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.

NOTE: Please see the following related documents for additional information:

• RAD.00031 Radioimmunotherapy and Somatostatin Receptor Targeted Radiotherapy
• DRUG.00040 Abatacept (Orencia^®)

Medically Necessary:

I. Chronic lymphocytic leukemia (CLL)
Rituximab is considered medically necessary for the treatment of CD20+ CLL.

II. Hodgkin and non-Hodgkin lymphoma (NHL)
Rituximab is considered medically necessary for any of the following indications:

1. Treatment of CD20+ lymphoma (Hodgkin or non-Hodgkin)
2. Maintenance therapy of CD20+ follicular B-cell non-Hodgkin lymphoma for up to two (2) years;
3. Zevalin^® (Ibritumomab tiuxetan, Biogen Idec Inc., Cambridge, MA) regimen- as part of the Zevalin therapeutic regimen for NHL (Note: See RAD.00031 Radioimmunotherapy and Somatostatin Receptor Targeted Radiotherapy)

III.   Rheumatoid Arthritis
Rituximab is considered medically necessary in combination with methotrexate (MTX) unless intolerant or contraindicated, as a treatment for adults with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.

IV. 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.

V.  Other Off label Indications
Rituximab is considered medically necessary for individuals with any of the following conditions:

1. Autoimmune hemolytic anemia, refractory; or
2. Graft Versus Host Disease (GVHD)- as third line of therapy or greater; or
3. Hairy Cell Leukemia, CD20+; or
4. Multicentric Castleman's disease (MCD), CD20+; or
5. Neuromyelitis Optica (NMO); or
6. Pemphigus vulgaris and other autoimmune blistering skin diseases (e.g., pemphigus foliaceus, bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita and paraneoplastic pemphigus) when refractory; or
7. Posttransplant lymphoproliferative disease, CD20+; or
8. Renal transplant:
   1. Pre-transplant to suppress panel reactive anti-HLA antibodies in individuals with high panel reactive antibody (PRA) levels to human leukocyte antigens (HLA); or
   2. Post-transplant in individuals with acute rejection who had received rituximab treatment pre-transplant; or
9. Systemic Autoimmune Disorders (e.g., 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
10. Thrombocytopenic purpura, immune or idiopathic – refractory to steroids; or
11. Waldenström's Macroglobulinemia

Investigational and Not Medically Necessary:

Use of rituximab is considered investigational and not medically necessary when the above criteria are not met.

Use of rituximab is considered investigational and not medically necessary 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 (Section V-H)

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. (Product Information Label, 2011).

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) (NCI, 2010). 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], 2010). According to the NCI (2010), 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.

Rheumatoid arthritis

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), 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;
• 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 (Golbin, 2007). The authors 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" (Globin, 2007). Based on this concept, rituximab is being studied for various indications including rheumatic, inflammatory and autoimmune diseases.

The American College of Rheumatology (ACR) Task Force Panel (TFP, 2008) has developed treatment recommendations concerning the therapeutic indications for rituximab in the treatment of rheumatoid arthritis (RA). 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 product label also notes "while the efficacy of rituximab was supported by two well-controlled trials in RA patients who had inadequate response to non-biologic DMARDs, but who had not failed TNF antagonist therapy, a favorable risk benefit relationship has not been established in this population. The safety and efficacy data of the concomitant use of biologic agents or DMARDs other than methotrexate to treat patients with rheumatoid arthritis is limited" (Product Information Label, 2010). 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.

In an updated consensus statement from the 10^th Annual Workshop on Advances in Targeted Therapies, Furst and colleagues (2008) noted category A evidence 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% 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 

A Cochrane report (Schulz, 2007) described results from a meta-analysis of seven randomized controlled trials involving 1943 individuals with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas. Better overall survival rates were observed in individuals treated with combination rituximab and other chemotherapy agents (R-chemo) (hazard ratio [HR] for mortality 0.65; 95% confidence interval (CI) 0.54 to 0.78). An overall response (relative risk of tumor response 1.21; 95% CI 1.16 to 1.27), and disease control (HR of disease event 0.62; 95% 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% CI 0.51 to 0.79) and in individuals with mantle cell lymphoma (HR for mortality 0.60; 95% 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 1143 individuals in five trials that compared observation or treatment upon relapse, versus rituximab as maintenance therapy. Meta-analysis of overall survival (OS) data was available for 985 individuals. Overall survival 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% 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% CI = 0.42 to 0.79) compared to that (HR for death = 0.68, 95% CI = 0.37 to 1.25) for previously untreated individuals. However, infection-related adverse events were higher (HR = 1.99, 95% 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 3, 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 8 weeks. At a median followup of 36 months in both groups, 3-year PFS was significantly prolonged at 74.9% (95% confidence interval [CI] 70.9 – 78.9) in the treatment group compared to 57.6% (53.2 – 62.0) in the observation cohort (p<0.0001). 

