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Literature review current through: Jun 2014. | This topic last updated: Apr 01, 2014.

INTRODUCTION — Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening syndrome of excessive immune activation. Prompt initiation of treatment for HLH is essential for the survival of affected patients.

The treatment and prognosis of patients with HLH and the macrophage activation syndrome (MAS), a form of HLH in patients with juvenile idiopathic arthritis and other rheumatologic conditions, will be discussed here. The genetics, clinical features, and diagnosis of HLH are presented separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

OVERVIEW AND INDICATIONS FOR TREATMENT — Hemophagocytic lymphohistiocytosis (HLH) is a progressive syndrome of unchecked immune activation and tissue damage. If left untreated, patients with HLH survive for only a few months, due to progressive multi-organ failure. In 1994, the Histiocyte Society organized the first treatment protocol for HLH (HLH-94), which dramatically increased this survival rate to 54 percent with a median follow-up of six years [1,2].

Often, the greatest barrier to treatment and a successful outcome for individuals with HLH is a delay in diagnosis. Several aspects of the clinical presentation of HLH contribute to this delay, including the rarity of the syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings. Diagnostic criteria for HLH are based upon those used in the major HLH studies, and therefore may be too stringent to capture all patients with HLH. Thus, treatment is appropriate for some who do not meet the strict diagnostic criteria but for whom there is a high degree of clinical suspicion for HLH. Any patient with suspected HLH should be seen by a hematologist, and those who are acutely ill should be transferred emergently to a facility where they can receive HLH therapy. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Evaluation and diagnostic testing' and 'Hematologist referral and pretreatment testing' below.)

The goal of therapy for patients with HLH is to suppress life-threatening inflammation by destroying immune cells. Induction therapy based on the HLH-94 protocol consists of a series of weekly treatments with dexamethasone and etoposide (VP-16), followed by cyclosporin. Intrathecal methotrexate is given to those with central nervous system disease. After induction, patients who are recovering are weaned off therapy, while those who are not improving are continued on therapy as a bridge to allogeneic hematopoietic cell transplantation (HCT). HCT will likely also be required in those with an HLH gene mutation and/or central nervous system disease.

In 2004, a new HLH protocol was initiated (HLH-2004). The major modifications were to use cyclosporin earlier (ie, during the induction phase of therapy), and to add hydrocortisone to the intrathecal methotrexate. Until the results of this trial are available, we prefer to treat patients with a regimen based on the HLH-94 protocol. (See 'Initial HLH-specific therapy' below.)

There is no one parameter that drives the decision to start HLH-specific therapy. If a patient is stable and the ferritin is stable below 10,000 or rises from 1000 to 3000 with only slightly elevated D-dimer and liver enzymes, this author would not start treatment. However, if those two parameters became progressively more abnormal, early initiation of at least dexamethasone treatment may halt the inflammation. Importantly, treatment should not be withheld while awaiting results of genetic or specialized immunologic testing. (See 'Hematologist referral and pretreatment testing' below and 'Acutely ill or deteriorating patients' below.)

Importantly, the appearance of hemophagocytosis on serial bone marrow studies is not necessarily a sign of disease worsening. For patients who also have a triggering infection or rheumatologic condition, treatment of the triggering condition should be initiated simultaneously with HLH-specific chemotherapy. (See 'Infection' below and 'MAS/rheumatologic conditions' below.)

When HLH is triggered by an acute infection or other condition (eg, rheumatologic condition), treatment of the trigger is appropriate because this may remove the stimulus for immune activation. Patients who are less acutely ill and stable may be able to tolerate treatment of the triggering condition alone without HLH-specific therapy; this strategy may allow some patients to avoid potentially toxic therapy. (See 'Clinically stable patients' below.)

Macrophage activation syndrome (MAS) is a form of HLH associated with juvenile idiopathic arthritis (JIA) and other rheumatologic conditions. Patients with MAS represent a subset of those with HLH for whom successful therapy of the underlying condition may produce a good response and allow the patient to avoid HLH-specific therapy. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS'.)

Patients with malignancy-induced HLH require control of the HLH followed by treatment of the underlying malignancy. Unless the malignancy can be cured and the stimulus for HLH permanently eliminated, we perform hematopoietic cell transplant. (See 'Initial HLH-specific therapy' below and 'Allogeneic hematopoietic cell transplant' below.)

HEMATOLOGIST REFERRAL AND PRETREATMENT TESTING — Rapid treatment of hemophagocytic lymphohistiocytosis (HLH) is essential, especially for those who are acutely ill or clinically deteriorating. (See 'Acutely ill or deteriorating patients' below.)

For all patients with suspected HLH, referral to a hematology or oncology specialist is urgently required in order to prepare for intensive chemotherapy and possible hematopoietic cell transplant (HCT). If a clinician with experience using the agents required for the HLH-94 protocol is not available, transfer to another facility should be initiated immediately.

Despite the significant improvement in survival with the HLH-94 protocol, mortality with HLH remains high. Thus, clinicians are encouraged to enroll patients in clinical trials testing HLH therapies or other clinical or research questions. (See 'Initial HLH-specific therapy' below.)

We perform the following pre-therapy testing in all patients:

HLA typing and search for an HCT donor – Patients with HLH gene mutations, hematologic malignancy, relapsing symptoms on or off therapy, and/or central nervous system disease will require HCT. Because the response to therapy is not known at the time therapy is started, all patients and appropriate family members should undergo HLA typing to facilitate identification of an HCT donor. Early initiation of HLA typing and selection of a donor shortens the pretransplantation interval, potentially improving the likelihood of survival [3]. If siblings are considered as potential donors, they should be tested for HLH gene mutations as well, to confirm that the donor does not have undiagnosed HLH. (See 'Allogeneic hematopoietic cell transplant' below and "Donor selection for hematopoietic cell transplantation".)

