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:
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.
2026-08-04 | 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.
2026-08-03 | 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.
2026-08-14 | 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.
2026-08-04 | 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.
2026-08-03 | 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.
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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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