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. Hemophagocytic lymphohistiocystosis johns hopkins medicine. Patients with all forms of hlh who were treated according to the hlh94 protocol had a 5year. In children, there are 2 large studies on denguehlh. Hereditary and acquired hemophagocytic lymphohistiocytosis ling zhang, md, jun zhou, md, and lubomir sokol, md, phd background. While paediatrichlh has been extensively characterised, similar studies in adults are limited. In the adult hlh protocol at utmdacc we have added alemtuzumab, a monoclonal antibody directed against cd52 an antigen expressed on. Documentation sheet for the initial therapy in hlh2004 week 18 to be sent to local subcentercoordinator, with followup report sheet 2 months after onset of therapy dexa mg vp16 150 mg ivm2. Hemophagocytic lymphohystiocytosis hlh is a hyperinflammatory syndrome caused by ineffective immune response to diverse stimuli, such as infections, metabolic products or tissue damage 1, 2. Hlh2004 chemoimmunotherapy includes etoposide, dexamethasone, cyclosporine a upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids.
Hlh outcome in patients treated with the hlh94 etoposidedexamethasone backbone p 5. Confirmed efficacy of etoposide and dexamethasone in hlh. Based on the treatment protocol, there were 23 patients received hlh2004 protocol 18 survive and 5 patients died and 12 patients received hlh94 protocol 9 patients survive and 3 patients died. 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. A sixteenyearold girl with still disease diagnosis developed a progressive multiorgan failure including acute respiratory distress. Hemophagocytic lymphohistiocytosis hlh is a condition of uncontrolled immune activation with a high mortality rate. Hlh2004 protocol pdf adobe acrobat treatment for hlh hemophagocytic lymphohistiocytosis, is a rare disorder of. Postbone marrow transplant patient management liams. Macrophage activation syndrome as a severe complication of the systemic form of juvenile idiopathic arthritis sjia is a prototype of aahs. Listing a study does not mean it has been evaluated by the u. Without therapy, survival of patients with active familial hlh is.
Hemophagocytic lymphohistiocytosis hlh is a lifethreatening disorder that can rapidly deteriorate and lead to multiple organ failure mof and death 1, 2. We would like to show you a description here but the site wont allow us. The full hlh2004 protocol is available by contacting the histiocytosis association of america. Unlike other iraes, hlh triggered by immune checkpoint blockade is not well described. Protocol, hlh2004, opened on january 1, 2004, and is based on the histiocyte societys original hlh94 protocol, which had previously opened on january 1, 1995, with some minor modifications. It is classified as primary familial or secondary acquired 3, 4. Treatment protocol the hlh94 treatment protocol includes 8 weeks of initial therapy, aiming at achieving a clinical remission, followed by a continuation therapy aiming at keeping the children alive and stable until an acceptable bmt donor becomes available figure 1. There is increased ectopic migration and proliferation of t cells, tissue infiltration by activated macrophages histiocytes, hyperactivation of lymphocytes, and prolonged release of proinflammatory cytokines.
Haemophagocytic lymphohisticytosisan underrecognized. Treatment protocol for hemophagocytic lymphohistiocytosis 2004 the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Given the success of the earlier hlh94 protocol, the hlh2004 protocol moved cyclosporine dosing to the beginning of induction and hydrocortisone was added to methotrexate as part of the intrathecal therapy. Hyperferritinemia in the critically ill child with. The hlh94 protocol induced remission or allowed the patient to undergo hsct in 71% of cases. Hlh is currently treated with a protocol or treatment program called hlh2004. Hlh2004, 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 hlh2004 5 figure 2 treatment protocol overview for hlh2004 6 figure 3 documentation sheet for the initial therapy in hlh2004 7. Hlh2004 may be improved by riskgroup stratification, less therapy reduction weeks 7 to 8 for verified fhl patients, and earlier hsct. The recommended therapeutic guideline for hlh was published by the histiocyte society in 1994 and revised in 2004, which greatly improved the survival in patients with hlh. Additional blood tests revealed elevated levels of soluble interleukin il2. Lymphohistiocytosis hemophagocytic lymphohistiocytosis. Clinical nurse specialist, jean marie colbert bone marrow transplant center. Currently, hlh 2004 diagnostic criteria are followed worldwide in spite of the presence of a newer proposal put forth by hlh society in 2009 6.
Patients with a positive family history and who received hsct after induction therapy according to the hlh94 protocol had a 5year survival of 50%. This program was created by an international team of doctors in 2004 to attempt to address the poor survival rates of patients with hlh. Subsequent hematopoietic stem cell transplantation hsct is recommended for patients with familial disease or molecular diagnosis, and patients with severe and. Malignancyassociated hlh mhlh often impedes adequate treatment of malignancy and has the worst outcome compared.
Hemophagocytic lymphohistiocytosis hlh is a rare disorder in children that is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia. Acquired hemophagocytic lymphohistiocytosis hlh triggered by a known or still to be recognized malignancy is a lifethreatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Frontiers hemophagocytic lymphohistiocytosis in children. The goal of this clinical research study is to compare the effect of adding either alemtuzumab or tocilizumab to the drug combination of etoposide and dexamethasone in controlling hlh. The hlh2004 protocol uses the presence of 58 criteria to diagnose hlh. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. The 2004 diagnostic criteria for hlh requires 5 out. Hlh as a serious complication of autoimmune diseases is commonly called macrophage activation syndrome or autoimmuneassociated hemophagocytic syndrome.
