small molecules

2026-09-23 | Simple LC-MS/MS Method for Ruxolitinib in Human Plasma and Its Clinical Application in Pediatric and Adult Patients.

Ruxolitinib is a Janus kinase inhibitor effective against graft-versus-host disease and hemophagocytic lymphohistiocytosis. However, clinical management is challenged by potential drug-drug interactions and adverse events. Although therapeutic drug monitoring (TDM) can optimize drug safety and efficacy, real-world pharmacokinetic data are limited. To address this gap, we established a simple and sensitive LC-MS/MS method with a total run time of 8.1 min. The method demonstrated linearity over a range of 0.5-100 ng/mL. The intra- and inter-day precision and accuracy met the acceptance criteria. The method was successfully applied to 8 pediatric and 10 adult patients. Measurable concentrations were confirmed in infants (<2 years). The observed trough concentrations varied widely, ranging from 0.69 to 22.2 ng/mL in pediatric patients and <0.5 to 80.6 ng/mL in adult patients. Notably, an intraindividual comparison in one adult case revealed that posaconazole co-administration increased the trough concentration by approximately 4-fold and the area under the plasma concentration-time curve by approximately 2-fold, compared with the period without azoles. In conclusion, we established a validated LC-MS/MS method that was applicable to the measurement of ruxolitinib concentrations in pediatric and adult patients in this single-center study. This method may contribute to the accumulation of pharmacokinetic data for future evaluation of TDM strategies.

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2026-09-16 | Precision immunomodulation for pediatric hemophagocytic lymphohistiocytosis in intensive care.

Hemophagocytic lymphohistiocytosis (HLH) and related cytokine storm syndromes are life-threatening hyperinflammatory disorders that frequently intersect with pediatric critical care. Critically ill children may present with fever, shock, cytopenias, liver dysfunction, coagulopathy, hyperferritinemia, respiratory failure, neurologic deterioration, and multiple organ dysfunction, creating substantial overlap with severe sepsis. Traditional diagnostic criteria remain foundational but do not identify the dominant mechanism or optimal therapy for an individual child. In this review, precision immunomodulation is defined operationally as matching the suspected trigger and clinical phenotype with pathway-informed biomarkers when available, drug-delivery feasibility during organ failure, and the plan for definitive disease control. Interferon-gamma activity may be supported by CXCL9; interleukin (IL)-1/IL-18 biology may support anakinra in macrophage activation syndrome; broader cytokine signaling may support Janus kinase inhibition in selected refractory HLH; and IL-6-directed therapy is primarily syndrome- and grade-directed in immune effector cell cytokine release syndrome. These markers are supportive rather than validated treatment thresholds. Targeted therapy must proceed alongside antimicrobial therapy, source control, organ support, infection surveillance, and early hematopoietic stem cell transplantation planning when indicated. This review provides a bedside framework for phenotype assignment, biomarker interpretation, intensive care unit-focused targeted therapy, extracorporeal bridge strategies, and reassessment at 24-72 h.

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2026-09-15 | [Clinical characteristics of intracranial suppurative infections caused by Streptococcus intermedius in 4 children].

