RARE DISEASE
Familial hemophagocytic lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis
Synonyms: Familial HLH
Synonyms: Familial HLH
Synonyms: Familial HLH
Drug discovery
4
drugs
With orphan designations
Overview
Familial hemophagocytic lymphohistiocytosis (FHLH) is a life-threatening autosomal recessive immune dysregulation disorder caused by genetic defects in lymphocyte cytotoxicity pathways (PRF1, UNC13D, STX11, STXBP2). It triggers uncontrolled T-cell/macrophage activation, cytokine storms, and multi-organ damage. Diagnostic hallmarks include fever, cytopenias, hepatosplenomegaly, hyperferritinemia, and hemophagocytosis. Untreated mortality approaches 100% within months [1][2][6].
Therapies
Induction: HLH-94/2004 protocols with dexamethasone + etoposide ± cyclosporine (55-61% 5-year survival) [3][12]
Refractory disease: FDA-approved IFNγ inhibitor emapalumab (response rate 63-70%) [8][14]
Definitive cure: Allogeneic HSCT required for survival (66% 5-year post-transplant survival) [5][13]
Categories: rare genetic diseases, rare immunological diseases, rare neoplastic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
828 drug discovery papers about Familial hemophagocytic lymphohistiocytosis, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
828 drug discovery papers about Familial hemophagocytic lymphohistiocytosis, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-07-31 | Beyond Infections: Clinical and Genetic Spectrum of Pediatric Immune Dysregulation Disorders
Aim: Primary immune regulatory disorders represent a rapidly expanding subgroup of inborn errors of immunity.Unlike classical infectionpredominant immunodeficiencies, these disorders may initially present with autoimmunity, lymphoproliferation, cytopenias, dermatologic disease, allergy, enteropathy, hemophagocytic lymphohistiocytosis, or malignancy. Materials and Methods:We conducted a retrospective single-center observational cohort study of children with genetically confirmed diseases of immune dysregulation who had been followed at a tertiary pediatric immunology center between 2005 and 2025.Patients were included if their molecular diagnosis was classified under the International Union of Immunological Societies (IUIS) category of diseases of immune dysregulation.Demographic, clinical, genetic, therapeutic, transplant-related, and outcome data were extracted from the medical records and analyzed descriptively.Results: Twenty-one children were included.Parental consanguinity was frequent (71.4%), and more than half of the cohort had a family history of primary immunodeficiency (57.1%).A substantial diagnostic delay was observed, with a median delay of 28 months (interquartile range, 8-105.5).The most common IUIS subcategory was regulatory T-cell defects (52.4%), followed by familial hemophagocytic lymphohistiocytosis syndromes with hypopigmentation (19.0%), autoimmune lymphoproliferative syndrome (14.3%), susceptibility to Epstein-Barr virus and lymphoproliferative conditions (9.5%), and immune dysregulation with colitis (4.8%).The main clinical features were lymphoproliferation (76.2%), hematologic abnormalities (66.7%) and autoimmunity (52.4%).Notably, malignancy was documented in 2 patients (9.5%).Antimicrobial prophylaxis was administered in 90.5% of the patients, immunoglobulin replacement in 66.7%, conventional immunosuppressive therapy in 38.1%, and biological or targeted therapy in 33.3%.Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients (38.1%); immune reconstitution was achieved in all of the surviving transplant patients.Conclusion: Pediatric diseases of immune dysregulation frequently present with non-infectious manifestations, particularly lymphoproliferation, cytopenias, autoimmunity, and dermatologic findings.Recognition beyond infection-centered warning signs, the integration of genetic testing, and the individualized use of targeted therapies or HSCT may improve care for this heterogeneous group of disorders.
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.
2026-08-11 | 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.
2026-07-31 | Beyond Infections: Clinical and Genetic Spectrum of Pediatric Immune Dysregulation Disorders
Aim: Primary immune regulatory disorders represent a rapidly expanding subgroup of inborn errors of immunity.Unlike classical infectionpredominant immunodeficiencies, these disorders may initially present with autoimmunity, lymphoproliferation, cytopenias, dermatologic disease, allergy, enteropathy, hemophagocytic lymphohistiocytosis, or malignancy. Materials and Methods:We conducted a retrospective single-center observational cohort study of children with genetically confirmed diseases of immune dysregulation who had been followed at a tertiary pediatric immunology center between 2005 and 2025.Patients were included if their molecular diagnosis was classified under the International Union of Immunological Societies (IUIS) category of diseases of immune dysregulation.Demographic, clinical, genetic, therapeutic, transplant-related, and outcome data were extracted from the medical records and analyzed descriptively.Results: Twenty-one children were included.Parental consanguinity was frequent (71.4%), and more than half of the cohort had a family history of primary immunodeficiency (57.1%).A substantial diagnostic delay was observed, with a median delay of 28 months (interquartile range, 8-105.5).The most common IUIS subcategory was regulatory T-cell defects (52.4%), followed by familial hemophagocytic lymphohistiocytosis syndromes with hypopigmentation (19.0%), autoimmune lymphoproliferative syndrome (14.3%), susceptibility to Epstein-Barr virus and lymphoproliferative conditions (9.5%), and immune dysregulation with colitis (4.8%).The main clinical features were lymphoproliferation (76.2%), hematologic abnormalities (66.7%) and autoimmunity (52.4%).Notably, malignancy was documented in 2 patients (9.5%).Antimicrobial prophylaxis was administered in 90.5% of the patients, immunoglobulin replacement in 66.7%, conventional immunosuppressive therapy in 38.1%, and biological or targeted therapy in 33.3%.Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients (38.1%); immune reconstitution was achieved in all of the surviving transplant patients.Conclusion: Pediatric diseases of immune dysregulation frequently present with non-infectious manifestations, particularly lymphoproliferation, cytopenias, autoimmunity, and dermatologic findings.Recognition beyond infection-centered warning signs, the integration of genetic testing, and the individualized use of targeted therapies or HSCT may improve care for this heterogeneous group of disorders.
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.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
4 orphan drug designations for Familial hemophagocytic lymphohistiocytosis, including 1 approved therapy.
4 orphan drug designations for Familial hemophagocytic lymphohistiocytosis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
fully human IgG1 monoclonal antibody directed against human signal regulatory protein (SIRP)alpha, SIRPbeta1, and SIRPgamma | antibodies | FDA | 2024-10-02 | — | Electra Therapeutics, Inc. |
Tadekinig alfa | proteins | EMA | 2016-10-14 | — | Yes Pharmaceutical Development Services GmbH |
Recombinant human anti-interferon gamma monoclonal antibody | antibodies | EMA | 2010-06-09 | — | Swedish Orphan Biovitrum AB (publ) |
emapalumab-lzsg [Gamifant] | antibodies | FDA | 2010-03-26 | 2018-11-20 | Swedish Orphan Biovitrum AB |
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