment achieved an overall response rate (ORR) of 85.7% and a complete remission (CR) rate of 71.4% over 16 months. Sintilimab as salvage therapy also restored complete donor chimerism post-transplant and cleared viral loads. Furthermore, novel combinations with ruxolitinib, venetoclax, or thalidomide achieved rapid clinical remission in EBV-HLH. Safety assessments indicated that PD-1 blockade following HSCT was associated with a high risk of graft-versus-host disease (GVHD). Caution is warranted when using PD-1 monoclonal antibodies, as immune system stimulation is a double-edged sword. The optimal timing, dosage, and safety of PD-1 monoclonal antibodies in HLH treatment merit further clinical research and exploration.
2026-06-19 | Targeting the cytokine storm: new therapies in the treatment of pediatric hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disorder characterized by immune hyper-activation and subsequent tissue and organ infiltration by proinflammatory cytokines. Primary HLH is caused by underlying genetic mutations in key genes responsible for cellular cytotoxicity, whereas secondary HLH is driven by infection, malignancy, and autoimmune disease as the underlying trigger for immune activation. Chemotherapy-based treatments for pediatric HLH have improved survival and outcomes for patients, however, there is a significant unmet need in the development of targeted therapies to limit drug toxicity and further improve overall survival. We review primary and secondary HLH, current treatment strategies, and present rationale and available evidence for emerging targeted therapies for this orphan disease, including the human monoclonal anti-IFN‑γ antibody emapalumab, the anti-CD52 monoclonal antibody alemtuzumab, and the JAK1/2 inhibitor ruxolitinib, in the treatment of pediatric HLH. Development of targeted therapies in pediatric HLH is critical to improve survival and overall outcomes for these patients. Emapalumab, alemtuzumab, and ruxolitinib show promising results, however, widespread use is limited by small, non-randomized trials in a heterogenous population. Further international collaborative efforts to develop clinical trials that compare conventional chemotherapy treatments head-to-head with these newer therapies are critical for advancement of these agents.
2026-06-18 | The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and functionally resets CD33+ myeloid-derived suppressor cells in patients with metastatic cancer: a phase 2 single-arm, open-label trial.
We previously demonstrated that the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalized, and decreases those cells' viability. Treatment of MDSCs with GO restores T-cell proliferation in co-culture, overcomes M-MDSC suppression of CAR-T cell proliferation, and enhances target-cell killing. Gemtuzumab Ozogamicin Therapy in Hemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome (GOTHAM) is a phase 2 single-arm clinical trial for which patients were eligible if they had a diagnosis of solid cancer with radiological or clinical evidence of disease progression, or primary or secondary hemophagocytic lymphohistiocytosis, or macrophage activation syndrome disease relapsing or refractory to treatment at enrollment. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-d intervals: days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Using 2 schedules of GO, we could not convincingly demonstrate safe feasibility in patients with solid cancer, because of neutropenia. However, GO reproducibly and significantly reduced circulating MDSCs. Importantly, there is consistent preliminary evidence that, upon rebound, the monocyte population of CD33+ cells is replaced with nonsuppressive monocytes. These data support the phase 1b dose-escalation testing of GO up to 2 mg/m2 in combination with immune checkpoint blockade and other immunotherapies in patients with solid cancer to find a dose that depletes and repolarizes MDSCs without causing undue neutropenia, paving the way to use GO as an immune potentiator in this patient population. Trial registration: ISRCTN 89158144.
2026-05-01 | C50-23 Hemophagocytic Lymphohystiocytosis, Macrophage Activation Syndrome, and Vexas Syndrome: A Spectrum of Immune Dysregulation
Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are overlapping clinical syndromes characterized by dysregulation of the immune system that result in profound systemic inflammation and end-organ damage.1 A third autoinflammatory process, VEXAS syndrome, stems from a genetic mutation that results in recurrent fevers, cytopenias, and joint, skin, and lung inflammation.2 We present a case of critical illness due to severe immune dysregulation. Case A 59-year-old female with no significant past medical history presented to an outside hospital with less than twenty-four hours of high-grade fevers, nausea, vomiting, and altered mental status. On presentation she was febrile, hypotensive, and mildly hypoxic. Workup demonstrated leukopenia, thrombocytopenia, a bandemia of 30%, lactic acidosis, direct hyperbilirubinemia, and acute kidney and liver injuries. CT abdomen demonstrated severe diffuse circumferential gallbladder wall edema concerning for acute cholecystitis. She was started on broad spectrum antibiotics, pressors , and intubated for respiratory failure in the setting of severe metabolic acidosis. Cultures and viral panel were negative. Rheumatologic workup was negative except for positive ANA. Her labs were notable for a ferritinemia over 16,000, triglycerides in the 400s, and soluble IL-2R of nearly 14,000.Hematology recommended a bone marrow biopsy which revealed intracytoplasmic vacuoles in erythroid and myeloid precursors with negative flow cytometry. These findings taken together prompted consideration of HLH/MAS versus VEXAS syndrome. Next generation sequencing was negative for pathogenic mutations ruling out VEXAS syndrome. She met five of eight clinical criteria for secondary HLH and was treated with a prolonged steroid taper and an IL-1 antagonist with initial improvement. Her course has been complicated by ongoing intermittent encephalopathy in the setting of possible recurrent HLH flares. Discussion HLH and MAS can result from primary genetic mutations or can be secondary to rheumatologic conditions (MAS) or infection, malignancy, or medications (HLH).1 Both have similar clinical presentations with cyclic fevers, cytopenias, hepatosplenomegaly, significantly elevated serum ferritin, and coagulopathies.3 Criteria for diagnosing secondary HLH includes five of eight of the following: fever > 38.5C, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis on tissue or bone marrow biopsy, low or absent natural killer cell activity, significantly elevated serum ferritin, and elevated soluble CD25 (soluble IL-2 receptor).4 Clinical suspicion can override strict criteria when not clearly met. Distinguishing between these syndromes guides therapy: treatment of the underlying rheumatologic disorder is the mainstay of treatment for MAS and VEXAS, whereas immunosuppression, anti-viral therapies, and/or chemotherapy agents are the mainstay for HLH.5,6 This abstract is funded by: N/A
other
2026-07-02 | Genome Editing for Familial Hemophagocytic Lymphohistiocytosis: Design Principles, Challenges, and Translational Perspectives.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by genetic defects in cytotoxic lymphocyte function. Current therapies can control disease activity, but transplantation of allogeneic hematopoietic stem and progenitor cells (HSPCs) remains the only curative option and is associated with substantial risks. These limitations have accelerated development of genome editing approaches enabling precise correction of disease-causing mutations in autologous cells. Familial HLH (FHL) represents a compelling target for genome editing, but successful and safe clinical translation has remained challenging. Preclinical studies demonstrate that targeted editing of key genes, such as PRF1 and UNC13D, can restore cytotoxic function in HSPCs and T cells. Translation to the clinic, however, depends on multiple factors, including the choice of target cell population, the level of functional correction required, and gene-specific constraints such as locus complexity and regulation of gene expression. In this review, we synthesize current progress in genome editing for FHL and highlight critical biological and technical barriers to clinical implementation. We propose a conceptual framework for designing genome editing strategies tailored to FHL, emphasizing the alignment of editing platform, gene architecture, and cellular context to enable effective and clinically translatable therapies.