Cardiac function – We also perform a baseline evaluation of cardiac function (ie, electrocardiogram and echocardiogram) prior to starting chemotherapy, because some patients develop cardiac complications from inflammation or chemotherapy.

Disease markers – It is important to be able to monitor disease response to therapy, because treatment may need to be escalated if the patient is not improving; and the distinction between chemotherapy toxicity and disease worsening disease may be difficult to make clinically. We do baseline immunologic studies (eg, soluble IL-2 receptor alpha [sCD25], soluble hemoglobin-haptoglobin scavenger receptor [sCD163]) as well as other markers of disease activity (eg, ferritin, fibrinogen, D-dimer, liver function tests). (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Immunologic profile' and 'Monitoring treatment response' below.)

CLINICALLY STABLE PATIENTS

Overview (clinically stable) — Patients who are clinically stable and have a condition responsible for triggering hemophagocytic lymphohistiocytosis (HLH; eg, infection, rheumatologic condition) may respond to treatment of the triggering condition alone (algorithm 1). The major triggering conditions are infection, rheumatologic conditions, and lymphoid malignancies. A search for these conditions can be undertaken in clinically stable patients, provided that the patient's status does not deteriorate. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Associated illnesses'.)

For those found to have an infection or rheumatologic condition who are clinically stable or improving, it may be possible to treat the triggering condition first without HLH-specific therapy and determine if resolution of the triggering condition is associated with clinical improvement. Deterioration during the search or therapy for the underlying condition is an indication to start HLH-specific therapy immediately. (See 'Infection' below and 'MAS/rheumatologic conditions' below.)

For patients with hematologic malignancies, HLH should be treated with HLH-specific therapy, followed by appropriate chemotherapy for the malignancy; often hematopoietic cell transplant will also be required. (See 'Initial HLH-specific therapy' below and 'Allogeneic hematopoietic cell transplant' below.)

Infection — Infection should be diagnosed rapidly, and empiric antibiotic, antifungal, antiviral, or antiparasitic therapy should be initiated depending on the suspected organism(s).

When active EBV infection is identified by finding >10,000 copies of EBV/mcg cellular DNA, we treat with rituximab 375 mg/m2 weekly for one to four weeks depending on how quickly the EBV DNA level drops. Although IVIG has been recommended by some investigators for treatment of EBV infection, we find that rituximab is much more effective.

It may be possible to treat HIV infection with resolution of HLH, allowing the patient to avoid HLH-specific therapy.

For those from areas in which visceral leishmaniasis is endemic and/or those with a high clinical suspicion or evidence of acute infection, diagnostic testing and appropriate treatment for the Leishmania parasite should be initiated. (See "Clinical manifestations and diagnosis of visceral leishmaniasis" and "Treatment of visceral leishmaniasis".)

Patients who are clinically stable and respond rapidly (eg, within two to three days) to treatment of the infection may be able to avoid HLH-specific chemotherapy. Importantly, however, initiation of HLH-specific therapy for severely ill patients should not be delayed while awaiting resolution of a system infection.

MAS/rheumatologic conditions — Some patients with an underlying condition that causes immunosuppression or disrupts immune homeostasis will respond to disease-specific therapy. We have had success treating the triggering condition alone and deferring HLH-specific therapy in patients with macrophage activation syndrome (MAS; ie, HLH associated with a rheumatologic condition).

If a patient with a rheumatologic condition is stable enough to delay HLH-specific therapy, we treat with a course of corticosteroids and/or other therapy for the underlying condition. For patients with MAS, increased immunosuppression for the underlying rheumatologic disorder is often effective without the need for HLH-specific therapy.

ACUTELY ILL OR DETERIORATING PATIENTS

Overview (acutely ill) — Patients with hemophagocytic lymphohistiocytosis (HLH) who have deteriorating organ function (eg, cardiovascular, pulmonary, renal, hepatic, or neurologic) should be treated immediately with HLH-specific treatment. Treatment should not be delayed while awaiting genetic or specialized immunologic testing (algorithm 1). (See 'Initial HLH-specific therapy' below.)

With such patients, there is typically concordance between clinical findings and laboratory abnormalities (eg, rising serum ferritin, D-dimer, liver enzyme, sCD25, or sCD163 levels). The following patient scenarios illustrate our approach to determining whether patients are ill enough to need HLH-specific therapy (see 'Initial HLH-specific therapy' below):

For a patient with fever, hepatomegaly, anemia (hemoglobin 8 g/dL) and thrombocytopenia (platelets 100,000/microL), stable clinical features, serum ferritin increasing from 3000 to 10,000 mcg/L, D-dimer increasing from 1500 to 4000 ng/mL, and ALT increasing from 100 to 500 international units/L over two days, we would initiate HLH-specific therapy (eg, dexamethasone and etoposide). If treatment is not initiated, the clinical factors will deteriorate. This patient is likely to have elevated sCD25 and abnormal NK cell function, but treatment should not be delayed while awaiting these results.

For a patient with fever, hepatomegaly, Hgb 10 g/dL, platelets 150,000/microL, any of the clinical factors deteriorating, serum ferritin increasing from 3000 to 50,000 mcg/dL, D-dimer increasing from 1500 to 4000 ng/mL, and ALT/AST approximately 200 international units/L, we would initiate HLH-specific therapy. This patient is likely to have elevated sCD25 and abnormal NK cell function, but treatment should not be delayed while awaiting these results.

