Medical Policy



Subject: Interferon gamma-1b (Actimmune®)
Document #: DRUG.00084 Current Effective Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the indications for interferon gamma-1b (Actimmune, Horizon Pharma Ireland Ltd., Dublin, Ireland; HZNP USA Inc., Roswell, GA), a biologic response modifier used in the management of chronic granulomatous disease, severe malignant osteopetrosis, and oncologic conditions.

Interferon gamma-1b is a biosynthetic (recombinant DNA origin) form of endogenous human interferon gamma containing 140 amino acids resulting from the fermentation of a genetically engineered Escherichia coli bacterium.

Position Statement

Medically Necessary:

Interferon gamma-1b is considered medically necessary for the treatment of any of the following conditions:

  1. Chronic granulomatous disease; or
  2. Severe malignant osteopetrosis; or
  3. Mycosis fungoides, including Sézary syndrome.

Investigational and Not Medically Necessary:

Interferon gamma-1b is considered investigational and not medically necessary when the criteria above are not met and for all other indications including, but not limited to, any of the following:

Rationale

Chronic Granulomatous Disease (CGD)

Interferon gamma-1b (Actimmune) received U.S. Food and Drug Administration (FDA) approval in 1999 as an orphan drug for use in reducing the frequency and severity of serious infections in adults and children 1 year of age or older with CGD. CGD is a heterogeneous group of primary inherited immunodeficiency disorders which increase the body's susceptibility to recurrent, potentially life-threatening bacterial and fungal infections and abnormal inflammatory responses that result in excessive granuloma formation (American Hospital Formulary Service® [AHFS® , 2010]). The exact mechanism by which interferon gamma-1b has a treatment effect on CGD has not been established (Actimmune Product Information [PI] label, 2016).

The clinical effectiveness and safety of interferon gamma-1b in the management of CGD was evaluated in a randomized, double-blind, placebo-controlled study of 128 adults and children (mean age, 14.6 years; range, 1-44 years) with different disease inheritance patterns of chronic CGD (The International Chronic Granulomatous Disease Cooperative Study Group, 1991) (Actimmune PI label, 2016). Participants were randomized to receive interferon gamma-1b or placebo as a subcutaneous injection 3 times weekly and allowed to continue anti-infective prophylaxis. The primary endpoint was the time to serious infection, defined as a clinical event requiring both hospitalization and administration of parenteral anti-infectives. The clinical trial was terminated early following demonstration of a statistically significant benefit of interferon gamma-1b compared to placebo in the time to serious infection (p=0.0036). The final analysis provided further support for the primary endpoint (p=0.0006), as participants receiving interferon gamma-1b (n=63) had a 67% lower risk of serious infection compared to placebo (n=65). In subgroup analysis, interferon gamma-1b provided this benefit regardless of the inheritance type of the disease, age, or concurrent use (or nonuse) of anti-infective prophylaxis. In those participants younger than 10 years of age, 81% receiving interferon gamma-1b compared with only 20% of those receiving placebo were free of serious infections during the study. Additional treatment benefit included a twofold reduction in the number of primary serious infections in the interferon gamma-1b group versus placebo (p=0.002) and the total number and rate of serious infections including recurrent events (56 in placebo vs. 20 in interferon gamma-1b; p≤0.0001). A reduction in the length of inpatient hospitalization for the treatment of all clinical events was reported in the interferon gamma-1b group (1493 total days [placebo] vs. 497 total days [interferon gamma-1b]; p=0.02). Interferon gamma-1b appeared to be most effective in reducing the incidence of adenitis, abscesses, cellulitis, and pulmonary infections; however, there was no evidence, that interferon gamma-1b had a clinically significant effect on other complications related to CGD (for example, granulomatous obstruction of the GI and genitourinary tracts, fistulas, and dermatitis).

In an open-label, uncontrolled, follow-up study, 28 adults and children with CGD (mean age, 16 years; range, 3-37 years) experienced a treatment benefit during continuous, long-term use of interferon gamma-1b given subcutaneously 3 times weekly for a mean of 880 days (range, 97-1375 days) (Weening, 1995). Most participants also received anti-infective prophylaxis (that is, antibacterials or antifungals). In a follow-up study of adults and children (mean age, 12.8 years; range, 0.8-34.7 years) who received interferon gamma-1b for CGD for an average duration of 2.5 years (range, 1-4.3 years), the overall rate of serious infections was 0.13 per patient year in the 30 participants evaluated for 12 months, lower than the infection rate reported with placebo during the initial phase of the study (1.1 per patient year) (Bemiller, 1995). Common adverse events were fever (23%), diarrhea (13%), and flu-like illness (13%). The investigators reported no serious adverse events were attributable to interferon gamma-1b therapy and no apparent effects on growth and development were observed.

