Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2019013
Category:	Pharmacy
Initiated:	November 2019
Last Review:	November 2025

Emapalumab-LZSG (e.g., Gamifant)

Description:

Emapalumab-LZSG (e.g., Gamifant) is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ), blocking its intracellular signaling to inhibit macrophage activation and the downstream release of proinflammatory cytokines. It is indicated for the treatment of adult and pediatric (newborn and older) individuals with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. Nonclinical data suggests that IFNγ plays a pivotal role in the pathogenesis of HLH by being hypersecreted.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to increased immune activation. HLH comprises two different conditions that may be difficult to distinguish from one another: a primary (genetic) and secondary (acquired) form. Primary HLH, otherwise known as familial hemophagocytic lymphohistiocytosis, refers to HLH caused by a gene mutation and is usually diagnosed within the first year of life. Secondary HLH can occur at any age and is generally triggered by another condition such as severe infections, malignancies, rheumatologic disorders, or metabolic diseases. Despite advances in molecular diagnosis it remains difficult to distinguish between primary and secondary forms of HLH as both can be triggered by infections or other immune activating events and gene mutations can be found in individuals of any age or with any family history. In primary (familial) HLH, symptoms usually develop within the first months or years of life. If left untreated survival is typically two to six months after symptoms first occur. Symptoms include fever, enlarged liver or spleen, skin rash, enlarged lymph nodes, breathing problems, abnormal bleeding, kidney abnormalities, heart problems, and increased risk for certain cancers.

Acquired HLH could be caused by infection, medications that suppress the immune system, autoimmune disease, immunodeficiency or cancer. Inherited HLH involves mutations in genes that typically signal destruction of activated immune cells. Treatment for acquired HLH includes treating the underlying cause. Treatment for inherited HLH is to suppress life-threatening inflammation by destroying immune cells. The Histiocyte Society established a treatment protocol in 1994 for HLH that includes management of the hyperinflammation using immunosuppression and/or chemotherapy as well as allogenic hematopoietic cell transplant. Induction therapy based on the HLH-94 protocol consists of a series of weekly treatments with dexamethasone and etoposide. Intrathecal methotrexate and hydrocortisone are given to individuals with central nervous system disease. After induction, those who are improving can be weaned off therapy. Those who are not improving are continued on therapy as a bridge to allogenic hematopoietic cell transplantation. Hematopoietic cell transplantation will be required in those with HLH gene mutation, central nervous system disease, or disease relapse.

Regulatory Status

November 20, 2018, Eemapalumab-lzsg (e.g., Gamifant) was approved by the U.S. Food and Drug Administration (FDA) for treatment of pediatric and adult individuals with primary HLH with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.

Emapalumab-lzsg (e.g., Gamifant) was approved by the U.S. Food and Drug Administration (FDA) on June 27, 2025, for expansion of the indication to include treatment of adult and pediatric (newborn and older) individuals with hemophagocytic lymphohistiocytosis (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.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior Approval is required for Emapalumab-LZSG (e.g. Gamifant)

INITIAL AND CONTINUATION APPROVAL will be for duration of the treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.

Effective January 15, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Emapalumab-lzsg (e.g., Gamifant) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria:

PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)

INITIAL APPROVAL:

1. Individual is newborn and older (Gamifant, 2025); AND

2. Individual has a diagnosis of Primary hemophagocytic lymphohistiocytosis (HLH) (Gamifant, 2025):

a. Refractory disease (see policy guidelines); OR

b. Recurrent disease (see policy guidelines); OR

c. Progressive disease; OR

d. Intolerance with conventional HLH therapy (etoposide & dexamethasone +/- methotrexate & hydrocortisone) or alemtuzumab (Gamifant, 2025; Locatelli, 2020); AND

e. Documentation of ONE of the following:

i. A gene mutation known to cause primary HLH: homozygosity or compound heterozygosity of verified HLH-associated mutations or of other immune regulatory genes AND clinical findings associated with HLH (Gamifant, 2025; Locatelli, 2020); OR

ii. Presence of at least Five out of the following 8 clinical characteristics (Gamifant, 2025; Locatelli, 2020):