For a patient with fever, hepatomegaly, Hgb 10 g/dL, platelets 150,000/microL; clinical factors stable, serum ferritin increasing from 3000 to 5000 mcg/dL, D-dimer stable at 1500 ng/mL, and ALT/AST approximately 100 international units/L, we would observe the patient, gather more data, and not treat unless further deterioration of clinical or laboratory factors occurred. The sCD25 may be slightly elevated and NK cell function may be normal.

For a patient with suspected or known underlying rheumatologic disease (sJIA, lupus) or inflammatory bowel disease, fever, hepatomegaly, Hgb 12 g/dL, platelets decreasing from 500,000/microL to 200,000/microL, serum ferritin 10,000 mcg/L, D-dimer 3000 ng/mL, and ALT/AST approximately 300 international units/L, we would initiate dexamethasone therapy. This patient may respond to steroids due to resolution of the rheumatologic or inflammatory trigger and may not require etoposide.

Initial HLH-specific therapy — Among patients who are acutely ill or deteriorating, we suggest HLH-specific therapy based on the HLH-94 protocol or enrollment in a clinical trial, rather than treatment based on the HLH-2004 protocol, because the results of HLH-2004 are unknown.

If the patient is not severely ill (eg, does not have deteriorating cardiovascular, pulmonary, renal, hepatic, or neurologic function), it may be possible to treat the triggering condition with the addition of corticosteroids, and to observe the patient for a response prior to initiating chemotherapy. For those who show clinical improvement upon treatment of the triggering condition, it may be possible to avoid chemotherapy, although this is the rare exception rather than the rule. (See 'Clinically stable patients' above.)

Therapy based on the HLH-94 protocol consists of eight weeks of induction therapy with etoposide (VP-16) and dexamethasone, with intrathecal therapy for those with CNS involvement [4]. (See 'CNS involvement' below.)

Etoposide (VP-16) is given at a dose of 150 mg/m2 for adults, and 5 mg/kg for children weighing <10 kg. The dose is given twice weekly for the first two weeks, and once weekly for weeks three through eight.

Dose reductions for etoposide include the following:

Creatinine clearance 10 to 50 mL/min – Reduce dose by 25 percent

Creatinine clearance <10 mL/min – Reduce dose by 50 percent

Creatinine clearance <10 mL/min and direct bilirubin >3 mg/dL – Reduce dose by 75 percent

We do not make dose reductions for isolated hyperbilirubinemia or neutropenia, unless the hyperbilirubinemia is especially severe (eg, bilirubin of 20 mg/dL). In such cases, we may give an initial etoposide dose reduction (eg, 75 mg/m2), and increase to full dose as liver function improves. For those with no remaining hepatic function, alemtuzumab is an alternative to etoposide. (See 'Alemtuzumab' below.)

Dexamethasone is the preferred corticosteroid because it can cross the blood-brain barrier. Dexamethasone is given intravenously or orally and tapered over the eight-week induction:

Weeks 1 and 2 – 10 mg/m2 daily

Weeks 3 and 4 – 5 mg/m2 daily

Weeks 5 and 6 – 2.5 mg/m2 daily

Week 7 – 1.25 mg/m2 daily

Week 8 – Taper dose to zero

The HLH-94 protocol also used cyclosporin starting at week nine (6 mg/kg daily in divided doses; target trough level 200 mcg/L). However, cyclosporin is associated with the development of the posterior reversible encephalopathy syndrome (PRES), and the benefit is unproven. Thus, we do not use cyclosporin. However, some hematologists do use cyclosporin in patients who are severely ill, along with aggressive control of blood pressure and close monitoring for PRES. (See 'Posterior reversible encephalopathy syndrome (PRES)' below.)

For those who do not show a response to this therapy within two to three weeks (eg, with improvement in clinical status and disease markers), salvage therapy should be considered. If the patient is still febrile and has unchanged hepatomegaly, it is unlikely the laboratory parameters will be improving. Usually patients requiring salvage therapy will have a minor, or no, drop in ferritin levels, D-dimer, or liver enzymes. If the patient has improved clinical function, but unchanged laboratory parameters, the decision of changing to salvage therapy must be highly individualized. (See 'Refractory or recurrent disease' below.)

Patients who initially respond well and then worsen upon tapering of chemotherapy can often be successfully retreated with the original agents. Clinical worsening during induction therapy should also prompt a search for a new or previously untreated associated condition that could affect the patient's clinical status or trigger worsening of the HLH. For distinction between disease worsening versus infection or therapy-related toxicities, following disease markers can be especially helpful. (See 'Monitoring treatment response' below.)

The ideal therapy for patients with HLH remains unknown. Clinicians are encouraged to enter patients in clinical trials such as the Hybrid ImmunoTherapy for HLH trial in the United States (HIT-HLH; NCT01104025) or the EURO-HIT-HLH trial in Europe (EudraCT2011-002052-14). The HLH-2004 trial is closed to accrual.

Induction therapy may be delayed in those with an associated condition who are stable enough to attempt therapy of the underlying condition first. (See 'Clinically stable patients' above.)

Severe liver disease — Treatment of patients with severe liver disease can be challenging, because etoposide (VP-16) is partially metabolized by the liver, and clinicians are concerned about administering etoposide to those with liver abnormalities. However, etoposide is an essential component of optimal therapy, and we do not omit it in those with liver abnormalities as long as some hepatic function is present.

For those with marked hepatic dysfunction or combined hepatic and renal dysfunction, we use an etoposide dose reduction (eg, 75 mg/m2) for the first dose, and increase the dose as the liver function improves.  