Wegener's Granulomatosis (WG) and Microscopic Polyangiitis (MPA)

The FDA approved the combination of rituximab and glucocorticoids as a treatment for adults with WG and MPA in April, 2011. WG disorder and MPA are subgroups of primary systemic small vessel vasculitis associated with ANCA, 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 pivotal randomized, double-blind, double-dummy, noninferiority trial enrolled 197 ANCA-positive individuals with WG or MPA (Stone, 2010). For remission induction, participants received rituximab 375mg/m² per week for 4 weeks and placebo-cyclophosphamide in the treatment group. The control group received standard therapy with cyclophosphamide 2mg/kg per day plus placebo-rituximab infusions. Individuals in the treatment group who achieved remission between 3 and 6 months were switched from placebo-cyclophosphamide to placebo-azathioprine. Participants in the control group who had a remission between 3 and 6 months were switched from cyclophosphamide to azathioprine. Both groups received glucocorticoid treatment of one to three pulses of 1000mg methylprednisolone followed by prednisone 1mg/kg/day. The dose was tapered by 5 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 0 and successful prednisone taper at 6 months. There were 99 individuals randomized to the rituximab group, and 98 assigned to the control group. In each group, approximately 49% 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 6 months of treatment without early treatment failure was achieved in 84 individuals in the rituximab group (85%) and 81 participants in the control group (83%). The primary end point was reached in 64% of the treatment group and 53% 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%) compared to 21 of 50 participants (42%, P = 0.01) in the control group. Adverse events occurred in 33 participants in the control group (33%) compared to 22 individuals in the rituximab group (22%). 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.

Other Off-Label Indications:

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

Autoimmune Hemolytic Anemia (AIHA)

Autoimmune hemolytic anemia 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 autoimmune hemolytic anemia 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)

Graft versus host disease 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 that 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%, with 23% (3 individuals) achieving CR, 15% PR and 30% 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 7 individuals with refractory chronic GVHD (cGVHD) who were treated with weekly rituximab doses of 375 mg/m² over four weeks. At 1-year follow-up, the overall response rate was 43% with PR in 3 participants, SD in 3 individuals and 1 participant had PD. The median reduction of steroids was 67%. At a median follow-up of 30 months, 5 participants were alive and 2 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 2-year actuarial survival was 76% and the overall response rate was 65%. Steroid therapy was reduced by 82%. There were 8 deaths during the study period with 3 cases of progressive cGVHD, 1 relapsed disease, 3 cases of sepsis and 1 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, 6 studies met inclusion criteria for review, of which 3 studies were prospective and 3 were retrospective studies. There were no randomized controlled trials. There were a total of 108 individuals in the 6 trials. The authors were unable to analyze the heterogeneity of the responses. The data suggest rituximab is effective in treating cutaneous chronic GVHD (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 offlabel use of rituximab as third-line treatment or greater, for refractory GVHD is based on the data from uncontrolled trials and case series which 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.

Hairy Cell Leukemia

Hairy cell leukemia is a mature B-cell, chronic lymphoproliferative disorder for which 10% of the individuals will not require any type of therapy (NCI, 2011). Characteristics include the presence of a leukemic cell with "hairy" cytoplasmic projections, pancytopenia and bone marrow involvement, including fibrosis. Treatment includes nucleoside analogs (e.g., cladribine, pentostatin), interferon-alpha, or splenectomy, with reported 5-year survival rates of more than 85% (NCI, 2011). The NCI (2011) 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^®_, 2011) 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 CD20+ hairy cell leukemia.

Hodgkin Disease (Lymphoma)

Schulz and colleagues (2007) reported long-term outcomes from a phase 2 trial in 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. 94% of fifteen individuals achieved an overall response, which included 8 individuals with complete remission (CR) and 6 individuals with partial remission (PR). Median time to progression (TTP) was 33 months with the median OS not reached. One NLPHL and three cHL individuals have died since enrollment.

