We describe a pediatric case of hemophagocytic lymphohistiocytosis with a. During treatment myopathy appeared due to dexamethasone. Hemophagocytic lymphohistiocytosis hlh is a rare disorder in children that is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia. A multidisciplinary approach to a complex clinical syndrome.
Ferritin levels were fall to approximately 0 gdl from 15000. This site is like a library, you could find million book here by using search box in the header. We here conducted a prospective study of 73 patients who were treated with hlh 2004 protocol in japan. Bc cancer protocol summary for treatment of hemophagocytic. In it is currently quite variable, in part duadults, e to the variability in underlying causes. Pdf hemophagocytic lymphohistiocytosis hlh is an immune disorder characterized by uncontrolled inflammation due to defective immune response. Hemophagocytic lymphohistiocytosis hlh is a disorder charecterised by immune dysregulation. The protocol included an initial intensive therapy with immunosuppressive and cytotoxic agents for 8 weeks, with the aim to induce remission of the disease activity figure 1. Hlh outcome in patients treated with the hlh 94 etoposidedexamethasone backbone p 5. Diagnostic and therapeutic guidelines for hemophagocytic. Listing a study does not mean it has been evaluated by the u.
Our treatment regimen was initiated due to the patients declining clinical status and concurrent hepatic. Hlh2004 chemoimmunotherapyincludesetoposide, dexamethasone,cyclos porine a upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. In 1991, the histiocyte society proposed a standardized set of 5 diagnostic criteria for hlh used for the prospective hlh94 clinical trial. We leveraged quality improvement qi techniques in the. Hemophagocytic syndrome hfs is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent. Mar 19, 2012 hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome mods, and critical illness. The hlh94 protocol induced remission or allowed the patient to undergo hsct in 71% of cases.
Case report a case of primary bone marrow, liver, and spleen. Moreover, in the hlh2004 protocol, in addition to i. 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. The information contained in these documents are a statement of. The hlh 2004 protocol modified this with early cyclosporin, but survival was not significantly. In hlh 2004 we provide additional therapy during this period as compared. Given the success of the hlh94 protocol, in 2004, a revised protocol called hlh 2004 was proposed, which aimed to 1 evaluate a revised initial and continuation therapy with an end goal of. The protocol could not be administrated full dose because of severe neutropenia. He was treated with dexamethasone, cyclopsporin and etoposide, but soon after starting treatment he showed dramatic responses with resolution of fever and correction of hepatitis, pancytopenia and. 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.
Hlh as a serious complication of autoimmune diseases is commonly called macrophage activation syndrome or autoimmuneassociated hemophagocytic syndrome. Gene testing for known hlhassociated mutations generally only done in. Hlh 2004 may be improved by riskgroup stratification, less therapy reduction weeks 7 to 8 for verified fhl patients, and earlier hsct. Hemophagocytic lymphohistiocytosis hlh used to have a dismal prognosis. A sixteenyearold girl with still disease diagnosis developed a progressive multiorgan failure including acute respiratory distress ards, anemia and thrombopenia. Our objective is to raise the importance of hfs early diagnosis by presenting a representative case. 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. Epsteinbarr virus and hemophagocytic lymphohistiocytosis.
Primary, genetic, as well as secondary forms of hlh have been described. For secondary hlh, including ebvhlh, immunochemotherapy based on the hlh 2004 protocol. Hereditary and acquired hemophagocytic lymphohistiocytosis ling zhang, md, jun zhou, md, and lubomir sokol, md, phd background. Hereditary and acquired hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis, also known as haemophagocytic lymphohistiocytosis british spelling, and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder. Treatment protocol for hemophagocytic lymphohistiocytosis 2004. How i treat hemophagocytic lymphohistiocytosis ncbi. The hlh2004 protocol, which moved csa into upfront induction treatment simultaneously with etoposide and dex should not be administered routinely. Familial hlh is inherited in an autosomal recessive manner. It may occur as a primary genetic condition due to mutations in genes important in the cytolytic secretory pathway that cause perforin. The primary autosomal recessive form, familial hemophagocytic lymphohistiocytosis fhl, has an estimated incidence of around 1.
Case report common variable immune deficiency associated. The patient was suspected as a case of hlh according to hlh 2004 protocol given the fact that he fulfilled the necessary criteria mentioned above. Henter ji1, horne a, arico m, egeler rm, filipovich ah, imashuku s, ladisch s, mcclain k, webb d, winiarski j, janka g. Hlh associated with viral infections is treated accordi ng to the hlh 2004 protocol, which includes etoposide. Secondary hemophagocytic lymphohistiocytosis has a high mortality rate among adults despite recent advances in treatment.
