LCD L38920: 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 on most B cells surface. Administration of Rituximab results in B—cell depletion. Initially used for anti-neoplastic therapy, it has been licensed for use in several autoimmune disorders. Labeled uses for Rituximab include chronic lymphocytic leukemia, non-Hodgkin lymphomas, pemphigus vulgaris, rheumatoid arthritis, Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (which includes microscopic polyangiitis, granulomatosis with polyangiitis (GPA) (formerly Wegener's Granulomatosis) and eosinophilic GPA (formally Churg–Strauss syndrome). It is thought to act primarily by depleting CD20-positive cells. 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 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 (see A58113 Off-Label Use of Anti-Cancer Drugs and Biologicals).

Coverage

For this policy:

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

An adverse event is 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 is the lack of an expected or desired effect related to therapy when the dosage and duration of therapy meet published standards.

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

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

If a patient is treated with Rituximab, they are expected to be treated with the standard doses per medical literature for the condition. After the initial treatment, re-treatment requires a positive response to Rituximab documented in the medical record.

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.

Immune thrombocytopenic purpura

This is addressed in LCD L38268 Immune Thrombocytopenia (ITP) Therapy.

Thrombotic thrombocytopenic purpura (acquired)

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.

Autoimmune hemolytic anemia (AIHA)

Rituximab may be covered as first-line treatment in patients with symptomatic, severe cold AIHA.

Rituximab may be covered as second-line therapy for refractory warm AIHA after failed first-line treatment.

Evans Syndrome

Rituximab may be considered as a second-line treatment for Evans syndrome after failed response to first-line therapies.

Multiple Sclerosis

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

Bullous pemphigoid

Rituximab may be considered in cases of refractory bullous pemphigoid, which has failed first-line therapy.

Membranous nephropathy

Rituximab may be considered in cases of refractory or resistant membranous nephropathy.

Rituximab may be considered for patients with membranous nephropathy with proteinuria of at least 5 grams per 24 hours in quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of the body surface area and had been receiving angiotensin-system blockade for at least three months to receive intravenous Rituximab (two infusions, 1000 mg each, administered 14 days apart).

Rituximab is otherwise considered investigational for first-line use.

Immunotherapy-related Encephalitis

Rituximab may be considered in immunotherapy related to encephalitis with positive autoimmune encephalopathy antibodies and limited or no improvement with first-line therapy.

For other uses, Rituximab is considered investigational for encephalitis.

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.

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.

Myasthenia Gravis

Rituximab may be considered for patients with MuSK-positive myasthenia gravis who have an unsatisfactory response to initial immunotherapy.

Rituximab may be considered in refractory AChR-Ab+ MG in patients who fail or do not tolerate other immunosuppressive agents.

Rituximab is considered investigational for other uses in myasthenia gravis, including initial treatment.

Neuromyelitis Optica

Rituximab may be considered in refractory cases of neuromyelitis optica that have failed first-line therapies.

Rituximab is considered investigational as first-line therapy for neuromyelitis optica.

Lupus nephritis

Rituximab is considered investigational for lupus nephritis for initial or first-line treatment.

Rituximab may be considered for lupus nephritis in patients refractory defined by at least six months of conventional therapy and has failed cyclophosphamide (CYC) or mycophenolate mofetil (MMF) treatments or is worsening despite three months of treatment with glucocorticoids plus CYC or MMF.

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.

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.

Hematopoietic Stem Cell Transplant

Rituximab may be considered as part of combination treatment for preparative regimens and post-transplantation maintenance.

Graft vs. Host Disease

Rituximab may be considered in cases of chronic graft-versus-host disease.

Rituximab is considered investigational as a first-line agent for graft-versus-host disease.

Non 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.

Sjorgren’s syndrome

Rituximab is considered investigational for Sjorgren’s syndrome.

Hemophilia

Acquired Hemophilia A (AHA) is a rare bleeding disorder that stems from neutralizing autoantibodies against coagulation factor VIII. 4 In 2020, Tiede and colleagues published an international recommendations guideline that proposed three suggestions for using Rituximab to treat acquired hemophilia conditions. 5

One recommendation suggested combining corticosteroids with Rituximab or a cytotoxic agent for first-line therapy in patients with FVIII 20 BU with a grade of 2B. This recommendation was based on the GTH-AH study, a prospective observational study with 102 patients included for analyses and a two-year UKHCDO observational study of 172 patients conducted by the United Kingdom Haemophilia Centre Doctors’ Organization to identify and characterize the presenting features and outcome of patients with acquired hemophilia A. 6 The GTH-AH study established the primary endpoint as the time to achieve a partial remission (PR), defined as FVIII activity restored to .50 IU/dL and no active bleeding after stopping any hemostatic drug for 24 hours. Secondary endpoints were time to complete remission (CR), defined as PR plus negative inhibitor test, prednisolone tapered to 15 mg/day, and any other immunosuppressive treatment stopped. Overall survival, adverse events, and causes of death were also considered. Partial remission was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII 7

Tiede and associates' second recommendation included a second-line therapy with Rituximab or a cytotoxic agent, whichever was not used during first-line therapy with a grade of 1B, also based on the GTH-AH study.