The National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guideline (CPG) (2011) 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. These recommendations were based on 2A category of evidence and uniform consensus. The peer-reviewed literature consists of case series and nonrandomized, uncontrolled trials. 

Multicentric Castleman's Disease, CD20+

Multicentric Castleman's disease (MCD) is an uncommon lymphoproliferative disorder which has been associated with human herpesvirus 8 (HHV-8) and Kaposi's sarcoma (KS) and may evolve towards 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 which 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% (95% confidence interval [CI], 71%-98%), EFS was 71% (95% CI, 48%-85%) and DFS was 77% (95% CI, 54% - 90%). Adverse events included exacerbation of KS lesions in eight of the twelve 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 1 – 49 months). One individual died before completion of the therapy regimen. Fourteen participants (67%) achieved radiologic response, and 20 individuals achieved remission of symptoms. At 2 years, the overall survival rate was 95% (95% CI, 86% - 100%) and the disease-free survival rate was 79% (CI, 52% - 100%) (Bowers, 2007).

NCCN CPG (2011) 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.

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). MRI 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 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 of 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/m² weekly for 4 weeks and 1000 mg infused twice, with a 2-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 median annualized pretreatment relapse rate was 1.7 relapses (range 0.5 – 5 relapses) and the median annualized posttreatment relapse rate was 0 (range 0 – 3.2 relapses, P <.001).

Because NMO is a rare, relapsing and debilitating disease, the offlabel use of rituximab as a treatment of NMO is based on the data from case series which demonstrated improvements in relapse rates. Specialty consensus opinion suggests the use of rituximab as treatment for NMO.

Nonimmunosuppresssed Primary Central Nervous System Lymphoma

Lymphoma limited to the cranial-spinal region without systemic disease is defined as primary central nervous system (CNS) lymphoma. According to the NCI (2009), 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 (2011) and NCCN (2011).

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 for individuals with refractory pemphigus vulgaris has been studied in open label, nonrandomized, uncontrolled case series. Joly and colleagues (2007) reported on 18 (86%) out of 21 individuals who achieved complete remission of severe, refractory pemphigus. 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^®_, 2010) notes rituximab is used off-label for the treatment of pemphigus vulgaris.

Posttransplant Lymphoproliferative Disorder 

Posttransplant lymphoproliferative disorder (PTLD) is a rare and life-threatening complication after organ transplantation. PTLD presents as a heterogenous 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 to 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% and a 5-year OS of 60%. 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% versus 21% (P < .0001) and OS 73% versus 33% (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 (Vo, 2010). 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% to 80% were transplanted 16% per year whereas PRA greater than 80% were transplanted less than 8% per year (Vo, 2010).

Vo and colleagues (2008) reported on 20 highly sensitized individuals treated between 2005 and 2007, with intravenous immune globulin (IVIG) and rituximab prior to kidney transplant. The phase 1-2 trial examined if the treatment protocol would improve transplantation rates with a reduction in the anti-HLA antibody levels. PRAs were "significantly reduced after treatment with IVIG and rituximab (77 ± 19% before the first infusion of IVIG, vs 44 ± 30% after the second infusion (P < 0.001)" (Vo, 2008). CD19+ cells were significantly reduced after rituximab treatment (mean percentage of total B cell lymphocytes, 6.12 ± 0.18 % prior to treatment, vs. 0.90 ± 0.02% after treatment, P< 0.001). Sixteen of the 20 participants received successful transplantation (6 received a deceased donor kidney; 10 received a living donor kidney). The remaining 4 participants have PRA levels greater than 50% and are awaiting a deceased donor kidney transplant. Mean follow-up was 22.1 ± 6 months with recipient and allograft survivals of 100% and 94%, respectively. One graft was lost due to severe rejection after a reduction of immunosuppressive therapy. Acute rejection occurred in 50% of the transplanted individuals. Acute antibody-mediated rejections (AMR) occurred in 31% of the episodes and 2 individuals had late (> 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, 5-27) prior to desensitization, but received transplants within 5 to 6 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% - 79% in 25% of individuals and 75% of the participants had PRA ≥ 80%. 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 % ± 35.6% versus post-treatment 67.1% ± 28.6% (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 4 months after receiving combination treatment with IVIG and rituximab. Acute rejection (AR) occurred in 37% of participants (8% cell mediated rejection (CMR) and 29% AMR). Nine individuals had graft losses, with AMR involved in 6 cases. Recipient and allograft survivals were 95% and 84%, respectively. The authors concluded, "IVIG and rituximab seems to offer significant benefits in reduction of anti-HLA antibodies allowing improved rates of transplantation for HS 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%, 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 6-months was 98.5% and death censored graft survival of 98%. Biopsy-proven acute rejections were not statistically significant with 11.6% in the rituximab group and 17.6% in the placebo cohort. The 3-year follow-up of this study population is ongoing (Tyden, 2009).

