INTRODUCTION — Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive, 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 — 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). Intrathecal methotrexate and hydrocortisone are 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 be required in those with an HLH gene mutation, central nervous system disease, or disease relapse.
In 2004, a new HLH protocol was initiated (HLH-2004). The major modifications were to use cyclosporine 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 clinically stable and the ferritin is consistently below 10,000 ng/mL or rises from 1000 to 3000 ng/mL 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.)
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 inflammatory 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 HLH is essential, especially for those who are acutely ill or clinically deteriorating. (See 'Acutely ill or deteriorating patients' below.)
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 . 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. The distinction between chemotherapy toxicity and 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, complete blood count, 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 HLH (eg, infection, rheumatologic condition) may respond to treatment of the triggering condition alone. 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 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). Thus, an extensive list of infectious agents should be tested for including Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), human herpesvirus 6 (HHV6), parvovirus, Bartonella, leishmaniasis, bacteria, and fungi.
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 intravenous immune globulin (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 "Visceral leishmaniasis: Clinical manifestations and diagnosis" and "Visceral leishmaniasis: Treatment".)
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. 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). (See "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)
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 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. (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/L, 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/L, 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. More than half of patients treated with the HLH-94 regimen achieve five-year survival .
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 . For the intrathecal therapy, we have chosen to add hydrocortisone to the intrathecal methotrexate. (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.
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 cyclosporine starting at week nine (6 mg/kg daily in divided doses; target trough level 200 mcg/L). However, cyclosporine is associated with the development of the posterior reversible encephalopathy syndrome (PRES), and the benefit is unproven. Thus, we do not use cyclosporine. However, some hematologists do use cyclosporine 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.)
When patients 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 'Relapsed or refractory 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.)
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, but excreted by the kidneys . Clinicians are often concerned about administering etoposide to HLH patients 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 .
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:
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. 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 cyclosporine use. If a patient receiving cyclosporine develops PRES, we stop the cyclosporine 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".)
HLH-2004 and other protocols — Alternative regimens have been used to treat HLH, but none has been directly compared with HLH-94 and no regimen has displayed clear superiority. Examples of other therapies include the following:
●The HLH-2004 protocol included the etoposide plus dexamethasone regimen used in HLH-94, but incorporated cyclosporine as part of initial therapy . HLH-2004 affirmed the efficacy of etoposide and dexamethasone, but did not show a benefit of incorporating cyclosporine as part of initial therapy.
●Therapy with combined antithymocyte globulin (ATG), corticosteroids, cyclosporine, and intrathecal methotrexate were used in 38 patients with familial HLH . 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 . 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 . 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.
●A prospective clinical trial using liposomal doxorubicin, etoposide, methylprednisolone (DEP) included refractory HLH patients with lymphoma-, EBV-, familial-, and unknown underlying disease-HLH . The overall response rate was 76 percent, 29 of 48 responders underwent hematopoietic stem cell transplants, and 46 percent of patients survived.
●Anakinra, intravenous immune globulin (IVIG), and corticosteroids have been used for HLH patients with underlying rheumatologic diseases and other causes of secondary HLH in pediatric and adult patients [12-14].
SUPPORTIVE CARE — Patients with 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 for patients with cytopenias due to the disease, chemotherapy, or 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 "Red blood cell transfusion in infants and children: Indications" 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 "Platelet transfusion: Indications, ordering, and associated risks".)
●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 in trauma patients", 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 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 "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Environmental precautions'.)
Patients who develop an infection while on treatment for HLH should have rapid diagnostic studies (eg, cultures, fungal serology, imaging) and treatment with broad-spectrum antimicrobial therapy directed at implicated organisms. (See "Diagnostic approach to the adult cancer patient 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 "Overview of intravenous immune globulin (IVIG) therapy", section on 'Dosing and administration'.)
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 "Initial 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 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 . 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
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. A review of 94 patients with HLH who received reduced intensity conditioning (RIC) found that 8 percent had CNS relapses; CNS relapse was often associated with a low level of donor chimerism .
