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Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens. This policy addresses intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG).

IVIG is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. IVIG has been used to correct immune deficiencies in patients with either inherited or acquired immunodeficiencies and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis.

Several SCIG products have also received FDA approval for the treatment of patients with certain primary immunodeficiencies. One SCIG product has been approved for chronic inflammatory demyelinating polyneuropathy, an acquired disorder of the peripheral nervous system.

Definitions

Immunoglobulins: Any of a group of large glycoproteins that are secreted by plasma cells and that function as antibodies in the immune response by binding with specific antigens. There are five subclasses of immunoglobulins: IgA, IgD, IgE, IgG, and IgM.

Hypogammaglobulinemia: An abnormally low concentration of gamma globulin (gamma globulins are made up primarily of lgG, IgA and IgM immunoglobulins) in the blood (after exclusion of monoclonal gammopathies), resulting in increased risk of infection.

Primary Humoral Immunodeficiency: A primary immunodeficiency disorder of B-cell differentiation and antibody production.

Note:

• Immunoglobulin therapy for treatment of pediatric acute onset neuropsychiatric syndrome (PANS)/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is covered according to the policy criteria below per Minnesota state mandate.
• This policy is not to be used for reviews of immunoglobulin therapy when administered in an inpatient setting.

I.    Intravenous Immunoglobulin (IVIG) Initial Review

Use of intravenous immunoglobulin (IVIG) may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• ONE of the following:
  • Primary Immunodeficiencies
    • Diagnosis of a primary humoral immunodeficiency, including but not limited to: 
      • Common variable immune deficiency (CVID); 
      • IgG subclass deficiency;
      • X-linked agammaglobulinemia (XLA or Bruton’s agammaglobulinemia);
      • Congenital agammaglobulinemia;
      • Primary hypogammaglobulinemia;
      • X-linked immunodeficiency;
      • Hyper-IgM syndrome;
      • Immunodeficiency with thrombocytopenia and eczema (Wiskott-Aldrich syndrome);
      • Hyper-IgE syndrome;
      • Severe combined immune deficiency (SCID);
      • Cellular immunodeficiency with immunoglobulins (Nezelof syndrome);
      • Thymic hypoplasia (DiGeorge’s syndrome);
      • Ataxia telangiectasia (Louis-Bar syndrome).
    • AND 
    • ONE of the following:
      • Agammaglobulinemia, as evidenced by ONE of the following:
        • Total serum IgG < 200 mg/dL; OR
        • Patients with an abnormal Bruton tyrosine kinase (BTK) gene/absence of BTK protein; OR
        • Absence of B lymphocytes;
      • OR
      • Hypogammaglobulinemia and ALL of the following:
        • Significant and recurrent infections (e.g., recurrent pneumonias, frequent episodes of bacterial sinusitis, and not just isolated chronic sinusitis); AND
        • Low serum IgG levels as demonstrated by ONE of the following: 
          • Total serum IgG level <700 mg/dL; OR 
          • Total serum IgG level at least 2 standard deviations below the normal age-adjusted mean; OR 
          • One or more serum IgG subclass levels at least 2 standard deviations below the normal age-adjusted mean in patients with normal levels of total serum IgG and IgM; 
        • AND
        • A demonstrated impaired response to immunization with protein AND/OR polysaccharide antigens:
          • For protein antigens: Serum antibody titers to tetanus and/or diphtheria should be obtained before immunization with tetanus and/or diphtheria vaccine and then three to four weeks after immunization. An abnormal response is defined as less than a four-fold rise in antibody titer.
          • For polysaccharide antigens: Serum antibody titers to pneumococcus should be obtained before immunization and then three to six weeks after immunization with a polyvalent pneumococcal polysaccharide vaccine (such as Pneumovax). An abnormal response is defined as less than a four-fold rise in titer.
  • Secondary Immunodeficiencies
    • Pediatric human immunodeficiency virus (HIV) infection with hypogammaglobulinemia; OR
    • Acquired hypogammaglobulinemia and/or significant and recurrent infections associated with ONE of the following:
      • B-cell chronic lymphocytic leukemia;
      • Multiple myeloma;
      • Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma);
      • Post-CD19-directed CAR-T cell therapy;
      • Post-CD20 therapy.
