Chemoimmunotherapy for hemophagocytic lymphohistiocytosis. Mar 10, 2020 secondary hlh was diagnosed according to fulfilling five of the eight criteria for hlh and negative genetic detection for primary hlh, and etoposide was administered according to the hlh 2004 protocol. A recent evidencebased algorithm has been proposed 2 using il1 blockade with anakinra fig. Because of high morbidity and mortality of this disease rapid diagnosis and treatment is necessary. Treatment of hemophagocytic lymphohistiocytosis with cyclophosphamide, vincristine, and prednisone. The hlh94 protocol drastically improved the nearly uniformly fatal outcome in pediatric hlh to a longterm survival 50%. Hemophagocytic lymphohistiocytosis is a potentially fatal disease characterized by excessive macrophage and lymphocyte activity. Case report a case of primary bone marrow, liver, and. Listing a study does not mean it has been evaluated by the u. Download fulltext pdf download fulltext pdf download fulltext pdf. Apr 16, 2020 based on the treatment protocol, there were 23 patients received hlh 2004 protocol 18 survive and 5 patients died and 12 patients received hlh 94 protocol 9 patients survive and 3 patients died. The safety and scientific validity of this study is the responsibility of the study.
Hemophagocytic lymphohistiocytosis due to streptococcus suis. Hyperferritinemia in the critically ill child with secondary. People with hlh usually develop symptoms within the first months or years of life. However, for patients who have genetic diseases which predispose them to the development of hemophagocytic lymphohistiocytosis hlh, ebv infection is a lifethreatening problem. Histiocyte society hlh2004 skion pdf book manual free. Pdf hemophagocytic lymphohistiocytosis hlh is a disorder. Recommendations for the management of hemophagocytic. The definition was later revised for the hlh2004 trial. Hereditary hlhs affect children and are caused by mutations in genes of the cytotoxic granule complex, resulting in defective pathogen. Filipovich, helmut gadner, shinsaku imashuku, diane komp, stephan ladisch, david webb, gritta janka.
American society for clinical pathology international meeting of the histiocyte society recommends an 8. The hlh 2004 protocol consists of a twoweek induction phase including etoposide. Mar 19, 2012 hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome mods, and critical illness. Pdf treatment of hemophagocytic lymphohistiocytosis with. Hemophagocytic lymphohistiocytosis hlh is a syndrome characterized by extreme immune activation, resulting in pathologic inflammation.
Immunochemotherapy is widely used to induce and maintain remission until hsct in primary hlh. The histiocyte society study group for hlh developed the hlh94 and hlh 2004 treatment protocols, and these are frequently also used by centers treating hlh in adults ahlh. Filipovich, helmut gadner, shinsaku imashuku, diane komp, stephan ladisch, david webb, and gritta janka, for the histiocyte. Cytarabine mercaptopurine, methotrexate no historical protocol trial closed. On january 1, 2004, a modified study protocol hlh 2004, which is still open with revised diagnostic criteria was introduced. There has been little consensus on how to treat shlh with the exception of mas complicating sjia, and often elements of the hlh 2004 protocol are used. Symptoms may include fever, enlarged liver or spleen, cytopenia decreased number of blood cells, and neurological abnormalities. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a pdf plugin installed and enabled in your browser. The diagnosis includes a spectrum of inherited or acquired. Specific sequences of infectious challenge lead to. Jan 01, 2005 the clinical data summarized are straightforward. Hlh in adults is a much more heterogeneous syndrome requiring a more individualized approach depending on the underlying trigger, disease severity and course, as well as genetic background. Hereditary and acquired hemophagocytic lymphohistiocytosis.
A sixteenyearold girl with still disease diagnosis developed a progressive multiorgan failure including acute respiratory distress ards, anemia and thrombopenia. Hemophagocytic syndromes hpss including hemophagocytic lymphohistiocytosis hlh in adults. Treatment of hemophagocytic lymphohistiocytosis with. Hemophagocytic lymphohistiocytosis secondary to babesia in. Opinion statement central nervous system cnshemophagocytic lymphohistiocytosis hlh is not a disease in itself, but it is part of a systemic immune response. Currently, hereditary or primary forms of the condition are distinguished from secondary or reactive forms 2,3,4. Mcclain, milen minkov, scott montgomery, vasanta nanduri, diego rosso, janinge henter.