For those with liver failure (ie, no hepatic function), treatment with alemtuzumab rather than etoposide may be appropriate. (See 'Alemtuzumab' below.)

CNS involvement — We give intrathecal chemotherapy to all patients with central nervous system (CNS) involvement, as assessed by clinical symptoms, cerebrospinal fluid (CSF) analysis, and intracranial magnetic resonance imaging (MRI). Occult HLH of the CNS (ie, elevated CSF protein and/or cellular pleocytosis without symptoms) is of great concern and should be treated. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Initial evaluation'.)

We start the intrathecal therapy as soon as lumbar puncture can be safely performed, (ie, once coagulopathy and thrombocytopenia are controlled). We do not consider ventilatory or blood pressure supportive care to be contraindications for doing a lumbar puncture. (See 'Bleeding' below.)

We favor the combination of intrathecal methotrexate and hydrocortisone, administered weekly. It is important to use preparations of these drugs that are specifically formulated for intrathecal use. The doses are based on the patient's age:

<1 year – Methotrexate 6 mg and hydrocortisone 8 mg

1 to 2 years – Methotrexate 8 mg and hydrocortisone 10 mg

2 to 3 years – Methotrexate 10 mg and hydrocortisone 12 mg

>3 years – Methotrexate 12 mg and hydrocortisone 15 mg

Intrathecal therapy is continued until at least one week after CNS involvement has resolved, based on both clinical and CSF analysis.

Changes in neurologic status during the course of treatment should be evaluated rapidly with CSF analysis and contrast-enhanced MRI of the brain. Evidence of CNS involvement should prompt initiation of intrathecal chemotherapy; bleeding or infection should be treated appropriately; and posterior reversible encephalopathy syndrome (PRES) should be treated with strict blood pressure control and elimination of potentially contributory medications. (See 'Supportive care' below and 'Posterior reversible encephalopathy syndrome (PRES)' below.)

CNS involvement by HLH is associated with a poor prognosis, especially in those who do not have a concurrent CNS infection. Thus, most patients with CNS involvement will require hematopoietic cell transplantation after completing induction therapy. (See 'Prognosis' below and 'Allogeneic hematopoietic cell transplant' below.)

Posterior reversible encephalopathy syndrome (PRES) — Patients with HLH are at risk of developing PRES, which presents with headache, altered consciousness, visual disturbances, and/or seizures. PRES is associated with characteristic findings on MRI (vasogenic cerebral edema predominantly in the posterior cerebral hemispheres). There are no specific diagnostic tests. (See "Reversible posterior leukoencephalopathy syndrome".)

PRES is reversible if recognized and treated promptly. If the patient has hypertension, this should be controlled as rapidly as possible. Electrolyte disturbances and fluid overload should be corrected, and infections should be treated.

PRES has specifically been associated with cyclosporin use. If a patient receiving cyclosporin develops PRES, we stop the cyclosporin immediately. We may also withdraw or lower the dose of other cytotoxic agents (eg, etoposide). We may reduce the dose of dexamethasone, but this increases the risk of HLH relapse. Intrathecal therapy is postponed until PRES resolves.

It is also critical to distinguish whether another cause of neurologic findings is contributing to neurologic deterioration (eg, intracranial hemorrhage, CNS infection). (See "Diagnosis of delirium and confusional states".)

Other regimens and the HLH-2004 protocol — Alternative regimens have been used to treat HLH; however, we prefer to use HLH-94-based therapy for all patients. Examples of other therapies include the following:  

Therapy with combined antithymocyte globulin (ATG), corticosteroids, cyclosporin, and intrathecal methotrexate were used in 38 patients with familial HLH [5]. Complete and partial responses were seen 73 and 24 percent, respectively, and 16 of 19 who went on to receive HCT were cured of their disease. Survival for the entire group was 55 percent.

Therapy with combined cyclophosphamide, vincristine, and prednisone was used in 15 adults with HLH, most of whom had a triggering infection, lymphoma, or rheumatologic condition [6]. These agents were given for eight weeks or until disease remission, whichever came first; one patient underwent HCT. Complete and partial responses were seen in 47 and 33 percent, respectively, and one-year overall survival was 67 percent.

Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy was used in 17 adult patients with HLH who had lymphoma, EBV infection, or no obvious trigger [7]. Treatment was given for six to eight cycles, and no patients underwent HCT. Complete and partial responses were seen in 41 and 18 percent, respectively. The two-year overall survival was 44 percent.

These regimens have not been as extensively tested as HLH-94, and none have been compared directly with HLH-94-based therapy in a clinical trial.

The HLH-2004 protocol was initiated by the Histiocyte Society in 2004 and closed in December 2011; study results are awaited. Patients enrolled in the study should continue treatment and monitoring as outlined in the study protocol.

The major modifications of the HLH-2004 protocol were to begin cyclosporin simultaneously with etoposide and to add hydrocortisone to the intrathecal methotrexate. Further details of this trial can be found online [8]. Until the results of this trial are available, we prefer to initiate treatment based on the HLH-94 protocol or on a clinical trial. (See 'Initial HLH-specific therapy' above.)

SUPPORTIVE CARE — Patients with hemophagocytic lymphohistiocytosis (HLH) are acutely ill and require constant attention to signs of organ dysfunction. Supportive care includes appropriate transfusions, prevention and treatment of bleeding, and prevention and treatment of opportunistic infections. Blood pressure control is important to minimize the risk of PRES.

