LCD L39297: Off-label Use of Rituximab and Rituximab Biosimilars

Background

Rituximab is an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets the CD20 antigen, a protein expressed most B cells surface results in B—cell depletion. Initially used for anti-neoplastic therapy, it has been licensed for use in several autoimmune disorders. Rituximab has been used off-label for a multitude of indications (1). Rituximab carries a black-box warning about the following risks associated with rituximab use: fatal infusion reactions, tumor lysis syndrome, severe skin and mouth reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy (2). Throughout the policy, rituximab refers to rituximab and biosimilar as appropriate.

The FDA initially approved rituximab on November 26, 1997. An alert was issued on September 25, 2013, by the FDA to highlight additional Boxed Warning information about Rituximab regarding patients with prior Hepatitis B virus (HBV) infection; HBV reactivation may occur when the body’s immune system is impaired. HBV cases and patient deaths continued to occur. In response, the FDA recommends screening and monitoring prior to and throughout rituximab’s duration in patients with prior HBV infection (3).

This policy addresses the off-labeled, non-compendia use of rituximab for non-anti-neoplastic conditions. The use of rituximab for labeled indications is covered and not addressed in this policy. Off-label use for anti-neoplastic therapy is not addressed in this policy.

Definitions:

First-line therapy - an agent used in the initial treatment of a condition.

Adverse event - a documented event that contraindicates further use of the medication or side effects that are not likely to be transient and resolve with further treatment or impair functional capacity and/or daily living activities.

Lack of efficacy - the lack of an expected or desired effect related to therapy when the dosage and duration of therapy meet published standards.

Refractory disease - when the patient fails to respond to all first-line therapies that are standard of care for the condition.

Relapse disease - a recurrence of the disease condition that does not respond to first-line treatments and/or standard of care therapies.

Indications of Coverage:

ANCA-associated vasculitis (AAV)

Rituximab is recommended for induction of remission in patients with severe or relapsing ANCA-associated vasculitis, particularly granulomatosis with polyangiitis and microscopic polyangiitis, as an alternative to cyclophosphamide. It is favored for maintenance therapy over azathioprine due to its superior efficacy in reducing relapse rates. Rituximab is recommended for patients unable to receive first-line therapies and as part of tailored treatment strategies based on individual risk factors. The safety profile of rituximab is comparable to cyclophosphamide, with fewer long-term concerns.

Antibody-mediated rejection (AMR)

Rituximab may be considered as second-line treatment or as part of a combination treatment for AMR in kidney, lung, and cardiac transplant patients.

Rituximab may be considered in highly sensitized patients as part of desensitization protocols awaiting donor transplants.

All other uses of rituximab for AMR prevention or treatment are considered investigational.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Rituximab may be considered in patients who have failed intravenous immunoglobulin (IVIG), glucocorticoids, and plasma exchange.

Rituximab is considered investigational for CIDP as a first line therapy

Hemophilia (acquired)

Rituximab may be considered in patients with acquired or refractory hemophilia as first-line combination therapy of corticosteroids and Rituximab.

Rituximab may also be considered as a second-line agent and for use in refractory disease.

Idiopathic inflammatory myopathy

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterized by muscle weakness and inflammation, but in anti-synthetase syndrome, arthritis and interstitial lung disease are more frequent and often inaugurate the disease.

Clinical practice guidelines recommend Rituximab as a treatment option for IIMs with extra muscular (lung) involvement from a large multi-disciplinary workgroup.(23) However, this is based on expert opinion, without supporting evidence.(24)

Immune-mediated myopathies

(Dermatomyositis (DM), Polymyositis (PM), Antisynthetase syndrome, Immune- mediated necrotizing myopathy (IMNM), Inclusion body myositis (IBM), Nonspecific myositis)

Rituximab may be considered in refractory cases of immune-mediated myopathies that have failed all first-line therapies.

For all other uses, rituximab is considered investigational for immune-mediated myopathies.

