CAM 060

Rituximab

Category:Prescription Drug   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:April 2014    

Description:
Rituximab (Rituxan®, Genentech, Inc., South San Francisco, CA) is a genetically engineered monoclonal antibody that targets a specific protein, known as CD20, found on the surface of normal and malignant B-lymphocytes.

 Policy:

  1. Chronic lymphocytic leukemia (CLL)
    • Rituximab is considered MEDICALLY NECESSARY for either of the following indications:
      • Chronic lymphocytic leukemia; or
      • Hairy Cell Leukemia.
  2. Hodgkin and non-Hodgkin lymphoma (NHL)
    • Rituximab is considered MEDICALLY NECESSARY for any of the following indications:
      • Treatment of CD20+ lymphoma (Hodgkin or non-Hodgkin); or
      • Treatment of Waldenström's Macroglobulinemia; or
      • Maintenance therapy of CD20+ follicular B-cell NHL for up to two years; or
      • Maintenance therapy of symptomatic relapsed or refractory lymphocyte predominant Hodgkin lymphoma following second-line therapy with rituximab; or
      • Zevalin® (Ibritumomab tiuxetan, Biogen Idec Inc., Cambridge, MA) regimen- as part of the Zevalin therapeutic regimen for NHL.
  3. Rheumatoid Arthritis
    • Rituximab is considered MEDICALLY NECESSARY when all of the following are met:
      • Individual is 18 years of age or older with moderately- to severely-active rheumatoid arthritis; and
      • Rituximab is given in combination with methotrexate (MTX) unless intolerant or contraindicated; and
      • Individual had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies, or has a medical contraindication to TNF therapy.
  4. Wegener's Granulomatosis (WG) and Microscopic Polyangiitis (MPA) Rituximab, in combination with glucocorticoids, is considered MEDICALLY NECESSARY for the treatment of individuals with Wegener's granulomatosis and microscopic polyangiitis.
  5. Other Indications
    • Rituximab is considered MEDICALLY NECESSARY  for individuals with any of the following conditions:
      • Acute lymphoblastic leukemia (ALL), de novo, when all of the following are met:
        • Individual has CD20+ Philadelphia chromosome-negative ALL; and
        • The individual is greater than or equal to 40 years of age; and
        • Rituximab is a component of an induction and consolidation regimen consisting of HyperCVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) alternating with high-dose methotrexate and cytarabine with rituximab; or
      • Autoimmune hemolytic anemia, refractory; or
      • Graft versus host disease (GVHD) as third line of therapy or greater; or
      • Multicentric Castleman's disease (MCD), CD20+; or
      • Neuromyelitis Optica (NMO); or
      • Pemphigus vulgaris and other autoimmune blistering skin diseases (for example, pemphigus foliaceus,
      • bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita and paraneoplastic pemphigus) when refractory; or
      • Post-transplant lymphoproliferative disease, CD20+; or
      • Renal transplant setting for either of the following indications:
        • Pre-transplant to suppress panel reactive anti-HLA antibodies in individuals with high panel reactive antibody (PRA) levels to human leukocyte antigens (HLA); or
        • Post-transplant in individuals with acute rejection who had received rituximab treatment pretransplant; or
      • Systemic autoimmune disorders (specifically, Cryoglobulinemia, Primary Sjögren Syndrome [SS], Systemic Lupus Erythematosus [SLE]) refractory to standard therapy (lack of response to corticosteroids and at least two immunosuppressive agents); or
      • Thrombocytopenic purpura, immune or idiopathic; or
      • Acquired inhibitors in individuals with hemophilia who fail cyclophosphamide and prednisone.
    • Central Nervous System (CNS) cancers- leptomeningeal metastases from lyphomas or primary CNS lymphoma

Use of rituximab is considered INVESTIGATIONAL when the above criteria are not met.

Use of rituximab is considered INVESTIGATIONAL for all other indications, including, but not limited to:

    • Graft versus host disease (GVHD) as first- or second-line therapy
    • Membranous glomerulonephropathy
    • Multiple sclerosis
    • Renal transplant rejection, except as specified above
    • myasthenia
    • immune checkpoint inhibitor-related toxicities

Dosage and Administration:
Administer only as an intravenous infusion.

Do not administer as an intravenous push or bolus.

Rituxan should only be administered by a health care professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur.

  • The dose for NHL is 375 mg/m².
  • The dose for CLL is 375 mg/m² in the first cycle and 500 mg/m2 in cycles 2-6, in combination with FC, administered every 28 days.
  • The dose as a component of Zevalin (Ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m².
  • The dose for RA in combination with methotrexate is two 1,000 mg intravenous infusions separated by two weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion.
  • The dose for GPA and MPA in combination with glucocorticoids is 375 mg/m²once weekly for 4 weeks.

Rationale:
Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen located on the cell surface of malignant and normal B-lymphocytes. Rituximab rapidly depletes circulating and tissue based B-cells and demonstrates a prolonged effect on cell depletion. Rituximab was originally approved in 1997 by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed, refractory, low-grade or follicular, B-cell non-Hodgkin lymphoma. Subsequently, the FDA approved additional specific indications for non-Hodgkin lymphoma and for moderately- to severely-active rheumatoid arthritis when there has been an inadequate response to other treatments. Rituximab is not recommended for use in individuals with severe, active infections (product information label, 2012).

Rheumatoid arthritis and other systemic autoimmune diseases involve complex, ongoing interactions between various types of cells and cell mediators in a cascade of inflammatory processes (Mease, 2008). B-cells are stimulated by activated T-cells to differentiate into plasma cells, which produce autoantibodies such as rheumatoid factor (RF). B-cells can also function as antigen-presenting cells (APCs) and may produce pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and activate T-cells in a self-perpetuating cycle (Mease, 2008; Sibilia, 2008). Mease and colleagues (2008) described the role of B-cell depletion and cell death by various mechanisms, which include, but are not limited to:

    • Complement-dependent cytotoxicity (CDC), involves the complement system protein C1q, formation of circular pores in the cell membrane resulting in cell lysis; and
    • Antibody-dependent cellular cytotoxicity (ADCC) involves recruitment of macrophages, natural killer cells and cytotoxic T-cells, which leads to cell membrane damage and cell lysis; and
    • Apoptosis, cell death as a result of molecular steps based on direct binding of rituximab to CD20.

The exact role of B-cells in the immunopathogenesis of rheumatoid arthritis and other autoimmune diseases is unclear. Rituximab rapidly depletes the circulating B-cells in the peripheral blood and the effect may be sustained for months after treatment is completed. However, the correlation between the measured amount of circulating B-cells compared to the volume of B-cells present in the bone marrow, spleen, lymph nodes or inflammatory tissue is unclear. Globin and colleagues (2007) noted, "The absence of CD20 on bone marrow stem cells and the earliest B-lymphocyte precursors allows for the regeneration of naïve B lymphocytes following rituximab therapy, with the potential of profound amelioration of autoimmunity." Based on this concept, rituximab is being studied for various indications, including rheumatic, inflammatory and autoimmune diseases.

Chronic Lymphocytic Leukemia
In February 2010, the FDA approved the combined use of rituximab with fludarabine and cyclophosphamide (FC) for the treatment of previously untreated and previously treated CD20+ chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) is an indolent form of non-Hodgkin lymphoma marked by immunologically less-mature lymphocytes and manifested by progressive accumulation of these cells in the blood, bone marrow and lymphatic tissues. The lymphocytes are characterized by immunophenotype (CD5- and CD23-positive B cells). Additionally, B-cell antigens CD19 and CD20 are also co-expressed on CLL lymphocytes. CLL may progress to a generally enlarged lymphatic system as well as complications resulting from pancytopenia (National Cancer Institute[NCI], 2013). According to the NCI (2013), treatment with "conventional doses of chemotherapy are not curative" for individuals with progressing CLL. Therefore, treatments to prolong disease-free survival for indolent and active disease continue to be studied.

Hairy Cell Leukemia
Hairy cell leukemia is a mature B-cell, chronic lymphoproliferative disorder for which 10 percent of the individuals will not require any type of therapy (NCI, 2013). Characteristics include the presence of a leukemic cell with "hairy" cytoplasmic projections, pancytopenia and bone marrow involvement, including fibrosis. Treatment includes nucleoside analogs (for example, cladribine, pentostatin), interferon-alpha or splenectomy, with reported five-year survival rates of more than 85 percent. The NCI (2013) notes rituximab can induce durable complete remissions in individuals with multiple relapsing or refractory disease after purine analog therapy or after interferon. The use of rituximab in relapsed or refractory hairy cell leukemia is limited to case reports and uncontrolled, retrospective case series. However, the American Hospital Formulary Service® (AHFS®, 2013) notes that rituximab is used off-label in the treatment of hairy cell leukemia. In addition, specialty consensus opinion suggests rituximab is indicated for treatment of hairy cell leukemia.