In a post-marketing safety database, clinically significant adverse events observed during interferon gamma-1b therapy in children under the age of 3 years (n=14) included 2 cases of hepatomegaly and 1 case each of atopic dermatitis, granulomatous colitis, Stevens-Johnson syndrome, and urticaria (Actimmune PI label, 2016).

Severe Malignant Osteopetrosis (SMO)

SMO is a rare inherited disorder characterized by defective osteoclast function leading to bone overgrowth and various neurologic and hematologic abnormalities. Those individuals with the most severe form of the disease develop blindness or anemia before 6 months of age as a result of overgrowth of bony structures, and many will die during the first decade of life because of poor resistance to infection, neurologic deficits, or bone failure (Key, 1995). In February 2000, the FDA approved interferon gamma-1b for use in delaying the time to disease progression in children and adults with SMO. The exact mechanism by which interferon gamma-1b has a treatment effect on SMO has not been established (Actimmune PI label, 2016).

The clinical effectiveness and safety of interferon gamma-1b in the management of SMO was evaluated in a randomized controlled trial of 16 individuals (mean age, 1.5 years; range, 1 month-8 years) who received 3 times weekly subcutaneous injections of either interferon gamma-1b plus calcitriol (n=11), or calcitriol alone (n=5) for at least 6 months. Treatment failure was considered to be disease progression as defined by death, clinically significant reduction in hemoglobin or platelet counts, a serious bacterial infection requiring antibiotics, or a 50 decibel (dB) decrease in hearing or progressive optic atrophy. Based on observational data, the median time to disease progression was significantly delayed in the interferon gamma-1b plus calcitriol arm (at least 165 days) versus calcitriol alone (65 days). In an analysis which combined data from this randomized controlled trial and a second study, 19 of 24 participants treated with interferon gamma-1b ± calcitriol for at least 6 months had reduced trabecular bone volume compared with baseline (Actimmune PI label, 2016).

In a small uncontrolled study, 8 children (mean age, 3 years; range, 1 month-11 years) with osteopetrosis received 3 times weekly subcutaneous injections of interferon gamma-1b (1.5 mcg/kg) for 6 months in conjunction with a low calcium diet (Key,1992). One participant acquired a cellulitis surrounding a central venous catheter and required antibiotics. In addition, there was evidence of improved bone resorption in all 8 children as documented by an increase in urinary calcium and hydroxyproline excretion.

In another small uncontrolled study in adults and children with osteopetrosis, interferon gamma-1b therapy was continued in some participants for up to 18 months (Key, 1995). In 6 participants for whom pretreatment data were available, there was a 96% decrease in the frequency of infections needing antibiotic therapy during interferon gamma-1b treatment. There were no adverse events requiring the discontinuation of therapy. Results of this study provide additional evidence that long-term therapy with interferon gamma-1b in individuals with osteopetrosis can decrease the incidence of infectious complications and increase bone resorption as documented by an increase in urinary hydroxyproline excretion and a decrease in trabecular bone on bone biopsy.

Off-FDA Label Uses of interferon gamma-1b

Mycosis Fungoides and Sézary Syndrome

The National Comprehensive Cancer Network® (NCCN® ) Clinical Practice Guidelines (CPGs) in Oncology® for T-cell lymphomas (NCCN, V2.2017) include a category 2A recommendation (based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate) for use of interferon gamma-1b in the treatment of mycosis fungoides and Sézary syndrome.

The peer-reviewed published medical literature includes, but is not limited to, numerous single and small case series and a small phase II clinical trial (Kaplan, 1990) evaluating treatment of mycosis fungoides and Sézary syndrome with interferon gamma-1b. More recently, a multisite, open-label, non-randomized, single-arm phase II study evaluated the efficacy and safety profiles of interferon gamma-1b in individuals diagnosed with stage IA-IIIA mycosis fungoides (Sugaya, 2014).