Haemophagocytic lymphohisticytosisan underrecognized. Treatment of hemophagocytic lymphohistiocytosis in adults. Because of increased neurotoxicity, 39 and absent the final analysis of hlh 2004, the current recommendation is not to use csa in the first couple of weeks. Hereditary and acquired hemophagocytic lymphohistiocytosis ling zhang, md, jun zhou, md, and lubomir sokol, md, phd background. Dec 18, 2015 hemophagocytic lymphohistiocytosis hlh is a severe hyperinflammatory syndrome that presents with unremitting fever, splenomegaly and cytopenia. As part of the hlh94 clinical trial, the histiocyte society proposed a standard definition of hlh in 1994. Confirmed efficacy of etoposide and dexamethasone in hlh.
Familial hemophagocytic lymphohistiocytosis genetic and. The clinical hallmarks of this syndrome, namely high fever, splenomegaly, bicytopenia, hypertriglyceridaemia, high serum ferritin 3000 ngml and sil2receptor 2400 ul, and proof of haemophagocytosis in bone marrow specimens, were included in the 2004 diagnostic criteria for primary hlh, which in contrast to secondary hlh, route back to. We describe a pediatric case of hemophagocytic lymphohistiocytosis with a. Dec 21, 2017 confirmed efficacy of etoposide and dexamethasone in hlh treatment. Hemophagocytic lymphohistiocytosis with immunotherapy. Hlh hlh 2004 protocol dexamethasone, ciclosporin no historical protocol trial closed lch cclg guidelines. Our objective is to raise the importance of hfs early diagnosis by presenting a representative case.
Currently, national multicentre research on the efficacy of the hlh 2004 treatment protocol is underway. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. It is a lifethreatening condition that can be defined as either primary or secondary hlh. The hlh 2004 criteria remain as the common diagnostic guide. Treatment of hemophagocytic lymphohistiocytosis with hlh. Alternatively, you can download the file locally and open with any standalone pdf reader.
Families who have faced an hlh diagnosis and philanthropists with the passion to support our children with the disease have banded together with our team to create the hlh center of excellence. Apr 16, 2010 hlh is currently treated with a protocol or treatment program called hlh 2004. Treatment protocol for hemophagocytic lymphohistiocytosis 2004 the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Hemophagocytic lymphohistiocytosis hlh, a rare but potentially fatal syndrome of immune hyperactivation, may be an underrecognized immunerelated adverse event irae. Hemophagocytic lymphohistiocytosis hlh associated with a malignant. Management is largely based on hlh2004 protocol for secondary cases and almost all cases of primary hlh require. Janinge henter, annacarin samuelssonhorne, maurizio arico, r. Hlh2004 protocol and allogeneic haematopoietic stem. We would like to show you a description here but the site wont allow us.
Hemophagocytic lymphohistiocytosis hlh is a rare disorder in children that is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia. Management is largely based on hlh2004 protocol for secondary. If you do not see its contents the file may be temporarily unavailable at the journal website. Hlh 2004, jan 2004 2 contents addresses study committee, local coordinators, study data manager 3 data safety monitoring board, senior advisors 4 figure 1 flow sheet for children with hlh in hlh 2004 5 figure 2 treatment protocol overview for hlh 2004 6 figure 3 documentation sheet for the initial therapy in hlh 2004 7. Increased levels of various cytokines and soluble interleukin2 receptor are biological markers of hlh. Secondary hemophagocytic lymphohistiocytosis has a high mortality rate among adults despite recent advances in treatment. Ann yeh 0 ahmed naqvi 3 janinge henter gritta janka 2 0 division of neurology, department of pediatrics, the hospital for sick children, university of toronto, toronto, on, canada 1 department of pediatrics. Treatment of hemophagocytic lymphohistiocytosis with hlh94. Hlh associated with viral infections is treated accordi ng to the hlh 2004 protocol. The primary autosomal recessive form, familial hemophagocytic lymphohistiocytosis fhl, has an estimated incidence of around 1. Bone marrow may or may not show evidence of hlh, hence. Hemophagocytic lymphohistiocytosis hlh is a condition in which the body makes too many activated immune cells macrophages and lymphocytes. Read online histiocyte society hlh 2004 skion book pdf free download link book now.