A case report of novel mutation in prf1 gene, which causes. Targeted highthroughput sequencing for genetic diagnostics. Hemophagocytic lymphohistiocytosis in a newborn infant. Hypercytokinemia which is the hallmark of hlh can result in end organ damage. Clinical features include repetitive fever, hepatomegaly. Hemophagocytic lymphohistiocytosis hlh was first described in. Prior to that point, a program known as hlh94 was used. Epsteinbarr virus ebv is a ubiquitous virus that infects nearly all people worldwide without serious sequela. Recommendations for the management of hemophagocytic. We would like to show you a description here but the site wont allow us. Sep 11, 2017 hemophagocytic lymphohistiocytosis hlh may be inherited or acquired due to nongenetic factors. Read online histiocyte society hlh 2004 skion book pdf free download link book now. Of the patients on the hlh 2004 protocol with followup data, seven patients 54% died due to complications related to hlh mean survival of 49 days, range 190 days. In contrast to pediatric hlh, adult hlh is more commonly secondary in nature and often therapy.
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. These preliminary data suggest that ruxolitinib is active, well tolerated, and manageable in the outpatient setting in patients with secondary haemophagocytic lymphohistiocytosis. Department of pediatrics, karolinska hospital, stockholm, sweden. Pdf on apr 30, 2017, sun young park and others published hemophagocytic lymphohistiocytosis find, read and cite all the research you need on researchgate. A molecular diagnosis consistent with hlh, and or fulfillment of five out of eight of the following diagnostic criteria fever, splenomegaly, cytopenias. Hyperferritinemia in the critically ill child with secondary. Deciding whether persistent neutropenia or thrombocytopenia is due to disease or etoposide will depend upon clinical judgement. Ruxolitinib in adult patients with secondary haemophagocytic.
In 1994, the histiocyte society organized the first treatment protocol for hlh hlh94, which dramatically increased this survival rate to 54 percent with a median followup of six years. Hemophagocytic lymphohistiocytosis hlh and macrophage activation syndrome mas were historically thought to be distinct entities, often managed in isolation. Hemophagocytic lymphohistiocytosis with immunotherapy. Lch 2006 02 hemophagocytic lymphohistiocytosis study group treatment protocol of the second international hlh study 2004 start of the study. Read online histiocyte society hlh2004 skion book pdf free download link book now. Frontiers hemophagocytic lymphohistiocytosis in children. Confirmed efficacy of etoposide and dexamethasone in hlh. Our patient was diagnosed with ebvdriven hlh as she fulfilled five of the eight required criteria for diagnosis, and she was started on chemotherapy with etoposide, dexamethasone and ciclosporin based on hlh 2004 protocol. We analyzed the underlying diseases, clinical characteristics, 1aboratory. This program was created by an international team of doctors in 2004 to attempt to address the poor survival rates of patients with hlh. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis hlh has had a dismal prognosis. Dec 18, 2015 hemophagocytic lymphohistiocytosis hlh is a severe hyperinflammatory syndrome that presents with unremitting fever, splenomegaly and cytopenia.
Hemophagocytic lymphohistiocytosis hlh is a potentially fatal hyperin. This initial therapy included etoposide, which is proapoptotic in hlh. 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. Deciding whether persistent neutropenia or thrombocytopenia is. Treatment of hemophagocytic lymphohistiocytosis with cyclophosphamide, vincristine, and prednisone. No statistical evidence showing hlh2004 is better than hlh94 hlh94 protocol with hlh2004 diagnostic criteria need trial comparing novel therapeutic approaches to hlh concepts adjusted for age and gender bergsten e, et al. Hlh2004 chemoimmunotherapyincludesetoposide, dexamethasone,cyclos. Jun 12, 2019 in children, there are 2 large studies on denguehlh.
An associated gene mutation may be found which impairs cytolytic lymphocyte function. The histiocyte society study group for hlh developed the hlh94 and hlh 2004. Histiocyte society hlh2004 skion pdf book manual free. Dexamethasone plays a significant role in a number of therapeutic regimens used in the pediatric form of hps, namely the hlh2004 protocol. Finally, for practical reasons, the hlh2004 diagnostic criteria do not include all. Currently, diagnosis is based on the hlh2004 criteria box 1 derived from the paediatric hlh2004 protocol, which has not been validated in adult patients with hlh. Lymphohistiocytosis according to the hlh2004 protocol.
Primary, or familial, hlh is when the condition is inherited. Treatment of hemophagocytic lymphohistiocytosis hlh has been developed primarily in pediatric centers, where familial hlh fhl is the leading cause of hlh in newborns and toddlers. 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. Treatment according to the hlh94 protocol leads to a complete remission rate of 50% and a 3year overall survival rate of 55% 9. Nasopharyngeal carcinoma associated with hemophagocytic. However, for patients who have genetic diseases which predispose them to the development. Secondary hemophagocytic lymphohistiocytosis in adults. Treatment of hemophagocytic lymphohistiocytosis with hlh. The treatment protocols hlh94 and hlh2004 have been established as scientific cornerstones. Unlike other iraes, hlh triggered by immune checkpoint blockade is not well described. Hlh in adults is a much more heterogeneous syndrome requiring a more individualized approach depending on the. Hemophagocytic lymphohistiocytosis is a potentially fatal disease characterized by excessive macrophage and lymphocyte activity. The treatment of hlh in children in whom genetic defects in t cell function often underlie the disease is standardized and protocol driven. In hlh2004 we provide additional therapy during this period as compared to in hlh94.
