Hlh 2004 protocol pdf

It was destruction of target cells by allowing the entry of therefore a major therapeutic advance when allogeneic granzymes, which trigger apoptosis. However, perforin hematopoietic stem cell transplantation HSCT was shown concentrations which are lower than necessary for pore to provide cure for FHL [51—53]. Recent studies suggest that entry of granzyme B overall in HLH at a median follow-up of 3. The encoded protein, Munc [48].

In addition, minor revisions are included, as series, respectively [42,43]. Not surprisingly in a should not automatically preclude HSCT [56]. The recom- disease characterized by severe cytopenias and an immuno- mended dosages for chemotherapy used in the preparative deficiency, dose modifications in HLH were common. In regimen and the graft-versus-host-disease GVHD prophy- particular, the doses of VP were decreased in a substantial laxis have been modified slightly in the HLH protocol number of the patients.

For dexamethasone, the amount to reflect more recent HSCT experience. During the first 4 years of HLH, six patients were HLH Study Design reported to have died during the first month of treatment and six more during the second month of treatment. It was The HLH protocol is designed for the patients with sometimes difficult to clarify whether death was caused by HLH, with or without evidence of familial or genetic disease, the disease or by its treatment, in particular in case of regardless of suspected or documented viral infections.

The infections associated with neutropenia. However, most Japanese experience has demonstrated that patients with deaths were considered to be due to the HLH disease by EBV infection and a clinical picture of HLH have a the reporting physicians.

Because of the data cited above, it significant advantage when treated according to this was proposed that treatment intensity be increased during the approach [57]. Initial therapy weeks 1—8 is based on first 2 months of therapy with a drug that does not induce etoposide, dexamethasone, and CSA; only selected patients myelotoxicity. As a result, in HLH CSA is initiated will receive intrathecal therapy with methotrexate and upfront instead of after 8 weeks.

For a general overview of the patient Continuation therapy. Of the six children who died treatments options in HLH, see Figure 1. All children with familial disease or with a cells and protein, and cytospin in case of CSF pleocytosis in diagnosis verified by genetic testing, as well as children with order to detect early reactivation in the CNS. As a minimum, a non-familial disease that is severe and persistent, or it is recommended to perform CSF analysis at the time of reactivated, are recommended to receive continuation systemic reactivation or new onset or reactivation of therapy with etoposide, dexamethasone, and CSA.

HSCT neurological symptoms. Brain MRI is also recommended at should be performed as early as possible, when an acceptable diagnosis in these situations.

Intrathecal therapy. With available HLH data, it has Patients less than 18 years of age at onset of therapy who not yet been possible to determine whether intrathecal fulfil the diagnostic criteria of HLH, and who have not therapy, in addition to the systemic HLH therapy, is received prior cytotoxic or CSA treatment for HLH, are beneficial or not. Systemic therapy, as provided in HLH, eligible to be enrolled.

It cannot be more and patients who do not fulfil the diagnostic criteria ruled out that intrathecal therapy may have additional will be studied separately. Similarly, patients with XLP, beneficial effects, at least in some patients, but potential Chediak—Higashi syndrome, Griscelli syndrome type 2, as side-effects also have to be considered [46,48,54,55]. The initial therapy covers the first tivation. As in HLH, up to four intrathecal doses are 8 weeks of treatment Fig. The complete protocol is recommended weeks 3—6, if the neurological symptoms are available for request at www.

With the potential broad-spectrum antibiotics until culture results are made beneficial effect of systemic corticosteroids in mind, it is available.

The supportive therapy includes prophylactic now suggested to add corticosteroids to the intrathecal cotrimoxazole, an oral antimycotic during the initial therapy, therapy. The estimated viral infections, and IvIG 0. The HLH results also suggest that some Continuation therapy.

Patients without a family history degree of disease activity at the time for transplantation of HLH and without genetic evidence of the disease are Pediatr Blood Cancer DOI Flow-sheet of treatment options for children with hemophagocytic lymphohistiocytosis in HLH If there is a treatable infection it should be treated but be aware that this may not be sufficient and the patient may need HLH-treatment in addition.

If HLH is persistent or recurring consider that the patient may have an undiagnosed inherited disease. HLH may also develop secondary to a number of other diseases as malignancies, rheumatic diseases, and metabolic disorders, requiring a different treatment. Start therapy if the patient has a genetically verified disease, a familial form of HLH, or if the disease is severe, persistent, or recurrent.

Increasing disease activity therapy is recommended, such as to restart from week 2, in may make it necessary to intensify the treatment in some which case the initial therapy may be less than 8 weeks, and children see below. Intrathecal Reactivation therapy. FHL is characterized by frequent therapy is recommended in cases of CNS-reactivation reactivations, or even more or less continuous disease [46,48,54]. HSCT has high priority. In particular, reactivation of the disease is common Salvage therapy.

The HLH protocol does not as therapeutic intensity is reduced, such as during the later include a salvage protocol. We want to mention an alternative part of the initial therapy. Accordingly, a reactivation will approach of inducing remission, with a regimen including a commonly respond to an intensification of the initial therapy. However, in our Reactivations may also occur following immune response experience ATG usually fails in patients that are non- triggering, such as infections and vaccinations.