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% 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 a hematologic disorder typically presenting 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 10⁹ cells/L, was observed in 43.6% of individuals. An overall response, defined as platelet count greater than 50 x 10⁹ cells/L, was noted in 62.5% 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 American Hospital Formulary Service^® (AHFS^®_, 2011) notes that rituximab is used as an off-label treatment of ITP. 

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, 2009). 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 dexamathasone, 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% (95% confidence interval [CI], 73% - 91%) which included 7% complete responses (CRs), 67% partial responses (PRs), and 9% minimal responses (MR). The 2-year PFS rate for all participants was 67% and for individuals who responded to DRC, 80%. 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 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^® (2011) includes the use of rituximab either as a single agent or in combination regimens as first-line therapy for Waldenström's macroglobulinemia. The peer-reviewed literature consists of case series.

The NCCN Clinical Practice Guideline (2011) 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^®, 2011) notes that rituximab is used as an off-label treatment of Waldenström's macroglobulinemia.

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 which 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. 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 (Bomback, 2009). 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. 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 which precluded pooled data analysis. Complete remission in 15 to 20% and partial remission in 35 to 40% 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)

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). The 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 1000 rituximab given intravenously on days 1 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%] from the control group and 11 participants [15.9%] 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". Singh noted "although all published (AMR) protocols report a variable rate of success, a major weakness of all current protocols is the lack of effective anti-plasma cell agents".

The published peer reviewed literature regarding off-label use of rituximab as a treatment for transplant rejection includes case series, phase 1 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.

Hodgkin Disease (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 2011, the National Cancer Institute (NCI) estimated new cases of Hodgkin disease at 8,830 compared with 66,360 new cases of non-Hodgkin lymphoma in the United States. The NCI reports chemotherapy and radiation therapy may cure more than 75% of all newly diagnosed Hodgkin disease. 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 (NCI, 2011).

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 infection-fighting 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 (2011), 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 5 years is approximately 50% to 60%, and 30% to 60% of individuals with aggressive disease can be cured. The vast majority of relapses occur in the first 2 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, 2011).

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 fifties 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 

Rituximab has Black Box Warnings which include the following (Product Information Label, 2011):

• Fatal infusion reactions within 24 hours of rituximab infusion occur; approximately 80% of fatal reactions occurred with first infusion). Monitor patients and discontinue rituximab infusion for severe reactions
• Tumor lysis syndrome (TLS)
• Severe mucocutaneous reactions, some with fatal outcomes;
• Progressive Multifocal Leukoencephalopathy (PML) resulting in death.

Rituximab is not recommended for use in individuals with severe, active infections.

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

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.

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

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.

Tumor Necrosis Factor (TNF) antagonists: A class of drugs (including, but not limited to infliximab, etanercept, and adalimumab) designed to neutralize inflammatory cytokines.

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

When services may be Medically Necessary when criteria are met:

