Emapalumab-lzsg (Gamifant)

Number: 0948

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses emapalumab-lzsg (Gamifant) for commercial medical plans.

1. Criteria for Initial Approval

   1. Primary Hemophagocytic Lymphohistiocytosis (HLH)

      Aetna considers emapalumab-lzsg (Gamifant) medically necessary for treatment of primary hemophagocytic lymphohistiocytosis (HLH) when all of the following criteria are met:

      1. Member has refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy (e.g., etoposide, dexamethasone, cyclosporine, antithymocyte globulin); and
      2. Member’s diagnosis of primary HLH was confirmed by either of the following:
          
         1. Mutation in one of the following genes: PRF1, UNC13D, STX11 and STXBP2; or
         2. Presence of at least 5 clinical signs and symptoms of HLH (see Appendix); and
      3. Possible causes of secondary or acquired forms of HLH (e.g., autoimmune disease, persistent infection, malignancy, or loss of inhibitory immune mechanisms) have been ruled out; and
      4. Member has been evaluated for tuberculosis (TB) risk factors and has undergone pretreatment screening for latent TB with the purified protein derivative (PPD) skin test or interferon gamma release assay; and
      5. If member has a positive test result or is at risk for TB, prophylactic treatment for TB must be initiated before starting therapy.

   2. Macrophage Activation Syndrome (MAS) in Known or Suspected Still’s Disease

      Aetna considers emapalumab-lzsg (Gamifant) medically necessary for treatment of macrophage activation syndrome (MAS) in known or suspected Still’s disease when all of the following criteria are met:

      1. Member has a confirmed or suspected diagnosis of systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still’s disease (AOSD) (see Appendix for clinical features associated with sJIA and AOSD); and
      2. Member has a confirmed diagnosis of active MAS (e.g., persistent fever, elevated and/or rising ferritin or other markers of inflammation/damage, cytopenias, hepatic dysfunction, coagulopathy, splenomegaly, CNS dysfunction); and
      3. Member has a documented inadequate response or intolerance to high-dose IV glucocorticoids (e.g., prednisolone given as 30 mg/kg pulses over 3 consecutive days); and
      4. Primary hemophagocytic lymphohistiocytosis (HLH), active infections, and malignancy have been evaluated for and ruled out; and
      5. Member has been evaluated for tuberculosis (TB) risk factors and has undergone pretreatment screening for latent TB with the purified protein derivative (PPD) skin test or interferon gamma release assay; and
      6. If member has a positive test result or is at risk for TB, prophylactic treatment for TB must be initiated before starting therapy.

      Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of emapalumab-lzsg (Gamifant) therapy medically necessary for primary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) in members who have achieved or maintained positive clinical response (e.g., improvement in any of the clinical or laboratory parameters used to demonstrate evidence of active disease on initial approval).

Dosage and Administration

Emapalumab-lzsg (Gamifant) is available as the following: 10 mg/2 mL (5 mg/mL) solution in a single-dose vial, 50 mg/10 mL (5 mg/mL) solution in a single-dose vial, and 100 mg/20 mL (5 mg/mL) solution in a single-dose vial for injection for intravenous infusion only.

Recommended Dosing

Primary Hemophagocytic Lymphohistiocytosis (HLH)

• The recommended starting dosage is 1 mg/kg as an intravenous infusion over 1 hour twice per week. Dexamethasone should be administered concomitantly with Gamifant.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (MAS) in Known or Suspected Still’s disease, including Systemic Juvenile Idiopathic Arthritis (sJIA)

• The recommended starting dose is 6 mg/kg, followed by 3 mg/kg every 3 days for 5 doses, then 3 mg/kg twice per week given as an intravenous infusion over 1 hour.

For both indications, the dose may be titrated up to a maximum of 10 mg/kg.