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 [3,16]:
●Homozygous or compound heterozygous HLH gene mutations
●Lack of response to initial HLH therapy
●Central nervous system (CNS) involvement
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 [3,10,17-23]. 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 patients with heterozygous HLH mutations is not known, and we manage these patients on a case-by-case basis guided by their clinical course. Management of siblings who are asymptomatic carriers of biallelic HLH mutations is discussed below. (See 'Asymptomatic carriers' below.)
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 and resolves with specific antiviral therapy; 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 .
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 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 on alternate 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 [25,26].
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. But two publications provide some insight.
Reduced-intensity conditioning for transplant of HLH patients was superior to myeloablative conditioning with 92 percent surviving with the former and only 43 percent with the latter in a single center study .
The two-year overall survival for adult and adolescent HLH patients after allogeneic stem cell transplant was 63 percent from another center . All patients with primary HLH survived but the survival for EBV-associated was 64 percent and tumor- or unknown associations 50 percent.
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 . (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 [27,29-33].
The toxicities associated with myeloablative regimens were illustrated in a review of 18 children with HLH, 16 of whom received myeloablative conditioning . 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 .
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. An international collaborative study reported that a donor chimerism level of 20 to 30 percent was sufficient to protect against late reactivation . 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 [36,37].
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 allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)
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 "Long-term care of the adult hematopoietic cell transplantation survivor".)
Second transplant — Re-transplantation of those with HLH recurrence after an initial transplant has been reported [26,38]. 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 'Relapsed or refractory disease' below.)
RELAPSED OR REFRACTORY DISEASE — Some patients are intolerant of initial therapy for HLH, while others have disease that is refractory to initial treatment or progresses as induction therapy is being tapered, after having achieved remission, or while awaiting hematopoietic cell transplantation (HCT). Refractory or relapsed (r/r) HLH may be manifest as clinical deterioration (eg, worsening fever, organomegaly, neurologic findings, hepatitis, pancytopenia) or by steadily increasing disease markers (eg, serum ferritin, sCD25, sCD163). It is important to recognize that a new infection or treatment-related toxicity (eg, from chemotherapy or antibiotic-associated thrombocytopenia) may mimic recurrent or progressive disease. (See 'Monitoring treatment response' above.)
No studies have directly compared various treatments for r/r HLH and we encourage participation in a clinical trial, when possible.
Outside of a clinical trial, we suggest treatment with emapalumab (interferon gamma blocking antibody) plus dexamethasone rather than etoposide plus corticosteroid, alemtuzumab, or other treatments, based on its favorable balance of efficacy and toxicity for r/r HLH.
For settings where emapalumab is not available, we offer treatment with alemtuzumab (anti-CD52 monoclonal antibody); before beginning alemtuzumab, we generally stop the etoposide and taper the dexamethasone, as dictated by response [6,39]. For patients with HLH that progresses while tapering induction therapy, we consider resumption of full-dose etoposide plus dexamethasone to be an acceptable option. (See 'Initial HLH-specific therapy' above.)
Treatment with emapalumab should begin at 1 mg/kg as an intravenous infusion over 1 hour, every 3 to 4 days, with concomitant dexamethasone 5 to 10 mg/m2 daily for the duration of therapy. The dose of emapalumab can be increased up to 10 mg/kg, according to the response in clinical status and laboratory markers. Prior to initiation of treatment, patients should be evaluated for tuberculosis and re-evaluated during treatment, as clinically indicated. We provide prophylaxis for Pneumocystis jirovecii and herpes zoster for the duration of treatment and monitor for Epstein-Barr virus, cytomegalovirus, and adenovirus every two weeks. Live and attenuated vaccines should not be given for the duration of therapy and for at least one month beyond the last dose. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Antimicrobial prophylaxis or pre-emptive therapy'.)