2026-05-15 | Genotoxicity profiling reveals distinct platform-and cell type-specific effects in therapeutic gene editing for genetic hyperinflammation.
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62%-89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type-specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR-Cas9. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.
2025-05-22 | Whole-genome sequencing reveals genetic backgrounds in Japanese patients with hemophagocytic lymphohistiocytosis treated with the HLH-2004 protocol.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition triggered by a combination of genetic predispositions and environmental factors. Reports of previous outcomes from the HLH-2004 protocol in Japan revealed patients with idiopathic HLH who had poor prognoses. This study aimed to reevaluate the genetic background of such patients to identify potential novel genetic variants. Whole-genome sequencing was performed on residual samples from HLH patients enrolled in a study of the HLH-2004 protocol in Japan, excluding those associated with Epstein-Barr virus infection. Sequence variants were interpreted based on the American College of Medical Genetics and Genomics standards and guidelines. Nineteen patients were analyzed, including seven diagnosed with familial HLH (FHL) and twelve with unknown causes. Among patients with FHL, five had variants in PRF1 and two in UNC13D, consistent with the original diagnoses. Genetic variants (all UNC13D) were identified in three of the 12 previously undiagnosed patients. One patient had an unknown outcome and the others died of HLH. Failure to establish a genetic diagnosis during initial evaluation may have negatively impacted the prognosis of patients with HLH. Comprehensive genetic studies and the development of early screening methods may improve treatment outcomes for HLH.
2025-03-10 | Gene therapy for inborn errors of immunity: Current clinical progress.
Hematopoietic stem cell transplant has been the single curative treatment for inborn errors of immunity (IEI) and is recommended for the most severe IEI conditions, such as severe combined immunodeficiency. However, adverse outcomes primarily due to histocompatibility differences between the donor and the patient are still of concern. Progress in genetic and molecular mechanisms, including new technology to insert DNA sequences in cell genomes, has allowed the development of strategies to treat genetic diseases by correcting gene defect in patients' cells. This technology is named gene therapy. Gene therapy approaches being developed for IEI are mediated by gene insertion, using a retroviral vector, or by gene editing, using a combination of a nuclease and a DNA template. After the unexpected occurrence of oncogenesis associated with the initial retroviral vector designs, significant advances have led to successful gene therapy clinical trials for 3 forms of severe combined immunodeficiency, which demonstrated the safety and efficacy of this approach. Active preclinical and clinical studies are ongoing for diverse IEI, including chronic granulomatous disease, leukocyte adhesion deficiency, severe congenital neutropenia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and familial forms of hemophagocytic lymphohistiocytosis.
2024-10-29 | Functional role of UNC13D in immune diseases and its therapeutic applications.
UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.
small molecules
2026-08-14 | Immune Checkpoint Inhibitor-Associated Hemophagocytic Lymphohistiocytosis: Clinical Presentation and Outcomes in Three Patients.
Immune checkpoint inhibitor therapy has become increasingly recognized as a trigger for hemophagocytic lymphohistiocytosis, a life-threatening hyperinflammatory syndrome that may lead to organ failure without timely interventions. Given the rarity of this entity, patients are often misdiagnosed with more common oncologic complications. In the present series, we describe 3 patients with diverse clinical pictures evaluated at hospital admissions, who were ultimately diagnosed with immune checkpoint inhibitor-associated hemophagocytic lymphohistiocytosis. Treatment consisted of dexamethasone combined with an immunosuppressive agent such as anakinra, ruxolitinib, or tocilizumab, with variable clinical responses among patients. These cases highlight the importance of maintaining a high index of suspicion for hemophagocytic lymphohistiocytosis in patients presenting with systemic inflammation during immune checkpoint inhibitor therapy.