Kaplan and colleagues (1990) evaluated the use of interferon gamma-1b in 16 individuals with various stages of cutaneous T-cell lymphoma (CTCL) who were previously treated with standard topical and/or systemic therapies. Some participants had previously received experimental treatment with retinoids, recombinant human interferon alfa-2a (rIFN-alpha 2a), or radiolabeled monoclonal antibodies. Most participants in this study had advanced stage disease. Objective partial responses were noted in 5 participants (31%) and lasted 3 months to > 32 months (median, 10 months). One of the 5 participants had previously had disease progression after an initial partial response with rIFN-alpha 2a. Six other participants (38%) showed minor or mixed responses. The most common adverse effects of interferon gamma-1b treatment included fever, weight loss, mild neutropenia, elevated lactate dehydrogenase, and elevated hepatic transaminases. Serious adverse effects occurred in 2 participants, including nephrotic syndrome (n=1) and cutaneous allergic reaction (n=1); however, neither of the adverse effects were life threatening, and all were reversible.

In an open-label, non-randomized, single-arm phase II study, Sugaya and colleagues (2014) administered intravenous interferon gamma-1b to 15 participants with stage IA-IIIA mycosis fungoides once daily over 5 days a week for the first 4 weeks, followed by subsequent intermittent injection. The primary efficacy endpoint was the overall skin response assessed according to the evaluation criteria for chemotherapeutics for malignant skin carcinomas. A total of 11 of 15 participants (73.3%) achieved the objective response. Three of the other 4 participants remained on treatment during the study with stable disease and 1 participant showed disease progression. The median duration of stable disease was not reached but was 170 days or more (range, 29 to ≥ 253 days). Nine participants (60.0%) achieved the objective response as assessed according to the modified severity weighted assessment tool. The most common drug-related adverse event was influenza-like illness occurring in all participants. Two serious adverse events were reported in 2 participants, including aggravation of mycosis fungoides (1 participant expired 50 days after the initiation of the study protocol) and aggravation of cataract (n=1), neither of which was considered directly related to the study drug. Another participant withdrew from the study due to drug-related cough, which disappeared after discontinuation of the drug. Overall, interferon gamma-1b was effective and well-tolerated in this population with mycosis fungoides.

Other Proposed Uses of interferon gamma-1b

Friedreich's Ataxia

Friedreich's ataxia (FRDA) is an autosomal recessive degenerative disorder caused by a deficiency of the protein frataxin and is associated with progressive ataxia, cardiomyopathy, scoliosis, diabetes, and loss of visual and hearing function. In 98% of individuals, FRDA is caused by homozygous, expanded guanine-adenine-adenine (GAA) repeats in the frataxin (FXN ) gene leading to impaired transcription and a decreased expression of the mitochondrial protein frataxin. The level of frataxin protein correlates with age of onset. In asymptomatic carriers, frataxin protein levels range from 30% to 80% of controls. It is suggested that restoration of frataxin protein levels to 30% of control levels in asymptomatic carriers may improve symptoms of the condition (Seyer, 2015). Interferon gamma-1b is being investigated in the treatment of individuals with FDRA.

Seyer and colleagues (2015) performed an open-label trial of the safety of interferon gamma-1b and its effect on frataxin levels and neurologic measures in 12 children (aged 8 to 17 years) with genetically confirmed FRDA. Subjects were recruited using the Friedreich Ataxia Research Alliance database on Clinicaltrials.gov (NCT01965327) and through the principal investigator's practice. Interferon gamma-1b was administered by subcutaneous injection 3 times weekly with dose increases from 10 to 50 mcg/m2 for 8 weeks. Safety assessments included laboratory testing, electrocardiogram, and monitoring of adverse events. The primary efficacy outcome measure was frataxin levels in multiple tissues. All subjects (n=12) were included in the safety analysis. Interferon gamma-1b was well tolerated with no serious adverse events; 2 subjects required dose reductions for severe flulike symptoms. Across 12 weeks of treatment, small changes in frataxin levels were observed in red blood cells, peripheral blood mononucleated cells, and platelets; however, the magnitude of all of these changes was very small and varied between tissues. The mean improvement in Friedreich Ataxia Rating Scale (FARS) score was equivalent to roughly 18 months of disease progression after 12 weeks of treatment (p=0.008). This was mainly reflected in change in the upper extremities subscale of the FARS examination (3.5 points improvement; p=0.02). Similar improvements were not observed on the 9-hole peg test (9HPT), a timed measurement of upper extremity fine motor skills. There were no changes observed in activities of daily living, Modified Fatigue Impact Scale (MFIS), or Pediatrics Quality of Life (PedsQL) scales. Change in FARS scores (Visit 5-Baseline) showed no relationship to level of interferon gamma-1b measured by assays or to frataxin protein level in whole blood or buccal cells measured at Visit 5. Although the investigators stated the significant improvement in FARS scores is "encouraging," larger placebo-controlled clinical trials of broader age groups and longer duration are required to determine if interferon gamma-1b may have beneficial effects on FRDA.

