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
846 drug discovery papers related to Primary hemophagocytic lymphohistiocytosis, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
846 drug discovery papers related to Primary hemophagocytic lymphohistiocytosis, with 3 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-07-09 | Successful Treatment of Adult Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis With Etoposide Guided by Plasma Epstein-Barr Virus DNA Monitoring: A Case Report.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. Epstein-Barr virus (EBV)-associated HLH is a major subtype of secondary HLH, requiring prompt diagnosis and treatment. However, treatment is particularly challenging in patients with severe coagulopathy and hepatic dysfunction. A previously healthy 23-year-old woman presented with a 2-week history of high-grade fever and cervical lymphadenopathy. Cytopenia, elevated lactate dehydrogenase levels, marked transaminase elevations, hyperferritinemia, and disseminated intravascular coagulation were observed. EBV-associated HLH was diagnosed based on bone marrow hemophagocytosis, an elevated whole blood EBV-DNA level (6.63 log IU/mL), and serological findings consistent with primary EBV infection. Initial treatment with methylprednisolone and cyclosporine A was followed by weekly oral etoposide, with careful monitoring in the setting of severe hepatic dysfunction. Clinical symptoms and laboratory abnormalities improved within 3 weeks of starting etoposide. Plasma EBV-DNA became undetectable during treatment, and oral etoposide was discontinued after the third weekly course on Day 18, with a total cumulative dose of 750 mg, corresponding to approximately 450 mg/m2. The patient showed no evidence of relapse at the 6-month follow-up, with sustained negativity of plasma EBV-DNA. This case suggests that timely etoposide-based therapy may be feasible in severe EBV-HLH when response and toxicity are carefully monitored. The authors have confirmed clinical trial registration is not needed for this submission.
2026-07-03 | Multiple recurrences of Talaromyces marneffei infection with HLH in an HIV-negative patient: a case report.
Talaromycosis complicated by hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition associated with high mortality, yet the management of recurrent disease in HIV-negative patients is not well defined. We report a 49-year-old man who presented with fever, lymphadenopathy, and an uncommon ulcerative scalp lesion that has been poorly documented in HIV-negative talaromycosis. Talaromyces marneffei (T. marneffei) infection was confirmed by blood culture, and HLH was subsequently diagnosed. Initial induction therapy with amphotericin B deoxycholate (AmB-D) followed by itraconazole (ITZ) maintenance resulted in clinical improvement; however, the patient experienced multiple recurrences over three years, including a recurrence while on ITZ. Immunological evaluation later revealed positive anti-interferon-γ autoantibodies (AIGA). Re-induction with liposomal amphotericin B (L-AmB) followed by maintenance posaconazole (PCZ) resulted in short-term remission, with no recurrence during three months of follow-up. This case demonstrates the successful management of recurrent talaromycosis with L-AmB induction followed by PCZ maintenance in an HIV-negative patient with AIGA-associated immunodeficiency presenting with initial HLH, highlighting the importance of early diagnosis, individualized antifungal strategies, and the potential utility of PCZ as maintenance therapy in high-risk 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.
2026-07-09 | Successful Treatment of Adult Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis With Etoposide Guided by Plasma Epstein-Barr Virus DNA Monitoring: A Case Report.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. Epstein-Barr virus (EBV)-associated HLH is a major subtype of secondary HLH, requiring prompt diagnosis and treatment. However, treatment is particularly challenging in patients with severe coagulopathy and hepatic dysfunction. A previously healthy 23-year-old woman presented with a 2-week history of high-grade fever and cervical lymphadenopathy. Cytopenia, elevated lactate dehydrogenase levels, marked transaminase elevations, hyperferritinemia, and disseminated intravascular coagulation were observed. EBV-associated HLH was diagnosed based on bone marrow hemophagocytosis, an elevated whole blood EBV-DNA level (6.63 log IU/mL), and serological findings consistent with primary EBV infection. Initial treatment with methylprednisolone and cyclosporine A was followed by weekly oral etoposide, with careful monitoring in the setting of severe hepatic dysfunction. Clinical symptoms and laboratory abnormalities improved within 3 weeks of starting etoposide. Plasma EBV-DNA became undetectable during treatment, and oral etoposide was discontinued after the third weekly course on Day 18, with a total cumulative dose of 750 mg, corresponding to approximately 450 mg/m2. The patient showed no evidence of relapse at the 6-month follow-up, with sustained negativity of plasma EBV-DNA. This case suggests that timely etoposide-based therapy may be feasible in severe EBV-HLH when response and toxicity are carefully monitored. The authors have confirmed clinical trial registration is not needed for this submission.
2026-07-03 | Multiple recurrences of Talaromyces marneffei infection with HLH in an HIV-negative patient: a case report.
Talaromycosis complicated by hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition associated with high mortality, yet the management of recurrent disease in HIV-negative patients is not well defined. We report a 49-year-old man who presented with fever, lymphadenopathy, and an uncommon ulcerative scalp lesion that has been poorly documented in HIV-negative talaromycosis. Talaromyces marneffei (T. marneffei) infection was confirmed by blood culture, and HLH was subsequently diagnosed. Initial induction therapy with amphotericin B deoxycholate (AmB-D) followed by itraconazole (ITZ) maintenance resulted in clinical improvement; however, the patient experienced multiple recurrences over three years, including a recurrence while on ITZ. Immunological evaluation later revealed positive anti-interferon-γ autoantibodies (AIGA). Re-induction with liposomal amphotericin B (L-AmB) followed by maintenance posaconazole (PCZ) resulted in short-term remission, with no recurrence during three months of follow-up. This case demonstrates the successful management of recurrent talaromycosis with L-AmB induction followed by PCZ maintenance in an HIV-negative patient with AIGA-associated immunodeficiency presenting with initial HLH, highlighting the importance of early diagnosis, individualized antifungal strategies, and the potential utility of PCZ as maintenance therapy in high-risk patients.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
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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