2026-08-11 | Case Report: Transjugular liver biopsy-confirmed lymphoma presenting as hemophagocytic lymphohistiocytosis with severe thrombocytopenia: a case series of three patients.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that can obscure underlying malignancies, particularly aggressive B-cell lymphoma. Severe cytopenias and coagulopathy often preclude conventional biopsy, delaying diagnosis. To assess the diagnostic utility of transjugular liver biopsy (TJLB) in adult patients presenting with HLH, transfusion-refractory thrombocytopenia, and predominant hepatic involvement, and to explore mechanisms of thrombocytopenia. Three adult patients with HLH, hepatic lesions, and severe thrombocytopenia unresponsive to platelet transfusions were retrospectively analyzed. Conventional biopsy was contraindicated due to bleeding risk. TJLB was performed for histopathological confirmation, followed by lymphoma-directed therapy. Laboratory, imaging, and histopathological data were reviewed. TJLB established aggressive B-cell lymphoma in all patients, enabling timely chemophagocytic therapy. Platelet counts normalized within 2-4 weeks (case 1 and 2), and HLH-related hyperinflammation resolved. Thrombocytopenia was multifactorial, reflecting hemophagocytosis, immune-mediated platelet destruction, hepatic sequestration, and cytokine-mediated suppression of megakaryopoiesis. HLH may be the first manifestation of occult lymphoma. TJLB is a safe, effective diagnostic strategy in patients with hepatic involvement and high bleeding risk, facilitating early curative therapy. These cases highlight the value of a multidisciplinary, risk-adapted diagnostic approach and provide mechanistic insight into cytopenia in HLH-associated lymphoma.
2026-08-11 | Treating hematologic immune dysregulation in inborn errors of immunity: a real-life multicenter study.
Hematologic immune dysregulation (H-ID) - including autoimmune cytopenia (AIC), lymphoproliferation (LPD), and hemophagocytic lymphohistiocytosis (HLH) - is a potentially life-threatening manifestation of inborn errors of immunity (IEI). Despite the availability of targeted therapies, its management remains challenging, with no standardized treatment strategies established. To evaluate the efficacy and safety of the available treatments for H-ID, with a specific focus on the treatment indications and outcome differences between targeted versus non-targeted therapies. This multicentric retrospective study included 116 patients with IEI and H-ID across Italian tertiary care centers. Data included treatment indications, response rate, and incidence of adverse events (AEs). We included patients with autoimmune lymphoproliferative immunodeficiencies (ALPID, 37.1%), humoral immunodeficiencies (31%), syndromic IEI (8.6%), and combined immunodeficiencies (8.6%). H-ID consisted of AIC (67.2%), LPD (71.6%), and HLH (9.5%). 85.3% of patients received treatment, including on-demand therapies (37.9%), long-term treatments (LTT, 84.8%), and hematopoietic stem-cell transplantation (HSCT; 9.1%). LTT included sirolimus (42.9%), mycophenolate mofetil (34.5%), rituximab (29.8%), and targeted therapies (17.9%). Sirolimus showed a higher complete response (CR) rate (61.1%), especially in ALPID patients and those with lymphoproliferation (72%). CR rate was significantly higher in patients receiving targeted therapies (80% vs 43.4%, p < 0.05). AEs were reported in 13.3% of cases, leading to drug withdrawal in 3.6%. The indications for LTT and HSCT in H-ID are still heterogeneous. Response rates are variable and influenced by the underlying diagnosis. Targeted therapies are associated with an improved response, the suboptimal molecular diagnosis rate currently limits their use.
2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
2026-08-02 | Effective Multi-agent Therapy With Anakinra, Corticosteroids and Mycophenolate in Immunotherapy-Associated Haemophagocytic Lymphohistiocytosis (HLH).
Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening complication of immune checkpoint inhibitor (ICI) therapy. Clinical overlap with sepsis contributes to delayed diagnosis and high mortality, showing the need for prompt recognition and targeted immunosuppression. This case presents a successful treatment pathway for HLH with high-dose methylprednisolone, mycophenolate mofetil (MMF) and anakinra, as well as emphasising the importance of early detection and management of HLH. A man in his sixties with stage IV cutaneous melanoma presented six weeks after the first cycle of ipilimumab and nivolumab immunotherapy with persistent high-grade fever, rigours, myalgia, malaise, and weight loss. Initial investigations revealed no infectious source, but computed tomography (CT) scans showed splenomegaly, and laboratory findings, including high ferritin, hypertriglyceridemia, high aspartate aminotransferase (AST), and low cell counts in two lines (lymphopenia and thrombocytopenia), met the modified HLH-2009 diagnostic criteria within 72 hours. Absence of melanoma progression, infection, or genetic predisposition suggested immunotherapy as the trigger. Treatment commenced on day 1 with anakinra and high-dose intravenous methylprednisolone, with mycophenolate mofetil added on day 3 due to worsening transaminitis, indicative of concurrent immunotherapy-induced hepatitis. The patient became afebrile within 48 hours, with ferritin normalising by day 10 and haematological and biochemical markers returning to normal. Anakinra was discontinued after 14 days. Complications included steroid-induced hyperglycemia, herpes simplex infection, and insomnia, all managed medically. At one-month follow-up, the patient remained asymptomatic with no HLH recurrence during immunosuppression tapering. This case highlights that steroids remain the primary acute treatment for HLH and immune-mediated disorders, with anakinra effectively inhibiting Interleukin-1 driven cytokine overproduction and mycophenolate mofetil addressing immune-related hepatitis. The combination of anakinra, mycophenolate mofetil, and high-dose methylprednisolone achieved rapid clinical and biochemical remission within 10 days, consistent with adult HLH consensus guidelines advocating early, multi-agent immunosuppression to prevent relapse in hyperinflammatory syndromes. Close monitoring of HLH biomarkers and a low threshold for suspicion in febrile patients on immunotherapy is recommended to facilitate timely intervention.
cell therapies
2026-08-04 | Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing.