Marcotulli and colleagues (2016) reported outcomes from a phase IIa clinical trial conducted in Italy of interferon gamma-1b use in individuals with FRDA. A total of 9 subjects (6 females and 3 males aged 21-38 years) with genetically confirmed disease were administered three subcutaneous escalating doses (100, 150 and 200 μg) of recombinant interferon gamma-1b over 4 weeks. The primary endpoint was the assessment of safety and tolerability of interferon gamma-1b as measured by the ability of the drug to increase frataxin levels in peripheral blood mononucleated cells. The secondary endpoint was the detection of changes of frataxin levels in peripheral blood mononucleated cells after each single escalating dose of the drug. Interferon gamma-1b was generally well tolerated; the primary adverse event was fever/hyperthermia. Concerning the secondary endpoint, increases in frataxin levels could be detected after 1 day and 7 days from each injection of interferon gamma-1b in 7 or fewer subjects, depending on the dose of interferon gamma-1b; however, these changes were not statistically significant. Limitations of this trial include the small sample size, lack of a control group, and short-term follow-up.

A search of the ClinicalTrials.gov database has identified two ongoing phase III multicenter clinical trials evaluating the use of interferon gamma-1b in children and adults with FRDA. The Safety, Tolerability and Efficacy of Actimmune Dose Escalation in Friedreich's Ataxia Study (STEADFAST; NCT02593773) and the open-label, long-term safety extension study (STEADFAST; NCT02797080) have an estimated primary outcome measure completion date of June 2017. The outcomes of these studies are expected to conclusively address the clinical efficacy of interferon gamma-1b in individuals with FRDA. At this time the FDA has not approved the use of interferon gamma-1b for the treatment of FRDA.

Idiopathic Pulmonary Fibrosis (IPF)

IPF is a chronic interstitial lung disease of unknown etiology that is characterized by fibrosis of the lung parenchyma. Interferon gamma-1b has been investigated in the treatment of individuals with IPF.

Raghu and colleagues (2004) reported on results of a double-blind, multinational trial of 330 individuals with IPF who were unresponsive to corticosteroid therapy. Over a median of 58 weeks, subcutaneous interferon gamma-1b therapy was not better than placebo in improving progression‐free survival, pulmonary function, or quality of life. A total of 10% of participants in the interferon gamma-1b group died, compared with 17% of participants in the placebo group (p=0.08). More pneumonias were reported among participants in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in both groups.

King and colleagues (2009) evaluated if treatment with interferon gamma-1b improved survival compared with placebo in a multicenter, randomized, double-blind, placebo-controlled clinical trial (INSPIRE) of individuals with IPF and mild-to-moderate impairment of pulmonary function. A total of 826 participants with IPF were enrolled from 81 centers in 7 European countries, the USA, and Canada. Participants were randomly assigned in a 2:1 ratio to receive 3 times per week subcutaneous interferon gamma-1b (n=551) or equivalent placebo (n=275). Eligible participants (aged 40 to 79 years) were diagnosed with IPF in the past 48 months, had a forced vital capacity of 55% to 90% of the predicted value, and a hemoglobin-corrected carbon monoxide diffusing capacity of 35% to 90% of the predicted value. The primary endpoint was overall survival time from randomization measured at the second interim analysis, when the proportion of deaths had reached 75 % of those expected by the study conclusion. At the second interim analysis, the hazard ratio for mortality in participants on interferon gamma-1b showed absence of minimum benefit compared with placebo (1.15, 95 % confidence interval [CI] 0.77 to 1.71; p=0.497), resulting in cessation of the study. After a median duration of 64 weeks on treatment, 80 (14.5%) participants on interferon gamma-1b and 35 (12.7%) on placebo had died. Almost all participants reported at least one adverse event, and more participants in the interferon gamma-1b group had signs and symptoms of influenza-like illness, fatigue, fever, and chills, than did those on placebo. Occurrence of serious adverse events (such as, pneumonia, respiratory failure) was similar in both treatment groups. Few participants discontinued treatment prematurely in either group. The investigators concluded that they could not recommend treatment with interferon gamma-1b since the drug did not improve survival for participants with IPF.