A multicenter study reported that emapalumab plus dexamethasone achieved 63 percent overall response (OR; 95% CI 42-81), including 26 percent complete response (CR), in 27 children with r/r HLH (median age 1.0 year) . Median duration of treatment was 48 days and the median time to response was 8 days. Estimated 12-month overall survival (OS) was 73 percent (95% CI 52-86 percent) and for the 70 percent of children who were able to proceed to HCT, estimated 12-month OS was 90 percent (95% CI 64-97 percent). Emapalumab was well-tolerated; a serious adverse event attributable to the drug was reported in 7 percent, there were no infusion reactions, and it did not appear to amplify adverse events associated with the underlying r/r HLH. Serum levels of CXCL9, a chemokine that is induced exclusively by interferon gamma, declined in parallel with improvements in clinical and laboratory parameters of HLH. The efficacy and safety of emapalumab have not been reported in adults.
Emapalumab is approved by the US Food and Drug Administration for treatment of adult and pediatric patients with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy .
Other treatments may also have utility for r/r HLH [42,43]. A review of 22 patients with refractory HLH who were treated with alemtuzumab (median dose, 1 mg/kg divided over four days) reported partial response in 86 percent, and 77 percent were able to undergo HCT . Viremia from cytomegalovirus and adenovirus were common complications of this therapy . The JAK2 inhibitor ruxolitinib also has activity in the setting of r/r HLH. Treatment with ruxolitinib (with or without glucocorticoids) in 25 patients (median age 27.5 years) with refractory HLH achieved 68 percent OR; median survival was 22 weeks . Median time to response was 2 weeks (range, 1 to 8 weeks), but 88 percent became afebrile within 24 hours. Cytopenias and elevated liver function tests were the most common adverse effects.
Survival — Without therapy, mortality of patients with HLH is high. As an example, those with an inherited mutation in an HLH gene have a survival of approximately two months without treatment [46,47]. In a series of 162 adults with HLH, 94 patients survived (58 percent) . Of the patients who did not survive, approximately half died within one month of diagnosis, especially those with hematologic malignancies.
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 :
●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 hematopoietic cell transplant (HCT), had a similar prognosis as those without familial disease, approximately half of whom had 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 intellectual disability 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) .
In adults, prognosis is worse in those with an underlying malignancy, older age, and some markers of disease severity. This was shown in a review of 162 adults with HLH, in which features associated with early death included underlying lymphoma, low platelet count, elevated aspartate aminotransferase (AST) and elevated lactate dehydrogenase (LDH), and age over 50 years . Treatment with etoposide was associated with better survival (odds ratio 0.21; 95% CI 0.05-0.94). Other series of adults have also demonstrated a worse prognosis when HLH is associated with malignancy, especially T cell lymphomas (median survival approximately one to two months for those with malignancy, compared with approximately two to four years for those without malignancy) [51,52]. A review of outcomes in adult HLH patients from three centers reported a 31 percent response with a medium survival of four months overall, but only three months in those with malignancy-associated HLH . A single center found adult patients with malignancy-associated HLH had median survivals of less than two months .
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 . 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 . (See 'Monitoring treatment response' above.)
Testing and counselling — We suggest testing siblings for the mutation identified in the affected patient (ie, index case). Families that carry HLH-associated mutations should receive counseling and education regarding risks and outcomes in family members, approaches to preventing acute illness, and birth control. Such evaluation and counseling should take place in a center with substantial experience with management of HLH.
Asymptomatic carriers — For asymptomatic carriers (ie, siblings who carry the same biallelic mutation as the index case), a decision regarding pre-emptive allogeneic hematopoietic cell transplantation (HCT) versus observation coupled with treatment after HLH develops must be individualized based on the specific mutation, institutional practice, and concerns of the family and/or patient. Preemptive transplantation for certain mutations (eg, PRF1) is associated with superior survival with acceptable toxicity, but the risk-benefit balance is less clear for some other mutations (eg, MUNC18-2 deficiency). Among the factors to be considered are variability in the age of onset, unpredictability of environmental triggers for HLH (eg, infections), the substantial risk of death from HLH even when asymptomatic carriers are carefully monitored, and ethical aspects of subjecting an asymptomatic individual (typically a child) to a procedure associated with significant treatment-related toxicity and risk of death .