Rheumatoid Arthritis
The FDA approved the use of rituximab in combination with methotrexate as a treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies (2006). The product information label (2012) states there is limited available safety data on the use of biologic agents or disease modifying antirheumatic drugs (DMARDs) other than methotrexate following rituximab treatment in individuals with rheumatoid arthritis. A favorable risk-benefit relationship has not been established to utilize rituximab in individuals with inadequate responses to non-biologic DMARDs and those who are methotrexate-naïve. Therefore, the use ofrituximab is not recommended if the individuals with rheumatoid arthritis have not had prior inadequate response.

In 2008, the American College of Rheumatology (ACR) Task Force Panel [TFP] had developed treatment recommendations concerning the therapeutic indications for rituximab in the treatment of rheumatoid arthritis (RA)(Saag). There was no agreement within the TFP and no statement made regarding the use of rituximab in the setting of early RA without features of a poor prognosis. The ACR (2008) reported the following:

The TFP recommended the use of rituximab in patients for whom methotrexate in combination with disease-modifying antirheumatic drugs (DMARDs) or sequential administration of other nonbiologic DMARDs led to an inadequate response, with high disease activity and features of a poor prognosis. The TFP did not recommend combinations of biologic agents, based in part on data suggesting a higher rate of adverse events with combinations and/or lack of additive efficacy.

The ACR 2012 (Singh, 2012) update of biologics in high-risk individuals with rheumatoid arthritis includes the following recommendations:

The panel only recommends starting or resuming rituximab in RA patients with: 1) a previously treated solid malignancy within the last five years, 2) a previously treated nonmelanoma skin cancer within the last five years, 3) a previously treated melanoma skin cancer or 4) a previously treated lymphoproliferative malignancy. Little is known about the effects of biologic therapy in patients with a history of a solid cancer within the past five years owing to the exclusion of such patients from participation in clinical trials and the lack of studies examining the risk of recurrent cancer in this subgroup of patients.

In an updated consensus statement from the 10th Annual Workshop on Advances in Targeted Therapies, Furst and colleagues (2008) noted evidence (category A) from randomized controlled trials supporting the combination of rituximab with MTX "yields better clinical efficacy for RA than monotherapy." Edwards and colleagues (2004) reported results from a double-blind, randomized controlled trial with 161 individuals with active rheumatoid arthritis. Individuals were randomly assigned to one of four cohorts – methotrexate, rituximab, rituximab plus cyclophosphamide or rituximab plus methotrexate. The primary endpoint was the proportion of individuals with an ACR 50, (improvement of at least 50 percent from baseline) response at 24 weeks. The group treated with rituximab monotherapy did not reach statistical difference when compared to the control group of methotrexate. However, the groups using rituximab in combination with cyclophosphamide or methotrexate showed statistically significant improvement in the ACR 50 scores compared to the control group at week 24.

Lymphoma (Hodgkin and non-Hodgkin)
Hodgkin Disease (Lymphoma)
Schulz and colleagues (2007) reported long-term outcomes from a phase II trial with 21 individuals with relapsed or refractory, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) with CD20-positive expression. Four individuals  were reclassified as CD10+ classic Hodgkin lymphoma (cHL) and two individuals were reclassified as Hodgkin lymphoma transformed to T-cell rich B-cell lymphoma (TCRBCL). Fifteen individuals had NLPHL confirmed by a reference laboratory and were evaluated for overall response. Standard doses of rituximab were infused weekly for a total of four weeks. An overall response was achieved in 94 percent of 15 individuals, which included eight complete remissions (CR) and six partial remissions (PR). Median time to progression (TTP) was 33 months with the median overall survival (OS) not reached. One NLPHL and three cHL individuals have died since enrollment.

The NCCN Clinical Practice Guideline (CPG) (2013) lists the off-label use of rituximab with or without radiation therapy or used in combination with other chemotherapy agents for treatment of Hodgkin lymphoma. Rituximab may also be used as maintenance therapy of symptomatic, relapsed or refractory lymphocyte predominant Hodgkin lymphoma after second line of therapy that included rituximab. These recommendations were based on 2A category of evidence and uniform consensus. The peer-reviewed literature consists of case series and nonrandomized, uncontrolled trials.

Non-Hodgkin Lymphoma
A Cochrane report (Schulz, 2007) described results from a meta-analysis of seven randomized controlled trials involving 1,943 individuals with follicular lymphoma, mantle cell lymphoma or other indolent lymphomas. Better OS rates were observed in individuals treated with combination rituximab and other chemotherapy agents (R-chemo) (hazard ratio [HR] for mortality 0.65; 95 percent confidence interval [CI] 0.54 to 0.78). An overall response (relative risk of tumor response 1.21; 95 percent CI 1.16 to 1.27) and disease control (HR of disease event 0.62; 95 percent CI 0.55 to 0.71) was noted in individuals treated with R-chemo versus those treated with chemotherapy alone. R-chemo improved overall survival in individuals with follicular lymphoma (HR for mortality 0.63; 95 percent CI 0.51 to 0.79) and in individuals with mantle cell lymphoma (HR for mortality 0.60; 95 percent CI 0.37 to 0.98). The authors concluded: "Concomitant treatment with rituximab and standard chemotherapy regimens should be considered the standard of care for individuals with indolent and mantle cell lymphomas who require therapy and for individuals with follicular lymphoma."

Vidal and colleagues (2009) performed a systematic review and meta-analysis of randomized controlled trials that studied the use of rituximab as maintenance therapy in individuals with follicular lymphoma. Induction therapy consisted of chemotherapy alone, chemotherapy with or without rituximab and rituximab alone. The meta-analysis included 1,143 individuals in five trials that compared observation or treatment upon relapse, versus rituximab as maintenance therapy. Meta-analysis of OS data was available for 985 individuals. OS was statistically significant and better in individuals treated with maintenance rituximab, versus those in the observation cohort or treated at the time of relapse (HR of death = 0.60, 95 percent CI = 0.45 to 0.79). With further analysis, the authors noted individuals with refractory or relapsed follicular lymphoma treated with maintenance rituximab therapy had a survival benefit (HR for death = 0.58, 95 percent CI = 0.42 to 0.79) compared to that (HR for death = 0.68, 95 percent CI = 0.37 to 1.25) of previously untreated individuals. However, infection-related adverse events were higher (HR = 1.99, 95 percent CI = 1.21 to 3.27) in the maintenance treatment group. Despite the higher rates of adverse events, the data from one trial did not show a negative impact on OS. The authors concluded maintenance rituximab therapy should be included as treatment for individuals with relapsed or refractory follicular lymphoma who responded to induction therapy. The risk and management of infections should be included in treatment decisions when utilizing rituximab.

A randomized, controlled, phase III PRIMA trial of two years of rituximab maintenance after first-line treatment of individuals with follicular lymphoma demonstrated significant progression-free survival (PFS) (Salles, 2010). This multicenter trial included an induction and a maintenance phase. After induction, 513 individuals were randomized to the observation group and 505 participants were assigned to the rituximab treatment group. The rituximab maintenance regimen included a total of 12 infusions of 375mg/m2 infused every eight weeks. At a median follow-up of 36 months in both groups, three-year PFS was significantly prolonged at 74.9 percent (95 percent CI 70.9 – 78.9) in the treatment group compared to 57.6 percent (53.2 – 62.0) in the observation cohort (p<0.0001).

Nonimmunosuppressed Primary Central Nervous System Lymphoma
Lymphoma that is limited to the cranial-spinal region without systemic disease is defined as primary central nervous system (CNS) lymphoma. According to the NCI (2013), diffuse large B-cell neoplasms comprise almost all primary CNS lymphomas. Treatment includes radiation therapy alone or with chemotherapeutic agents. Retrospective, uncontrolled case series have investigated the off-label use of rituximab for the treatment of primary CNS lymphoma. Wong (2004) reported five individuals with complete radiographic responses and two partial responses in a retrospective review of seven individuals who received rituximab induction prior to temozolomide treatments. Median duration of response was six months and the median survival was eight months. The authors noted the sequential dosing of rituximab prior to temozolomide appears to sensitize the CD20+ B-cells. Larger trials are needed to confirm the findings. The off-label use of rituximab for refractory or relapsed primary CNS lymphoma is reported by the NCI (2013) and is an NCCN level 2A category of evidence and uniform consensus recommendation (2013).

