Emapalumab-lzsg (Gamifant)

Number: 0948

Policy

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

  • Member has refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy; and
  • Member’s diagnosis of primary HLH was confirmed by either of the following:

    • Mutation in one of the following genes: PRF1, UNC13D, STX11 and STXBP2; or
    • Presence of 5 out of the following 8 criteria: 

      • Fever;
      • Splenomegaly;
      • Cytopenias affecting 2 of 3 lineages in the peripheral blood: hemoglobin less than 9 g/dL [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 triglycerides greater than or equal to 265 mg/dL) or hypofibrinogenemia (less than or equal to 1.5 g/L);
      • Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver with no evidence of malignancy;
      • Low or absent natural killer (NK)-cell activity;
      • Ferritin greater than or equal to 500 mcg/L;
      • Soluble CD25 (soluble IL-2 receptor alpha) greater than or equal to 2400 U/mL, or above age-adjusted, laboratory-specific normal levels (defined as 2 standard deviation from the mean); and
         
  • 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
  • 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
  • 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 continued treatment with emapalumab-lzsg medically necessary for members with primary HLH who have achieved or maintained positive clinical response.

Aetna considers emapalumab-lzsg experimental and investigational for all other indications.

Dosing Recommendations

Gamifant is indicated for intravenous infusion only. 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.

Source: Sobi 2018.

Background

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.

Secondary Hemophagocytic Lymphohistiocytosis in Adults

England and colleagues (2020) 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, 2020) 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”.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

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

ICD-10 codes covered if selection criteria are met:

D76.1 Hemophagocytic lymphohistiocytosis

The above policy is based on the following references:

  1. Allen CE, McClain KL. Hematology. Am Soc Hematol Educ Program. 2015;2015:177-182.
  2. England JT, Abdulla A, Biggs CM, et al. Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes. Blood Rev. 2020 May 15 [Online ahead of print].
  3. Henter JI, Aricò M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28(5):342-7. 
  4. Henter JI, Horne A, Arico M et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131.
  5. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1):4-14.
  6. Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-1822.
  7. McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2019.
  8. McClain KL. Treatment and prognosis of hemophagocytic lymphohistiocytosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2018; June 2020.
  9. Sobi Inc. Gamifant (emapalumab-lzsg) injection, for intravenous use. Prescribing Information. Reference ID: 4352960. Waltham, MA: Sobi; revised November 2018.
  10. U.S. Food and Drug Administration (FDA). FDA approves first treatment specifically for patients with rare and life-threatening type of immune disease. FDA News Release. Silver Spring, MD: FDA; November 20, 2018. 
  11. Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood. 2019;134(21):1783-1786.
  12. Yildiz H, Van Den Neste E, Defour JP, et al. Adult haemophagocytic lymphohistiocytosis: A review. QJM. 2020 Jan 14 [Online ahead of print].