  • Organ and Stem-Cell Transplantation
    • Prior to solid organ transplantation, for treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients and those receiving an ABO incompatible organ; OR
    • Following organ transplantation, for treatment of antibody-mediated rejection; OR
    • Following hematopoietic stem-cell transplantation, for treatment of related immunodeficiencies.
  • Hematologic Disorders
    • Idiopathic thrombocytopenic purpura (ITP); OR
    • Neonatal alloimmune thrombocytopenia (NAIT)/ fetal and neonatal alloimmune thrombocytopenia (FNAIT); OR
    • Warm antibody autoimmune hemolytic anemia, refractory to corticosteroids and splenectomy; OR
    • Pure red cell aplasia due to parvovirus B19; OR
    • Hemolytic disease of the fetus and newborn (erythroblastosis fetalis); OR
    • HIV-associated thrombocytopenia; OR
    • Post-transfusion purpura.
  • Neurologic Disorders
    • Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome); OR
    • Chronic inflammatory demyelinating polyneuropathy (CIDP); OR
    • Myasthenia gravis, when ONE of the following criteria are met:
      • Myasthenic crisis (i.e., an acute episode of respiratory muscle weakness); OR
      • Myasthenia gravis in patients with chronic debilitating disease (e.g., restricted daily activities and symptomatic at rest or worse) despite treatment with cholinesterase inhibitors, or complications from or failure of steroids and/or azathioprine; OR
    • Multifocal motor neuropathy in patients with conduction block and anti-GM1 antibodies; OR
    • Pediatric acute onset neuropsychiatric syndrome (PANS)/Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and ALL of the following: 
      • Diagnosis is not otherwise explained by another known neurologic or medical disorder; AND 
      • Free of strep infections and other treatable infections; AND 
      • Laboratory testing confirms patient is not IgA deficient; OR
    • Stiff-person syndrome (Moersch-Woltman syndrome), after incomplete response to conventional therapy (e.g., benzodiazepines, baclofen); OR
    • Lambert-Eaton myasthenic syndrome (LEMS)
  • Rheumatic and Inflammatory Disorders
    • Kawasaki disease (mucocutaneous lymph node syndrome); OR
    • Dermatomyositis that has not responded to treatment with prednisone and immunosuppressant therapy (e.g., azathioprine, methotrexate); OR
    • Polymyositis that has not responded to treatment with prednisone and immunosuppressant therapy (e.g., azathioprine, methotrexate)
  • Dermatologic Disorders
    • Autoimmune Mucocutaneous Blistering Diseases, for treatment of the following conditions in patients with severe, progressive disease despite treatment with conventional medical therapy (e.g., corticosteroids, azathioprine, cyclophosphamide):
      • Pemphigus vulgaris;
      • Pemphigus foliaceus;
      • Bullous pemphigoid;
      • Mucous membrane pemphigoid;
      • Bullous systemic lupus erythematosus (SLE);
      • Epidermolysis bullosa acquisita OR
    • Toxic epidermal necrolysis (TEN)
  • Other Disorders
    • Toxic shock syndrome due to staphylococcal or streptococcal infection, refractory to conventional therapy; OR
    • Management of immune checkpoint inhibitor related toxicity and ALL of the following: 
      • ONE of the following toxicities related to immunotherapy: 
        • Severe or life-threatening bullous dermatitis when used as an adjunct to rituximab;
        • Stevens-Johnson syndrome (SJS); 
        • Toxic epidermal necrolysis (TEN);
        • Severe myasthenia gravis; 
        • Demyelinating disease (optic neuritis, transverse myelitis, acute demyelinating encephalomyelitis [ADEM]); 
        • Myocarditis refractory to 24-48 hours of starting high-dose methylprednisolone therapy; 
        • Moderate or severe Guillain-Barre Syndrome or severe peripheral neuropathy toxicity used in combination with high-dose methylprednisolone; 
        • Moderate pneumonitis refractory to 48-72 hours of corticosteroids or severe pneumonitis refractory to 48 hours of methylprednisolone therapy; 
        • Encephalitis used in combination with high-dose methylprednisolone for severe or progressing symptoms or if oligoclonal bands are present; 
        • Moderate, severe, or life-threatening steroid-refractory myositis for significant dysphagia, life-threatening situations, or cases refractory to corticosteroids;
      • AND 
      • Receiving therapy with an immune checkpoint inhibitor (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab);
• AND 
• For commercial health plan members only, IVIG is administered in accordance with site of service criteria (see policy XI-06); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