1. Fever greater than or equal to 38.5 C; OR

2. Splenomegaly; OR

3. Peripheral blood cytopenias affecting two of the three cell lineages:

a. Hemoglobin (Hgb) less than 9 gram per deciliter of blood (for infants greater than 4 weeks, Hgb less than 10 gram per deciliter of blood); OR

b. Platelet count of less than 100,000 per microliter of blood; OR

c. Neutrophils less than 1,000 cells per microliter of blood; OR

4. One of the following:

a. Hypertriglyceridemia defined as fasting triglycerides greater than or equal to 265 milligrams per deciliter of blood mg/dL (greater than 3 millimoles per liter of blood); OR

b. Hypofibrinogenemia defined as fibrinogen less than or equal to 150mg/dL; OR

5. Hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy; OR

6. Low or absent natural killer cell activity; OR

7. Ferritin greater than or equal to 500 micrograms per liter of blood (a ferritin greater than 3,000 micrograms per liter of blood is more specific for HLH; a ferritin greater than 10,000 micrograms per liter of blood is highly suggestive of HLH especially in children with no reason for iron overload); OR

8. Soluble CD25 greater than or equal to 2400 units per milliliter of blood; AND

iii. Emapalumab-lzsg will be administered with dexamethasone (Gamifant, 2025; Locatelli, 2020); AND

iv. The individual is a candidate for hematopoietic stem cell transplant (Locatelli, 2020; Trottestam, 2011; Jordan, 2011); OR

v. Emapalumab is being used as part of the induction or maintenance phase of stem cell transplant, which is to be discontinued at the initiation of conditioning for stem cell transplant (Locatelli, 2020; Trottestam, 2011; Jordan, 2011).

CONTINUATION OF THERAPY:

1. Individual continues to meet the initial approval criteria; AND

2. Individual has clinical response to treatment (improvement in initial clinical or laboratory parameters); AND

3. Documentation is provided that individual is experiencing residual active disease; AND

4. Documentation is provided that individual has not received a successful hematopoietic stem cell transplant; AND

5. Dose has been titrated to the minimum dose and frequency necessary to achieve satisfactory improvement as defined by FDA labeling for Emapalumab-lzsg (e.g., Gamifant).

HLH/MACROPHAGE ACTIVATION SYNDROME (MAS)

INITIAL APPROVAL:

1. Individual is newborn and older (Gamifant, 2025); AND

2. Individual has a diagnosis of HLH/macrophage activation syndrome (MAS); AND

3. Individual has known or suspected Still’s disease, [i.e., systemic Juvenile Idiopathic Arthritis (sJIA) or adult-onset Still’s disease (AOSD)] (Gamifant, 2025); AND

4. Individual has had an inadequate response or intolerance to high-dose glucocorticoids; OR

5. Individual has recurrent MAS; AND

6. Documentation of the following (Gamifant, 2025):

a. Ferritin greater than 684 micrograms per liter of blood; AND

b. Two of the following:

i. Platelet count is less than or equal to 181,000 cells per microliter of blood; OR

ii. AST greater than 48 units per liter; OR

iii. Triglycerides greater than 156 milligrams per deciliter of blood; OR

iv. Fibrinogen less than or equal to 360 milligrams per deciliter of blood.

CONTINUATION OF THERAPY:

1. Individual continues to meet the initial approval criteria; AND

2. Documentation is provided that individual has clinical response to treatment (improvement in initial clinical or laboratory parameters).

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Emapalumab-lzsg (e.g., Gamifant) for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.

For members with contracts without Primary Coverage Criteria, Emapalumab-lzsg (e.g., Gamifant), for any indication or circumstance not described above, is considered not Medically Necessary or is investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

POLICY GUIDELINES

Prescribing provider responsible for ensuring individual has been evaluated for tuberculosis risk factors and has undergone pretreatment screening for latent TB and/or other specific pathogen favored by IFN gamma neutralization (e.g., histoplasma) (Locatelli, 2020).

Do not administer live or live attenuated vaccines to individuals receiving Emapalumab-lzsg (e.g., Gamifant).

Prescribing provider should consider prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections will be administered prior to starting Emapalumab-lzsg (e.g., Gamifant).

Refractory disease is defined as unresponsive to treatment.

Recurrent disease is defined as the return of disease after a period of remission or after it was thought to have been successfully treated.

DOSAGE AND ADMINISTRATION

For FDA labeled indications, Emapalumab-lzsg (e.g., Gamifant) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.

Primary HLH:

For IV use only. Recommended starting dose, administer 1mg/kg twice a week. Doses subsequent to the initial dose may be increased on clinical and laboratory criteria (see FDA label).
May be titrated up to a maximum of 10 mg/kg.
Administer until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity.