Anemia or thrombocytopenia — Transfusions should be given as done for other patients with pancytopenia, chemotherapy, and HCT. For platelet transfusions, we use a higher threshold platelet count than used for other thrombocytopenic patients, because of the coagulation abnormalities and higher risk of bleeding with HLH.

Red blood cell transfusions are guided by the hemoglobin level and symptoms. (See "Red blood cell transfusions in the newborn" and "Indications for red blood cell transfusion in infants and children" and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)

We typically maintain the platelet count >50,000/microL with platelet transfusions for patients during induction. This value is higher than used for patients who are thrombocytopenic for other reasons and for those receiving chemotherapy and HCT, due to the combined hemostatic defects in patients with HLH. (See 'Bleeding' below and "Clinical and laboratory aspects of platelet transfusion therapy".)

We transfuse fresh frozen plasma (FFP), thawed plasma (when available) or cryoprecipitate to treat bleeding if the fibrinogen is low. (See "Clinical use of plasma components".)

For all transfusions, we use leukofiltration and irradiation to prevent CMV infection, alloimmunization, and transfusion-associated graft-versus-host disease. (See "Immunologic transfusion reactions".)

Bleeding — Patients with HLH are at high risk for bleeding due to thrombocytopenia, platelet function defects, inflammation, disseminated intravascular coagulation, and coagulation factor defects from liver failure.

Major bleeding should be treated immediately with platelet transfusions, as well as FFP, thawed plasma, or cryoprecipitate. Other products such as prothrombin complex concentrates, recombinant factor VIIa, and antifibrinolytic agents may rarely be required. (See "Coagulopathy associated with trauma", section on 'Pharmaceutical hemostatic agents'.)

In addition to using transfusion to maintain a threshold platelet count, we do the following to reduce the risk of bleeding:

For premenopausal females, we induce amenorrhea using a depot gonadotropin releasing hormone (GnRH) agonist (eg, leuprolide acetate). (See "Heavy or irregular uterine bleeding during chemotherapy".)

For patients who require an invasive procedure (eg, lumbar puncture, central line placement, other surgical procedure), we maintain the platelet count >50,000/microL and correct the coagulopathy to within 25 percent above the upper limit of normal for the PT and aPTT.

We do not use heparin or other anticoagulant therapy, because of a high risk for CNS bleeds, unless the patient has a clear indication (eg, development of venous thromboembolism).

We have not used antifibrinolytic therapy in patients with HLH.

Infection — Patients with HLH are at risk of developing infections during therapy due to underlying pancytopenia, immune defects, and immunosuppressive/cytotoxic therapy.

Patients should receive intensive acute care nursing and neutropenic precautions. Prophylaxis for opportunistic organisms including Pneumocystis jirovecii and fungal organisms should be administered to all patients (eg, trimethoprim-sulfamethoxazole and fluconazole). (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Evaluation and management of fever in children with non-chemotherapy-induced neutropenia".)

Patients who develop an infection while on treatment for HLH should have rapid diagnostic studies (eg, cultures, imaging) and treatment with broad-spectrum antimicrobial therapy directed at implicated organisms. (See "Diagnostic approach to the adult presenting with neutropenic fever" and "Overview of neutropenic fever syndromes" and "Fever in children with chemotherapy-induced neutropenia" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

For those with underlying immunodeficiency and hypogammaglobulinemia, or those who develop hypogammaglobulinemia from HLH-specific therapy, we give intravenous immune globulin (IVIG) as well, at a dose of 500 mg/kg. (See "General principles in the use of immune globulin", section on 'Overview of dosing'.)

Blood pressure control — Patients with HLH are at risk of developing PRES. To decrease this risk, we use aggressive blood pressure control. Blood pressure thresholds and choice of antihypertensive agents are discussed separately. (See 'Posterior reversible encephalopathy syndrome (PRES)' above and "Management of hypertensive emergencies and urgencies in children" and "Evaluation and treatment of hypertensive emergencies in adults".)

MONITORING TREATMENT RESPONSE

During initial therapy — The response to initial therapy is a major factor in determining the need for additional therapy including hematopoietic cell transplant (HCT). Response to induction therapy is monitored by assessing the patient clinically and using hemophagocytic lymphohistiocytosis (HLH) disease-specific markers.

Markers of clinical response — We generally do the following to monitor the clinical status of the patient:

Physical examination focused on temperature, rashes, lymphadenopathy, hepatosplenomegaly, neurologic findings, and organ-specific findings noted on presentation

Complete blood count with differential

Coagulation studies including PT, aPTT, fibrinogen, and D-dimer

Ferritin, renal function, and electrolytes if previously abnormal

Liver function tests including ALT, AST, total bilirubin, GGT, and LDH

CSF analysis for those with neurologic or CSF abnormalities

This evaluation is done daily for patients who are acutely ill, with the exception of CSF analysis, which is done at each intrathecal treatment. The monitoring interval can be extended as the values normalize.

For the majority of patients, these parameters will identify organ involvement and correlate with the course of the HLH (eg, worsening or responding to therapy). However, it is possible that some of these will worsen due to a new infection or treatment toxicity. Thus, we also monitor disease-specific markers as outlined in the following section.

Disease-specific markers — Disease specific markers correlate with the response to therapy and are especially helpful in distinguishing disease worsening from another complication (eg, infection or treatment toxicity). We do the following:

Serum ferritin is measured daily for patients who are acutely ill, and less frequently as the value improves.

Lymphocyte and cytokine markers (eg, soluble IL-2 receptor alpha [sCD25], soluble hemoglobin-haptoglobin scavenger receptor [sCD163]) are monitored weekly. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Immunologic profile'.)

