1. Aetna considers rituximab (Rituxan) medically necessary for any of the following indications: 
   
   
   1. Non-Hodgkin's lymphoma; or
   2. Second-line treatment of persons with relapsed or refractory CD20 positive chronic lymphocytic leukemia: or 
   3. Relapsed or refractory hairy cell leukemia in persons who have failed at multiple (two or more) courses of cladribine; or
   4. Symptomatic persons with stage III-IV nodular lymphocyte-predominant Hodgkins disease who are refractory or intolerant to standard chemotherapy; or
   5. Treatment of refractory immune or idiopathic thrombocytopenic purpura; or
   6. Waldenström’s macroglobulinemia; or
   7. Refractory autoimmune hemolytic anemia; or
   8. Post-transplant lymphoproliferative disorder; or
   9. Multicentric Castleman's disease (angiofollicular lymph node hyperplasia); or  
   10. Corticosteroid-refractory pemphigus vulgaris or pemphigus foliaceus; or
   11. Prophylaxis of rejection in sensitized kidney transplant recipients with donor specific antibodies; or
   12. In combination with methotrexate to reduce signs and symptoms and to slow the progression of structural damage in adult patients with moderately-to severely- active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.

   The efficacy of more than two infusions in 48 weeks is unknown.

2. Aetna considers rituximab (Rituxan) experimental and investigational for all other indications because its effectiveness for these indications has not been established, including (not an all inclusive list): 

   1. Chronic inflammatory polyneuropathy/IgM-associated polyneuropathy
   2. Cryoglobulinemia
   3. Thrombotic thrombocytopenic purpura
   4. Segmental glomerulosclerosis
   5. Neuromyelitis optica
   6. Wegener's granulomatosis
   7. Systemic lupus erythematosus 
   8. Dermatomyositis
   9. Birdshot retinochoroidopathy
   10. Graft-versus-host disease
   11. Immune complex vasculitis
   12. Multiple sclerosis
   13. Polymyositis
   14. Sarcoidosis.

Non-Hodgkin's lymphoma (NHL) is a cancer of the lymphatic tissue causing enlargement of lymph nodes and generalized symptoms (Wake, et al., 2002).  It is a heterogeneous condition. Follicular lymphoma behaves in an indolent fashion, with a median survival of 8-12 years.  However, it is incurable and most patients with the disease will die from it.

According to the literature, management of NHL consists of intermittent treatment when the disease relapses and causes symptoms.  The aim is to maximize quality of life by inducing remission, abolishing the symptoms associated with relapse, with minimal treatment side-effects. Cancer-specific treatment is not usually instituted while the patient is asymptomatic ('watchful waiting').  According to available guidelines, first-line therapy of NHL is usually oral chlorambucil (or an equivalent alkylating agent).  Second-line treatment is usually an anthracycline-containing chemotherapy regime.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.  It is given as an intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).  Rituximab represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the adverse effects associated with chemotherapy.  A pivotal study (Linch, 2001) has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL.

Regarding the evidence of effectiveness of rituximab for relapsed or refractory NHL, a British National Health Service assessment reached the following conclusions (Wake, 2002): "The extent to which beneficial effects are outweighed by adverse events is impossible to quantify. Qualitatively, rituximab is probably effective. Any impression of a poor ratio of benefit to disbenefit should be tempered by the observation that incomplete response rates and severe adverse events are common to all currently used third-line treatments for follicular NHL. The absence of direct comparative data makes it very difficult to assess whether the ratio of benefits to disbenefits with rituximab is better, worse or the same as currently used alternatives."

The U.S. Pharmacopoeial Convention (2003) has concluded that rituximab (Rituxan) is accepted for the following off-label indications: a) as first-line treatment of diffuse aggressive NHL; b) treatment of relapsed or refractory diffuse aggressive NHL; c) first-line treatment of intermediate to high-grade NHL; and d) first-line treatment of low-grade NHL.

The U.S. Pharmacopoeial Convention (2002) has concluded that rituximab is also effective for second-line treatment of patients with relapsed or refractory CD20 positive chronic lymphocytic leukemia (CLL). Chronic lymphocytic leukaemia is essentially the bloodstream form of non-Hodgkin's lymphoma, and is the most common type of leukemia.  The disease usually progresses slowly and many people with chronic lymphocytic leukemia do not need treatment for months or years.  Chronic lymphocytic leukemia mainly affects older people and is rare in people under age 40.