A retrospective international study reported outcomes of 32 asymptomatic carriers who carried the same biallelic genetic defect as their index case sibling; median age of asymptomatic carriers at diagnosis was five months . Preemptive allogeneic HCT was performed in 16 asymptomatic carriers, and 15 remained alive without HLH after median follow-up of 39 months. Six other asymptomatic carriers did not develop HLH during the period of follow-up, and among 10 asymptomatic carriers who did develop HLH, only six were alive (two deaths from HLH progression and two from treatment-related mortality). Outcomes appeared to vary with the specific mutation. Children with PRF1 mutations (the most common cause of HLH) were most likely to have onset of HLH early in life and had the closest concordance with the age of onset in the index case sibling; 7 of 11 asymptomatic carriers with PRF1 mutations developed HLH within one month from diagnosis . Conversely, MUNC18-2 deficiency was associated with a milder form of HLH and only one of five asymptomatic carriers experienced HLH during more than three years of follow-up.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SUMMARY AND RECOMMENDATIONS
●Diagnosis – Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of multi-organ failure caused by unchecked macrophage- and lymphocyte-mediated inflammation. Underlying causes include inherited disorders of perforin-mediated cell-killing (primarily in infants/young children) and malignant, infectious, and autoimmune conditions in others.
HLH is diagnosed using clinical, laboratory, immunologic, and molecular criteria, as described separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
•Disease markers – Liver and kidney function tests, ferritin, sCD25, sCD163, CXCL9
•Tissue typing – For HLH caused by an inherited mutation, HLA typing of the patient and genetic testing of potential related transplant donors
●Treatment – Patients can be gravely ill and may require urgent management; often, the greatest barrier to successful treatment is a delay in diagnosis. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Diagnosis'.)
We encourage enrollment in a clinical trial, but we otherwise choose treatment according to clinical status:
•Acutely ill or clinically deteriorating – For acutely ill patients, we suggest treatment using the HLH-94 protocol (ie, etoposide and dexamethasone), with intrathecal therapy for those with central nervous system (CNS) involvement (Grade 2C), as described above.
Patients with CNS involvement should receive intrathecal hydrocortisone and methotrexate and may be considered for subsequent allogeneic hematopoietic cell transplantation (HCT). (See 'Allogeneic hematopoietic cell transplant' above.)
•Clinically-stable – For patients with no deterioration of heart, lung, liver, kidney, or neurologic function, we suggest initial empiric treatment for the suspected underlying condition, rather than the HLH-94 protocol. However, patients must be monitored closely and treatment escalated if there is clinical deterioration. (See 'Clinically stable patients' above.)
Examples include antimicrobials for triggering infections, glucocorticoids for rheumatologic condition, or antineoplastics for cancers. For the rare adult with homozygous (or compound heterozygous) HLH gene mutations, we proceed to allogeneic HCT, using a graft from an unaffected donor. (See 'Source and preparative regimen' above.)
●Supportive care – All patients with HLH require blood product support for cytopenias and antimicrobials for prevention/management of infections. (See 'Supportive care' above.)
●Monitoring – Patients receiving treatment require daily clinical monitoring, laboratory studies, including markers of inflammation, and evaluation of cerebrospinal fluid with each intrathecal treatment. (See 'Monitoring treatment response' above.)
●Relapsed/refractory HLH – For patients with refractory or recurrent (r/r) HLH after HLH-94, we suggest treatment with emapalumab (interferon gamma blocking antibody) plus dexamethasone, alemtuzumab (anti-CD52 monoclonal antibody), ruxolitinib, or liposomal doxorubicin with etoposide and methylprednisolone (Grade 2C). (See 'Relapsed or refractory disease' above.)
•Indications – Allogeneic HCT is often given for (see 'Allogeneic hematopoietic cell transplant' above):
-Homozygous (or compound heterozygous) HLH gene mutations
-Treatment-resistant r/r HLH
-Hematologic malignancies that cannot be cured by other methods
•Graft source – For mutation-associated HLH, the donor must not have the same mutation. (See 'Source and preparative regimen' above.)
ACKNOWLEDGMENT — UpToDate acknowledges the contributions of the late Laurence A Boxer, MD as a section editor for this topic.