If additional markers are especially high at presentation, we may re-evaluate these half-way through induction therapy (eg, NK cell function, viral titers).

HCT is indicated for those who do not fully recover (eg, have complete resolution of fever, organomegaly, cytopenias, coagulation studies) by the end of the initial eight weeks of induction chemotherapy; we continue etoposide and dexamethasone therapy and perform HCT as soon as a donor is available. Some patients continue to have serum ferritin in the 500 to 1000 ng/mL range and liver enzymes two to four times above normal for one to two months, but by three months all laboratory parameters should be normal. A relapse is signaled by fever, organomegaly, and steadily increasing ferritin, D-dimer, and liver enzymes, with falling hemoglobin level and platelet count. (See 'Allogeneic hematopoietic cell transplant' below.)

After induction and/or HCT — For those with disease remission (either after induction therapy alone or induction therapy followed by HCT), we continue to monitor closely for disease recurrence and treatment complications after discharge from the hospital. We see the patient at least monthly during the first year, and quarterly or semi-annually thereafter [3]. We typically perform the following evaluations for asymptomatic patients at every visit:

Physical examination for rashes, lymphadenopathy, hepatosplenomegaly

Complete blood count with differential

Liver function tests including ALT, AST, bilirubin, GGT, LDH

Fibrinogen and D-dimer

Serum ferritin

Importantly, many patients who have undergone HCT will experience a disease flare two to three weeks post transplant, which can be treated with etoposide and dexamethasone. CNS abnormalities that fail to resolve during the initial post-transplantation period can be treated with intrathecal therapy until full donor immune reconstitution occurs.

For those who had CNS disease, we do a CSF analysis once during the first 100 days after HCT, even if the patient is asymptomatic. We also do contrast-enhanced MRI of the brain to document resolution of abnormalities if these were present. Although there are no data to suggest when HLH abnormalities should be expected to resolve, six months is a reasonable estimate.

Patients are also instructed to seek medical attention rapidly for fever, signs of infection, neurologic changes, and any other concerning symptoms that suggest HLH recurrence.

Because case reports have suggested that vaccinations can trigger HLH, we withhold all vaccinations during the first six months following therapy. Once we resume vaccinations, we administer them one at a time rather than giving several in the same visit, to minimize the risk of causing an immunologic event that could trigger HLH recurrence.

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT

Indications — To attain long-term cure of the disease, we suggest hematopoietic cell transplant (HCT) in patients with the following underlying conditions, based on their high mortality rate and high risk of relapse [3,9]:

Homozygous or compound heterozygous hemophagocytic lymphohistiocytosis (HLH) gene mutations

Lack of response to initial HLH therapy

Central nervous system (CNS) involvement

Hematologic malignancy that cannot be cured

Most HLH-inducing hematologic malignancies are persistent triggers of HLH (likely from persistent antigen presentation) and will continue to induce HLH unless allogeneic HCT is performed [3,7,10-16]. Therefore, we suggest HCT following HLH-specific therapy in the setting of a hematologic malignancy that cannot be cured with conventional chemotherapy. However, if one can treat the HLH and cure the malignancy, and the patient has normal natural killer (NK) cell function, a transplant may not be required.

The need for HCT in those with heterozygous HLH mutations is not known, and we manage these patients on a case-by-case basis guided by their clinical course.

In practice, the indications for HCT apply to almost all young children (eg, less than two years of age). The only situation in which we would not perform HCT for a young child is if the HLH was clearly triggered by a viral infection; the disease was completely treated by induction therapy; NK cell function was normal following therapy; and laboratory evaluation remained normal for six months.

Patients with HLH have underlying immune defects and organ damage that affect their ability to tolerate HCT. The greater risk of transplant-related morbidity and mortality in this population necessitates that transplantation be done at a center with experience using HCT for HLH if at all possible [17].

Preparation for allogeneic HCT should be initiated at the time of diagnosis, and should include HLA typing and search for a suitable HCT donor. Genetic studies should also be sent at the time of diagnosis so that the results of these studies are available and can be incorporated into the decision to pursue HCT. The possibility of an occult predisposition or undiagnosed HLH in a sibling donor due to heterozygosity or homozygosity for an HLH gene mutation should be factored into the donor selection process. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetic and HLA testing'.)

For those who require HCT, therapy should be continued after the initial eight weeks with etoposide 150 mg/m2 given every two weeks, alternating with dexamethasone 10 mg/m2 for three consecutive days, administered every two weeks.

Remission of HLH prior to transplant is associated with less transplant-associated morbidity, so we try to induce remission in all patients. This must be balanced with the need to initiate HCT as soon as possible due to the risk of disease recurrence and the potential toxicities of a longer duration of etoposide administration (eg, myelodysplasia, acute leukemia).

Source and preparative regimen — There are insufficient data to specify the optimal source of hematopoietic cells (eg, bone marrow, peripheral blood, or umbilical cord blood). Various sources have been used, but none have been compared in a randomized trial due to the rarity of the disease [18,19].

The most appropriate donor for HCT needs to be determined on a case-by-case basis. Siblings may be heterozygous or homozygous for HLH mutations, so genetic analysis should be done to ensure that the donor does not have undiagnosed HLH.

No trials comparing reduced intensity conditioning (RIC) with myeloablative regimens have been conducted. In the absence of direct comparative data, we suggest RIC regimens rather than myeloablative regimens in order to reduce the high transplant-associated morbidity and to improve survival [20]. (See "Preparative regimens for hematopoietic cell transplantation".)

Support for the use of RIC in patients with HLH undergoing HCT comes from several small series that have shown greater survival with RIC compared with reported survival for myeloablative regimens. Survival rates in the range of 75 to 100 percent have been reported in series of 10 to 30 patients who received RIC regimens [20-25].