Published evidence from Phase I and Phase II trials have shown that rituximab has activity against CLL with acceptable toxicity.  Perry and Rasool (2001) stated that "[t]herapy with monoclonal antibodies has been evaluated in patients with CLL.  The most useful agent in clinical trials so far appears to be CAMPATH-1H, an antibody directed at CD52. Rituxan (rituximab) also is effective as a second-line or third-line treatment and may assume a more prominent role in the future."  The National Cancer Institute's PDQ on Chronic Lymphocytic Leukemia (January 2002) states that "CAMPATH- 1H and rituximab (monoclonal antibodies) are under clinical evaluation. Higher doses of rituximab than those used for other non- Hodgkin lymphomas are required."

An April 2001 Cancer Care Ontario Evidence Review of rituximab, however, concluded that "[t]he response rates reported for CLL/SLL continue to be lower than for other histologies and appear lower than those reported for other agents used in this disease."  A Toronto Regional Cancer Centre Guideline for CLL (2001) states that "When used in routine doses/scheduling, the chimeric anti-CD20 monoclonal antibody rituximab has been disappointing in the management of CLL."

Guidelines from the National Comprehensive Cancer Network (NCCN, 2006) state that rituximab is an option to induce lymphocyte depletion in selected symptomatic persons with stage III-IV nodular lymphocyte-predominant Hodgkin's disease (HD) who are not candidates for chemotherapy or observation. This was an NCCN category 2b recommendation, defined as "nonuniform NCCN consensus (but no major disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate". There are several published phase II studies of rituximab for lymphocyte predominance Hodgkin's disease (LPHD) (Younes, et al., 2003; Ekstrand, et al., 2003; Rehwald, et al., 2003). Additional studies of rituximab for LPHD are currently ongoing.

Younes, et al. (2003) examined the potential role of infiltrating benign B cells in classic HD lesions in supporting the survival of malignant Hodgkin and Reed-Sternberg (H/RS) cells. The authors initiated a pilot study of rituximab, which is used to primarily deplete normal B cells from HD lesions. Patients with recurrent, classic HD who had received a minimum of two prior treatment regimens, regardless of whether H/RS cells expressed CD20, were treated with 6 weekly doses of 375 mg/m2 rituximab to selectively deplete infiltrating benign B cells. Objective tumor response was determined 3 weeks after completion of the last dose of rituximab and every 3 months thereafter.  Serum samples were collected from patients before they started rituximab therapy and 3 weeks after the final course of rituximab. Serum cytokine levels of interleukin 6 (IL-6), IL-10, IL-12, IL-13, and interferon gamma were determined using commercially available enzyme-linked immunosorbent assay kits.  Twenty-two patients with nodular sclerosis histology were evaluable for treatment response.  Five patients (22%) achieved partial or complete remission that lasted for a median of 7.8 months (range, 3.3-14.9 months).  Remissions were observed in patients only at lymph node and splenic sites, but not at extra-nodal sites, and were irrespective of CD20 expression by H/RS cells.  Furthermore, systemic (B) symptoms resolved in 6 of 7 patients after therapy.  In two patients, partial remissions were associated with a decline in serum IL-6 levels.  The authors concluded that current data suggest that rituximab therapy in patients with recurrent, classic HD can alter serum IL-6 cytokine levels, can improve B symptoms, and may result in clinical remissions.

Ekstrand, et al. (2003) stated that LPHD is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy.  The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy.  In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2.  Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease.  All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%).  Acute treatment-related adverse events were minimal.  With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months.  Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL).  All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2.  Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in the trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD.  Further clinical trials are needed to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.

In a phase 2 study, Rehwald, et al. (2003) evaluated the safety and efficacy of rituximab in patients with relapsed LPHD or other CD20(+) subtypes of Hodgkin disease (HD).  Eligibility criteria required expression of the CD20 antigen on more than 30% of malignant cells. Fourteen patients were treated with 4 weekly intravenous infusions of rituximab (375 mg/m2). All patients had at least one prior chemotherapy (median, 2).  The median time from first diagnosis was 9 years. Adverse events, such as rhinitis, fever, chills, and nausea, were usually transient and of mild to moderate grade, allowing outpatient treatment in most cases.  All patients completed treatment and were eligible for a response.  The overall response in 14 assessable patients was 86%, with 8 complete remissions and 4 partial remissions, and 2 patients with progressive disease. At a median follow-up of 12 months, 9 of 12 responders were in remission. The median duration of response has not been reached yet (20+ months). The authors concluded that rituximab is both safe and effective in a subgroup of CD20(+) patients with HD.