Secondary hemophagocytic lymphohistiocytosis has a high mortality rate among adults despite recent advances in treatment. Subsequent hematopoietic stem cell transplantation hsct is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent. Hemophagocytic lymphohistiocytosis hlh is a severe hyperinflammatory syndrome that presents with unremitting fever, splenomegaly and cytopenia. Hlh2004 protocol pdf adobe acrobat treatment for hlh. Hereditary and acquired hemophagocytic lymphohistiocytosis. Treatment of hemophagocytic lymphohistiocytosis with hlh. Increased levels of various cytokines and soluble interleukin2 receptor are biological markers of hlh. Aims haemophagocytic lymphohistiocytosis hlh is divided into paediatric primary and adult secondary types. In adults, many different conditions, including infections and cancer, can cause hlh. Copinion treatment of hemophagocytic lymphohistiocytosis. Hlh is a progressive syndrome of unchecked immune activation and tissue damage. 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. According to the hlh2004 protocol, hlh can be defined as fulfillment of at least five of eight clinical and laboratory criteria. Hemophagocytic syndrome hfs is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent.
Zhu reported that 714 paediatric patients 50% who were treated with the hlh2004 protocol ultimately died. Primary hlh is an autosomal recessive disorder caused by a number of different perforin signaling mutations. Presentation of hemophagocytic lymphohistiocytosis due to. There has been little consensus on how to treat shlh with the exception of mas complicating sjia, and often elements of the hlh2004 protocol are used. Hemophagocytic lymphohistiocytosis hlh and macrophage activation syndrome mas were historically thought to be distinct entities, often managed in isolation. How to treat involvement of the central nervous system in. Because of increased neurotoxicity, 39 and absent the final analysis of hlh2004, the current recommendation is not to use csa in the first couple of weeks. A collaborative approach, which incorporates expertise from subspecialties that previously treated hlhmas independently, is needed.
Management of hemophagocytic lymphohistiocytosis hlh in. If left untreated, patients with hlh survive for only a few months, due to progressive multiorgan failure. There was no statistically significant in mortality and. We analyzed the underlying diseases, clinical characteristics, 1aboratory. Our objective is to raise the importance of hfs early diagnosis by presenting a representative case. Hlh2004 chemoimmunotherapyincludesetoposide, dexamethasone,cyclos porine a upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids.
Hemophagocytic lymphohistocytosis hlh is a rare but fatal hyperinflammatory syndrome caused by uncontrolled proliferation of activated macrophages and t lymphocytes secreting high amounts of inflammatory cytokines. Hemophagocytic lymphohistiocytosis refers to a potentially fatal clinical syndrome of hyperinflammation and progressive immunemediated organ damage due to overstimulated but ineffective immune response 1. The safety of the drug combinations will also be studied. Treatment of hemophagocytic lymphohistiocytosis with. Lch 2006 02 hemophagocytic lymphohistiocytosis study group treatment protocol of the second international hlh study 2004 start of the study. Successful treatment of recurrent malignancyassociated.
Primary, genetic, as well as secondary forms of hlh have been. B in hlh2004, csa aiming at 200 gl trough value is administered already upfront during the initial therapy, a modification from hlh94 where csa is not administered until the continuation therapy. The hlh94 protocol was used as a treatment guideline, 1 and dexamethasone and etoposide therapy were initiated. French investigators have therefore proposed an adapted webbased diagnostic tool, the hscore, which comprises selected criteria from hlh2004 with grading according to severity. Alemtuzumab or tocilizumab in combination with etoposide. Hemophagocytic lymphohistiocytosis hlh is a rare but lifethreatening hyperinflammatory. Hemophagocytic lymphohistiocytosis hlh is a clinical syndrome of abnormal immune activation causing excess inflammation. This study aims to evaluate the significance of the hlh diagnostic criteria as well as other clinical parameters in adults with bone marrow evidence of. Hemophagocytic lymphohistiocytosis with immunotherapy. Hemophagocytic lymphohistiocytosis hlh is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Hemophagocytic lymphohistiocytosis hlh, a rare but potentially fatal syndrome of immune hyperactivation, may be an underrecognized immunerelated adverse event irae. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
Hlh is complicated to be diagnosed as there are many common symptoms with other. Diagnostic tests for genetic hlh include functional assessment of lymphocyte cytotoxicity and guided genetic testing. Treatment protocol for hemophagocytic lymphohistiocytosis 2004. In 1994, the histiocyte society organized the first treatment protocol for hlh hlh94, which dramatically increased this survival rate to 54 percent with a. Currently, national multicentre research on the efficacy of the hlh2004 treatment protocol is underway. Since cnshlh is a condition leading to the most severe late effects of hlh, early expert consultation is recommended. The diagnosis of hlh in adults should be based on the hlh2004 diagnostic criteria in conjunction with clinical judgment and the patients history strong consensus. Hemophagocytic lymphohistiocytosis hlh is a rare disease that usually occurs in infants and young children. A recent evidencebased algorithm has been proposed 2 using il1 blockade with anakinra fig. Diagnostic criteria developed for the pediatric hlh2004 protocol have been widely adopted in adult medicine without systematic validation. Alemtuzumab, etoposide, tocilizumab, and dexamethasone are not fda approved for the. Treatment of hemophagocytic lymphohistiocytosis in adults. Hlh occurs in patients with genetic background for this condition, in the setting of immunodeficiency, as well as in healthy individuals. The hlh2004 protocol, which moved csa into upfront induction treatment simultaneously with etoposide and dex should not be administered routinely.
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