HLH/MAS in Still’s Disease:

For IV use only. Recommended starting dose, 6 mg/kg, followed by 3 mg/kg every 3 days for 5 does, then 3 mg/kg twice per week.
May be titrated up to a maximum of 10 mg/kg.
Discontinue when individual no longer requires therapy for the treatment of HLH/MAS.

Emapalumab-Izsg is available as:

10 mg/2 mL (5 mg/mL) solution in single-dose vial.
50 mg/10 mL (5 mg/mL) solution in single-dose vial.
100 mg/20 mL (5 mg/mL) solution in single-dose vial.
50 mg/2 mL (25 mg/mL) solution in single-dose vial.
100 mg/4 mL (25 mg/mL) solution in single-dose vial.
250 mg/10 mL (25 mg/mL) solution in single-dose vial.
500 mg/20 mL (25 mg/mL) solution in single-dose vial.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.

Effective November 2023 to January 14, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

Emapalumab-lzsg meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) in individuals who meet ALL the following criteria:

Documented diagnosis of primary HLH based on ONE of the following:

a. A gene mutation known to cause primary HLH: homozygosity or compound heterozygosity of verified HLH-associated mutations or of other immune regulatory genes AND clinical findings associated with HLH (FDA, 2018; Locatelli, 2020); OR

b. Presence of least Five out of the following 8 clinical characteristics (FDA, 2018; Locatelli, 2020):

i. Fever > 38.5 C

ii. Splenomegaly

iii. Peripheral blood cytopenias affecting two of the three cell lineages:

1. Hemoglobin < 9g/dL (for infants > 4weeks, Hgb < 10 g/dL)

2. Platelet count < 100,000 microL

3. Neutrophils < 1,000 microL

iv. One of the following:

1. Hypertriglyceridemia defined as fasting triglycerides ≥ 265 mg/dL (> 3 mmol/L)

2. Hypofibrinogenemia defined as fibrinogen ≤ 150mg/dL

v. Hemophagocytosis in bone marrow, spleen or lymph nodes with no evidence of malignancy

vi. Low or absent natural killer cell activity

vii. Ferritin ≥ 500 mcg/L (a ferritin > 3,000 mcg/dL is more specific for HLH; a ferritin >10,000 mcg/dL is highly suggestive of HLH especially in children with no reason for iron overload)

viii. Soluble CD25 ≥ 2400 U/mL; AND

2. The individual has refractory, recurrent, or progressive disease having received conventional HLH therapy or demonstrates intolerance to conventional HLH therapy (etoposide & dexamethasone +/- methotrexate & hydrocortisone) or alemtuzumab (FDA, 2018; Locatelli, 2020); AND

3. The individual has been evaluated for tuberculosis risk factors and has undergone pretreatment screening for latent TB and/or other specific pathogen favored by IFN gamma neutralization (e.g., histoplasma) (Locatelli, 2020); AND

4. Prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections will be administered prior to starting Emapalumab-lzsg (FDA, 2018); AND

5. Emapalumab-lzsg will be administered with dexamethasone (FDA, 2018; Locatelli, 2020); AND

6. The individual is a candidate for hematopoetic stem cell transplant (Locatelli, 2020; Trottestam, 2011; Jordan, 2011); AND

7. Emapalumab is being used as part of the induction or maintenance phase of stem cell transplant, which is to be discontinued at the initiation of conditioning for stem cell transplant (Locatelli, 2020; Trottestam, 2011; Jordan, 2011); AND

8. The requested dose is in accordance with the FDA labeling (FDA, 2018).

Dosage and Administration

Dosing per FDA Guidelines

For IV use only. Recommended starting dose, administer 1mg/kg twice a week. Doses subsequent to the initial dose may be increased on clinical and laboratory criteria (see FDA label).

Administer until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity.

Emapalumab-Izsg is available as 10 mg/2 mL (5 mg/mL) solution and 50 mg/10 mL (5 mg/mL) solution in single-dose vials.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Emapalumab-lzsg does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of secondary or acquired HLH or any other indication not listed above.