Patients with all forms of hlh who were treated according to the hlh 94 protocol had a 5year. Presentation of hemophagocytic lymphohistiocytosis due to. Filipovich, eiichi ishii, gritta janka, stephan ladisch, kai lehmberg, kenneth l. Hemophagocytic syndrome hfs is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent. Treatment protocol the hlh94 treatment protocol includes 8 weeks of initial therapy, aiming. The pathogenesis of shlh, unlike primary hlh, which is primarily genetic, is poorly understood. Autoimmuneassociated hemophagocytic syndromemacrophage. Prevalence and outcome of secondary hemophagocytic. Prior to that point, a program known as hlh 94 was used. There was no statistically significant in mortality and laboratory data at diagnosis between two groups. Read online histiocyte society hlh2004 skion book pdf free download link book now. As a part of a themed collection of articles on ebv infection and human primary immune deficiencies.
Oct 01, 2002 janinge henter, annacarin samuelssonhorne, maurizio arico, r. Given the success of the earlier hlh 94 protocol, the hlh 2004 protocol moved cyclosporine dosing to the beginning of induction and hydrocortisone was added to methotrexate as part of the intrathecal therapy. An associated gene mutation may be found which impairs cytolytic lymphocyte function. Hemophagocytic syndromes hpss including hemophagocytic. Epsteinbarr virus and hemophagocytic lymphohistiocytosis. We analyzed the underlying diseases, clinical characteristics, 1aboratory. Presentation of hemophagocytic lymphohistiocytosis due to a. Treatment protocol for hemophagocytic lymphohistiocytosis 2004. Diagnostic criteria for hlh used in the hlh2004 trial2. Rituximab, etoposide, methylprednisolone, highdose cytarabine, and cisplatin in the treatment of secondary hemophagocytic lymphohistiocytosis with classical hodgkin lymphoma.
Hemophagocytic lymphohistiocytosis hlh is a lifethreatening immunodeficiency and multiorgan disease that affects people of all ages and ethnic groups. The hlh 2004 protocol consists of a twoweek induction phase including etoposide, cyclosporin a. Patients can be affected following immune activation after an oncologic, autoimmune or infectious trigger. Epsteinbarr virus ebv is a ubiquitous virus that infects nearly all people worldwide without serious sequela.
Hemophagocytic lymphohistiocytosis secondary to babesia in an immunocompetent adult. Download histiocyte society hlh 2004 skion book pdf free download link or read online here in pdf. Familial form of hlh disease, which is an autosomal recessive hematological disorder is due to diseasecausing mutations in several genes. Lch 2006 02 hemophagocytic lymphohistiocytosis study group treatment protocol of the second international hlh study 2004 start of the study. Henter ji1, horne a, arico m, egeler rm, filipovich ah, imashuku s, ladisch s, mcclain k, webb d, winiarski j, janka g.