Waldenström's Macroglobulinemia
Lymphoplasmacytic lymphoma is an indolent lymphoproliferative disease also known as Waldenström's macroglobulinemia. Waldenström's macroglobulinemia usually includes involvement of the bone marrow, lymph nodes, spleen and may develop into hyperviscosity syndrome. The monoclonal serum paraprotein immunoglobulin M (IgM) gammopathy is typically associated with Waldenström's (NCI, 2013). Treatment of acute symptoms usually includes plasmapheresis and long-term management of individuals with serum viscosity of four or less is typically managed with chemotherapeutic agents.

Dimopoulos and colleagues (2007) reported on a series of 72 symptomatic individuals with Waldenström's macroglobulinemia (WM) in a phase II study. The enrolled individuals were treated with dexamethasone, rituximab and cyclophosphamide (DRC) over a period of five days. The regimen was repeated every 21 days for a period of six months. Responses were evaluated on an intention-to-treat analysis. The overall response rate was 84 percent (95 percent CI, 73 percent - 91 percent), which included 7 percent complete responses (CRs), 67 percent partial responses (PRs) and 9 percent minimal responses (MR). The two-year PFS rate for all participants was 67 percent and for individuals who responded to DRC, 80 percent. Grade 3 or 4 neutropenia occurred in seven individuals. Twenty infectious episodes with one death were recorded.

The Fourth International Workshop on Waldenström's macroglobulinemia (Dimopoulos, 2009) updated treatment recommendations include rituximab-based therapies, which may be the preferred first line of therapy as a single agent or in combination regimens for most individuals with Waldenström's macroglobulinemia. The authors noted, "Reuse of a first-line single agent or combination is reasonable if an individual achieved an unmaintained response that lasted for at least 12 months." Additional considerations when determining the choice of salvage therapy include first-line therapy used, quality and duration of response and specific variables such as age, performance status and side effects. The NCI Adult non-Hodgkin Lymphoma Treatment PDQ® (2013) includes the use of rituximab either as a single agentor in combination regimens as first-line therapy for Waldenström's macroglobulinemia. The peer-reviewed literature consists of case series.

The NCCN Clinical Practice Guideline (2013) recommends the off-label use of rituximab as a single agent along with plasmapheresis for treatment of symptomatic hyperviscosity for Waldenström's macroglobulinemia. Additional indications include follow-up treatment as a single agent for progressive or relapsed disease and palliative treatment. Single agent use in individuals with an M-protein greater than 5g/dL is discouraged. These recommendations are based on 2A category of evidence and uniform consensus. The peer-reviewed literature consists of case series and nonrandomized trials.

The American Hospital Formulary Service® (AHFS®, 2013) notes that rituximab is used as an off-label treatment of Waldenström's macroglobulinemia.

Wegener's Granulomatosis (WG) and Microscopic Polyangiitis (MPA)
WG disorder and MPA are subgroups of primary systemic small vessel vasculitis associated with ANCA (antineutrophil cytoplasmic antibodies), also known as ANCA-associated vasculitis (AAV). AAV causes blood vessels to become inflamed or swollen and, as a result, blood flow is restricted. The respiratory tract and kidneys are frequently the primary targets (Keogh, 2006). In early 2011, the recommendation was made by several specialty societies to change the name of WG to granulomatosis with polyangiitis, abbreviated as GPA (Falk, 2011). WG is a rare and rapidly progressive, immune mediated disorder that is typically treated with glucocorticosteroids and cytotoxic agents. However, relapsing disease and long-term toxicities as a result of standard therapies continue to pose challenges. Activated B-lymphocytes have been correlated with disease activity and response to therapies (Stone, 2010).

The FDA approved the combination of rituximab and glucocorticoids as a treatment for adults with WG and MPA in April 2011. Use of concomitant immunosuppressants other than corticosteroids has not been studied in individuals with GPA or MPA exhibiting peripheral B-cell depletion following treatment with rituximab (product information label, 2013).

The pivotal randomized trial was Rituximab in ANCA-Associated Vasculitis (RAVE), which was a double-blind, double-dummy, noninferiority trial that enrolled 197 ANCA-positive individuals with WG or MPA (Stone, 2010). For remission induction, participants received rituximab 375mg/m2 per week for four weeks and placebo-cyclophosphamide in the treatment group. The control group received standard therapy with cyclophosphamide 2mg/kg per day plus placeborituximab infusions. Individuals in the treatment group who achieved remission between three and six months were switched from placebo-cyclophosphamide to placebo-azathioprine. Participants in the control group who had a remission between three and six months were switched from cyclophosphamide to azathioprine. Both groups received glucocorticoid treatment of one to three pulses of 1,000mg methylprednisolone followed by prednisone 1mg/kg/day. The dose was tapered by five months to have glucocorticoids discontinued for individuals who were in remission. Primary endpoints were Birmingham Vasculitis Activity Score for  Wegener's Granulomatosis (BVAS/WG) of zero and successful prednisone taper at six months. There were 99 individuals randomized to the rituximab group, and 98 assigned to the control group. In each group, approximately 49 percent of the participants were newly diagnosed. Mean BVAS/WG entry scores were 8.5 ± 3.2 in the treatment group and 8.2 ± 3.2 in the control group. Completion of six months of treatment without early treatment failure was achieved in 84 individuals in the rituximab group (85 percent) and 81 participants in the control group (83 percent). The primary end point was reached in 64 percent of the treatment group and 53 percent of the control group, which met the criterion for noninferiority (P<0.001). In a subset analysis, 34 of 51 individuals with relapsing disease at baseline and treated with rituximab had reached the primary end point (67 percent) compared to 21 of 50 participants (42 percent, P = 0.01) in the control group. Adverse events occurred in 33 participants in the control group (33 percent) compared to 22 individuals in the rituximab group (22 percent). Stone and colleagues (2010) concluded treatment with rituximab and glucocorticoids was not inferior to the standard regimen of cyclophosphamide and glucocorticoids for remission induction in severe relapsing ANCA associated vasculitis.

Specks and colleagues (2013) provided updated data for the RAVE trial. The primary outcome was complete remission of disease by 6 months with remission maintained at 18 months. A total of 64 percent of individuals treated with rituximab had achieved CR at 6 months, with CR maintained at 12 months and 18 months at 48 percent and 39 percent, respectively. The control group had corresponding rates of CR at 6, 12 and 18 months of 53 percent, 39 percent and 33 percent. There was no significant difference in mean duration of CR between the treatment groups (P =0.76). The authors noted the criterion for noninferiority was met (P<0.001), but the criterion for superiority was not. At 18 months, there were no significant differences between the treatment groups in the number or rates of total adverse events, serious adverse events or nondisease related adverse events. There were two deaths in each group. The authors noted additional study is needed to determine "whether conventional remission-maintenance therapy or repeated B-cell depletion with rituximab is more effective in preventing relapses after initial induction of remission with rituximab."

Other Indications:
Based on the results from published data, rituximab treatment for other indications that are not currently approved by the FDA continue to be investigated.

Acquired Inhibitors in Hemophilia
A rare condition of acquired inhibitors in individuals with hemophilia may occur and could cause life-threatening bleeding. Replacement factors are used as prophylaxis and treatment of bleeding episodes in hemophiliacs. The development of high titers of inhibitors resulting from antibodies to the replacement factor is a serious complication and decreases the efficacy of hemophilia therapy. Due to the low incidence rate of acquired inhibitors, published data consists of case reports, case series and reviews (Collins, 2009; Kruse-Jarres, 2011; Sperr, 2007; Wiestner, 2002). Treatment typically involves immune tolerance and/or depletion of inhibitors with immune suppression with prednisone and cyclophosphamide (Kruse-Jarres, 2011; Sperr, 2007). For those individuals without a sufficient reduction in inhibitors with standard immunosuppression with cyclophosphamide and prednisone, rituximab therapy has resulted in a CR rate of inhibitor reduction of 77 percent (Sperr, 2007). Published data demonstrate the use of rituximab after failure of cyclophosphamide and prednisone immunosuppression can reduce acquired inhibitors and allow therapeutic results from factor replacement in hemophiliacs (Collins, 2009; Kruse-Jarres, 2011; Sperr, 2007; Wiestner, 2002). Additionally, specialty consensus opinion suggests the use of rituximab to treat individuals with acquired inhibitors and who have failed cyclophosphamide and prednisone treatment.