In an update to a Cochrane review first published in 2003, Spagnolo and colleagues (2010) reviewed the available peer-reviewed published studies and concluded that interferon gamma-1b has not been shown to affect survival for the treatment of IPF.

Other Uses of interferon gamma-1b

The clinical efficacy and safety of interferon gamma-1b have been studied for the treatment of other conditions, including, but not limited to, advanced ovarian and primary peritoneal cancer (Alberts, 2008; Apte, 2006; Schmeler, 2009), atopic dermatitis (Jang, 2000; Stevens, 1998), brain tumors (Kane, 2010), chronic hepatitis C (Couzigou, 2013; Soza, 2005), invasive fungal infection following hematopoetic stem cell transplantation (HSCT) (Koziner, 2002; Safdar, 2004) or solid organ transplantation (renal) (Armstrong-James, 2010), (primary melanoma (high risk or regional lymph node metastasis) (Kleeberg, 2004), hormone refractory prostate cancer (Hildebrand, 2007), metastatic renal cell cancer (Elhilali, 2000; Gleave, 1998; Small 1998), and pulmonary tuberculosis (Gao, 2011). The evidence in the peer-reviewed medical literature consists of blinded and non-blinded randomized controlled trials, retrospective case series, and systematic reviews that demonstrate limited response times or significantly shorter overall survival time, and/or a reduction in quality of life measurements in participants receiving interferon gamma-1b compared to other therapies (such as, chemotherapy, combination therapies, or antiviral agents). To date, the FDA has not cleared interferon gamma-1b for use in the treatment of any of these conditions.

Background/Overview

Chronic Granulomatous Disease (CGD)

CGD is an inherited disorder in which certain immune system cells (phagocytes) do not function properly leading to ongoing and severe infection. In CGD, immune system cells are unable to kill some types of bacteria and fungi. This disorder leads to chronic and recurrent infections. The condition is often discovered very early in childhood. Milder forms may be diagnosed in adulthood. About half of CGD cases are passed down through families as a recessive, X-linked trait, such that males are more likely to get the disorder than females.

Antibiotics are used in CGD for both in treatment and to prevent infections. Interferon gamma-1b has been shown to help prevent and reduce the number of severe infections. Surgery may be needed to treat some abscesses. The only treatment considered curative for CGD is a bone marrow or stem cell transplant. Early death occurs most commonly from repeated lung infections.

Severe Malignant Osteopetrosis (SMO)

The U.S. National Library of Medicine (NLM, 2017) describes osteopetrosis as a bone disease that makes bones abnormally dense and prone to fracture. All forms of osteopetrosis are inherited (autosomal dominant, autosomal recessive, or X-linked), their characteristics involve an abnormal increase in the density of bones, and they are distinguished by the severity of their signs and symptoms. Autosomal recessive osteopetrosis (ARO) is the most rare and severe form of the disorder that appears in early infancy, affecting 1 in 250,000 people. The disease is frequently fatal during the first decade of life. SMO is a form of osteopetrosis that is sometimes referred to as marble bone disease or malignant infantile osteopetrosis (MIOP). While exact numbers are not known, it is thought that about 1 in 250,000 children are born with SMO. SMO is associated with a lower life expectancy, with most untreated children dying within the first 10 years of life (Stark, 2009). As a result of the condition, abnormal bone development occurs, which may result in bone fractures, problems with vision and hearing, and abnormal appearance of the face and head. In addition, because the abnormal buildup of bone tends to narrow the space inside the bone marrow, blood disorders such as anemia, bleeding problems because of low platelets, and a decreased ability to fight infections due to low white blood cells may occur.

Interferon gamma-1b is effective for use in delaying the time to disease progression in some children and adults with SMO. Bone marrow transplantation may be curative therapy, but an acceptable donor can be found for only 40% of individuals with SMO (Key, 1995).