The UNC13D gene encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in lymphocytes and the protein responsible for familial hemophagocytic lymphohistiocytosis (FHL). As an essential mediator of perforin release from cytotoxic T and NK cells, Munc13-4 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed "perforinopathy" manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13-4 deficiency, its association with autoimmune neuropathy remains largely unrecognized. We report two patients with a unique disease trajectory, presenting initially with autoimmune neuropathy before developing progressive FHL several years later. Both patients met the HLH-2004 diagnostic criteria, including fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. Genetic analysis revealed heterozygous UNC13D mutations: in Case 1, a nonsense (c.3193C>T; p.Arg1065*) and a missense (c.1135G>A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447 + 1G>A) and a paternal missense mutation (c.1241G>T; p.Arg414Leu). Case 1 underwent hematopoietic stem cell transplantation (HSCT), with significant recovery of weakness and numbness, and no recurrence of fever or lymphadenopathy at one year. Case 2 succumbed to disease progression after no timely, suitable allogeneic hematopoietic stem cell donor could be found. Our findings identify autoimmune neuropathy as a potential harbinger of FHL in perforinopathy, suggesting these neurological manifestations may be the initial phenotype of an underlying cytotoxic dysfunction. This temporal association mandates heightened clinical vigilance for immunodeficiency in patients with refractory neuropathy, particularly when accompanied by axonal degeneration or systemic inflammation. Recognizing this novel disease continuum has immediate diagnostic and therapeutic implications, as early genetic identification creates a critical window for potentially curative intervention with HSCT before irreversible multi-organ damage occurs. These cases expand the clinical spectrum of perforinopathy and challenge current diagnostic paradigms, emphasizing the need for an integrated neurological and immunological evaluation for unexplained autoimmune neuropathy.
2026-05-22 | Hematopoietic stem cell transplantation as a curative treatment for Nck-associated protein 1-like (HEM1) deficiency: A first case report.
We report two siblings with hematopoietic protein 1 (HEM1), also named Nck-associated protein 1-like (NCKAP1L), deficiency and varying clinical phenotype and the first case of successful hematopoietic stem cell transplantation for recurrent infections and EBV-induced hemophagocytic lymphohistiocytosis, showing curative potential.
2026-02-12 | Successful reduced-intensity cord blood transplantation in infants with familial hemophagocytic lymphohistiocytosis type 2.
Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare congenital disorder caused by PRF1 mutations that leads to life-threatening hemophagocytic lymphohistiocytosis during infancy. Hematopoietic cell transplantation (HCT) is the only curative treatment, but optimal transplantation strategies remain unclear. We report two cases of infants with FHL2 successfully treated with cord blood transplantation (CBT) following reduced-intensity conditioning (RIC). Case 1: A 1 month-old boy presented with fever, pancytopenia, and multi-organ failure. Genetic testing identified compound heterozygous PRF1 mutations. After immunochemotherapy, he underwent RIC-CBT at 2 months of age. Engraftment occurred on day 16, complicated by grade II acute graft-versus-host disease (GVHD) and sinusoidal obstruction syndrome, both successfully managed. He remains alive and disease-free 10 years post-transplant with complete donor chimerism. Case 2: A 1 month-old girl presented with fever, respiratory failure, and pancytopenia. She was diagnosed with FHL2 due to a homozygous PRF1 mutation. Following immunochemotherapy, she underwent RIC-CBT at 3 months of age. Engraftment occurred on day 15, without GVHD. She developed remains alive and disease-free 2.5 years later, with stable donor-dominant mixed chimerism (approximately 90%). These cases highlight the feasibility and efficacy of immunochemotherapy followed by RIC-CBT in infants with FHL2.
2025-12-24 | Primary Hemophagocytic Lymphohistiocytosis: A Severe Immune Dysregulatory Disease with Various Genotypic Features and Outcomes: A Cross-Sectional Study from a Tertiary Pediatric Center.
Inborn errors of immunity (IEIs) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment, and hematopoietic stem cell transplantation (HSCT) as curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years. The study included 30 patients with primary HLH/IEI who were diagnosed and treated in the departments of pediatric hematology, immunology, and oncology of the Ankara University Faculty of Medicine Children’s Hospital and Bone Marrow Transplantation Unit from 2000 to 2025. Of the 30 patients, 18 were boys and 12 were girls. The median age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the median age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than 5 days, with a mean duration of 13.30±14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%) and hepatomegaly in 25 (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 (76.6%), and thrombocytopenia in 30 (100%). Genetic evaluation was performed for all patients and a causative gene was identified in 19 of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26.6%), followed by UNC13D defect (FHLH3) in 4 patients (13,3%). HSCT was performed for 17 patients (56.6%), with 6 receiving transplants from matched related donors, 4 from matched sibling donors, 5 from matched unrelated donors, and 2 from mismatched related donors. Thirteen patients remain alive, with mean survival of 119.89 months. Seventeen patients (56.6%) died, primarily due to multiorgan dysfunction syndrome, acute respiratory distress syndrome, HLH reactivation, septic shock, or heart failure. HSCT patients had a significantly longer survival (mean: 165.6 months) compared to patients who did not undergo HSCT (45.36 months; p<0.01). Admission to the pediatric intensive care unit, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p<0.05). Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with the results of national and international cohorts, confirm that HSCT remains the only curative option for familial HLH and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.
2025-11-20 | Hemophagocytic lymphohistiocytosis in the context of hepatitis-associated severe aplastic anemia: A case report.
