Coverage Policy Manual
Policy #: 2019013
Category: Pharmacy
Initiated: November 2019
Last Review: November 2023
  Emapalumab-LZSG (e.g., Gamifant)

Description:
Emapalumab 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.
 
Coding
 
See CPT/HCPCS Code section below.

Policy/
Coverage:
Prior Approval is required for Emapalumab-LZSG (e.g. Gamifant)  
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective November 2023
 
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 HLH in individuals who meet ALL the following criteria:
 
    1. 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 dexamethasoneFDA, 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:
    1. 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:
              • Hemoglobin <9g/dL(for infants > 4wks, Hgb < 10 g/dL)
              • Platelet count <100,000 microL
              • Neutrophils <1,000 microL
          • One of the following:
              • Hypertriglyceridemia defined as fasting triglycerides 265 mg/dL (> 3 mmol/L)
              • Hypofibrinogenemia defined as fibrinogen 150mg/dL
          • 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 dexamethasoneFDA, 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, thrombocytopena (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.

CPT/HCPCS:
C9399Unclassified drugs or biologicals
J3590Unclassified biologics
J9210Injection, emapalumab lzsg, 1 mg

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 or to the Tyson Group Health Plan participants.
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