Mycosis Fungoides and Sézary Syndrome

Mycosis fungoides and Sézary syndrome are rare types of malignant (cancerous) CTCLs, a group of non-Hodgkin lymphomas (NHL) that primarily develop in the skin and at times progress to involve lymph nodes, blood, and visceral organs (NCCN, 2017). Mycosis fungoides first appears on the skin and can spread to the lymph nodes or other organs such as the spleen, liver, or lungs. In Sézary syndrome, significant cancerous T-cells are found in the blood and individuals experience lymphadenopathy (National Cancer Institute [NCI] PDQ® , 2016). Based on data from the NCI's Surveillance, Epidemiology, and End Results Program (SEER) registries from 1998 to 2002, the annual incidence rate of CTCL was 9.6 per 1 million persons. According to a population-based study of 3384 cases of cutaneous lymphomas diagnosed during 2001-2005, CTCLs accounted for 71% of cases compared with 29% for cutaneous B-cell lymphomas. Mycosis fungoides is the most common type of CTCLs, accounting for about 50% to 70% of CTCL cases while Sézary syndrome accounts for only 1% to 3% of cases (NCCN, 2017). The prognosis of individuals with mycosis fungoides and Sézary syndrome is based on the extent of disease at presentation (stage). The presence of lymphadenopathy and involvement of peripheral blood and visceral organs increase in likelihood with worsening cutaneous involvement and define poor prognostic groups. The median survival following diagnosis varies according to stage; individuals with stage IA disease may have a median survival of 20 or more years. In contrast, more than 50% of individuals with stage III through stage IV disease die as a result of mycosis fungoides or secondary cancers, with a median survival of < 5 years (NCI PDQ, 2016).

The initial treatment of individuals with mycosis fungoides and Sézary syndrome with patch/plaque disease consists of skin-directed therapies, localized or generalized, with the addition of milder systemic therapy for refractory, persistent, or progressive disease. Systemic therapies (that is, extracorporeal photopheresis, interferons, systemic retinoids, or histone deacetylase inhibitors) are preferred over traditional chemotherapy for individuals with unfavorable prognostic features and who have not responded to initial skin-directed therapies. Chemotherapy is considered a treatment option for those individuals who do not respond to biologic therapy or have very aggressive or extracutaneous disease. "Due to the rarity of the condition and the need for an individualized approach, referral to a multidisciplinary academic specialty center is preferred" (NCCN, 2017).

PI Label Information for interferon gamma-1b (Actimmune PI label, 2016)

Contraindications, Warnings and Precautions

Drug Interactions and Adverse Reactions

Definitions

Granulomas: Masses of immune cells that form at sites of infection or inflammation.

Interferon: A biological response modifier (a substance that can improve the body's natural response to infections and other diseases). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. The body normally produces these substances. They are also made in the laboratory to treat cancer and other diseases (NCI, 2016).

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Medically Necessary:

HCPCS    
J9216 Injection, interferon, gamma-1b, 3 million units [Actimmune]  
     
ICD-10 Diagnosis  
C84.00-C84.09 Mycosis fungoides
C84.10-C84.19 Sézary disease

When services may be Medically Necessary when criteria are met:
For the procedure code listed above, for the following diagnoses:

ICD-10 Diagnosis  
D71 Functional disorders of polymorphonuclear neutrophils (chronic granulomatous disease)
Q78.2 Osteopetrosis