Hemophagocytic lymphohistiocytosis (HLH) is a severe immune dysregulation syndrome. Hepatitis-associated severe aplastic anemia (SAA) is a specific subtype of acquired aplastic anemia characterized by concomitant hepatitis, leading to a challenging diagnosis and poor prognosis. Here, we present a rare case of HLH in the context of hepatitis-associated SAA, emphasizing the need for early recognition and individualized management. The patient, a 19-year-old male, presented with recurrent fever, jaundice, and cytopenias, indicative of hepatitis. Bone marrow aspiration and biopsy suggested SAA, while peripheral blood next-generation sequencing detected Candida tropicalis infection on 2 separate occasions. Despite combination antifungal therapy with amphotericin B and posaconazole, the bilirubin level continued to rise. Additional tests revealed an elevated soluble CD25 level of 3659 U/mL, decreased natural killer cell activity of 1.8%, and a serum ferritin level > 2000 μg/L. The final diagnosis was HLH. Dexamethasone and ruxolitinib were administered to control the fever. Subsequently, the patient underwent HLA-matched allogeneic bone marrow and peripheral blood hematopoietic stem cell transplantation for SAA. The patient's symptoms, including fever and fatigue, resolved. This case highlights that HLH should be considered in SAA patients with unexplained fever, poor response to anti-infectives, and elevated bilirubin. A treatment strategy addressing both bone marrow failure and hyperinflammation is essential. In this patient, allogeneic hematopoietic stem cell transplantation served as a successful curative intervention by targeting the shared pathophysiology of HLH and SAA. However, given the inherent limitations of a single case, the generalizability of our findings and the efficacy of allogeneic hematopoietic stem cell transplantation require validation through larger, controlled studies.
proteins
2026-06-12 | Cyclic Fevers in Pregnancy: A Case of Parvovirus-Related Hemophagocytic Lymphohistiocytosis.
Parvovirus B19 typically causes mild symptoms in healthy adults, including fever, rash, and arthralgias. Certain immunocompromised adult populations, including those with immunodeficiencies or hematologic disease, are at risk of clinically significant complications, including transient aplastic crisis. Further, in pregnant patients, there is a risk of transplacental viral transmission, which may lead to severe fetal anemia, nonimmune hydrops fetalis, and intrauterine fetal demise. The clinical course of parvovirus B19 in pregnant patients with underlying hematologic disease has not been well reported. In this case report, we present a 27-year-old pregnant patient with sickle cell beta thalassemia who was infected with parvovirus B19 at 20 weeks of gestation. She experienced a prolonged hospitalization characterized by persistent maternal vaso-occlusive crisis with concomitant transient aplastic crisis. There was suspected vertical transmission of the virus, leading to concern for severe fetal anemia and termination of the pregnancy. The patient continued to have cyclic fevers, bicytopenia, and a constellation of laboratory findings leading to a diagnosis of postviral hemophagocytic lymphohistiocytosis (HLH). She was successfully treated with pulse dose corticosteroids and an Interleukin-1 receptor antagonist with subsequent improvement of her symptoms and laboratory markers. This report highlights the distinct diagnostic and management challenges of parvovirus B19 in pregnant patients with comorbid hematologic disease, including a rare but serious sequela of the infection, and the risk for severe maternal and fetal complications.
2026-05-04 | Severe Adult HLH/MAS With SPTCL-Like Panniculitis: A Phenotype-Guided, Resource-Adapted Therapeutic Strategy Without Cytotoxic Therapy.
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory conditions with heterogeneous triggers and overlapping clinical phenotypes. Diagnostic uncertainty is particularly challenging in resource-limited settings, where advanced molecular and immunophenotypic investigations are not readily available. A 31-year-old woman presented with recurrent febrile episodes, trilineage cytopenias, hyperferritinemia (peak 16,970 ng/mL [reference: < 200 ng/mL]), hypofibrinogenemia, and progressive necrotic panniculitis plaques involving both lower extremities. Histopathological evaluation revealed lobular panniculitis with adipocyte necrosis and absence of vasculitis. While these findings raised strong concern for subcutaneous panniculitis-like T-cell lymphoma (SPTCL), definitive diagnosis was precluded by the absence of immunophenotyping, T-cell receptor clonality studies, and HAVCR2 mutation testing-all unavailable in our setting. The HScore was 216 (> 99% probability of HLH/MAS). A striking feature was the persistent dissociation between markedly elevated ferritin and low C-reactive protein (CRP) values (ratio < 0.002), consistent with a non-IL-6-dominant, interferon-γ-driven hyperinflammatory state. Based on this phenotype, a sequential treatment strategy combining therapeutic plasma exchange (TPE), intravenous immunoglobulin (IVIG), and cyclosporine A (CyA) was implemented without cytotoxic chemotherapy. The patient demonstrated significant clinical and biochemical improvement, with resolution of cytopenias and progressive decline in ferritin. This case highlights the diagnostic overlap between autoimmune panniculitis, SPTCL, and HLH/MAS, and underscores the importance of phenotype-guided management in complex hyperinflammatory syndromes. It further illustrates that effective treatment can be achieved without cytotoxic therapy in selected patients, even in the absence of definitive molecular diagnosis.
2026-05-01 | Novel perspectives on the rare hemophagocytic lymphohistiocytosis: insights from a multi-center retrospective cohort.
Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a rare clinical disease that is highly challenging to diagnose, has a low long-term survival rate and a high mortality rate. Currently, due to the particularity of HLH and the lack of effective understanding of the severity and prognosis of the disease in clinical practice, HLH patients are often missed or misdiagnosed in clinical practice, causing them to miss the best opportunity for diagnosis and treatment. This study aimed to retrospectively summarize and analyze the clinical characteristics, diagnosis and treatment, and prognosis of HLH patients from four medical centers, aiming to explore the risk factors affecting the prognosis of HLH patients and further enhance the understanding of HLH. The clinical data of 162 patients with HLH diagnosed in four medical centers from May 2017 to May 2025 were collected. The general conditions, laboratory results, diagnosis and treatment processes, and prognosis of these patients were analyzed, and univariate and multivariate analyses of prognostic factors were conducted. A total of 162 HLH patients were included in this study, of whom 90 cases survived (55.56%), 72 cases died (44.44%), and there were 78 male patients (48.15%) and 84 female patients (51.85%), with a median age at onset of 52 years (range: 1-83 years). The most common etiological factor was Epstein-Barr virus (EBV) infection, and the primary presenting symptom was fever. First-line treatment primarily involved anti-infective therapy and symptomatic management, which was administered to 147 cases (90.74%). Prognostic analysis revealed that age, history of malignancy, infection history, presence of dermatological symptoms, APTT, INR, PCT, CRP, TG, TBIL, ferritin level, sCD25, lactate, SOFA score and time to treatment initiation, glucocorticoid monotherapy, gamma globulin treatment were significantly associated with patient outcomes in HLH. Tumor history, ferritin level, sCD25, lactate, SOFA score, time to treatment initiation, gamma globulin treatment were independent risk factors for mortality. Univariate Cox regression analysis identified that age, tumor history, history of rheumatic and autoimmune disorders, CRP, ferritin level, sCD25, lactate, SOFA score and time to treatment initiation, chemotherapy, glucocorticoid monotherapy, gamma globulin treatment were significant prognostic factors for OS in HLH patients. Multivariate analysis confirmed that tumor history, CRP, ferritin level, sCD25, lactate, SOFA score and time to treatment initiation, chemotherapy, glucocorticoid monotherapy, gamma globulin treatment were independent prognostic factors affecting OS in HLH patients. Age, APTT, INR, ferritin level, SOFA score, time to treatment initiation, glucocorticoid monotherapy, gamma globulin treatment were independent prognostic factors affecting OS in infection-triggered HLH patients. While age, INR, ferritin level, SOFA score, time to treatment initiation, chemotherapy were independent prognostic factors affecting OS in malignancy-associated HLH patients. Combined therapy regimens (especially chemotherapy combined with gamma globulin, glucocorticoid combined with gamma globulin) showed better clinical efficacy and survival benefits in the treatment of HLH. HLH is a rare clinical disease, EBV was the predominant trigger for HLH. Prognostic factors differed between infection- and malignancy-associated subgroups. Combined regimens, particularly those including gamma globulin, offered superior survival benefits, underscoring the need for etiology-specific treatment strategies.
2026-02-11 | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Bacillus Calmette-Guérin (BCG): A Steroid-Sparing Strategy in a Patient Awaiting Cardiac Surgery-A Case Report.
We report a case of hemophagocytic lymphohistiocytosis (HLH) secondary to disseminated Bacillus Calmette-Guérin (BCG) infection in an 80-year-old man treated with intravesical BCG for non-muscle-invasive bladder cancer. The patient presented with several weeks of constitutional symptoms including night sweats, fatigue, weight loss, confusion, and pancytopenia. Laboratory studies revealed profound inflammation, coagulopathy, and hepatocellular injury. HLH was suspected clinically and supported by a high H-score. Extensive infectious and autoimmune workup was negative. Mycobacterium bovis was subsequently isolated from urine and bone marrow cultures, which confirmed a diagnosis of disseminated BCG infection. The patient was treated with a combination of antimycobacterial therapy (isoniazid, rifampin, and ethambutol), intravenous immunoglobulin (IVIG), corticosteroids, and anakinra. Anakinra, an interleukin-1 receptor antagonist, was used both to minimize high-dose steroids, given the protracted inflammatory response anticipated with Mycobacterium infection, and to prevent steroid-related complications related to cardiac surgery. This therapeutic strategy was associated with improvement of cytopenias, normalization of inflammatory markers, and gradual clinical recovery. This case highlights the rare but serious complication of HLH triggered by disseminated BCG and suggests that targeted immunomodulation with anakinra may be a useful adjunct in selected, complex presentations of infection-associated HLH.
2026-01-30 | Hemophagocytic lymphohistiocytosis associated with extranodal NK/T cell lymphoma, nasal type or aggressive NK cell leukemia: a retrospective multicenter study of Jiangsu Cooperative Lymphoma Group (JCLG).
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95% CI, 1.08-3.83; P = 0.029), platelet count < 20 × 10⁹/L (HR, 2.70; 95% CI, 1.46-4.99; P = 0.002), and Epstein-Barr virus DNA (whole blood) > 33,850 copies/mL (HR, 1.97; 95% CI, 1.01-3.81; P = 0.045). ECOG performance status ≥ 2 (HR, 2.00; 95% CI, 1.24-3.23; P = 0.004) and platelet count < 20 × 10⁹/L (HR, 7.61; 95% CI, 2.14-27.09; P = 0.002) were independent risk factors for poor OS. Therefore, we recommend asparaginase-based regimens as first-line therapy for treatment-naive adult patients with HLH related to NK-cell malignancies. Future multicenter prospective studies are warranted to optimize asparaginase-containing regimens, evaluate novel combination strategies, and establish precision risk-prediction models to guide clinical practice.
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2026-07-25 | Haemophagocytic lymphohistiocytosis: a life threatening complication of lymphoma.
Haemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome leading to organ damage and death, may arise as a complication of lymphomas (L-HLH). L-HLH diagnosis is challenging and optimal treatment strategies, influenced by factors such as timing of onset, lymphoma subtype and disease severity, remain ill-defined. This narrative review summarises recent evidence to support clinicians in navigating the competing priorities posed by L-HLH, including the urgent need to control inflammation, establish a diagnosis and initiate lymphoma-directed therapy, while minimising toxicity and avoiding unnecessary immunosuppression. While HLH-94 and H-score diagnostic criteria were not specifically designed for L-HLH, the optimised HLH inflammatory index (OHI) was developed in L-HLH patients and predicts the risk of multiorgan failure (MOF) but also benefit from etoposide. Recent evidence also highlights improved survival with early administration of lymphoma targeting drugs while, in critically unwell patients, non-myelosuppressive treatment with anakinra, ruxolitinib and intravenous immunoglobulins (IVIg) might offer a survival advantage. Finally, novel markers such as C-X-C motif chemokine ligand 9 (CXCL-9), recently shown to identify patients responding to interferon γ blockade, might become more widely available in the future. L-HLH encompasses a wide range of clinical presentations that force clinicians to balance competing priorities. Recent evidence improves patients stratification and supports early administration of lymphoma targeting drugs when feasible, etoposide in high risk patients and non-myelosuppressive regimens in critically unwell patients.