Objective: To investigate the clinical features, therapeutic strategies, and outcomes of intracranial suppurative infections caused by Streptococcus intermedius (S. intermedius) in children. Methods: A case series study was conducted involving 4 children diagnosed with central nervous system (CNS) infections attributed to S. intermedius at the Capital Center for Children's Health, Capital Medical University from January 2020 to January 2026. Their demographics, clinical presentations, laboratory findings, neuroimaging features, microbiological results, treatment regimens, and prognoses were reviewed. Results: Among 4 children 3 were male and 1 was female, aged 10-15 years. All 4 children presented acutely with fever and headache as the initial symptoms; 3 children presented with vomiting, 2 children with drowsiness and seizures. Cerebrospinal fluid (CSF) analysis showed elevated white blood cell counts in all 4 children, elevated protein levels in 3 children. Brain MRI revealed sinusitis in all 4 children, with predominant right-sided involvement. All intracranial suppurative lesions were adjacent to the right-sided sinus inflammatory foci, including multiple brain abscesses in 1 child, subdural empyema in 2 children, and concurrent brain abscess with subdural empyema in 1 child. S. intermedius was confirmed in all 4 children via various microbiological methods: metagenomic next-generation sequencing (mNGS) of subdural pus in 1 child, targeted NGS (tNGS) of CSF in 1 child, culture of deep sinus pus obtained intraoperatively in 1 child, and both culture and tNGS of brain abscess pus in the remaining child. All 4 children received comprehensive treatment, including targeted antimicrobial therapy, anticonvulsant therapy, intracranial pressure reduction management, and multidisciplinary surgical interventions including craniotomy with abscess excision, burr-hole drainage of subdural empyema, and endoscopic sinus surgery. One child developed secondary hemophagocytic lymphohistiocytosis during the disease course. After a follow-up period of 1.5-5.5 years, all 4 children achieved clinical recovery, resumed normal academic and daily activities, and exhibited no significant neurological sequelae. Conclusions: Pediatric intracranial infections caused by Streptococcus intermedius primarily affecting older children and adolescents. These infections are highly associated with adjacent infectious foci, particularly sinusitis, and exhibiting a propensity for localized abscesses or empyema formation. Timely and targeted antibiotic therapy coupled with surgical intervention is associated with favorable prognosis in this population.

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2026-09-12 | Differential efficacy and safety of ruxolitinib in primary versus secondary hemophagocytic lymphohistiocytosis: a systematic review and meta-analysis

Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, has demonstrated therapeutic potential in both primary and secondary hemophagocytic lymphohistiocytosis (pHLH & sHLH), but quantitative evidence comparing its efficacy and safety across subtypes remains lacking. Given the absence of randomized controlled trials evaluating RUX in HLH, we conducted a systematic review and single-arm meta-analysis to assess RUX-based regimens. Eighty-three studies comprising 542 patients were included, of which 27 were single-arm trials or cohort studies and 56 were case reports/series. The pooled overall response (OR) rate was 87.2% (95% CI, 80.8–92.7%; I 2 = 55.0%), with pHLH achieving 100% versus 82.4% in sHLH ( p = 0.005). Overall survival (OS) rates were 91.6% at 2 months (95% CI, 85.1% to 96.7%; I 2 = 37.8%), 81.6% at 6 months (95% CI, 69.5% to 91.7%; I 2 = 66.5%), and 73.9% at 1 year (95% CI, 56.3% to 88.9%; I 2 = 76.9%); pHLH demonstrated superior 2-month survival compared to sHLH (100% vs. 87.7%, p = 0.005). These findings remained robust in sensitivity analyses excluding case reports. The most frequent adverse events were infections (9.3%), neutropenia (7.5%), and hepatic dysfunction (7.0%), with higher rates of pancreatic injury and severe hematological toxicities in pHLH. This largest evidence synthesis to date supports the efficacy of RUX-based regimens in HLH, with higher pooled short-term response estimate in pHLH than in sHLH. Despite inherent limitations of rare disease research, these findings provide critical guidance for clinical practice and future trial design. PROSPERO (CRD42025639580).

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2026-09-11 | Envenomation-Induced Hemophagocytic Lymphohistiocytosis (HLH): First Reported Adult Case Following A Spider Bite.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome driven by dysregulated activation of cytotoxic T lymphocytes and macrophages. While infections and malignancies represent the most frequently identified triggers, HLH precipitated by arthropod envenomation is exceptionally rare, with prior reports confined predominantly to paediatric populations. A 65-year-old male with multiple comorbidities developed progressive fever, cytopenias, extreme hyperferritinaemia (>8,000 ng/ml), and multiorgan dysfunction following a suspected spider bite to the inner left thigh. Evaluation revealed markedly elevated soluble interleukin-2 receptor (sCD25 >4,000 pg/ml) and CXCL9 (35,623 pg/ml; 55-fold above the upper limit of normal), along with reduced natural killer (NK) cell counts. Bone marrow biopsy confirmed haemophagocytosis. The patient fulfilled 6 of 8 HLH-2004 diagnostic criteria, with an HScore of approximately 197, corresponding to a >90-95% probability of HLH. Treatment with high-dose corticosteroids, ruxolitinib, and anakinra resulted in rapid suppression of inflammatory markers. The course was complicated by acute kidney injury requiring temporary haemodialysis. By early 2026, the patient achieved normalization of all laboratory parameters and returned to near-baseline functional status. This case illustrates an exceptionally rare adult presentation of envenomation-associated secondary HLH. Clinicians should consider HLH in patients with persistent fever, cytopenias, and extreme hyperferritinaemia following arthropod exposure. Early immunomodulatory therapy, including cytokine-directed agents such as ruxolitinib and anakinra, may avert irreversible organ damage in the absence of cytotoxic etoposide-based therapy. First documented adult case of spider bite-associated HLH, expanding awareness of a rare but fatal presentation.Guides internists to consider HLH when fever, cytopenias, and extreme hyperferritinaemia persist after envenomation.Emphasizes that early immunomodulatory therapy can prevent irreversible organ damage.