Acute Lymphoblastic Leukemia (ALL)
ALL is an aggressive type of leukemia that involves an overabundance of lymphoblasts or lymphocytes in the bone marrow and the peripheral blood. This condition is also called acute lymphocytic leukemia. Treatment of ALL includes combination chemotherapy and may include radiation (NCI, 2013). The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guideline in Oncology (NCCN Guidelines®, 2013) includes rituximab as a treatment option with the Hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high-dose methotrexate and cytarabine) regimen for individuals with CD20+, Philadelphia chromosome-negative ALL. This 2A off-label recommendation was based on improved CR duration rate and OS rates from phase II trials.

Autoimmune Hemolytic Anemia (AIHA)
AIHA is typically idiopathic or secondary to another diagnosis, and involves the production of autoantibodies and the hemolysis of red blood cells (RBCs). AIHA is an uncommon condition with cases classified as warm AIHA or cold agglutinin disease. Treatment of AIHA depends on this classification and typically includes corticosteroids, immunosuppressants, immunoglobulin and splenectomy. Rituximab, as an alternative treatment for refractory AIHA, is limited to small retrospective case series, case reports and uncontrolled trials. Further investigation is ongoing to determine whether rituximab achieves durable, effective, long-term results to improve overall health outcomes.Specialty consensus opinion recommends the use of rituximab for treatment of this condition.

Graft Versus Host Disease (GVHD)
GVHD may occur in transplant recipients as a result of a T-cell mediated reaction to antigens from a donated hematopoietic stem cell graft. Symptoms include anorexia, gastrointestinal symptoms, jaundice, skin rash or blisters, a dry mouth or dry eyes. Treatment of GVHD includes steroids, calcineurin inhibitors, immunosuppressants, T-cell depleting agents and extracorporeal photopheresis. There has been published literature regarding various treatment and prophylaxis regimens for GVHD, as well as varying response rates. However, individuals who are unresponsive or are refractory to corticosteroids and standard therapies have a poor prognosis and there is no standard treatment in this setting (Teshima, 2009). The published literature consists of retrospective, case series and uncontrolled trials studying the role of rituximab as a treatment for refractory GVHD.

Investigators hypothesize B-cells and other factors may have a role in GVHD (Cutler, 2006). Low-dose (50 mg/m2) rituximab was used to treat 13 individuals with steroid-refractory GVHD. An overall response rate of 69 percent, with 23 percent (three individuals) achieving CR, 15 percent PR and 30 percent mixed response (MR), was reported by von Bonin (2008). Two individuals developed complications due to infection, with one death. Teshima and colleagues (2009) reported results from a phase II trial of seven individuals with refractory chronic GVHD (cGVHD) who were treated with weekly rituximab doses of 375 mg/m2 over four weeks. At one-year follow-up, the overall response rate was 43 percent with PR in three participants, stable disease (SD) in three individuals and one participant had progressive disease (PD). The median reduction of steroids was 67 percent. At a median follow-up of 30 months, five participants were alive and two deaths from infection were noted. In a retrospective study by GITMO (Gruppo Italiano Trapianto Midollo Osseo; Zaja, 2007), 38 participants with refractory GVHD were treated with rituximab. The two-year actuarial survival was 76 percent and the overall response rate was 65 percent. Steroid therapy was reduced by 82 percent. There were eight deaths during the study period with three cases of progressive cGVHD, one relapsed disease, three cases of sepsis and one sudden death.

Kharfan-Dabaja and colleagues (2009) performed a review and meta-analysis of rituximab as a treatment for steroid-refractory chronic GVHD. From the published literature, six studies met inclusion criteria for review, of which three studies were prospective and three were retrospective studies. There were no randomized controlled trials. There were a total of 108 individuals in the six trials. The authors were unable to analyze the heterogeneity of the responses. The data suggest rituximab is effective in treating cutaneous cGVHD; however, the response was not noted in other organs. The authors concluded the "evidence generated through this systematic review demonstrates the gaps in the existing evidence base related to the efficacy of rituximab in treating patients with steroid-refractory cGVHD. This underscores the need for well-designed and adequately powered prospective studies to conclusively address this issue."

The off-label use of rituximab as third-line treatment or greater for refractory GVHD is based on the data from uncontrolled trials and case series that demonstrated improvement in GVHD and reduction of steroid use. Based on the data for refractory GVHD, the safety and efficacy of rituximab as a prophylaxis and as first-line therapy for GVHD are being studied.

Multicentric Castleman's Disease, CD20+
Multicentric Castleman's disease (MCD) is an uncommon lymphoproliferative disorder, which has been associated with human herpes virus 8 (HHV-8) and Kaposi's sarcoma (KS), and may evolve toward HHV-8-associated non-Hodgkin lymphoma (Gerard, 2007; Mylona, 2008). An increased prevalence of MCD is noted in human immunodeficiency virus (HIV) infection. A systematic review of the published literature on MCD conducted by Mylona and colleagues (2008) identified 84 individuals in 25 studies that met criteria for analysis. Chemotherapy treatment data was available for 75 out of the 84 individuals. Rituximab was utilized as first- or second-line therapy in seven of the 75 individuals. Five cases have led to complete responses. The authors highlighted there were three cases of responders with worsening of existing KS.

In a prospective, open-label phase II trial, four weekly rituximab infusions were given to 24 individuals with HIV-associated MCD (Gerard, 2007). One individual died as a result of progressive MCD before completing the infusions and one individual died at day 112 from infection related respiratory failure. The primary endpoint was a sustained remission (SR) at day 60 while remaining off of other chemotherapeutic agents. Seventeen of 22 individuals achieved SR at day 60 and remained off of chemotherapy at day 365. The authors concluded the estimated OS rate was 92 percent (95 percent CI, 71 percent-98 percent), event-free survival (EFS) was 71 percent (95 percent CI, 48 percent-85 percent) and disease-free survival (DFS) was 77 percent (95 percent CI, 54 percent - 90 percent). Adverse events included exacerbation of KS lesions in eight of the 12 individuals who had pre-existing KS.

In a single-group, open-label, phase II trial, 21 individuals with HIV-associated MCD were treated with rituximab as first-line treatment. The median follow-up was 12 months (range one – 49 months). One individual died before completion of the therapy regimen. Fourteen participants (67 percent) achieved radiologic response and 20 individuals achieved remission of symptoms. At two years, the overall survival rate was 95 percent (95 percent CI, 86 percent - 100 percent) and the DFS rate was 79 percent (CI, 52 percent - 100 percent) (Bowers, 2007).

NCCN CPG (2013) recommends the off-label use of rituximab in combination regimens to treat CD20+ AIDS-related diffuse large B-cell lymphoma and lymphoma associated with Castleman's disease. These recommendations were based on level 2A category of evidence and uniform consensus.

Neuromyelitis Optica (NMO)
Neuromyelitis optica is a rare, inflammatory, demyelinating central nervous system (CNS) disease that selectively targets the optic nerve and spinal cord (Jacob, 2007). Magnetic resonance spine imaging often reveals longitudinally extensive transverse myelitis (LETM), defined as large, contiguous lesions over three or more vertebral segments. A specific serum antibody (NMO-Ig-G/aquaporin-4) has been identified in individuals with NMO along with perivascular  immunoglobulin deposition and B-cell participation in the activated complement lytic pathway (Jacob, 2007). Glucocorticoids, plasmapheresis and immunosuppressants have been used to treat NMO. Cree and colleagues (2005) reported results from an open-label series of eight consecutive individuals with NMO who were treated with rituximab. At an average follow-up of 12 months, six individuals have remained free from attacks. Five individuals received retreatment with rituximab when CD19+ cells were detectable. The authors noted the possibility that previous immunosuppression may have confounded results, or the timing of the rituximab was attributable to the natural onset of remission.