2026-07-09 | Advances in PD-1 monoclonal antibody therapy for hemophagocytic syndrome.
Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is a severe inflammatory condition, while the standard treatment still has limitations. With the conscious in-depth research on the pathogenesis, PD-1 (programmed cell death protein-1) monoclonal antibody has shown positive prospects in the treatment of HLH. This study retrospectively analyzed the clinical efficacy, and safety profile of PD-1 inhibitors in the treatment of HLH. A total of 15 studies was involved, covering with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and related malignancies. In pediatric patients with chronic active EBV infection (CAEBV) and refractory/relapsed EBV-HLH, sintilimab induced partial or complete clinical remission, and successfully served as a bridge therapy to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Retrospective studies on adult refractory/relapsed EBV-HLH showed that nivolumab treatment achieved an overall response rate (ORR) of 85.7% and a complete remission (CR) rate of 71.4% over 16 months. Sintilimab as salvage therapy also restored complete donor chimerism post-transplant and cleared viral loads. Furthermore, novel combinations with ruxolitinib, venetoclax, or thalidomide achieved rapid clinical remission in EBV-HLH. Safety assessments indicated that PD-1 blockade following HSCT was associated with a high risk of graft-versus-host disease (GVHD). Caution is warranted when using PD-1 monoclonal antibodies, as immune system stimulation is a double-edged sword. The optimal timing, dosage, and safety of PD-1 monoclonal antibodies in HLH treatment merit further clinical research and exploration.
2026-06-19 | Targeting the cytokine storm: new therapies in the treatment of pediatric hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disorder characterized by immune hyper-activation and subsequent tissue and organ infiltration by proinflammatory cytokines. Primary HLH is caused by underlying genetic mutations in key genes responsible for cellular cytotoxicity, whereas secondary HLH is driven by infection, malignancy, and autoimmune disease as the underlying trigger for immune activation. Chemotherapy-based treatments for pediatric HLH have improved survival and outcomes for patients, however, there is a significant unmet need in the development of targeted therapies to limit drug toxicity and further improve overall survival. We review primary and secondary HLH, current treatment strategies, and present rationale and available evidence for emerging targeted therapies for this orphan disease, including the human monoclonal anti-IFN‑γ antibody emapalumab, the anti-CD52 monoclonal antibody alemtuzumab, and the JAK1/2 inhibitor ruxolitinib, in the treatment of pediatric HLH. Development of targeted therapies in pediatric HLH is critical to improve survival and overall outcomes for these patients. Emapalumab, alemtuzumab, and ruxolitinib show promising results, however, widespread use is limited by small, non-randomized trials in a heterogenous population. Further international collaborative efforts to develop clinical trials that compare conventional chemotherapy treatments head-to-head with these newer therapies are critical for advancement of these agents.
2026-06-18 | The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and functionally resets CD33+ myeloid-derived suppressor cells in patients with metastatic cancer: a phase 2 single-arm, open-label trial.
We previously demonstrated that the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalized, and decreases those cells' viability. Treatment of MDSCs with GO restores T-cell proliferation in co-culture, overcomes M-MDSC suppression of CAR-T cell proliferation, and enhances target-cell killing. Gemtuzumab Ozogamicin Therapy in Hemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome (GOTHAM) is a phase 2 single-arm clinical trial for which patients were eligible if they had a diagnosis of solid cancer with radiological or clinical evidence of disease progression, or primary or secondary hemophagocytic lymphohistiocytosis, or macrophage activation syndrome disease relapsing or refractory to treatment at enrollment. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-d intervals: days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Using 2 schedules of GO, we could not convincingly demonstrate safe feasibility in patients with solid cancer, because of neutropenia. However, GO reproducibly and significantly reduced circulating MDSCs. Importantly, there is consistent preliminary evidence that, upon rebound, the monocyte population of CD33+ cells is replaced with nonsuppressive monocytes. These data support the phase 1b dose-escalation testing of GO up to 2 mg/m2 in combination with immune checkpoint blockade and other immunotherapies in patients with solid cancer to find a dose that depletes and repolarizes MDSCs without causing undue neutropenia, paving the way to use GO as an immune potentiator in this patient population. Trial registration: ISRCTN 89158144.