For members with contracts without primary coverage criteria, emapalumab-lzsg, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective prior to November 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Emapalumab-lzsg meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of primary HLH in individuals who meet ALL of the following criteria:

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

Documented diagnosis of primary HLH based on ONE of the following:

a. A gene mutation known to cause primary HLH: homozygosity or compound heterozygosity of verified HLH-associated mutations or of other immune regulatory genes AND clinical findings associated with HLH (FDA, 2018; Locatelli, 2020). OR

b. Presence of least Five out of the following 8 clinical characteristics (FDA, 2018; Locatelli, 2020):

Fever > 38.5 C
Splenomegaly
Peripheral blood cytopenias affecting two of the three cell lineages:
One of the following:
Hemophagocytosis in bone marrow, spleen or lymph nodes with no evidence of malignancy
Low or absent natural killer cell activity
Ferritin ≥ 500 mcg/L (a ferritin > 3,000 mcg/dL is more specific for HLH; a ferritin >10,000 mcg/dL is highly suggestive of HLH especially in children with no reason for iron overload)
Soluble CD25 ≥ 2400 U/mL AND

2. The individual has refractory, recurrent, or progressive disease having received conventional HLH therapy or demonstrates intolerance to conventional HLH therapy (etoposide & dexamethasone +/- methotrexate & hydrocortisone) or alemtuzumab (FDA, 2018; Locatelli, 2020) AND

3. The individual has been evaluated for tuberculosis risk factors and has undergone pretreatment screening for latent TB and/or other specific pathogen favored by IFN gamma neutralization (e.g. histoplasma) (Locatelli, 2020) AND

4. Prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections will be administered prior to starting Emapalumab-lzsg (FDA, 2018) AND

5. Emapalumab-lzsg will be administered with dexamethasone (FDA, 2018; Locatelli, 2020) AND

6. The individual is a candidate for hematopoetic stem cell transplant (Locatelli, 2020; Trottestam, 2011; Jordan, 2011) AND

7. Emapalumab is being used as part of the induction or maintenance phase of stem cell transplant, which is to be discontinued at the initiation of conditioning for stem cell transplant (Locatelli, 2020; Trottestam, 2011; Jordan, 2011) AND

8. The requested dose is in accordance with the FDA labeling (FDA, 2018).

Dosage and Administration

For IV use only. Recommended starting dose, administer 1mg/kg twice a week. Doses subsequent to the initial dose may be increased on clinical and laboratory criteria (see FDA label).

Administer until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Emapalumab-lzsg does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of secondary or acquired HLH or any other indication not listed above.

For members with contracts without primary coverage criteria, emapalumab-lzsg is considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

The efficacy of emapalumab was evaluated in a multicenter, open-label, single-arm trial NI-0501-04 (NCT01818492) in 27 pediatric patients with suspected or confirmed primary HLH witheither refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy. 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 with active infections caused by specific pathogens favored by IFNγ neutralization were excluded from the trial (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. Twenty-two patients (81%) enrolled onto the open-label extension study which monitored patients for up to 1 year after hematopoietic stem cell transplantation (HSCT) or after the last emapalumab infusion (NI-0501-05; NCT02069899). The study treatment duration was up to 8 weeks after which patients could continue treatment on the extension study. 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%). 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.

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.

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 mg/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 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. The most common serious adverse reactions (≥ 3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in two (6%) of patients and included septic shock and gastrointestinal hemorrhage.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome generally occurring in early childhood. The monoclonal antibody emapalumab binds and neutralizes interferon γ (IFNγ). This study aimed to determine an emapalumab dosing regimen when traditional dose-finding approaches are not applicable, using pharmacokinetic-pharmacodynamic analyses to further clarify HLH pathogenesis and confirm IFNγ neutralization as the relevant therapeutic target in pHLH.

Initial emapalumab dosing (1 mg/kg) for pHLH patients participating in a pivotal multicenter, open-label, single-arm, phase 2/3 study was based on anticipated IFNγ levels and allometrically scaled pharmacokinetic parameters estimated in healthy volunteers. Emapalumab dosing was adjusted based on estimated IFNγ-mediated clearance and HLH clinical and laboratory criteria. Frequent dosing and emapalumab dose adaptation were used to account for highly variable IFNγ levels and potential target-mediated drug disposition.

High inter- and intra-individual variability in IFNγ production (assessed by total IFNγ levels, range: 102 -106 pg/mL) was observed in pHLH patients. Administering emapalumab reduced IFNγ activity, resulting in significant improvements in clinical and laboratory parameters and a reduced risk of adverse events, mainly related to pHLH. Modelled outcomes supported dose titration starting from 1 mg/kg, with possible increases to 3, 6 or 10 mg/kg based on re-evaluation of parameters of disease activity every 3 days.