Jacob and colleagues (2008) reported retrospective, multicenter data on a series of 25 individuals with NMO treated with rituximab. The rituximab regimens utilized were 375 mg/m two weekly for four weeks and 1,000 mg infused twice, with a two-week interval between infusions. Median follow-up of 19 months (range 6-40 months) occurred with five participants  discontinuing treatment. In addition, two deaths were attributed to disease progression and sepsis. The authors reported the median annualized pretreatment relapse rate was 1.7 relapses (range 0.5 – five relapses) and the median annualized post-treatment relapse rate was 0 (range 0 – 3.2 relapses, P <.001). Because NMO is a rare, relapsing and debilitating disease, the off-label use of rituximab as a treatment of NMO is based on the data from case series that demonstrated improvements in relapse rates. Specialty consensus opinion suggests the use of rituximab as treatment for NMO.

Pemphigus Vulgaris and Other Autoimmune Blistering Skin Diseases
Autoimmune blistering skin diseases are rare, and treatment with corticosteroids and immunosuppressive drugs may not control disease, leading to increased morbidity and mortality. Rituximab treatment for individuals with refractory pemphigus vulgaris has been studied in open label, nonrandomized, uncontrolled case series. Joly and colleagues (2007) reported on 18 (86 percent) out of 21 individuals who achieved complete remission of severe, refractory pemphigus with rituximab therapy. With a median follow-up of 34 months, 18 individuals were free of disease and eight of these individuals had stopped corticosteroid therapy. In another similar study (Allen, 2007) the investigators note rituximab "appears to be effective in the treatment of refractory disease." Additionally, the American Hospital Formulary Service® (AHFS®, 2013) notes rituximab is used off-label for the treatment of pemphigus vulgaris.

Post-transplant Lymphoproliferative Disorder
Post-transplant lymphoproliferative disorder (PTLD) is a rare and life-threatening complication after organ transplantation. PTLD presents as a heterogeneous group of lymphoproliferative disorders resulting from immune suppression, and the prognosis is dependent on additional risk factors such as the presence of Epstein-Barr virus (EBV). The primary treatment of PTLD has been a reduction in immunosuppression. However, many individuals fail to respond to reduction and modifications of the immunosuppression therapy.

Lee and colleagues (2007) performed a systematic review of six studies of PTLD treatment with rituximab as a single agent or in combination with chemotherapy. A majority of the individuals involved in the studies were CD20+. There have been case reports and phase II trials reported, but there is a lack of randomized, prospective, head-to-head  comparisons of treatment regimens. The authors noted results from the limited trials, in combination with some long-term retrospective follow-up data, demonstrated rituximab therapy as a single agent or in combination, produced an ORR of 50-100 percent and a five-year OS of 60 percent. Prospective, randomized controlled trials are needed to identify the optimal timing and treatment regimens for individuals with PTLD that have failed immunosuppressive therapy.

In a retrospective, multi-center analysis of 80 solid organ transplant (SOT) recipients, Evens (2010) noted individuals treated with first-line rituximab, with or without chemotherapy, had significantly improved PFS and OS. Of the 80 SOT recipients with PTLD, 59 individuals had early treatment with rituximab. With a median 40-month follow-up, significant differences in the rituximab-treated cohort were noted with PFS 70 percent versus 21 percent (P < .0001) and OS 73 percent versus 33 percent (P= .0001).

Renal Transplant
Renal transplantation is used for individuals with end-stage renal disease (ESRD). The demand for kidney transplantation has outpaced the supply of organs, thus increasing the wait-time until transplantation. Additionally, wait times are increased when there is difficulty in matching organs to recipients resulting from sensitization with reactive human leukocyte antigen (HLA)-specific antibodies. Vo (2010) reported, "The rate of transplantation with any level of sensitization is difficult to transplant." Individuals with panel reactive antibodies (PRA) 10 percent to 80 percent were transplanted 16 percent per year, whereas PRA greater than 80 percent were transplanted less than 8 percent per year.

A phase I-II trial examined if a treatment protocol, consisting of intravenous immune globulin (IVIG) and rituximab, administered prior to kidney transplantation, would improve transplantation rates by reducing anti-HLA antibody levels in highly sensitized individuals. 20 individuals, who were highly sensitized, were treated with the combination regimen between 2005 and 2007. Vo and colleagues (2008) reported PRAs were "significantly reduced after treatment with IVIG and rituximab (77 ± 19 percent before the first infusion of IVIG, vs. 44 ± 30 percent after the second infusion (P < 0.001)." CD19+ cells were significantly reduced after rituximab treatment (mean percentage of total B cell lymphocytes, 6.12 ± 0.18 percent prior to treatment, vs. 0.90 ± 0.02 percent after treatment, P< 0.001). Sixteen of the 20 participants received successful transplantation (six received a deceased donor kidney; 10 received a living donor kidney). The remaining four participants had PRA levels greater than 50 percent and were awaiting a deceased donor kidney transplant. Mean follow-up was 22.1 ± 6 months with recipient and allograft survivals of 100 percent and 94 percent, respectively. One graft was lost due to severe rejection after a reduction of immunosuppressive therapy. Acute rejection occurred in 50 percent of the transplanted individuals. Acute antibody-mediated rejections (AMR) occurred in 31 percent of the episodes and two individuals had late (greater than 6 months) AMR episodes. Individuals with AMR were treated with methylprednisolone, rabbit antithymocyte globulin and rituximab. Recipients of deceased donor kidneys had a mean waiting list time of 12 years (range, five-27) prior to desensitization, but received transplants within five to six months after receiving combination treatment with IVIG and rituximab.

In 2010, Vo and colleagues reported on 76 HLA-sensitized individuals who were treated with IVIG and rituximab prior to kidney transplantation during 2006 and 2009. The study examined the efficacy of IVIG and rituximab on the reduction of anti-HLA antibodies that led to kidney transplantation with incurring the risk of AMR and immediate graft loss. All participants were deemed high immunologic risks with PRA 30 percent - 79 percent in 25 percent of individuals and 75 percent of the participants had PRA ≥ 80 percent. Thirty-one individuals received living donor (LD) and 45 individuals received deceased donor (DD) kidney transplants. Data from 39 individuals show mean pretreatment class I PRA was 79.7 percent ± 35.6 percent versus post-treatment 67.1 percent ± 28.6 percent (P= 0.0001). Recipients of deceased donor kidneys had a mean waiting list time of 95 ± 46 months prior to desensitization, but received transplants within four months after receiving combination treatment with IVIG and rituximab. Acute rejection (AR) occurred in 37 percent of participants (8 percent cell mediated rejection [CMR] and 29 percent AMR). Nine individuals had graft losses, with AMR involved in 6 cases. Recipient and allograft survivals were 95 percent and 84 percent, respectively. The authors concluded, "IVIG and rituximab seems to offer significant benefits in reduction of anti-HLA antibodies, allowing improved rates of transplantation for highly sensitized patients, especially those awaiting DD, with acceptable antibody-mediated rejection and survival rates at 24 months" (Vo, 2010). Additional analysis in a randomized trial was encouraged.

Tyden (2009) reported results from 140 individuals transplanted on a prospective, double-blind, randomized, placebo-controlled study. Participants meeting criteria, including PRA less than 50 percent, were randomized to induction therapy (tacrolimus, mycophenolate mofetil and steroids) plus rituximab versus induction therapy plus placebo. One hundred thirty-six participants fulfilled the criteria for analysis. Treatment failure was the primary endpoint, with 10 occurrences in the rituximab group and 14 in the placebo group (P=0.348). Rejection episodes occurred 8 times in the treatment cohort versus 12 episodes in the placebo group (P=0.317). Although rejection episodes in the treatment group "tended to be less severe," survival in both groups at six months was 98.5 percent and death censored graft survival of 98 percent. Biopsy-proven acute rejections were not statistically significant, with 11.6 percent in the rituximab group and 17.6 percent in the placebo cohort. The three-year follow-up of this study population is ongoing.

Systemic Autoimmune Disorders (Cryoglobulinemia, Primary Sjögren Syndrome [SS], Systemic Lupus Erythematosus [SLE])
Rituximab has been increasingly used for a variety of systemic autoimmune diseases (SAD). In a systematic review of the published literature, Ramos-Casals and colleagues (2008) noted, due to the lack of randomized controlled trials and the heterogeneity in clinical features in the SAD population, definitive off-label recommendations for biologic agents were difficult to make. However, based on the therapeutic response of >80 percent in individuals, the authors noted rituximab should be considered a first choice biologic agent for treatment for individuals with cryoglobulinemia, primary SS and SLE who are refractory to standard therapy (lack of response to corticosteroids and at least two immunosuppressive agents). Immunosuppressive agents utilized for the treatment of SS include cyclosporine, methotrexate, azathioprine, corticosteroids, hydroxychloroquine, d-penicillamine, thalidomide and nucleoside analogues (Mavragani, 2007). In addition, specialty consensus opinion suggests the use of rituximab for treatment of SAD.