In cases of responders. It is therefore suggested that salvage therapy is reactivation, broad-spectrum antibiotics, antiviral therapy, discussed with the local sub-center. Note that early after and antifungal therapy should also be considered as HSCT, the immunodysregulation may induce a sHLH supportive or therapeutic measures. Schematic treatment overview of the HLH protocol. For information on whether to start continuation therapy and perform stem-cell transplantation, see text and Figure 1.

The complete protocol is available for request at www. These studies have all been successful and Stopping therapy. Stopping therapy is only recom- they have improved diagnostics and therapy, and increased mended in children with complete resolution of the disease. This causes the of ferritin, serum transaminases, and sCD It is possible to identify a cohort of individuals with PRF gene The choice of the donor rests with the treating mutations by the use of flow cytometry for the perforin physician.

If an HLA-identical relative is not available, protein [17]. Moreover, it has also recently been shown that a matched unrelated donor is recommended. The risk of the cytotoxicity defect can be grouped in four subtypes [18], a sibling carrying the disease must be considered.

The goals are to: 1 gather biological siblings may also have persistently decreased NK-cell material in order to identify additional genetic defects; activity [16].

Outcome in the HLH associations; 4 and study the biological and clinical study with regard to various donors has been presented significance of cytotoxic subgroups. It is therefore recom- [57].

Results with mismatched donors are improving mended that study patients be analyzed for genetic muta- [52,53,56,58,59]. The use of peripheral blood or cord blood HSCT may be considered, at the discretion of the physician. The preparative regimen for HSCT and the GVHD prophylaxis Survival for patients with HLH has improved dramatically rests with the transplantation unit, but a suggested regimen is during the last decades as has the understanding of the provided.

It proposes including etoposide, in addition to underlying biological mechanisms. The HLH treatment busulfan and cyclophosphamide, in the conditioning regi- protocol has been widely accepted, and patients from men, in accordance with previous experiences [48,53]. The 29 countries have been registered in the database.

Based on dosages suggested are outlined in the complete protocol, the cumulative experiences from HLH and other studies, a available for request at www. In haploiden- order to attempt to further improve diagnosis, therapy and tical and antigen mismatched unrelated transplants, T-cell- biological understanding, participation in HLH clinical trials depletion may need to be considered.

Since there is evidence is encouraged. Familial hemophagocytic and methotrexate may be substituted by mycophenolate lymphohistiocytosis primary HLH. Hematol Oncol Clin North Am ;— Additional treatment for unrelated donor transplants 2. Infection- and malignancy- include ATG [53]. There are limited data lymphohistiocytosis. It is — Case Rep Hematol. Published online Dec Albaraa T. Alfaraidi , 1 Abdulaziz A.

Alqarni , 1 Mohammed T. Aqeel , 1 Turki A. Albalawi , 1 and Ahmed S. Hejazi 2. Abdulaziz A. Mohammed T. Turki A. Ahmed S. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Hejazi: moc. Received Oct 6; Accepted Dec Alfaraidi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Associated Data Data Availability Statement Any inquiries about the availability of data presented in this study may be directed to the corresponding author. Abstract Hemophagocytic lymphohistiocytosis HLH is a life-threatening hyperinflammatory syndrome that causes systemic inflammation which can progress to multiorgan failure and death. Introduction Hemophagocytic lymphohistiocytosis HLH is a life-threatening hyperinflammatory syndrome characterized by hypercytokinemia and lymphohistiocytic proliferation.

Case Presentation A year-old male, known to have glucosephosphate dehydrogenase G6PD deficiency, was admitted to our hospital due to pancytopenia accompanied by a high-grade intermittent fever of unknown origin for the last eight months which was not relieved by antipyretics. Open in a separate window. Figure 1. Table 1 An overview of relevant laboratory parameters during the clinical course of the patient. Discussion Familial HLH are a group of autosomal recessive diseases that occur frequently in consanguineous families [ 8 ].

Conclusion The diagnosis of HLH remains challenging as patients present with nonspecific symptoms. Acknowledgments The authors would like to thank the patient and his family for their approval and cooperation. Data Availability Any inquiries about the availability of data presented in this study may be directed to the corresponding author.

Ethical Approval Approval from an ethics committee was not required according to the institution policy. Consent Informed written consent was obtained from the patient for the publication of this case report. Conflicts of Interest The authors declare that they have no conflicts of interest. References 1. Al-Samkari H. Hemophagocytic lymphohistiocytosis. Annual Review of Pathology: Mechanisms of Disease. Morimoto A.

Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatrics International. Janka G. Familial hemophagocytic lymphohistiocytosis.

European Journal of Pediatrics. Schram A. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. British Journal of Haematology. Griffin G. Hemophagocytic lymphohistiocytosis: an update on pathogenesis, diagnosis, and therapy. Elyamany G. Hemophagocytic lymphohistiocytosis: single-center series of 12 cases from Saudi Arabia. Clinical Medicine Insights: Pediatrics. Esteban Y. Please refer to this study by its ClinicalTrials.

More Information. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH study. Epub Sep HLH Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH study. Blood Adv. Hemophagocytic lymphohistiocytosis. National Library of Medicine U. National Institutes of Health U.

Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Hemophagocytic Lymphohistiocytosis. Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Study Start Date :.