The variable and unanticipated extremely high IFNγ concentrations in patients with pHLH are reflected in parameters of disease activity. Improved outcomes can be achieved by neutralizing IFNγ using frequent emapalumab dosing and dose adaptation guided by clinical and laboratory observations. (Jacqmin P, Laveille C, Snoeck E, et.al., 2022)

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2024. No new literature was identified that would prompt a change in the coverage statement.

2025 Update

The efficacy of GAMIFANT was evaluated in two open-label, single arm, multicenter studies which enrolled a total of 39 patients with hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response to high-dose glucocorticoid treatment.

In each study, patients were required to fulfill the following criteria for enrollment: confirmed or suspected diagnosis of sJIA or AOSD; a diagnosis of active MAS with ferritin >684 ng/mL and any 2 of these 4 laboratory criteria: platelet count ≤181×109 /L, AST >48 U/L, triglycerides >156 mg/dL, or fibrinogen levels ≤360 mg/dL; an inadequate response to high-dose IV glucocorticoids. Patients with active infections caused by specific pathogens favored by IFNγ neutralization were excluded from the trial (e.g., mycobacteria and Histoplasma Capsulatum).

In each study, GAMIFANT was administered at an initial dose of 6 mg/kg, followed by at least 3 mg/kg every 3 days until Day 16, and then twice weekly thereafter. Glucocorticoids and anakinra (< 4 mg/kg/d) could be co-administered for the treatment of Still’s disease.

The pooled analysis includes all patients from Study NI-0501-06 (NCT 03311854) and Study NI-0501-14 (NCT05001737). These two studies enrolled 39 patients who received GAMIFANT, and 37 patients completed the studies (95%). The majority of patients were female (80%) and the median age was 12.0 years (range: 0.9 to 64 years). The racial distribution was White (74%), Asian (10%), Black or African American (5%), and Other (3%), with 3 patients not reporting race (8%). Ethnicity was only collected in Study NI-0501-14 in which 88% reported Not Hispanic or Latino with 3 patients not reporting ethnicity (12%). At baseline, patients had elevated ferritin levels (median 6833 µg/L), elevated ALT (median 259 U/L), and elevated LDH (median 954 U/L).

The efficacy of GAMIFANT was based on complete response (CR), a composite endpoint consisting of clinical resolution of MAS signs and symptoms (a visual analogue scale (VAS), of ≤1 cm [range 0 to 10 cm]) and the following 7 laboratory parameter endpoints: WBC count and platelet count above the lower limit of normal (LLN), LDH, AST and ALT below 1.5×the upper limit of normal (ULN), fibrinogen >100 mg/dL, and ferritin levels decreased ≥80% from values at screening or baseline (whichever was higher) or <2000 ng/mL, whichever was lower. (Gamifant, 2025)

CPT/HCPCS:

References:

George M. R.(2014) Hemophagocytic lymphohistiocytosis: review of etiologies and management. Journal of blood medicine, 5, 69–86. doi:10.2147/JBM.S46255

Blood. 2011;118(15): 4041.(2011) How I treat hemophagocytic lymphohistiocytosis. Jordan, MB, et al.

Department of Health and Human Services(2017) “Hemophagocytic Lymphohistiocytosis.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, 11 Sept. 2017, rarediseases.info.nih.gov/diseases/6589/hemophagocytic-lymphohistiocytosis.

Gamifant [package insert](2018) Gamifant [package insert] Waltham, MA: Sobi; November 2018.

Henter, Jan-Inge, et al.(2002) “Treatment of Hemophagocytic Lymphohistiocytosis with HLH-94 Immunochemotherapy and Bone Marrow Transplantation.” Blood, vol. 100, no. 7, 2002, pp. 2367–2373., doi:10.1182/blood-2002-01-0172.

Jacqmin P, Laveille C, Snoeck E, Jordan MB, Locatelli F, Ballabio M, de Min C.(2022) Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: A pharmacometric model-based approach. Br J Clin Pharmacol. 2022 May;88(5):2128-2139. doi: 10.1111/bcp.15133. Epub 2021 Dec 21. PMID: 34935183; PMCID: PMC9305196.

Locatelli F., Jordan M.B., Allen C., et al.(2020) Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med 2020; 382:1811-1822.

Trottestam H., et al.(2011) Chemoimmunotherapy for HLH: long-term results of the HLH-94 treatment protocol. Blood. 2011; 118: 4577.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.