Thrombocytic Purpura, Idiopathic or Immune
Idiopathic thrombocytopenic purpura (ITP), also known as primary immune thrombocytopenic purpura, is an immune mediated hematologic disorder characterized by impaired production of platelets in the bone marrow and destruction of the peripherally circulating platelets. These individuals typically present with low platelet counts, bleeding episodes and platelet autoantibodies. Treatment may include maintaining hemostatic levels, administering prednisone and immune globulin and in severe cases, splenectomy.

Arnold and colleagues (2007) performed a systematic review of rituximab as a treatment of ITP in adults. Nineteen studies including a total of 313 individuals were identified for evaluation of efficacy and 29 articles including a total of 306 individuals were identified for assessment of safety. The authors noted an absence of controlled studies. In 16 out of 19 studies, rituximab was given at standard weekly dosing for up to 4 weeks. Complete response, noted by a platelet count greater than 150 x 10 9  cells/L, was observed in 43.6 percent of individuals. An overall response, defined as platelet count greater than 50 x 10 9  cells/L, was noted in 62.5 percent individuals treated with rituximab. Median duration of response was 10.5 months and a median follow-up was 9.5 months. Evaluation of all deaths in rituximab-treated individuals identified 9 deaths out of 306 individuals, with 2 deaths attributed to rituximab administration. The authors concluded  from the uncontrolled studies that rituximab treatment improved platelet counts. However, prospective, randomized  controlled trials are encouraged to identify the optimal timing and dose of rituximab for the treatment of ITP.

The first report from a phase III, open-label trial of rituximab as first-line of therapy for ITP was reported by Gudbrandsdottir (2013). Individuals who were newly diagnosed adults with ITP and platelet counts ≤ 25 X 10 9 /L or ≤ 50 X 109 /L with concomitant bleeding symptoms were randomized to treatment with dexamethasone alone (DXM) or in combination with rituximab (RTX + DXM). Between 2006 and 2011, a total of 137 individuals were randomized. Four participants did not have complete data available for analysis. The DXM group included 71 individuals who received DXM 40 mg/day for 4 days. The treatment group of 62 individuals received DXM and rituximab 375 mg/m two weekly for four weeks. In addition, up to six cycles of supplemental DXM every one to four weeks was allowed. The median follow-up was  922 days. Fifty-eight percent of participants in the RTX + DXM group met the primary endpoint of sustained response (i.e., platelets ≥ 50 X 109/L) at six months follow-up compared to 37 percent treated with DXM alone in the control group (P =.02). The time to relapse was defined as a decrease in platelet counts to < 50 X 109/L following initial response to therapy. The RTX + DXM group had a significantly longer time to relapse compared to the DXM group (P=.03). An increased incidence of grade 3 to 4 adverse events was observed in the RTX + DXM group (P=.04).

 The American Hospital Formulary Service® (AHFS®, 2013) notes that rituximab is used as an off-label treatment of ITP.

Other Proposed Uses:
The published literature includes investigation of rituximab treatment for various other off-label uses. However, the published literature consists of case reports, small case series, non-randomized and uncontrolled trials that preclude reliable conclusions on safety and long-term net health outcomes.

Membranous Nephropathy (MN)
Membranous nephropathy involves the abnormal thickening of the glomerular basement membrane and is a leading cause of nephrotic syndrome. The majority of MN cases occur from unknown causes and secondary MN may be a result of other predisposing diseases, infection or medical therapy. In most cases, conservative treatment with renin-angiotensin system (RAS) blockade is provided. Immunomodulatory therapies (e.g., alkylating agents, calcineurin inhibitors and corticosteroids) are used to treat individuals who are unresponsive to conservative therapy. Rituximab has been used to treat MN and reported in numerous case reports and series. Bomback and colleagues (2009) performed a  systematic review of 21 articles involving 85 individuals with biopsy-proven MN treated with rituximab as primary or secondary immunosuppression. The majority of the individuals in the analysis were reported from two centers. However, there were significant variations in selection criteria, previous treatments and rituximab treatment protocols that precluded pooled data analysis. Complete remission in 15 to 20 percent and partial remission in 35 to 40 percent of individuals with refractory disease were similar to response rates for alkylating agents and calcineurin inhibitors. The authors cautioned the response rates from case series were "not valid for direct comparisons to the randomized clinical trial-based data on alkylating agents and calcineurin inhibitors." Although positive case series have been published, Bomback (2009) concluded rituximab as a treatment for MN should not be provided outside of a research setting. Large, randomized controlled trials are needed to determine the optimal schedule, dose and long-term safety and efficacy.

Multiple Sclerosis (MS)
In a Cochrane review (He, 2011) of a randomized, double-blind trial investigating rituximab to treat relapsing and remitting MS (RR-MS), the authors concluded the available evidence was inconclusive and did not support any treatment recommendations at this time. Larger trials with longer follow-up are needed to evaluate the treatment. Treatment of MS with rituximab has been published in phase I studies (Bar-Or, 2008), case reports, case series and nonrandomized, uncontrolled trials (Naismith, 2010). A manufacturer-sponsored Phase II/III randomized, double-blind, placebo-controlled multicenter trial to evaluate the safety and efficacy of rituximab as a treatment for primary progressive multiple sclerosis (PPMS) failed to meet the primary endpoints (Genentech press release, 2008). A randomized, double-blind, placebo-controlled trial included 439 participants who were evaluated over a period of 96 weeks. There were no significant differences in the primary endpoint, which was time to confirmed disease progression between the rituximab treatment group and the placebo cohort (Hawker, 2009).

Hauser and colleagues (2008) reported results from a phase II, double-blind trial with 104 participants with relapsing-remitting MS. The 48-week trial included 69 participants randomized to 1,000 rituximab given intravenously on days one and 15, and 35 participants randomized to placebo infusion. The primary endpoint of the study was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging (MRI) brain scans at weeks 12, 16, 20 and 24. Twenty-four percent of the 104 participants discontinued from the trial before week 48 (14 participants [40 percent] from the control group and 11 participants [15.9 percent] in the treatment group). In the intention to treat analysis, there was a reduction of total gadolinium-enhancing lesion counts with rituximab treatment (mean 0.5 lesions) versus placebo (5.5 lesions). The authors concluded the trial data suggests rituximab "may be an option for treating relapsing-remitting multiple sclerosis, provided the observed efficacy and safety profile are sustained in larger and longer-term controlled trials" (Hauser, 2008).

The published peer-reviewed literature regarding the off-label use of rituximab to treat multiple sclerosis is not sufficient to draw reasonable conclusions regarding the long-term clinical effectiveness and improvement on net health outcomes and safety.

Transplant Rejection
Published case reports, case series and reviews have reported the use of rituximab for treatment of transplant rejection. A prospective, randomized trial of 20 individuals with acute renal transplant rejection compared rituximab versus standard of care immunosuppression. One-year outcomes with some benefit for recovery of graft function were reported, Zarkhin (2008). The study had short-term follow-up and further investigation for B-cell mediated graft rejection was recommended. In a review of antibody-mediated rejection (AMR) by Singh (2009), the suppression or depletion of B-cells by rituximab was noted as one treatment option to treat AMR. Other treatments of AMR include suppression of T-cell dependent antibody responses; removal of donor reactive antibody and blockade of the residual alloantibody. However, Singh and colleagues (2009) concluded, "Rituximab deletes the naïve B-cell pool, but has no effect on plasma cells" and the efficacy of rituximab in the treatment of AMR "remains poorly understood. Although all published (AMR) protocols report a variable rate of success, a major weakness of all current protocols is the lack of effective antiplasma cell agents."

The published peer-reviewed literature regarding off-label use of rituximab as a treatment for transplant rejection includes case series, phase I and pilot studies. This is not sufficient to draw reasonable conclusions regarding the long-term clinical effectiveness, optimal anti-rejection regimen and safety of rituximab as a treatment for solid organ transplant rejection. Prospective, randomized control trials are needed to determine the clinical effectiveness and net health outcomes of rituximab therapy on transplant grafts and overall survival.