Given the paucity of effective, nonmyelosuppressive therapies, these preliminary findings have important therapeutic implications for patients with haemophagocytic lymphohistiocytosis and other cytokinerelease. We report the final results of hlh94, the largest prospective diagnostictherapeutic hlh study so far. This means that to be affected, a person must have a change mutation in both copies of the responsible gene in each cell. Though it was underdiagnosed earlier now it is increasingly being diagnosed across the world with better awareness among physicians. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis. It is a lifethreatening condition that can be defined as either primary or secondary hlh. Request pdf outcomes in children with hemophagocytic lymphohistiocytosis treated using hlh 2004 protocol in japan recent advances in intensive chemo and immunotherapy have contributed to the. Apr 16, 2010 hlh is currently treated with a protocol or treatment program called hlh2004. All books are in clear copy here, and all files are secure so dont worry about it. According to the hlh2004 protocol, hlh can be defined as fulfillment of at least five of eight clinical and laboratory criteria. However, there were no signs of hematological recovery. Diagnostic criteria developed for the pediatric hlh 2004 protocol have been widely adopted in adult medicine without systematic validation. Fibrinogen and coagulation studies remained within normal limits.
Autoimmuneassociated hemophagocytic syndromemacrophage. For primary hlh, hematopoietic stem cell transplantation is the only accepted curative therapy, although cord blood transplantation with a reducedconditioning regimen has been used with superior outcomes. Zhu reported that 714 paediatric patients 50% who were treated with the hlh 2004 protocol. The first international treatment protocol for hlh was organized by the. Presentation of hemophagocytic lymphohistiocytosis due to a. Outcomes in children with hemophagocytic lymphohistiocytosis.
French investigators have therefore proposed an adapted webbased diagnostic tool, the hscore, which comprises selected criteria from hlh 2004. According to hlh2004 protocol for diagnostic guidelines 111, diagnosis of hlh can be established after fulfillment of either one or two of the following criteria. Patients with a positive family history and who received hsct after induction therapy according to the hlh94 protocol had a 5year survival of 50%. Patients with all forms of hlh who were treated according to the hlh94 protocol had a 5year. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis in hlh94, the first prospective. 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. Case report a case of primary bone marrow, liver, and.
Hemophagocytic lymphohistiocytosis hlh is a severe hyperinflammatory syndrome induced. Subsequent hematopoietic stem cell transplantation hsct is recommended for patients with familial disease or molecular diagnosis, and patients with severe and. Hemophagocytic lymphohistiocytosis hlh is a rare but lifethreatening hyperinflammatory. Hemophagocytic lymphohistiocytosis hlh, a rare but potentially fatal syndrome of immune hyperactivation, may be an underrecognized immunerelated adverse event irae. Treatment protocol for hemophagocytic lymphohistiocytosis 2004 the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. It is not clear how many of them achieved an initial full remission and if they had deviations from the etoposide dosing scheme, which were allowed in the protocol. We therefore performed cord blood transplantation with reducedintensity conditioning, and she achieved complete remission for over 2 years. Our objective is to raise the importance of hfs early diagnosis. Treatment of hemophagocytic lymphohistiocytosis in adults. Perforin gene mutation in familial haemophagocytic. The most dangerous period after hlh diagnosis is the first 2 months. Familial hemophagocytic lymphohistiocytosis genetic and.
Currently, national multicentre research on the efficacy of the hlh 2004 treatment protocol is underway. The patient was suspected as a case of hlh according to hlh2004 protocol given the fact that he fulfilled the necessary criteria mentioned above. Pdf treatment of hemophagocytic lymphohistiocytosis with. Patients can be affected following immune activation after an oncologic, autoimmune or infectious trigger. We here conducted a prospective study of 73 patients who were treated with hlh2004 protocol in japan. Diffuse large bcell lymphoma in an adolescent female. Ebvhlh, familial hlh fhl, and hlh of unknown etiology were seen in 41, 9, and 23 patients. Rituximab, etoposide, methylprednisolone, highdose. Macrophage activation syndrome as a severe complication of the systemic form of juvenile idiopathic arthritis sjia is a prototype of aahs.
The hlh2004 protocol is modified from hlh94 protocol in two ways. Open access protocol diagnostic biomarkers for adult. A collaborative approach, which incorporates expertise from subspecialties that previously treated hlh mas independently, is needed. Most patients with hlh have severe cytopenias at initiation of therapy and this is generally not a contra indication to initiation of treatment. Treatment of hemophagocytic lymphohistiocytosis with hlh94.
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. Histiocyte society hlh2004 hemophagocytic lymphohistiocytosis study group. Currently, the hlh94 protocol, perhaps with individual adaptation, may be used in the following. Treatment of hemophagocytic lymphohistiocytosis with.