The toxicities associated with myeloablative regimens were illustrated in a review of 18 children with HLH, 16 of whom received myeloablative conditioning [26]. This study found a survival of 78 percent with a high incidence of complications:

Infection (72 percent)

Hepatic veno-occlusive disease (38 percent)

Respiratory complications (50 percent)

Acute graft-versus-host disease (44 percent)

Half of these children required admission to the intensive care unit during their transplant; three deaths were from multiorgan failure and one from pulmonary hemorrhage [26].

Management after HCT — Following HCT, patients need to be monitored for disease recurrence, primary loss of the allograft, and HCT complications.

Monthly monitoring for disease recurrence is similar to that for patients who have completed induction therapy alone. Patients are instructed to seek medical attention rapidly for fever, signs of infection, neurologic changes, and any other concerning symptoms that suggest HLH recurrence. (See 'Monitoring treatment response' above.)

For those who had CNS involvement, we do a cerebrospinal fluid (CSF) analysis once during the first 100 days after HCT, even if the patient is asymptomatic. We also do contrast-enhanced MRI of the brain to document resolution of abnormalities if these were present. Although there are no data to suggest when HLH abnormalities should be expected to resolve, six months is a reasonable estimate. CNS abnormalities that fail to resolve can be treated with intrathecal therapy during the initial post-transplantation period until full donor immune reconstitution occurs. (See 'CNS involvement' above.)

Loss of the allograft is common after HCT for HLH, and the "safe" level of donor chimerism is unknown. Therefore, we monitor donor engraftment on a weekly basis during the first months after transplant, using appropriate polymorphic markers for genetic differences between the recipient and donor [27,28]. (See "Specific issues related to hematopoietic cell transplantation in beta thalassemia", section on 'Mixed chimeric state'.)

We attempt to increase the donor graft component if chimerism decreases to less than 50 to 60 percent. We first reduce graft-versus-host disease prophylaxis, and if this is ineffective, we use donor lymphocyte infusions when possible. (See "Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation", section on 'Donor lymphocyte infusions'.)

Survivorship issues specific for children who have undergone HCT have been published by the Children's Oncology Group at www.survivorshipguidelines.org/. General issues related to monitoring and management of treatment toxicity following HCT are discussed separately. (See "The approach to hematopoietic cell transplantation survivorship".)

Second transplant — Re-transplantation of those with HLH recurrence after an initial transplant has been reported [19,29]. However, many patients experience a disease flare two to three weeks after HCT that can be treated with etoposide and dexamethasone without the need for retransplantation. (See 'Refractory or recurrent disease' below.)

REFRACTORY OR RECURRENT DISEASE

General approach — Some patients' disease does not respond to induction therapy for hemophagocytic lymphohistiocytosis (HLH), and others have disease recurrence while awaiting hematopoietic cell transplant (HCT) or following remission. A relapse is typically signaled by the development of fever, organomegaly, and steadily increasing ferritin, D-dimer, and liver enzymes, with falling hemoglobin and platelet levels. Our general approach to the treatment of patients with refractory or recurrent disease is as follows:

Patients who initially have disease remission with HLH-94-based therapy (ie, etoposide and dexamethasone) will often benefit from retreatment using the same regimen. In patients who have initially had a remission or a good response, we repeat the same therapy.

If disease worsens during induction therapy while etoposide and dexamethasone are being tapered, we re-escalate the doses of these agents to full dose.

Disease worsening may be identified by clinical deterioration (eg, worsening neurologic findings, hepatitis, pancytopenia) or by increasing disease markers (eg, serum ferritin, sCD25, sCD163).

Importantly, recurrent disease may also be mimicked by development of a new infection or by toxicity of the chemotherapy agents or other medications (eg, drug-induced thrombocytopenia from antibiotics). Clinical worsening should thus prompt a thorough search for new infections and evaluation for drug toxicity. Markers of disease activity are also especially helpful for distinguishing disease progression from infection and drug toxicity. (See 'Monitoring treatment response' above.)

Alemtuzumab — We use additional agents if there is clinical deterioration despite maximum doses of etoposide and dexamethasone based on the HLH-94 protocol, or if there is no sign of clinical improvement after the first two to three weeks of treatment. Our first choice is alemtuzumab, a monoclonal antibody to the CD52 protein expressed on the surface of mature T cells and possibly NK cells [30]. Alemtuzumab has shown promise in patients with refractory disease [31]. In a review of 22 patients treated with alemtuzumab for refractory HLH (median dose, 1 mg/kg divided over four days), partial responses were seen in 86 percent, and 77 percent were able to undergo HCT [32]. Viremia from cytomegalovirus and adenovirus were common complications of this therapy.

PROGNOSIS

Survival — Without therapy, mortality of patients with hemophagocytic lymphohistiocytosis (HLH) is high. As an example, those with an inherited mutation in an HLH gene have a survival of approximately two months without treatment [33,34]. In contrast, patients treated on the HLH-94 protocol had a median survival of 54 percent at 6.2 years (249 patients, median age eight months) [1,2]. Additional prognostic information from the HLH-94 study included the following [2]:

Those with neurologic involvement had a lower survival than those without neurologic involvement (40 versus 67 percent).

Patients younger than six months of age had a lower survival than those older than six months (41 versus 65 percent).

Those with familial disease, most of whom underwent allogeneic HCT, had a similar prognosis as those without familial disease, approximately half of whom had hematopoietic cell transplant (HCT). No patient with familial disease survived without HCT.

