Hemophagocytic lymphohistiocytosis Surapon Wiangnon Faculty of Medicine Mahasarakham University KKU Histiocytes are myeloid origin hematopoietic cells that populate at tissues Cell Origins of Histiocytic Diseases Stem cell Macrophage DC Precursor Mesenchymal Precursor cell Myeloid Monocyte DC Precursor CD68 CD1+, CD14+ CD11c CD14+ CD1 – HLADR+ HLADR+ CD23 CD68 CD21 CD11c CD35 CD207 DCSIGN CD68 CD206 CD1a CD205 Fxllla CD163 Follicular High CD1a int S100 int Interstitial Macrophage DC Dermal Langerhans cell CD14+DC CD1a+DC Malignant Histiocytosis LCH LCH, ECD JXG HLH/RDD DC, dendritic cell; JXG, juvenile xanthogranuloma; ECD, Edheim Chester disease; RDD, Rosai-Dorfman disease; HLH, hemophagocytic lymphohistiocytosis Histiocytosis syndrome ❖ Dendritic cell (histiocyte) proliferation - Langerhans cell histiocytosis (LCH) - Juvenile xanthogranulomas (JXG) & related disorders - Solitary histiocytomas of various DC phenotype ❖ Macrophage proliferation - Hemophagocytic lymphohistiocytosis (HLH) - Sinus histiocytosis with massive lymphadenopathy (SHML, Rosai-Dorfman disease) - Solitary histiocytoma of macrophage phenotype ICD-10 Langerhans cell histiocytosis, C96.0 Hemophagocytic lymphohistiocytosis, D76.1 Malignant histiocytosis, C96.8 HLH มีกลุ่มย่อยดังนี้ Familial Hemophagocytic Lymphohistiocytosis Infectious-associated hemophagocytosis (IAHS) Malignant-associated hemophagocytosis (MAHS) Macrophage Activation Syndrome (MAS) refractory to steroid Hemophagocytic lymphohistiocytosis: HLH Hyperinflammatory disorder: hypercytokinemia, and excessively activated lymphocytes and histiocytes, characterized by cytopenia, hepatosplenomegaly, DIC, hyperferritinemia, and hemophagocytosis Int J Hematol, 2007 HLH Primary Secondary Genetic disease Infection, auto- immune/inflammatory, Familial HLH: FHL lymphoma, post-SCT Epidemiology of HLH ▪ 1/50,000 live-born children (FHLH, Swedish registry) ▪ 80% of FHL, Sx onset in the first year of life ▪ Likely to be under-diagnosed Pathogenesis of primary HLH Target cells Postulated mechanisms Effector cells CD8+T cell, CD56+NK cells Incomplete Infected exclusion of Endoplasmic Immune synapse cells infected cells reticulum/Golgi- Perforin & Granzyme complex lysosome Activated Incomplete T cells fratricide killing (CTL, Th) of activated T cells IFN 18 / g 12 Production of - Docking, priming, IL cytotoxic granules Persistent fusion and stimulation of FHL2 Trafficking and degranulation antigens sorting FHL3-5 (PAMP/DAMP) Grscelli sx. II Chediak-Higashi sx. Antigen presenting cells Hermansky-Pudlak sx II (APC)/ Macrophage HLH-2004 Dx Guidelines The Dx of HLH can be established if one of either 1 or 2 below is fulfilled (1) A molecular Dx consistent with HLH (2) Dx criteria for HLH fulfilled (5 out of 8 criteria below) ① Fever ② Splenomegaly ③ Cytopenias (affecting ≥2 of 3 lineages in PB): Hgb <90 g/L (in infants <4 weeks: Hgb <100 g/L) Platelets <100ⅹ109/L Neutrophils <1.0ⅹ109/L ④ Hypertriglyceridemia and/or hypofibrinogenemia: Fasting triglycerides ≥3.0 mmol/L (i.e., ≥265 mg/dl) Fibrinogen ≤1.5 g/L ⑤ Hemophagocytosis in BM or spleen or LN ⑥ Low or absent NK-cell activity ⑦ Ferritin ≥500 mg/L ⑧ Soluble CD25 (sIL-2 receptor) ≥2,400 U/ml Hemophagocytosis Classification of HLH Primary, genetic