Source: Sobi, 2025b

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
86480	Tuberculosis test, cell mediated immunity antigen response measurement; gamma interferon
86481	Tuberculosis test, cell mediated immunity antigen response measurement; enumeration of gamma interferon – producing T cells in cell suspension
86580	Skin test; tuberculosis, intradermal
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J9210	Injection, emapalumab-lzsg, 1 mg
Other HCPCS codes related to the CPB:
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J7637	Dexamethasone, inhalation solution, compounded product, administered through dme, concentrated form, per milligram
J7638	Dexamethasone, inhalation solution, compounded product, administered through dme, unit dose form, per milligram
J8540	Dexamethasone, oral, 0.25 mg
J8541	Dexamethasone (hemady), oral, 0.25 mg
J8560	Etoposide; oral, 50 mg
J9181	Injection, etoposide, 10 mg
J7502	Cyclosporine, oral, 100 mg
J7504	Lymphocyte immune globulin, antithymocyte globulin, equine, parenteral, 250 mg
J7511	Lymphocyte immune globulin, antithymocyte globulin, rabbit, parenteral, 25 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Injection, cyclosporine, 250 mg
ICD-10 codes covered if selection criteria are met:
D76.1	Hemophagocytic lymphohistiocytosis
M06.1	Adult-onset Still's disease
M08.20 - M08.2A	Juvenile rheumatoid arthritis with systemic onset

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Gamifant is indicated for the treatment of:

  • Adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.
  • Adult and pediatric (newborn and older) patients with HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS.

Emapalumab-lzsg is available as Gamifant (Sobi Inc) and is an interferon gamma (IFNγ) blocking antibody. Specifically it functions as a monoclonal antibidody which binds to and neutralizes IFNγ. It has been suggested that IFNγ plays an important role in the pathogenesis of HLH by being hypersecreted (Sobi, 2025b).

Per the prescribing information, emapalumab-lzsg (Gamifant) carries the following warnings and precautions:

• Infections: Gamifant may increase the risk of fatal and serious infections arising from mycobacteria, Herpes Zoster virus, and Histoplasma Capsulatum due to IFNγ neutralization.
• Live vaccines: Live or live attenuated vaccines should not be administered to patients receiving Gamifant and for at least 4 weeks after the last dose of Gamifant.
• Infusion-related reactions: Infusion-related reactions including drug eruption, pyrexia, rash, erythema, and hyperhidrosis were reported with Gamifant treatment in 27% of patients.

The most common adverse reactions (≥ 20%) include infections, hypertension, infusion-related reactions, and pyrexia (Sobi, 2025b).

Primary Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. In HLH, natural killer cells and/or cytotoxic lymphocytes fail to eliminate activated macrophages. This lack of normal feedback regulation results in excessive macrophage activity and highly elevated levels of interferon gamma and other cytokines. In addition to antigen presentation and cytokine production, macrophages can also phagocytize host cells. Hemophagocytosis refers to the engulfment (literally "eating") of host blood cells by macrophages. Hemophagocytosis is characterized by the presence of red blood cells, platelets, or white blood cells (or fragments of these cells) within the cytoplasm of macrophages. Hemophagocytosis can be observed in biopsies of immune tissues (lymph nodes, spleen, liver) or bone marrow aspirates/biopsies. Although it can be a marker of excessive macrophage activation and supports the diagnosis of HLH, hemophagocytosis alone is neither pathognomonic of, nor required for, the diagnosis of HLH.

HLH presents as a febrile illness associated with multiple organ involvement and the initial signs and symptoms of HLH can resemble common infections, fever of unknown origin, hepatitis, or encephalitis. HLH most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages. Primary HLH is also called familial hemophagocytic lymphohistiocytosis (FHL), and refers to HLH caused by a gene mutation, either at one of the FHL loci or in a gene responsible for one of several immunodeficiency syndromes. Secondary HLH refers to the presence of the HLH phenomenon in patients without a known familial mutation that occurs secondary to another condition (e.g., viral illness, autoimmune disease, and lymphoma). Both primary and secondary HLH can be triggered by infections or other immune activating events, and gene mutations can be found in individuals of any age and with any family history.

The goal of therapy for patients with HLH is to suppress life-threatening inflammation by destroying immune cells. The HLH standard of care outlined in the HLH-94 protocol by the Histiocyte Society includes management of the hyper-inflammation using immunosuppression and/or chemotherapy as well as trigger-directed treatment. 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.

On November 20, 2018, the U.S. Food and Drug Administration (FDA) approved Gamifant (emapalumab-lzsg) intravenous injection for the treatment of pediatric (newborn and older) and adult members with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. Emapalumab-lzsg is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ). Emapalumab-lzsg is produced in Chinese Hamster Ovary cells by recombinant DNA technology.