Of the 124 who underwent allogeneic HCT, five-year survival was 66 percent. Survival was better in those who were in remission at the time of HCT than those who were not (72 versus 58 percent). Causes of death included transplant-related toxicities, graft failure, relapse of HLH, multiorgan failure, and infection.

Of the patients who did not undergo HCT, 49 were in remission one year or more after completing therapy; these patients were more likely to be older (median age 24 months) and female (61 percent), and to have less CNS disease or hepatomegaly; many were from Japan (57 percent).

Long-term sequelae of disease and/or treatment included late neurologic effects that ranged from severe mental retardation to learning disabilities and nerve paresis (19 percent); and other organ damage such as renal impairment, obstructive bronchiolitis, and growth retardation (16 percent). One patient developed acute myeloid leukemia and survived following HCT.

Patients with the highest serum ferritin have the worst prognosis, and a slower rate of decline in serum ferritin during therapy confers a worse prognosis. In a review of 48 patients with HLH (half of whom were less than two years of age), a decrease in serum ferritin by less than 50 percent during the first three weeks of therapy was associated with markedly higher mortality than a ferritin decrease of 96 percent or greater (odds ratio 17.42, 90% CI 1.65-1.84) [35]. Malignancy-associated HLH was shown to confer a worse prognosis in a series of 62 adults (median survival 1.4 months, compared with 22.8 months for those without malignancy) [36]. Most of the malignancies were T cell lymphomas.

Improvements in survival are expected to come from increased disease recognition with earlier diagnosis; improvements in HCT and reductions in HCT-associated morbidity; and disease-specific immunotherapies.

Relapse — It appears that most patients who relapse do so within a year of the initial acute illness [3]. Relapse is more likely in those with HLH gene mutations compared with those without mutations.

The risk of relapse should be minimized by reducing exposure to triggering conditions if possible. This includes maintaining control of underlying rheumatologic conditions and hematologic malignancies, and preventing infections and other alterations of immune homeostasis. Since recurrences following vaccination have been reported, we avoid vaccination for the first six months after treatment and then administer vaccinations one-at-a-time rather than combining several vaccinations during the same visit [37]. (See 'Monitoring treatment response' above.)

FAMILY COUNSELING — Families with known hemophagocytic lymphohistiocytosis (HLH) mutations should receive counseling and education regarding the risks of the disease in asymptomatic family members, approaches to preventing acute illness, and birth control.

SUMMARY AND RECOMMENDATIONS

Untreated patients with hemophagocytic lymphohistiocytosis (HLH) have a survival of months, due to progressive multi-organ failure. Often the greatest barrier to treatment is delayed diagnosis. Survival can be dramatically increased with HLH-specific therapy. Therapy should be based on the diagnosis or a high clinical suspicion of HLH, and should not be delayed while awaiting specialized immunologic testing or genetic analysis. (See 'Overview and indications for treatment' above.)

Patients should be urgently referred to a hematology or oncology specialist (algorithm 1). Pretreatment testing of cardiac function and disease markers should be done in all patients. HLA typing of all patients and appropriate family members, and genetic testing of potential sibling donors should be sent in anticipation of possible hematopoietic cell transplant (HCT). (See 'Hematologist referral and pretreatment testing' above.)

Patients with HLH who are clinically stable can undergo treatment for a triggering condition (eg, infection, macrophage activation syndrome, other rheumatologic condition) or continued search for a triggering condition. Rarely, these patients may be able to avoid cytotoxic therapy. (See 'Clinically stable patients' above.)

Among patients who are acutely ill or deteriorating, we suggest HLH-specific therapy based on the HLH-94 protocol or enrollment in a clinical trial, rather than treatment based on the HLH-2004 protocol (Grade 2C). HLH-94-based therapy includes etoposide and dexamethasone given at tapering doses over eight weeks, with intrathecal methotrexate and hydrocortisone for those with central nervous system (CNS) involvement (algorithm 1). We do not use cyclosporin routinely, although some hematologists do. (See 'Acutely ill or deteriorating patients' above.)

Patients should receive transfusions of red blood cells and platelets as needed (target platelet count >50,000/microL during induction); we give fresh frozen plasma, thawed plasma, or cryoprecipitate for bleeding if the fibrinogen is low. Additional supportive measures include induction of amenorrhea and use of prophylactic antibiotics. (See 'Supportive care' above.)

The response to initial therapy is a major factor in determining the need for additional therapy including HCT. Response to induction therapy is monitored clinically by laboratory testing and with HLH disease-specific markers. (See 'Monitoring treatment response' above.)

For those with HLH gene mutations, refractory disease, CNS involvement, and hematologic malignancies that cannot be cured, we suggest allogeneic HCT following induction therapy (Grade 2C). For those undergoing HCT, we suggest reduced intensity conditioning regimens rather than myeloablative regimens (Grade 2C). Loss of the allograft is a concern; we attempt to maintain at least 50 percent donor chimerism. (See 'Allogeneic hematopoietic cell transplant' above.)

Disease that is refractory to induction therapy is treated with additional agents such as the anti-CD52 monoclonal antibody alemtuzumab before transplant. Disease relapse or worsening during chemotherapy taper can be treated with the original agents at full dose. (See 'Refractory or recurrent disease' above.)

CNS involvement in the early post-transplant period can be treated with intrathecal therapy while awaiting full immune engraftment. (See 'Management after HCT' above.)

Median survival for patients with HLH is approximately 50 percent with HLH-94-based treatment. Poor prognostic factors include younger age, CNS involvement, and failure of therapy to induce a remission prior to HCT. (See 'Prognosis' above.)

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