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cell therapies

2026-08-20 | Hematopoietic stem cell transplantation in an adult patient with primary hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition characterized by uncontrolled immune activation and excessive production of pro-inflammatory cytokines, which may rapidly progress to multiorgan failure. Despite efforts to simplify the diagnosis and treatment of this entity, it remains a major challenge in clinical practice, especially in adults. We report a case of suspected primary HLH in an adult patient with a prolonged history of recurrent inflammatory episodes and a fulminant presentation requiring intensive care support. Despite the absence of identifiable genetic mutations, the clinical course was highly suggestive of an underlying primary immune dysregulation. The patient achieved remission with HLH-2004–based therapy and subsequently underwent haploidentical hematopoietic stem cell transplantation (HSCT) due to high risk of recurrence. Seven months after transplantation, she remains in complete remission with full donor chimerism and only mild chronic graft-versus-host disease. This case highlights the diagnostic complexity of adult HLH, the limitations of genetic testing, and supports early consideration of HSCT in selected high-risk patients.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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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antibodies

2026-09-04 | Hemophagocytic Lymphohistiocytosis Complicated With Reversible Cardiomyopathy and Severe Sinus Node Dysfunction.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome causing multiorgan failure. While cardiac involvement is recognized, associated conduction-system abnormalities are exceedingly rare and poorly described. A 60-year-old male presented with fever, pancytopenia, and progressive shock, meeting diagnostic criteria for HLH. His clinical course was acutely complicated by transient cardiomyopathy and frequent episodes of sinus arrest. Following the initiation of HLH-directed therapy, the patient experienced a complete recovery of both systolic function and sinus node conduction by day 10. This case identifies severe sinus node dysfunction as a reversible manifestation of HLH-related cytokine storm. Prompt initiation of immunosuppressive therapy led to complete recovery of left ventricular function and sinus node activity, highlighting the reversible nature of the HLH-related myocardial injury. This case highlights the importance of early identification of HLH-related cardiac involvement as it is critical to prevent irreversible damage and improve outcomes in these patients.

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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.

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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.

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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.

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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.

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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.

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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.

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2025-12-18 | [Intravascular large B-cell lymphoma of the nasal turbinate presenting with hemophagocytic lymphohistiocytosis: a case report and literature review].

Intravascular large B cell lymphoma (IVLBCL) is a rare, aggressive subtype of diffuse large B cell lymphoma, with nasal turbinate involvement being uncommon. We report a 51-year-old woman with a 1-month history of fever of unknown origin. Laboratory findings showed cytopenia, hypertriglyceridemia, elevated ferritin, increased soluble CD25, and bone marrow hemophagocytosis. No infectious cause was identified. PET-CT revealed abnormal (18)F-fluorodeoxyglucose (FDG) uptake in the nasal turbinates. Turbinate biopsy revealed tumor cells localized predominantly within vascular lumens, positive for CD20, BCL6, PAX5, and MUM1, with a Ki-67 index >60%, confirming a diagnosis of IVLBCL with hemophagocytic lymphohistiocytosis (HLH). The patient received one cycle of the DEP regimen (liposomal doxorubicin, etoposide, and methylprednisolone) for HLH, followed by five cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and consolidation with auto-HSCT, achieving sustained complete remission. IVLBCL outcomes are heterogeneous; early diagnosis and prompt treatment improve survival, and R-CHOP plus auto-HSCT may be an effective strategy.

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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.

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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.

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