Immune thrombocytopenic purpura (ITP)

Rituximab will be covered when all of the following criteria are met:

• Documented lack of response of at least one first line therapy

• Documented risk for bleeding (at least one of the following)

• Severe ITP (bleeding symptoms)

• Risk factors for bleeding are present

• In preparation for procedures or surgery with risk of bleeding

• Professional or lifestyle risk for trauma

• Persistent or chronic disease (>6 months)

Immunoglobulin G4-related disease (IgG4-RD)

Rituximab may be considered a second-line therapy in refractory or relapsed cases of IgG4-RD that have failed all first-line therapies, or there is an absolute contraindication to glucocorticoid use.

For all other uses, rituximab is considered investigational for IgG4-RD.

Minimal change disease

Rituximab may be considered for children with steroid-dependent, steroid-sensitive nephrotic syndrome who have continuing frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing agents or who have serious adverse effects of therapy.

Rituximab may be considered in adult patients with frequently relapsing or glucocorticoid-dependent minimal change disease who have also failed to attain a durable remission with cyclophosphamide or calcineurin inhibitors.

Rituximab in adults with glucocorticoid-resistant MCD is investigational.

Rituximab for first- or second-line therapy for minimal change disease is investigational.

Multiple sclerosis

Rituximab may be considered a second-line option in patients with refractory or remitting multiple sclerosis who failed first-line therapy.

Sjögren’s and systemic sclerosis

Rituximab may be considered when corticosteroids and other immunosuppressive agents were ineffective

Rituximab is considered investigational for Sjögren’s syndrome as a first line therapy

Susac Syndrome

Rituximab may be considered for use in Susac Syndrome in patients with severe or extremely severe disease presentations, particularly when initial treatments such as corticosteroids and intravenous immunoglobulin (IVIG) are inadequate. It is often incorporated into a multi-drug regimen alongside mycophenolate mofetil for more aggressive management. While the use of rituximab is based primarily on case reports and clinical observations, it plays a significant role in managing severe or resistant cases of Susac Syndrome due to the absence of standardized treatment protocols.

Thrombotic thrombocytopenic purpura (TTP)

Rituximab may be considered in patients with severe, refractory, or relapsed thrombotic thrombocytopenic purpura (acquired) who have failed first-line therapy (plasma exchange and glucocorticoids).

The use of rituximab for initial therapy and relapse prevention is investigational.

Limitations of Coverage:

Behcet’s syndrome

Rituximab is considered investigational for Behcet’s syndrome.

Cerebral ataxia

Rituximab is considered investigational for cerebral ataxia.

Polyarteritis nodosa

Rituximab is considered investigational for polyarteritis nodosa. Use in refractory cases may be considered on a case to case basis.

ANCA-Associated Vasculitis (AAV)

ANCA-associated vasculitis (AAV) is an autoimmune disorder characterized by inflammation of small to medium blood vessels often leading to damage in vital organs such as the kidneys and lungs. In recent years, rituximab—a monoclonal antibody that depletes B cells targeting the CD20 antigen—has gained prominence as a treatment option for AAV (88). According to guidelines from sources like the American College of Rheumatology/Vasculitis Foundation and the KDIGO 2024 Clinical Practice Guideline, rituximab is recommended for both induction and maintenance of remission in AAV due to its efficacy and safety profile (89,90).

The efficacy of rituximab has been validated through randomized controlled trials like RAVE and RITUXVAS, showing comparable or superior remission induction compared to cyclophosphamide, especially in patients with relapsing disease (91). The MAINRITSAN and RITAZAREM trials further support its superiority over azathioprine for maintenance therapy, exhibiting reduced relapse rates and effective long-term disease control (91,92).

Safety assessments indicate a favorable profile for rituximab, with lower risks of malignancies and fertility issues compared to traditional cyclophosphamide therapy and manageable adverse effects primarily involving infections and infusion reactions (91).