Here we describe a model of shlh that recapitulates many aspects of human shlh. Unlike other iraes, hlh triggered by immune checkpoint blockade is not well described. Primary, genetic, as well as secondary forms of hlh have been described. Langerhans cell histiocytosis mercaptopurine, prednisolone no cclg relapsed resistant lch lch. This program was created by an international team of doctors in 2004 to attempt to address the poor survival rates of patients with hlh. The etoposidebased treatment protocol hlh94 consisted of 8 weeks of induction therapy and subsequent continuation therapy until hematopoietic stem cell transplantation hsct for patients with familial, relapsing, or severe and persistent hlh. How to treat involvement of the central nervous system in. The international histiocyte society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis hlh or macrophage activation syndrome mas should be treated with the same immunosuppressantcytotoxic. The 2004 treatment protocol formulated at the second. Histologic features reported for skin lesions in hlh are variable, but cutaneous hemophagocytosis has only been reported by smith et al, 4 and all of those cases were associated with deep lymphoid infiltrates ie, cytophagic histiocytic panniculitis. The cumulative experiences from hlh94 and other studies have led to the development of a new treatment protocol presented here, hlh 2004, which includesupdateddiagnosticand therapeutic guidelines from the.
Hlh is extremely rare, and more unusual is the isolated central nervous system presentation. Bc cancer protocol summary for treatment of hemophagocytic. Confirmed efficacy of etoposide and dexamethasone in hlh treatment. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Curr treat options neurol how to treat involvement of the central nervous system in hemophagocytic lymphohistiocytosis. Zhu reported that 714 paediatric patients 50% who were treated with the hlh 2004 protocol ultimately died. All books are in clear copy here, and all files are secure so dont worry about it. Hemophagocytic lymphohistiocytosis hlh has had a dismal prognosis.
According to the hlh 2004 protocol, hlh can be defined as fulfillment of at least five of eight clinical and laboratory criteria. A 12yearold girl presented with fever, rash, hepatosplenomegaly, pancytopenia, and elevated levels of ferritin and soluble cd25. Frontiers hemophagocytic lymphohistiocytosis in children. Fhl is the leading cause of hlh in newborns and toddlers. The cumulative experiences from hlh94 and other studies have led to the development of a new treatment protocol presented here, hlh2004, which includesupdateddiagnosticand therapeutic guidelines from the. Web to pdf convert any web pages to highquality pdf files. For example, the induction phase of the pediatric hlh 2004 protocol consists of 8 weeks of etoposidebased therapy, and treatment after. Adult secondary hemophagocytic lymphohistiocytosis shlh is a fulminant hyperinflammatory syndrome with mortality exceeding 80% in spite of stateoftheart medical care. Hemophagocytic lymphohistiocytosis hlh is a rare but lifethreatening hyperinflammatory.
The hlh 2004 protocol, which moved csa into upfront induction treatment simultaneously with etoposide and dex should not be administered routinely. Individualized therapy is essential for hlh, not simply referring to hlh 2004 or hlh1994. Download histiocyte society hlh2004 skion book pdf free download link or read online here in pdf. Management is largely based on hlh 2004 protocol for secondary cases and almost all cases of primary hlh require. Pdf how to treat involvement of the central nervous system. The difference between the hlh 2004 and the es csa and adds intrathecal injection 5, 11. Frontiers severe recurrent fever episodes with clinical. Use pdf download to do whatever you like with pdf files on the web and regain control. Department of internal medicine, division of hematologyoncology, nyu winthrop hospital, mineola, new york. Hemophagocytic lymphohistiocytosis hlh is a severe hyperinflammatory syndrome that presents with unremitting fever, splenomegaly and cytopenia. The clinical and research pioneers at cincinnati childrens are committed. Hemophagocytic lymphohistiocytosis hlh is a rare but potentially lethal disorder characterized by erratic immune activation. Patients with a positive family history and who received hsct after induction therapy according to the hlh 94 protocol had a 5year survival of 50%. How i treat hemophagocytic lymphohistiocytosis ncbi.
The hlh 94 protocol induced remission or allowed the patient to undergo hsct in 71% of cases. The term secondary hlh is used when your doctor thinks the condition may have occurred for a variety of other noninherited reasons. Targeted highthroughput sequencing for genetic diagnostics. Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis. The treatment protocols hlh94 and hlh2004 have been established as scientific cornerstones for diagnosis, classification, and treatment of. Primary, or familial, hlh is when the condition is inherited. A case report of novel mutation in prf1 gene, which causes. In a similar hlh2004 treatment protocol main difference was the use of.
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