The U.S. Pharmacopoeial Convention has concluded that rituximab is indicated for treatment of Waldenström’s macroglobulinemia. Dimopolous, et al. (2002) reported on 27 patients with symptomatic Waldenström’s macroglobulinemia who were treated with rituximab.  Twelve patients (44%; 95% confidence interval, 25.5% to 64.7%) achieved a partial response after treatment with rituximab. Median time to response was 3.3 months (range, 2.2 to 7.1 months).  The median time to progression for all patients was 16 months, and with a median follow-up of 15.7 months, nine of 12 responding patients remain free of progression.  The investigators reported that approximately one fourth of patients experienced some mild form of infusion-related toxicity, usually fever and chills.  The U.S. Pharmacopoeial Convention has also concluded that rituximab is indicated for treatment of idiopathic thrombocytopenic purpura. This conclusion is based on the results of several single-institution cohort studies that have reported on response rates exceeding 50%, and only minor adverse events.  Stasi, et al. (2001) stated that "[I]n view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted." 

Rituximab may be considered for persons with relapsed or refractory hairy cell leukemia who have failed at least two courses of cladribine. The National Cancer Institute information on hairy cell leukemia (NCI, 2007) states that rituximab can be used for relapsed or refractory hairy cell leukemia after failure of purine analog therapy (i.e., cladribine). "Rituximab can induce durable complete remissions with minimal toxic effects in the majority of patients with relapsing or refractory disease after purine analog therapy. The lack of subsequent immunosuppression with rituximab has made this treatment the first choice among relapsing patients in the absence of a clinical trial." The largest clinical trial of rituximab for hairy cell leukemia reported to date (Nieva, et al., 2003) reported that rituximab "has only modest single-agent activity in cladribine-failed HCL patients when compared with other agents active in this disease."

Rituximab has been investigated for use in a number of other indications, including thrombotic thrombocytopenic purpura, cryoglobulinemia, chronic inflammatory polyneuropathy, multiple myeloma, idiopathic autoimmune hemolytic anemia, and rheumatoid arthritis.

Rituximab has been investigated for use in thrombotic thrombocytopenic purpura.  However, current evidence is limited to case reports and small case series (Yomtovian, et al., 2004).

A number of reports have indicated the usefulness of rituximab in the treatment of subjects with warm agglutinin autoimmune hemolytic anemia not responding to conventional treatment including corticosteroids and splenectomy (Zecca, et al., 2001; D'Arena, et al., 2006; Gupta, et al., 2002; Shanafelt, et al., 2003; Mantadakis, et al., 2004) and to cold agglutinin disease not responding to conventional treatments (Schollkopf, et al., 2006; Berentsen, et al., 2004).

Rituximab has also been investigated in the treatment of cryoglobulinemia (see, e.g., Zaja, et al., 2003; Sansonno, et al., 2003; Arzoo, et al., 2002; Baronciani, et al., 2002).  However, controlled studies are needed to better define the value of rituximab for this indication (Zaja, et al., 2003).  Consensus Panel Recommendations from the Second International Workshop on Waldenström’s Macroglobulinemia (Gertz, et al., 2003) did not list rituximab among effective interventions for symptomatic mixed cryoglobulinemia (MC).

A recently published Cochrane systematic evidence review (Hughes, et al., 2003) concluded that there is inadequate evidence of the effectiveness of rituximab in the treatment of chronic inflammatory polyneuropathy. 

An uncontrolled, 3-month study of rituximab in 19 subjects with multiple myeloma has shown promising results in a subgroup of subjects who expressed CD20 on their bone marrow plasma cells (Treon, et al., 2002).