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

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Allen KJ, Wolverton SE. The efficacy and safety of rituximab in refractory pemphigus: a review of case reports. J Drugs Dermatol. 2007; 6(9):883-889.
2. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007; 146(1):25-33.
3. Bomback AS, Derebail VK, McGregor JG, et al. Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol. 2009; 4:734-744.
4. Bower M, Powles T, Williams S, et al. Brief communication: rituximab in HIV-associated multicentric Castleman Disease. Ann Intern Med. 2007; 147:836-839.
5. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005; 105:49-53.
6. Cree BA, Lamb S, Morgan K, et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005; 64(7):1270-1272.
7. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006; 108:756-762.
8. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007; 25(22):3344-3349.
9. Dimopoulos MA, Gertz MA, Kastritis, et al. Update on treatment recommendations from the Fourth International Workshop on Waldenström's Macroglobulinemia. J Clin Oncol. 2009; 27(1):120-126.
10. Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 2008; 148(2):124-134.
11. Edwards JCW, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004; 350(25):2572-2581.
12. Evens AM, David KA, Helenowski I, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. 2010; 28(6):1038-1046.
13. Furst DE, Keystone EC, Kirkham B, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases. Ann Rheum Dis. 2008; 67(Suppl III):iii2 – iii25.
14. Gerard L, Berezne A, Galicier L, et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus-associated multicentric Castleman's Disease: ANRS 117 CastlemaB Trial. J Clin Oncol. 2007; 25:3350-3356.
15. Golbin JM, Specks U. Targeting B lymphocytes as therapy for ANCA-associated vasculitis. Rheum Dis Clin N Am. 2007; 33:741-754.
16. Hauser SL, Waubant E, Arnold DL, et al., for the HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008; 358(7):676-688.
17. Hawker K, O'Connor P, Freedman MS, et al., for the OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis. Results of a randomized double-blind placebo-controlled multicenter trial. Annals of Neurol. 2009; 66(4):460-471.
18. Jacob A, Matiello M, Wingerchuk DM, et al. Neuromyelitis optica: changing concepts. J Neuroimmunology. 2007; 187:126-138.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. Mavragani CP, Moutsopoulos. Conventional therapy of Sjogren's Syndrome. Clin Rev Allerg Immunol. 2007; 32:284-291.
28. Mease PJ. B cell-targeted therapy in autoimmune disease: rationale, mechanisms, and clinical application. J Rheumatol. 2008;35(7):1245-1255. 
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. Sibilia J, Gottenberg JE, Mariette X. Rituximab: a new therapeutic alternative in rheumatoid arthritis. Joint Bone Spine 2008; 75:526-532.
36. 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. 
37. 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.
38. Teshima T, Nagafuji K, Henzan H, et al. Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease. Int J Hematol. 2009; 90:253-260.
39. 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.
40. 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.
41. 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.
42. Wong ET, Tishler R, Barron L, Wu JK. Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer. 2004; 1010(1):139-145.
43. 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.
44. 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.
45. 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.
46. 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.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. American College of Rheumatology. 2008 Recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis & Rheumatism (Arthritis Care & Research). 2008; 59(6):762–784.
2. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2011.
3. Falk RJ, Gross WL, Guillevin L, et al.; American College of Rheumatology; American Society of Nephrology; European League Against Rheumatism. Arthritis Rheum. 2011; 63(4):863-864.
4. Genentech, Inc.  Genentech and Biogen Idec announce top-line results from a phase II/III clinical trial of rituxan in primary-progressive multiple sclerosis. Press Releases. South San Francisco, CA: Genentech, Inc.; April 2008. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11147. Accessed October 2, 2011.
5. National Comprehensive Cancer Network^®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 12, 2011.
6. NCCN Clinical Practice Guidelines in Oncology™. © 2011 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 12, 2011.
   • Central Nervous System Cancers (V.2.2011). January 31, 2011.
   • Hodgkin Disease/Lymphoma (V.2.2011). May 4, 2011.
   • Multiple Myeloma (V.1.2012). July 26, 2011.
   • Non-Hodgkins Lymphoma (V.4.2011). August 24, 2011.
7. Rituxan [Product Information]. South San Francisco, CA. Genentech, Inc.; April 19, 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103705s5344lbl.pdf. Accessed on October 10, 2011.
8. Rituximab (systemic). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last Update August 23, 2011. Available at: http://www.thomsonhc.com. Accessed on October 10, 2011.
9. Schulz H, Bohlius J, Skoetz N, et al. Chemotherapy plus rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma. Cochrane Database Syst Rev. 2007;(4): CD003805.
10. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009; (4):CD007848.

1. National Cancer Institute (NCI). Available at: http://www.cancer.gov/cancertopics/alphalist. Accessed on November 17, 2010.

• Adult Hodgkin Lymphoma Treatment (PDQ^®). Last modified July 28, 2011.
• Adult Non-Hodgkin's Lymphoma Treatment (PDQ). Last modified July 28, 2011.
• Childhood Non-Hodgkin Lymphoma Treatment (PDQ) Last modified August 4, 2011.
• Chronic Lymphocytic Leukemia (PDQ). Last modified December 3, 2010.
• Hairy Cell Leukemia Treatment (PDQ). Last modified February 28, 2011.
• Multiple Myeloma and Other Plasma Cell Neoplasms Treatment (PDQ). Last modified January 28, 2011.
• Primary CNS Lymphoma Treatment (PDQ): Last modified September 1, 2011.

Monoclonal Antibody
Rituxan

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