II.   Subcutaneous Immunoglobulin (SCIG) Initial Review

Use of subcutaneous immunoglobulin (SCIG) therapy may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• ONE of the following:
  • Primary Immunodeficiencies
    • Diagnosis of a primary humoral immunodeficiency, including but not limited to: 
      • Common variable immune deficiency (CVID); 
      • IgG subclass deficiency;
      • X-linked agammaglobulinemia (XLA or Bruton’s agammaglobulinemia);
      • Congenital agammaglobulinemia;
      • Primary hypogammaglobulinemia;
      • X-linked immunodeficiency;
      • Hyper-IgM syndrome;
      • Immunodeficiency with thrombocytopenia and eczema (Wiskott-Aldrich syndrome);
      • Hyper-IgE syndrome;
      • Severe combined immune deficiency (SCID);
      • Cellular immunodeficiency with immunoglobulins (Nezelof syndrome);
      • Thymic hypoplasia (DiGeorge’s syndrome);
      • Ataxia telangiectasia (Louis-Bar syndrome).
    • AND 
    • ONE of the following:
      • Agammaglobulinemia, as evidenced by ONE of the following:
        • Total serum IgG < 200 mg/dL; OR
        • Patients with an abnormal Bruton tyrosine kinase (BTK) gene/absence of BTK protein; OR
        • Absence of B lymphocytes. OR
      • Hypogammaglobulinemia and ALL of the following:
        • Significant and recurrent infections (e.g., recurrent pneumonias, frequent episodes of bacterial sinusitis, and not just isolated chronic sinusitis); AND
        • Low serum IgG levels as demonstrated by ONE of the following: 
          • Total serum IgG level <700 mg/dL; OR 
          • Total serum IgG level at least 2 standard deviations below the normal age-adjusted mean; OR 
          • One or more serum IgG subclass levels at least 2 standard deviations below the normal age-adjusted mean in patients with normal levels of total serum IgG and IgM; 
        • AND
        • A demonstrated impaired response to immunization with protein AND/OR polysaccharide antigens:
          • For protein antigens: Serum antibody titers to tetanus and/or diphtheria should be obtained before immunization with tetanus and/or diphtheria vaccine and then three to four weeks after immunization. An abnormal response is defined as less than a four-fold rise in antibody titer.
          • For polysaccharide antigens: Serum antibody titers to pneumococcus should be obtained before immunization and then three to six weeks after immunization with a polyvalent pneumococcal polysaccharide vaccine (such as Pneumovax). An abnormal response is defined as less than a four-fold rise in titer.
  • Neurologic Disorders
    • Chronic inflammatory demyelinating polyneuropathy (CIDP);
• AND
• For commercial health plan members only, SCIG is administered in accordance with site of service criteria (see policy XI-06).

III.  Intravenous Immunoglobulin (IVIG) and Subcutaneous Immunoglobulin (SCIG) Renewal Review

Use of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Previously approved for therapy through the initial review process; AND
• The renewal request is for the same indication previously approved; AND
• Continued positive clinical response to immunoglobulin therapy (e.g., reduced number and/or severity of infections, decreased use/elimination of prophylactic antibiotics, functional improvement),stabilization and/or slowing of disease progression; AND
• For commercial health plan members only, IVIG or SCIG is administered in accordance with site of service criteria (see policy XI-06).