Secondary, acquired FHLH Infection associated Chromosome 9 linkage (FHL1) virus (EBV,CMV,HSV,VSV) PRF1 mutations (FHL2) bacteria (mycoplasma) UNC13D mutations (FHL3) parasite, fungus STX11 mutations (FHL4) Autoimmune associated STXBP2 mutations (FHL5) sJIA, SLE, IBD, Kawasaki, AOSD Albinism syndromes Malignancy associated LYST mutations T-cell lymphoma (Chediak-Higashi syndrome) RAB27A mutations Metabolic disease associated (Griscelli syndrome) Gaucher disease, Other immunodeficiencies Lysinuric protein intolerance SH2D1A mutations (XLP1) Post organ transplantation XIAP mutations (XLP2) ITK (IL-2-inducible T-cell kinase) deficiency Secondary (Acquired) HLH ▪ Infection-associated Hemophagocytic Syndrome (IAHS) - Virus, bacteria, fungi, protozoa, leishmania - IAHS proved to be dangerous like 1° HLH ▪ Autoimmune-associated (RAHS) ▪ Malignancy-associated (MAHS) ▪ Post-transplant Secondary hemophagocytic lymphohistiocytosis in children: an analysis of etiology and outcome. Veerakul G, J Med Assoc Thai. 2002 • N =52, 1989 -1998. • IAHS,N=15 • MAHS, N = 25 (NHL 15, leukemia 7, MDS 1, LCH 1, histiocytic sarcoma 1) • idiopathic HLH = 12 • Causative organisms for IAHS: Salmonella (3), Staphylococcus (2), Enterobactor (2), dengue virus (3), malaria (2), EBV (1), Serratia marcesens (1), Penicillium maneffei (1) • 15 (28.8%) - died during the acute phase, and other 4 died of their subseque nt malignant diseases. • poorer prognosis and patients' age < 3 years , or MAHS (p=0.005) Principles of HLH Treatment 1. Suppression of hyperinflammation - Corticosteroids, IVIG, Cyclosporin, ATG, Anticytokine agents 2. Elimination of activated immune cells and (infected) APCs (CTLs, histiocytes) - Corticosteroids, Etoposide, T-cell Ab (Alemtuzumab, ATG), Rituximab 3. Elimination of trigger - Anti-infectious therapy 4. Replacement of defective immune system - Hematopoietic stem cell transplantation 1994 2004 HLH 94/2004 Protocol Backbone: VP-16* + Dexa + CSA • Etoposide: potent selective deletion of activated T-cell, efficient suppression of inflammatory cytokine producti on • CSA: inhibit gamma-IFN • Dexa: Long half life, CSF • Non-verified FLH with complete resolution of disease, stop Tx after 8 weeks • IVIG (for IAHS only) *2/600 develop cancer Indication of HSCT for HLH (Flow-sheet of HLH-2004) Genetically Continuation verified or therapy until familial SCT disease Persistent Continuation Patients Start Initial Non-familial, therapy until with HLH 8 weeks non-genetically SCT chemotherapy verified Resolved Stop Non-familial, therapy Non-genetically verified Continuation Reactivation therapy until SCT 1994 2004 (N=369) 5 yr survival (%) 54 (CI, 48-60) 61 (CI, 56-67) W* 59 (CI, 52-67) W/o* 64 (CI, 57-71) CSA Wk 9 Upfront Pre-HSCT mortality (%) 27 19 p= 0.64 5yr-Survival post HSCT 66% 67% IT+ steroid; Upfront CSA 22% 17% VS. late neuro. Sequele *With/without genetically verified Blood 2017 Hyperferritinemia Maximum ferritin over 10,000 mg/L Pediatr Blood Cancer 2008:1227 Survival HLH 2004 Post HSCT Key points, HLH 2004 Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 .06). HLH-2004 may be improved by risk-group stratification, less therapy reduction weeks 7 to 8 for verified FHL patients, and earlier HSCT. Blood 2017.