Background/Overview:
Hodgkin Diease (also known as Hodgkin Lymphoma)
In Hodgkin disease, cells in the lymphatic system grow abnormally and may spread beyond the lymphatic system. As the disease progresses, it compromises the body's ability to fight infection. Many initial signs and symptoms may be similar to those of influenza, such as fever, fatigue and night sweats. Hodgkin disease is distinguished by the presence of an abnormal Reed-Sternberg cell in the lymphoma tissue. Eventually, tumors develop. Hodgkin disease most commonly affects people between the ages of 15 and 34 and people older than age 55.

In 2013, the NCI reported chemotherapy and radiation therapy may cure more than 75 percent of all newly diagnosed Hodgkin disease cases. Advances in diagnosis, staging and treatment of Hodgkin disease have helped to make this once uniformly fatal disease highly treatable with the potential for full recovery. The national mortality rate for adult Hodgkin lymphoma has fallen more rapidly than for any other malignancy.

Non-Hodgkin Lymphoma 
NHL is a collection of more than a dozen different cancers of the lymphatic system, which generates the body's immune defenses. This system includes a network of channels akin to blood vessels through which lymphocytes -- important white blood cells of the immune system -- patrol the body for invading microbes. Along these lymphatic routes in the neck, armpits, abdomen and groin are clusters of bean-shaped lymph nodes that house platoons of the infectionfighting lymphocytes. These cells also cluster in areas that serve as gateways to the body, including the mucous membranes lining the respiratory and digestive tracts, and the skin. Lymphocytes travel in the bloodstream, as well. The lymphatic system also includes such organs as the spleen, thymus and tonsils.

According to the NCI (2013), NHL can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas. Indolent NHL types have a relatively good prognosis with a median survival as long as 10 years, but they usually are not curable in advanced clinical stages. Early stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of these individuals can be cured with intensive combination chemotherapy regimens. In general, with modern treatment of individuals with NHL, overall survival at five years is approximately 50 percent to 60 percent, and 30 percent to 60 percent of individuals with aggressive disease can be cured. The vast majority of relapses occur in the first two years after therapy. The risk of late relapse is higher in individuals with a divergent histology of both indolent and aggressive disease.

Indolent NHL is usually responsive to radiation therapy and chemotherapy. However, a continuous rate of relapse is usually seen in advanced stages. Individuals can be re-treated with considerable success as long as the disease histology remains low grade. Individuals who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support (NCI, 2013).

Rheumatoid Arthritis
Rheumatoid arthritis is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness and loss of function in the joints. If left untreated it may lead to joint destruction and progressive disability. Rheumatoid arthritis affects 2.1 million Americans, usually striking people between the ages of 20 and 60, and people in their mid to late 50s are especially vulnerable. Rheumatoid arthritis is three times more common in women than in men. Arthritis and related musculoskeletal conditions such as rheumatoid arthritis cost the U.S. economy nearly $125 billion per year in medical care and indirect expenses such as lost wages and production. The traditional pharmacologic approach consists of nonsteroidal anti-inflammatory drugs (NSAIDs) to reduce pain, swelling and inflammation, plus a DMARD such as MTX to slow the course of the disease and prevent joint and cartilage destruction.

Adverse Events and Warnings
Black box warnings from the FDA product information label (2013) include the following:

    • Rituximab administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80 percent of fatal reactions occurred in association with the first infusion. Carefully monitor individuals closely during infusions. Discontinue rituximab infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions.
    • Severe, including fatal, mucocutaneous reactions can occur in individuals receiving rituximab. Hepatitis B virus (HBV) reactivation can occur in individuals treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure and death. Screen all individuals for HBV infection before treatment initiation, and monitor individuals during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation.
    • Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in individuals receiving rituximab.

Additional warnings from the FDA product information label (2013) include:

    • Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure and death can occur in individuals treated with rituximab. The median time to the diagnosis of hepatitis among individuals with hematologic malignancies was approximately 4 months after the initiation of rituximab and approximately one month after the last dose.
    • Serious, including fatal, bacterial, fungal and new or reactivated viral infections can occur during and following the completion of rituximab-based therapy. Infections have been reported in some individuals with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus and hepatitis B and C.
    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of rituximab for individuals who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.
    • Severe, including fatal, renal toxicity can occur after rituximab administration in individuals with NHL. Renal toxicity has occurred in individuals who experience tumor lysis syndrome and in individuals with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and rituximab is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue rituximab in individuals with a rising serum creatinine or oliguria.
    • Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in individuals receiving rituximab in combination with chemotherapy.
    • The safety of immunization with live viral vaccines following rituximab therapy has not been studied, and vaccination with live virus vaccines is not recommended.

Definitions: 
Complete response (CR): The disappearance of all signs of cancer as a result of treatment; also called complete remission; does not indicate the cancer has been cured.

Disease free survival (DFS): In cancer, the length of time after primary treatment for a cancer ends that the individual survives without any signs or symptoms of that cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.

Disease modifying anti-rheumatic drugs (DMARDs): A variety of medications (i.e., methotrexate, sulfasalazine, hydroxychloroquine) that work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis, including rheumatoid arthritis.

Event free survival (EFS): In cancer, the length of time after primary treatment for a cancer ends that the individual remains free of certain complications or events that the treatment was intended to prevent or delay. These events may include the return of the cancer or the onset of certain symptoms, such as bone pain from cancer that has spread to the bone. In a clinical trial, measuring the event-free survival is one way to see how well a new treatment works.

Line of therapy:

    • First-line therapy: The first or primary treatment for the diagnosis, which may include surgery, chemotherapy, radiation therapy or a combination of these therapies.
    • Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.
    • Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

Maintenance therapy: Treatment given to help keep cancer from coming back after it has disappeared following the initial therapy.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Nonbiologic disease modifying antirheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown. Includes azathioprine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds, penicillamine and sulfasalazine.

Partial response (PR): A decrease in the size of a tumor or in the amount of cancer in the body, resulting from treatment. Also called partial remission.

Progressive disease (PD): Cancer that is growing, spreading or getting worse.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of illness or disease.

Stable disease (SD): Cancer that is neither decreasing nor increasing in extent or severity.

Tumor necrosis factor (TNF) antagonists: A class of drugs (including, but not limited to, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) designed to neutralize inflammatory cytokines.