IV.   Experimental/Investigative Uses

All other uses of intravenous immunoglobulin (IVIG) OR subcutaneous immunoglobulin (SCIG) are considered EXPERIMENTAL/INVESTIGATIVE, including but not limited to treatment of the following conditions due to the lack of clinical evidence demonstrating an impact on improved health outcomes:

• Acquired factor VIII inhibitors;
• Acute myocarditis;
• Adrenoleukodystrophy;
• Alzheimer’s disease;
• Aplastic anemia;
• Asthma;
• Autism spectrum disorders;
• Autoimmune/immune-mediated neutropenia;
• Behçet syndrome;
• Birdshot retinopathy;
• Chronic fatigue syndrome;
• Chronic sinus infections (unless the sinus infection is a symptom of one of the primary immunodeficiencies listed above. Chronic sinus infection is common in most primary immunodeficiencies listed, especially antibody deficiency with normal or near-normal immunoglobulins);
• Complex regional pain syndrome;
• Crohn’s disease;
• Cystic fibrosis;
• Diabetes mellitus;
• Diamond-Blackfan anemia;
• Epilepsy;
• Fisher syndrome;
• Hemolytic uremic syndrome;
• Hemophagocytic lymphohistiocytosis;
• Immune optic neuritis;
• Inclusion body myositis;
• Methylenetetrahydrofolate reductase (MTHFR) deficiency;
• Multiple sclerosis (relapsing-remitting and chronic, progressive);
• Necrotizing fasciitis;
• Nonimmune thrombocytopenia;
• Noninfectious uveitis;
• Opsoclonus myoclonus;
• Other vasculitides besides Kawasaki disease, including polyarteritis nodosa, Goodpasture syndrome, and vasculitis associated with other connective tissue diseases;
• Paraneoplastic syndromes;
• Paraproteinemic neuropathy;
• POEMS syndrome (polyneuropathy organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes);
• Polyradiculoneuropathy (other than chronic inflammatory demyelinating polyneuropathy);
• Post-polio syndrome;
• Recurrent fetal loss;
• Recurrent otitis media;
• Refractory recurrent pericarditis;
• Refractory rheumatoid arthritis;
• Sepsis (neonatal or in adults);
• Thrombotic thrombocytopenic purpura.

Documentation Submission

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization. In addition, the following documentation must also be submitted:

Initial Review

• Clinical notes describing the diagnosis and clinical features of the diagnosis.
• For patients with primary humoral immunodeficiencies, including common variable immune deficiency (CVID) and IgG subclass deficiency (see medical necessity criteria specific to these conditions, in sections I and II above):
  • Clinical notes clearly documenting significant and recurrent infections (e.g., recurrent pneumonias, frequent episodes of bacterial sinusitis, and not just isolated chronic sinusitis); AND
  • Laboratory results including the patient's serum immunoglobulin levels AND the age-adjusted reference ranges for the laboratory performing the tests.
• For commercial health plan members only, the site of service for IVIG or SCIG administration is specified, including CMS place of service code (see policy XI-06). If IVIG or SCIG is administered in a hospital outpatient facility, a clear explanation for the medical necessity of the site of service MUST be submitted, including documentation for one or more of the site of service criteria provided in policy XI-06.
• For commercial health plan members only, when step therapy requirements apply for the requested indication, documentation for one or more of the step therapy supplement criteria MUST be provided (see policy II-242).
  

Renewal Review

• Documentation of prior approval for the requested agent for the same indication through the initial review process.
• Documentation, since most recent approval, supporting continued positive clinical response, such as substantial improvement in disease condition or a reduction in disease progression. Examples include clinical notes documenting reduced number and/or severity of infections, decreased use/elimination of prophylactic antibiotics, or functional improvement.
• For commercial health plan members only, the site of service for IVIG or SCIG administration is specified, including CMS place of service code (see policy XI-06). If IVIG or SCIG is administered in a hospital outpatient facility, a clear explanation for the medical necessity of the site of service MUST be submitted, including documentation for one or more of the site of service criteria provided in policy XI-06.

Link to Pre-Authorization Form:  https://www.bluecrossmn.com/sites/default/files/DAM/2023-01/Immunoglobulin-Therapy-Pre-Auth-Request-Form-Medical-Policy-II-51.pdf