Edwards, et al. (2004) reported on the results of an multicenter randomized controlled clinical trial of rituximab in rheumatoid arthritis, which found that a single course of two infusions of rituximab alone or in combination provided significant improvement in disease symptoms for 48 weeks..   The investigators randomly assigned 161 adults who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate ; rituximab; rituximab plus cyclophosphamide; or rituximab plus methotrexate.  Eligible patients had active disease despite treatment with at least 10 mg of methotrexate per week. Active disease was defined by the presence of at least eight swollen and eight tender joints and at least two of the following: a serum C-reactive protein level of at least 15 mg per liter, an erythrocyte sedimentation rate of at least 28 mm per hour, or morning stiffness lasting longer than 45 minutes.  In addition, eligible patients were seropositive for rheumatoid factor. At 24 weeks, the proportion of patients with 50% improvement in disease symptoms according to ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43%, p = 0.005) and the rituximab-cyclophosphamide combination (41%, p = 0.005) than with methotrexate alone (13%). In all groups treated with rituximab, a significantly higher proportion of patients had a 20% improvement in disease symptoms according to the ACR criteria (65 to 76% versus. 38%, p < 0.025) or had EULAR responses (83 to 85% versus 50%, p < 0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group.  The investigators reported that the majority of adverse events occurred with the first rituximab infusion.  At 24 weeks, serious infections occurred in one patient (2.5%) in the control group and in four patients (3.3%) in the rituximab groups.  Peripheral-blood immunoglobulin concentrations remained within normal ranges.  The investigators concluded that in patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in diseases symptoms at both 24 and 48 weeks.

In an open label study, Cree, et al. (2005) reported their findings of 8 patients with worsening neuromyelitis optica who were treated with rituximab.  Treatment was well tolerated.  Six of eight patients were relapse free and median attack rate declined from 2.6 attacks/patient/year to 0 attacks/patient/year (p = 0.0078).  Seven of 8 patients experienced substantial recovery of neurological function over 1 year of average follow-up.  The pre-treatment median Expanded Disability Status Scale score was 7.5, and at follow-up examination was 5.5 (p = 0.013).  These investigators noted that the apparently robust effects of rituximab deserve further investigation through controlled trials.

In a case series report, Eriksson and colleagues (2005) reported their findings of 2 women with myeloperoxidase-ANCA-positive microscopic polyangiitis and 7 patients (5 men and 2 women) with proteinase 3-ANCA-positive Wegener's granulomatosis.  All patients were resistant to conventional therapy or had relapsed repeatedly after cessation of cyclophosphamide (Cyc).  The cases were treated with intravenous infusions of rituximab once a week 2 times (3 cases) or 4 times (6 cases).  To prevent formation of antibodies to rituximab, mycophenolate mofetil (5 patients), azathioprine (1 patient), or a short course of Cyc (2 patients) were added or allowed to continue.  Main outcome measures were remission at 6 months assessed with Birmingham vasculitis activity score.  The cases were followed 6 to 24 months and relapse rate was also noted.  Eight of 9 patients responded completely and 1 case responded partially.  Pulmonary X-ray improved (4 cases), progress of lower extremity gangrene stopped (1 case), remission of neuropathy was stable (1 patient), renal vasculitis went into remission (2 cases), and severe musculoskeletal pain improved (1 case).  Minor relapse in the nose occurred in 2 cases.  No adverse events or major infections were noted.  These investigators concluded that rituximab seems promising and safe in ANCA-positive vasculitis, and controlled studies should be conducted.

In an open-label uncontrolled pilot study (n = 7), Levine (2005) reported their findings of 7 adult patients with dermatomyositis (DM), 6 of whom had longstanding illness that was responding inadequately to a number of currently available immunosuppressive agents.  All patients received 4 intravenous infusions of rituximab given at weekly intervals.  Patients were followed up for up to 1 year without further treatment with rituximab.  One patient was lost to follow-up.  The principal effectiveness outcome was muscle strength, measured by quantitative dynomometry.  All 6 evaluable patients exhibited major clinical improvement, with muscle strength increasing over baseline by 36 to 113 %.  Maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab.  CD20+ B cells were effectively depleted in all patients by 12 weeks.  Four patients experienced a return of symptoms that coincided with the return of B cells before the 52-week end point.  Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells.  Other symptoms of DM (e.g., rash, alopecia, and reduced forced vital capacity) improved markedly in patients with these symptoms.  Rituximab was well-tolerated, with no treatment-related severe or serious adverse events during the observation period of this study.  The authors concluded that the results of this small open-label study of DM patients treated with rituximab provided sufficiently encouraging results to justify a more formal evaluation of the value of B cell depletion therapy in the treatment of DM.  Furthermore, in a review on "B cell-targeted therapy in diseases other than rheumatoid arthritis", Looney (2005) stated that "depletion of B cells during rituximab therapy was associated with improvement in global disease activity …. further controlled studies are warranted to optimize rituximab as monotherapy and to develop combination therapies in patients with refractory autoimmune diseases".