The efficacy of emapalumab was studied in in a clinical trial of 27 pediatric patients with suspected or confirmed primary HLH with either refractory, recurrent or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy (NI0501-04; NCT01818492). Patients were required to fulfill the following criteria for enrollment: primary HLH based on a molecular diagnosis or family history consistent with primary HLH or five out of the 8 criteria fulfilled: fever, splenomegaly, cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin < 9 , platelets < 100 x 109/L, neutrophils < 1 x 109/L), hypertriglyceridemia (fasting triglycerides > 3 mmol/L or ≥ 265 mg/dL) and/or hypofibrinogenemia (≤ 1.5 g/L), hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy, low or absent NK-cell activity, ferritin ≥ 500 mcg/L, soluble CD25 ≥ 2400 U/mL. Patients had to have evidence of active disease as assessed by treating physician. Patients had to fulfill one of the following criteria as assessed by the treating physician: having not responded or not achieved a satisfactory response or not maintained a satisfactory response to conventional HLH therapy, or intolerance to conventional HLH treatments. Patients were excluded from the trial if they had active infections caused by specific pathogens favored by IFNγ neutralization (e.g., mycobacteria and Histoplasma Capsulatum). Patients received prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections.

Twenty-seven patients enrolled and received treatment in the study and twenty patients (74%) completed the study. Seven patients (26%) were prematurely withdrawn. The study treatment duration was up to 8 weeks after which patients could continue treatment on the extension study. Twenty-two patients (81%) enrolled onto the open-label extension study which monitored patients for up to 1 year after HSCT or after the last emapalumab infusion (NI-0501-05; NCT02069899). All patients received an initial starting dose of emapalumab of 1 mg/kg every 3 days. Subsequent doses could be increased to a maximum of 10 mg/kg based on clinical and laboratory parameters interpreted as unsatisfactory response. Forty-four percent of patients remained at a dose of 1 mg/kg, 30% of patients increased to 3-4 mg/kg and 26% of patients increased to 6-10 mg/kg. The median time to dose increase was 27 days (range: 3-31 days) with 22% of patients requiring a dose increase in the first week of treatment. All patients received dexamethasone as background HLH treatment with doses between 5 to 10 mg/m2/day. Cyclosporine A was continued if administered prior to screening. Patients receiving methotrexate and glucocorticoids administered intrathecally at baseline could continue these treatments.

In Study NI-0501-04, the median patient age was 1 year (0.2 to 13). Fifty-nine percent of the patients were female, 63% were Caucasian, 11% were Asian, and 11% were Black. A genetic mutation known to cause HLH was present in 82% of patients. The most frequent causative mutations were FHL3-UNC13D (MUNC 13-4) (26%), FHL2-PRF1 (19%), and Griscelli Syndrome type 2 (19%). At baseline entry into the study, 78% of patients had elevated ferritin levels, thrombocytopenia (70% with platelet count of < 100 x 109cells/L), hypertriglyceridemia (67%) with triglyceride level > 3 mmol/L. Central nervous system findings were present in 37% of patients. Forty-one percent of patients had active infections not due to specific pathogens favored by IFNγ neutralization at the time of emapalumab initiation. All patients received previous HLH treatments. Patients received a median of 3 prior agents before enrollment into the trial. Prior regimens included combinations of the following agents: dexamethasone, etoposide, cyclosporine A, and anti-thymocyte globulin.

The efficacy of emapalumab was based upon overall response rate (ORR) at the end of treatment, defined as achievement of either a complete or partial response or HLH improvement. ORR was evaluated using an algorithm that included the following objective clinical and laboratory parameters: fever, splenomegaly, central nervous system symptoms, complete blood count, fibrinogen and/or D-dimer, ferritin, and soluble CD25 (also referred to as soluble interleukin-2 receptor) levels. Complete response was defined as normalization of all HLH abnormalities (i.e., no fever, no splenomegaly, neutrophils > 1x109/L, platelets > 100x109/L, ferritin < 2,000 g/L, fibrinogen > 1.50 g/L, D-dimer < 500 ug/L, normal CNS symptoms, no worsening of sCD25 > 2-fold baseline). Partial response was defined as normalization of ≥ 3 HLH abnormalities. HLH improvement was defined as ≥ 3 HLH abnormalities improved by at least 50% from baseline.

The study showed that 17 out of the 27 patients (63 %; 95% CI: 0.42, 0.81; p = 0.013) experienced an overall response. A complete response was seen in 7 patients (26%), a partial response in 8 patients (30%), and HLH improvement was seen in 2 patients (7.4%). The median duration of first response, defined as time from achievement of first response to loss of first response, was not reached (range: 4 to more than 56 days). Seventy percent (19/27) of patients proceeded to HSCT.