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  23. Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab. Retrospective analysis of 25 patients. Arch Neurol. 2008; 65(11):1443-1448.
  24. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med. 2007; 357:545-552.
  25. Jones RB, Tervaert JWC, Hauser T, et al.; for the European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vaculitis. N Engl J Med. 2010; 363(3):211-220.
  26. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005; 23(18):4079-4088.
  27. Keogh KA, Ytterberg SR, Fervenza FC, et al. Rituximab for refractory Wegener's granulomatosis. Report of a prospective, open-label pilot trial. Am J Respir Crit Care Med. 2006; 173:180-187.
  28. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, et al. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009; 15:1005-1013.
  29. Kruse-Jarres R. Current controversies in the formation and treatment of alloantibodies to factor VIII incongenital hemophilia A. Hematology. 2011; 2011:407-412.
  30. Lee JJ, Lam MSH, Rosenberg A. Role of chemotherapy and rituximab for treatment of posttransplant lymphoproliferative disorder in solid organ transplantation. Annals of Pharmacotherapy. 2007; 41:1648-1659.
  31. Magnasco A, Ravani P, Edefonti A, et al. Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol. 2012; 23(6):1117-1124.
  32. Martinez Del Pero M, Chaudhry A, Jones RB, et al. B-cell depletion with rituximab for refractory head and neck Wegener's granulomatosis: a cohort study. Clinical Otolaryngology. 2009; 34:328-335.
  33. Mavragani CP, Moutsopoulos. Conventional therapy of Sjögren's Syndrome. Clin Rev Allerg Immunol. 2007; 32:284-291.
  34. Mease PJ. B cell-targeted therapy in autoimmune disease: rationale, mechanisms, and clinical application. J Rheumatol. 2008;35(7):1245-1255.
  35. Mylona E, Baraboutis IG, Lekakis LJ, et al. Multicentric Castleman's Disease in HIV infection: a systematic review of the literature. AIDS Rev. 2008; 10:25-35.
  36. Naismith RT, Piccio L, Lyons JA, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis. A 52-week phase II trial. Neurol. 2010; 74(23): 1860- 1867.
  37. Quinn JP, Mohamedbhai, Chipperfield, et al. Efficacy of rituximab in combination with steroids in refractory chronic lymphocytic leukemia. Leukemia and Lymphoma. 2008; 49(10):1995-1998.
  38. Rovin BH, Furie R, Latinis K, et al; LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012; 64:1215-1226.
  39. Rummel MJ, Niederle N, Maschmeyer G, et al.; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicenter, randomised, phase 3 non-inferiority trial. Lancet. 2013; Feb 19. pii: S0140-6736(12)61763-2. doi: 10.1016/S0140-6736(12)61763-2.
  40. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomized controlled trial. Lancet. 2011; 377:42-51.
  41. Schultz H, Rehwald U, Morschhauser F, et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSF). Blood. 2008; 111(1):109-111.
  42. Scully M, McDonald V, Cavenagh J, et al. A phase II study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-1753.
  43. Sibilia J, Gottenberg JE, Mariette X. Rituximab: a new therapeutic alternative in rheumatoid arthritis. Joint Bone. Spine 2008; 75:526-532.
  44. Silverman GJ, Boyle DL. Understanding the mechanistic basis in rheumatoid arthritis for clinical response to anti-CD20 therapy: the B-cell roadblock hypothesis. Immunol Rev. 2008; 223:175-185.
  45. Specks U, Merkel PA, Seo P, et al.; RAVE-ITN Research Group. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013; 369(5):417-427.
  46. Stone JH, Merkel PA, Spiera R, et al., for the RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010; 363(3):221-232.
  47. Teshima T, Nagafuji K, Henzan H, et al. Rituximab for the treatment of corticosteroid-refractory chronic graftversus- host disease. Int J Hematol. 2009; 90:253-260.
  48. Thomas DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010; 28(24): 3880-3889.
  49. Vidal L, Gafter-Gvili, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009; 101:248-255.
  50. Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation. 2010; 89(9):1095-1102.
  51.  von Bonin M, Oelschlägel U, Radke J, et al. Treatment of chronic steroid-refractory graft-versus-host disease with low-dose rituximab. Transplantation. 2008; 86(6):875-879.
  52. Wiestner A, Cho HJ, Asch AS, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood. 2002; 100(9):3426-3428.
  53. Wong ET, Tishler R, Barron L, Wu JK. Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer. 2004; 1010(1):139-145.
  54. Zaja F, Baccarani M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood. 2010; 115(14):2755-2762.
  55. Zaja F, Bacigalupo A, Patriarca F, et al.; for the GITMO (Gruppo Italiano Trapianto Midollo Osseo). Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant. 2007; 40:273-277.
  56. Zarkhin V, Li L, Kambham N, et al. A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant. 2008; 8(12):2607-2617.
  57. Zent CS, Call TG, Shanafelt TD, et al. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer. 2008; 113(8):2110-2118.
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  59. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database of Systematic Reviews. 2012; (11):CD008079. 
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    • Central Nervous System Cancers (V.2.2013). April 25, 2013.
    • Hodgkin Disease/Lymphoma (V.2.2013). May 24, 2013.
    • Non-Hodgkins Lymphoma (V.2.2013). September 6, 2013. 
    • Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma (V.2.2013). August 15, 2012
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Coding Section

Codes Number Description
HCPCS  J9310 (code deleted as of 01/01/2019) Injection, rituximab, 100 mg
  J9311 (effective 01/01/2019)  Injection, rituximab, 10 mg and hyaluronidase 
  J9312 (effective 01/01/2019)  Injection, rituximab, 10 mg  
ICD-9 Diagnosis 042 Human immunodeficiency virus [HIV] disease
  058.89 Other human herpesvirus infection (Human herpesvirus 8 infection)
  070.41 Acute hepatitis C with hepatic coma
  070.44 Chronic hepatitis C with hepatic coma
  070.51 Acute hepatitis C without mention of hepatic coma
  070.54 Chronic hepatitis C without mention of hepatic coma
  070.70-070.71 Unspecified viral hepatitis C
  176.0-176.9 Kaposi's sarcoma
  200.00-200.88 Lymphosarcoma and reticulosarcoma and other specified malignant tumors of lymphatic tissue
  201.00-201.98 Hodgkin's disease
  202.00-202.98 Other malignant neoplasms of lymphoid and histiocytic tissue
  204.00-204.92 Lymphoid leukemia
  238.77 Post-transplant lymphoproliferative disorder (PTLD)
  273.2 Other paraproteinemias (cryoglobulinemia)
  273.3 Macroglobulinemia (Waldenström's macroglobulinemia)
  279.41-279.49 Autoimmune disease, not elsewhere classified
  279.50-279.53 Graft-versus-host disease
  283.0 Autoimmune hemolytic anemias
  286.52 Acquired hemophilia
  287.31 Immune thrombocytopenic purpura (idiopathic thrombocytopenic purpura)
  341.0 Neuromyelitis optica
  446.0 Polyarteritis nodosa (specified as microscopic polyangiitis)
  446.4 Wegener's granulomatosis
  581.81 Nephrotic syndrome in diseases classified elsewhere
  585.1-585.9 Chronic kidney disease
  694.0-694.9 Bullous dermatoses (pemphigus)
  695.15 Toxic epidermal necrolysis (epidermolysis)
  710.0 Systemic lupus erythematosus
  710.2 Sicca syndrome (Sjögren's disease)
  714.0-714.9 Rheumatoid arthritis
  757.39 Other specified anomalies of skin (epidermolysis bullosa)
  785.6 Enlargement of lymph nodes (multicentric Castleman's disease)
 

996.80-996.89

Complications of transplanted organ
  V42.0 Organ or tissue replaced by transplant; kidney
  V58.11-V58.12 Encounter for antineoplastic chemotherapy and immunotherapy
ICD-10 Diagnosis  B10.89 Other human herpes virus infection (Human herpes virus 8 infection)
  B17.10-B17.11 Acute hepatitis C
  B18.2 Chronic viral hepatitis C
  B19.20-B19.21 Unspecified viral hepatitis C
  B20 Human immunodeficiency virus (HIV) disease
  C46.0-C46.9 Kaposi's sarcoma
  C81.00-C81.99 Hodgkin lymphoma
  C82.00-C85.99 Follicular, non-follicular, mature T/NK-cell, and other specified and unspecified types of non-Hodgkin lymphoma
  C88.0 Waldenström macroglobulinemia
  C91.00-C91.92 Lymphoid leukemia
  D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
  D59.0-D59.1 Drug-induced, other autoimmune hemolytic anemias
  D68.311 Acquired hemophilia
  D69.3 Immune thrombocytopenic purpura (idiopathic thrombocytopenic purpura)
  D89.1 Cryoglobulinemia
  D89.810-D89.89 Other specified disorders involving the immune mechanism, not elsewhere classified (Graft-versus-host disease, ALPS)
  G36.0 Neuromyelitis optica (Devic)
  L10.0-L10.9 Pemphigus
  L12.0-L12.9 Pemphigoid (epidermolysis bullosa)
  M05.00-M05.9 Rheumatoid arthritis with rheumatoid factor
  M06.00-M06.09 Rheumatoid arthritis without rheumatoid factor
  M06.80-M06.9 Other specified rheumatoid arthritis and rheumatoid arthritis, unspecified
  M31.30-M31.31 Wegener's granulomatosis
  M31.7 Microscopic polyangiitis
  M32.0-M32.9 Systemic lupus erythematosus (SLE)
  M35.00-M35.09 Sicca syndrome (Sjögren)
  N01.0-N01.9 Rapidly progressive nephritic syndrome
  N04.0-N04.9 Nephrotic syndrome
  N06.0-N06.9 Isolated proteinuria with specified morphological lesion
  N08 Glomerular disorders in diseases classified elsewhere
  N18.1-N18.9 Chronic kidney disease (CKD)
  Q81.0-Q81.9 Epidermolysis bullosa
  R59.0-R59.9 Enlarged lymph nodes (multicentric Castleman's disease)
  T86.00-T86.99 Complications of transplanted organs and tissue
  Z48.22 Encounter for aftercare following kidney transplant
  Z51.11-Z51.12 Encounter for antineoplastic chemotherapy and immunotherapy
  Z94.0 Kidney transplant status

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

 "Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

04/11/2019 

Adding myasthenia and immune checkpoint inhibitor-related toxicities as investigational. 

01/07/2019 

Updating with 2019 codes 

04/02/2018 

Annual review, adding medical necessity criteria for central nervous system cancers (leptomeningeal metastases from lymphoma and primary CNS lymphoma. No other changes made. 

04/19/2017 

Annual review, no change to policy intent. 

04/27/2016 

Annual review, no change to policy intent. 

04/28/2015 

Annual review, no change to policy intent. Added coding.

4/1/2014

NEW POLICY


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