When services are Investigational and Not Medically Necessary:
For the procedure code listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Alberts DS, Marth C, Alvarez RD, et al.; GRACES Clinical Trial Consortium. Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: results from a prospectively designed analysis of progression-free survival. Gynecol Oncol. 2008; 109(2):174-181.
  2. Apte SM, Vadhan-Raj S, Cohen L, et al. Cytokines, GM-CSF and IFN gamma administered by priming and post-chemotherapy cycling in recurrent ovarian cancer patients receiving carboplatin. J Transl Med. 2006; 4:16.
  3. Armstrong-James D, Teo IA, Shrivastava S, et al. Exogenous interferon-γ immunotherapy for invasive fungal infections in kidney transplant patients. Am J Transplant 2010; 10:1796-1803. 
  4. Bemiller LS, Roberts DH, Starko KM, et al. Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. Blood Cells Mol Dis. 1995; 21:239-247.
  5. Couzigou P, Pérusat S, Bourlière M, et al. Interferon-gamma with peginterferon alpha-2a and ribavirin in nonresponders patients with chronic hepatitis C (ANRS HC16 GAMMATRI). J Gastroenterol Hepatol. 2013; 28(2):329-334.
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  7. Elhilali MM, Gleave M, Fradet Y, et al. Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma. BJU Int. 2000; 86(6):613-618.
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  16. Kleeberg UR, Suciu S, Brocker EB, et al. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. 2004; 40(3):390-402.
  17. Koziner B, Dengra C, Cisneros M, Glancszpigel R. Double-blind prospective randomized comparison of interferon gamma-1b versus placebo after autologous stem cell transplantation. Acta Haematol. 2002; 108(2):66-73.
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  19. Marth C, Windbichler GH, Hausmaninger H, et al. Interferon-gamma in combination with carboplatin and paclitaxel as a safe and effective first-line treatment option for advanced ovarian cancer: results of a phase I/II study. Int J Gynecol Cancer. 2006; 16(4):1522-1528.
  20. Pappas PG, Bustamante B, Ticona E, et al. Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis. 2004; 189(12):2185-2191.
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  22. Safdar A, Rodriguez G, Ohmagari N, et al. The safety of interferon-gamma-1b therapy for invasive fungal infections after hematopoietic stem cell transplantation. Cancer. 2005; 103(4):731-739.
  23. Schmeler KM, Vadhan-Raj S, Ramirez PT, et al. A phase II study of GM-CSF and rIFN-gamma1b plus carboplatin for the treatment of recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer. Gynecol Oncol. 2009; 113(2):210-215.
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  28. Stevens SR, Hanifin JM, Hamilton T, et al. Long-term effectiveness and safety of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged serum IgE levels. Arch Dermatol. 1998; 134(7):799-804.
  29. Sugaya M, Tokura Y, Hamada T, et al. Phase II study of i.v. interferon-gamma in Japanese patients with mycosis fungoides. J Dermatol. 2014; 41(1):50-56.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Actimmune [Product Information]. Dublin, Ireland (Roswell, GA). Horizon Pharma Ireland Ltd (HZNP USA Inc.); July 2016. Available at: http://www.actimmune.com/pdf/ACTIMMUNE_PI_Effective_US%207-16.pdf. Accessed on March 3, 2017.
  2. Interferon gamma-1b. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated February 2, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 3, 2017.
  3. Interferon gamma- 1b Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 1, 2010. Accessed on March 3, 2017.
  4. National Comprehensive Cancer Network® . NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on March 3, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology® . © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on March 3, 2017.
    • T-cell Lymphomas (V2.2017). Revised February 21, 2017.
  6. Spagnolo P, Del Giovane C, Luppi F, et al. Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2010;(9):CD003134.
  7. U.S. National Institutes of Health (NIH). ClinicalTrials.gov. Search results: interferon gamma-1b AND Friedreich's ataxia. Available at: https://clinicaltrials.gov/ct2/results?term=interferon+gamma 1b+AND+Friedreich%27s&Search=Search . Accessed on March 3, 2017.
Websites for Additional Information
  1. Immune Deficiency Foundation. Chronic granulomatous disease. Available at: http://primaryimmune.org/. Accessed on March 3, 2017.
  2. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms. Available at: http://www.cancer.gov/publications/dictionaries/cancer-terms. Accesses on March 3, 2017.
  3. National Cancer Institute (NCI). Mycosis Fungoides and Sézary Syndrome-Treatment (PDQ® ). March 3, 2016. Available at: http://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq. Accessed on March 3, 2017.
  4. U.S. National Library of Medicine® (NLM). Genetics Home Reference. Osteopetrosis. Reviewed September 2010. Published March 7, 2017. Available at: https://ghr.nlm.nih.gov/condition/osteopetrosis . Accessed on March 3, 2017.
Index

Biological Response Modifier Therapy

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated formatting in Position Statement section. Added Friedreich's ataxia and invasive fungal infections, post-transplantation to the INV and NMN statement. Updated Rationale, Background, References, and Websites for Additional Information sections.
New 05/05/2016 MPTAC review.
New 05/04/2016 Hematology/Oncology Subcommittee review. Initial document development.