The most common adverse reactions (≥ 20%) were: infections, hypertension, infusion-related reactions, and pyrexia.  Serious adverse reactions were reported in 53% of patients and included: infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in two (6%) of patients and included septic shock and gastrointestinal hemorrhage. Patients should be advised that they should not receive live or live attenuated vaccines during emapalumab treatment.

Adult-Onset Still's Disease

Gabr and colleagues (2020) described the case of a 22-year-old woman with adult-onset Still's disease (AOSD) who was newly diagnosed in the setting of secondary macrophage activation syndrome (MAS), a rare, life-threatening inflammatory disease with 50 % mortality due to multi-organ failure.  She met the diagnostic criteria of AOSD and MAS, while genetic testing excluded primary causes of MAS.  She had high fevers, anemia, thrombocytopenia, splenomegaly, hematophagocytosis, and elevated serum ferritin (37,950 ng/ml) and CD25 levels (11,870 pg/ml), which remained unresponsive to corticosteroids and anakinra.  Her serum interferon gamma (IFN-γ) levels were elevated (7 pg/ml).  She was markedly responsive to IFN-γ blockade with emapalumab that eliminated her fevers and all MAS-associated laboratory abnormalities.  The authors concluded that this report provided initial evidence for therapeutic efficacy for IFN-γ blockade in AOSD and secondary MAS.  Moreover, these researchers stated that these findings warrant further examination of the clinical efficacy of emapalumab in patients with AOSD and secondary MAS.

Secondary Hemophagocytic Lymphohistiocytosis in Adults

England and colleagues (2021) noted that a subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "cytokine storm syndrome" (CSS).  These investigators compared the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary HLH (sHLH), idiopathic multi-centric Castleman disease (iMCD), and CAR-T cell therapy associated cytokine release syndrome (CRS).  These researchers stated that improved mechanistic understanding of hyper-inflammatory syndromes has led to therapies targeting specific cytokines implicated in disease pathogenesis.  Emapalumab is a monoclonal antibody targeting IFNγ that has demonstrated efficacy with ORRs of over 60 % in a study of pediatric HLH (Locatelli et al, 2020).  Based on this trial the FDA approved emapalumab for use in refractory, recurrent, or progressive primary HLH in both children and adults.  Although there is concern of secondary infections, especially from organisms responsive to IFNγ driven immune reactions, the medication has been well-tolerated in the majority of patients including those with infectious complications prior to therapy.  However, these researchers stated that data are limited in the use of emapalumab for sHLH in adults.

Yildiz and associates (2020) updated knowledge on adult HLH pathophysiology, identified the numerous causes, and aided clinicians make early diagnosis and initiate treatment.  By means of Embase, these investigators searched relevant articles published from January 1, 2010 to October 31, 2019, with the MESH term “hemophagocytic lymphohistiocytosis; macrophagic activation syndrome; adult”.  The mean age at presentation was approximately 50 years, with a male predominance.  The most frequent disease associations were hematological diseases, viral or bacterial infections, and autoimmune diseases.  The pathophysiologic mechanism was probably the combination of inherited genetic mutations and extrinsic triggers.  The mortality rate was 26.5 % to 74.8 %.  H-score was more efficient than HLH-2004 criteria to identify HLH, with diagnostic sensitivity and specificity of 90 % and 79 %, respectively.  18F-FDG PET/CT is potentially useful for detecting underlying disease and the extent of sHLH.  Disease-specific treatment should be administered as soon as possible.  Treatment with corticosteroids combined or not with etoposide is the mainstay of treatment.  Monoclonal antibodies and JAK pathway inhibitors showed promise of being effective.   The authors concluded that in adult HLH, infectious diseases, autoimmune disease and malignancy should be suspected so that disease-specific treatment can be administered promptly.  Treatment with corticosteroids combined or not with etoposide is the mainstay of treatment, but new therapies show promise of being effective.  One of the key words listed in this review was “emapalumab”.

Furthermore, an UpToDate review on “Treatment and prognosis of hemophagocytic lymphohistiocytosis” (McClain, 2023) states that “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”.