2026-05-01 | C50-23 Hemophagocytic Lymphohystiocytosis, Macrophage Activation Syndrome, and Vexas Syndrome: A Spectrum of Immune Dysregulation
Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are overlapping clinical syndromes characterized by dysregulation of the immune system that result in profound systemic inflammation and end-organ damage.1 A third autoinflammatory process, VEXAS syndrome, stems from a genetic mutation that results in recurrent fevers, cytopenias, and joint, skin, and lung inflammation.2 We present a case of critical illness due to severe immune dysregulation. Case A 59-year-old female with no significant past medical history presented to an outside hospital with less than twenty-four hours of high-grade fevers, nausea, vomiting, and altered mental status. On presentation she was febrile, hypotensive, and mildly hypoxic. Workup demonstrated leukopenia, thrombocytopenia, a bandemia of 30%, lactic acidosis, direct hyperbilirubinemia, and acute kidney and liver injuries. CT abdomen demonstrated severe diffuse circumferential gallbladder wall edema concerning for acute cholecystitis. She was started on broad spectrum antibiotics, pressors , and intubated for respiratory failure in the setting of severe metabolic acidosis. Cultures and viral panel were negative. Rheumatologic workup was negative except for positive ANA. Her labs were notable for a ferritinemia over 16,000, triglycerides in the 400s, and soluble IL-2R of nearly 14,000.Hematology recommended a bone marrow biopsy which revealed intracytoplasmic vacuoles in erythroid and myeloid precursors with negative flow cytometry. These findings taken together prompted consideration of HLH/MAS versus VEXAS syndrome. Next generation sequencing was negative for pathogenic mutations ruling out VEXAS syndrome. She met five of eight clinical criteria for secondary HLH and was treated with a prolonged steroid taper and an IL-1 antagonist with initial improvement. Her course has been complicated by ongoing intermittent encephalopathy in the setting of possible recurrent HLH flares. Discussion HLH and MAS can result from primary genetic mutations or can be secondary to rheumatologic conditions (MAS) or infection, malignancy, or medications (HLH).1 Both have similar clinical presentations with cyclic fevers, cytopenias, hepatosplenomegaly, significantly elevated serum ferritin, and coagulopathies.3 Criteria for diagnosing secondary HLH includes five of eight of the following: fever > 38.5C, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis on tissue or bone marrow biopsy, low or absent natural killer cell activity, significantly elevated serum ferritin, and elevated soluble CD25 (soluble IL-2 receptor).4 Clinical suspicion can override strict criteria when not clearly met. Distinguishing between these syndromes guides therapy: treatment of the underlying rheumatologic disorder is the mainstay of treatment for MAS and VEXAS, whereas immunosuppression, anti-viral therapies, and/or chemotherapy agents are the mainstay for HLH.5,6 This abstract is funded by: N/A
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2026-07-02 | Genome Editing for Familial Hemophagocytic Lymphohistiocytosis: Design Principles, Challenges, and Translational Perspectives.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by genetic defects in cytotoxic lymphocyte function. Current therapies can control disease activity, but transplantation of allogeneic hematopoietic stem and progenitor cells (HSPCs) remains the only curative option and is associated with substantial risks. These limitations have accelerated development of genome editing approaches enabling precise correction of disease-causing mutations in autologous cells. Familial HLH (FHL) represents a compelling target for genome editing, but successful and safe clinical translation has remained challenging. Preclinical studies demonstrate that targeted editing of key genes, such as PRF1 and UNC13D, can restore cytotoxic function in HSPCs and T cells. Translation to the clinic, however, depends on multiple factors, including the choice of target cell population, the level of functional correction required, and gene-specific constraints such as locus complexity and regulation of gene expression. In this review, we synthesize current progress in genome editing for FHL and highlight critical biological and technical barriers to clinical implementation. We propose a conceptual framework for designing genome editing strategies tailored to FHL, emphasizing the alignment of editing platform, gene architecture, and cellular context to enable effective and clinically translatable therapies.
2026-05-15 | Genotoxicity profiling reveals distinct platform-and cell type-specific effects in therapeutic gene editing for genetic hyperinflammation.
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62%-89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type-specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR-Cas9. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.
2025-05-22 | Whole-genome sequencing reveals genetic backgrounds in Japanese patients with hemophagocytic lymphohistiocytosis treated with the HLH-2004 protocol.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition triggered by a combination of genetic predispositions and environmental factors. Reports of previous outcomes from the HLH-2004 protocol in Japan revealed patients with idiopathic HLH who had poor prognoses. This study aimed to reevaluate the genetic background of such patients to identify potential novel genetic variants. Whole-genome sequencing was performed on residual samples from HLH patients enrolled in a study of the HLH-2004 protocol in Japan, excluding those associated with Epstein-Barr virus infection. Sequence variants were interpreted based on the American College of Medical Genetics and Genomics standards and guidelines. Nineteen patients were analyzed, including seven diagnosed with familial HLH (FHL) and twelve with unknown causes. Among patients with FHL, five had variants in PRF1 and two in UNC13D, consistent with the original diagnoses. Genetic variants (all UNC13D) were identified in three of the 12 previously undiagnosed patients. One patient had an unknown outcome and the others died of HLH. Failure to establish a genetic diagnosis during initial evaluation may have negatively impacted the prognosis of patients with HLH. Comprehensive genetic studies and the development of early screening methods may improve treatment outcomes for HLH.
2025-03-10 | Gene therapy for inborn errors of immunity: Current clinical progress.
Hematopoietic stem cell transplant has been the single curative treatment for inborn errors of immunity (IEI) and is recommended for the most severe IEI conditions, such as severe combined immunodeficiency. However, adverse outcomes primarily due to histocompatibility differences between the donor and the patient are still of concern. Progress in genetic and molecular mechanisms, including new technology to insert DNA sequences in cell genomes, has allowed the development of strategies to treat genetic diseases by correcting gene defect in patients' cells. This technology is named gene therapy. Gene therapy approaches being developed for IEI are mediated by gene insertion, using a retroviral vector, or by gene editing, using a combination of a nuclease and a DNA template. After the unexpected occurrence of oncogenesis associated with the initial retroviral vector designs, significant advances have led to successful gene therapy clinical trials for 3 forms of severe combined immunodeficiency, which demonstrated the safety and efficacy of this approach. Active preclinical and clinical studies are ongoing for diverse IEI, including chronic granulomatous disease, leukocyte adhesion deficiency, severe congenital neutropenia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and familial forms of hemophagocytic lymphohistiocytosis.
2024-10-29 | Functional role of UNC13D in immune diseases and its therapeutic applications.
UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.
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Drug Discovery Landscape
2 orphan drug designations for Primary hemophagocytic lymphohistiocytosis.
2 orphan drug designations for Primary hemophagocytic lymphohistiocytosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
human monoclonal antibody based on an IgG1 lambda framework against human interferon gamma | antibodies | FDA | 2022-09-01 | — | Elixiron Immunotherapeutics (Hong Kong) Limited |
tadekinig alfa | proteins | FDA | 2017-01-12 | — | AB2 Bio Ltd |
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