Macrophage Activation Syndrome (MAS)

Macrophage activation syndrome (MAS), a subtype of hemophagocytic lymphohistiocytosis (HLH), represents a serious complication associated with rheumatic diseases, particularly in conditions such as Still's disease, which encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease. HLH/MAS is characterized by a rare systemic disorder driven by hyperinflammation mediated by interferon-gamma (IFN-γ). Common clinical manifestations of this condition include persistent high fever, elevated ferritin levels, cytopenias, coagulopathies, and hepatosplenomegaly (Sobi, 2025a).

On June 27, 2025, the U.S. Food and Drug Administration approved emapalumab-lzsg (Gamifant) to treat both adult and pediatric patients, including newborns, diagnosed with hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) associated with known or suspected Still's disease, such as systemic juvenile idiopathic arthritis (sJIA). This approval is specifically for patients who have not responded adequately to glucocorticoids or who experience recurrent MAS. The FDA approval was supported by pooled data from two pivotal clinical trials: the Phase 3 study NI-501-14 (NCT05001737) and NI-0501-06 (NCT03311854). In these studies, 54% (21 out of 39) of participants achieved a complete response by Week 8, while 82% (32 out of 39) attained clinical remission of MAS, defined as a visual analog scale (VAS) score of 1 cm or less at the same time point. The safety and tolerability profile of Gamifant was consistent with findings from previous clinical investigations. Among patients with HLH/MAS related to Still's disease, the most frequently reported adverse events (occurring in 20% or more of patients) included viral infections, such as cytomegalovirus infection or reactivation, as well as rashes (Sobi, 2025a; 2025b).

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Appendix

Clinical Signs and Symptoms of Hemophagocytic Lymphohistiocytosis (HLH)

• Fever
• Splenomegaly
• Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood: hemoglobin less than 9 g/dL [hemoglobin less than 10 g/dL in infants younger than 4 weeks], platelets less than 100,000/microliter, neutrophils less than 1,000/microliter)
• Hypertriglyceridemia (fasting triglyceride greater than or equal to 265 mg/dL) or hypofibrinogenemia (less than or equal to 150 mg/dL)
• Hemophagocytosis in bone marrow or spleen or lymph nodes or liver with no evidence of malignancy
• Low or absent natural killer (NK) cell activity
• Ferritin greater than or equal to 500 ng/mL
• Soluble CD25 (soluble IL-2 receptor alpha) level greater than or equal to 2400 U/mL, or above age-adjusted, laboratory-specific normal levels (defined as 2 standard deviation from the mean)

Source: Sobi, 2025b

Operational Case Definition of New Onset systemic Juvenile Idiopathic Arthritis

1. Patient should have:

   • Age 6 months to 18 years
   • Fever for at least 2 weeks
   • Arthritis in one or more joints (6 weeks duration not required)
   • At least one of the following:
     
     
     • Evanescent erythematous rash
     • Generalized lymphadenopathy
     • Hepatomegaly or splenomegaly
     • Pericarditis, pleuritis and/or peritonitis.

2. Patient should not have any of the following:

   1. Infection: including concomitant active or recurrent chronic bacterial, fungal or viral infection at presentation; nor underlying infection which may mimic initial presentation of sJIA
   2. Malignancy
   3. Positive screening test for TB without documented past treatment
   4. Prior treatment for SJIA other than NSAIDs or short term steroids
   5. Immunization with live virus vaccines within the 4 weeks prior to enrollment.

Source: DeWitt et al. (2012)

Yamaguchi Diagnostic Criteria for Adult-onset Still’s Disease

• Major Criteria

  • Fever ≥ 39 degrees Celsius persisting for ≥ 1 week
  • Arthralgia/arthritis persisting for greater than or equal to 2 weeks
  • Typical rash
  • White blood cell count greater than or equal to 10×109/L (> 80% neutrophils)
    
    

• Minor Criteria

  • Sore throat
  • Lymphadenopathy and/or splenomegaly
  • Increased serum aminotransferase or lactate dehydrogenase levels (after other causes have been excluded)
  • Negative IgM rheumatoid factor and antinuclear antibodies (immunofluorescence assay)
    
    

• Exclusion Criteria

  • Infections, in particular sepsis and infectious mononucleosis
  • Malignancy, in particular lymphoma
  • Other rheumatic diseases, in particular polyarteritis nodosa and vasculitis in the course of rheumatoid arthritis

For the diagnosis of Adult-onset Still’s disease, ≥ 5 criteria must be met, including ≥ 2 major. In members with any of the exclusion criteria, the diagnosis is excluded.

Source: Yamaguchi et al., 1992

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References