In an open-label study, Mok and colleagues (2007) reported the effectiveness and toxicity of rituximab in the treatment of refractory polymyositis. Adult patients with active polymyositis as evidenced by persistent proximal muscle weakness, elevated creatine kinase (CK) level, and features of active myositis on electromyography who were refractory to corticosteroids and at least 2 other immunosuppressive agents were recruited. While immunosuppressive agents were continued, rituximab (375 mg/m2) was given by intravenous infusion weekly for 4 consecutive weeks. Patients were followed-up 4-weekly for serial assessment of muscle power, serum muscle enzymes, physician's and patient's global impression of disease activity, disability, and quality of life scores. Four patients (3 women, 1 man) were studied. The mean age was 53 +/- 11 years and the mean duration of polymyositis was 4.8 +/- 3.3 years. All had persistently active myositis for at least 2 years. At Week 28, significant improvement in the mean proximal muscle power scores and reduction in CK levels in comparison to baseline were observed. Two patients had return of full muscle power with significant drop in CK level. There was a trend of improvement in disability scores as well as both the mental and physical components of the Medical Outcomes Study Short Form-36 Health Survey scores. Rituximab was well-tolerated. The authors concluded that rituximab is an option to be considered in refractory polymyositis, however, further controlled trials are needed to confirm its effectiveness.

There is evidence for the effectiveness of rituximab for post-transplant lymphoproliferative disorders (PTLD) (Cincinatti Hospital Children's Medical Center, 2003). PTLD is a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Oertel, et al. (2005) reported on the results of a multicenter phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m(2) of rituximab. The mean follow-up time was 24.2 months. The investigators reported that rituximab therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living at the time of the report. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. The investigators concluded that rituximab proved to be well tolerated and effective in the treatment of PTLD.

There is emerging evidence for the effectiveness of rituximab in Castleman's disease (CD). Two clinical classifications of CD have been described: unicentric (unifocal or localized) and multicentric (multifocal or generalized) (Dispenzieri & Gertz, 2005). The unicentric presentation responds well to surgical resection and is associated with a benign course. The multicentric presentation requires systemic therapy and prognosis is guarded. Associated systemic symptoms are common. There is an increased incidence of CD in patients with HIV. The human herpes virus-8 is associated with nearly all of the HIV-associated CD cases and nearly 50% of non-HIV cases. Interleukin (IL)-6 has also been shown to play a significant role in the pathogenesis of the disease. Paraneoplastic and autoimmune entities are not uncommon in the disorder. Variable benefit has been achieved with rituximab (Dispenzieri & Gertz, 2005; Ide, et al., 2006; Casquero, et al., 2006; Marcelin, et al., 2003). Patients with CD are at increased risk for developing frank malignant lymphoma.

Joly, et al. (2007) found that a single cycle of rituximab is an effective treatment for pemphigus vulgaris of pemphigus foliaceus. The investigators  studied 21 patients with pemphigus vulgaris or pemphigus foliaceus whose disease had not responded to an 8-week course of 1.5 mg of prednisone per kilogram of body weight per day (corticosteroid-refractory disease), who had had at least two relapses despite doses of prednisone higher than 20 mg per day (corticosteroid-dependent disease), or who had severe contraindications to corticosteroids. Patients were treated with four weekly infusions of 375 mg of rituximab per square meter of body-surface area. Eighteen of 21 patients had a complete remission at 3 months after the end of treatment. In 8 of the 18 patients, this remission was maintained without corticosteroid or immunosuppressive therapy after a median follow-up of almost 3 years. One patient developed pyelonephritis and another died of septicemia. The investigators concluded that a single cycle of rituximab is an effective treatment for pemphigus (Joly, et al., 2007). The investigators warned that, because of its potentially severe side effects, its use should be limited to the most severe types of the disease. An editorialist noted that this study demonstrated the value of a multicenter approach to accomplish relevant clinical research in orphan diseases such as pemphigus (Diaz, 2007).

Ahmed and Wong (2007) noted that mixed cryoglobulinemia (CG) is a systemic immune complex-mediated disease that involves small-to-medium vessel vasculitis, provoked by the CG containing immune complexes that precipitate in cold. It is associated with hepatitis C virus (HCV) infection in 80 % of patients. Mixed CG-mediated vasculitis can affect the kidney, liver and heart.  Laboratory parameters show presence of cryoglobulin, and in most cases of mixed CG, rheumatoid factor IgM kappa. The current treatment strategy of HCV-associated CG includes targeting the viral trigger HCV with a combination of anti-viral medication, interferon-alpha and ribavirin, or the downstream pathogenic events by means of plasmapheresis, steroids or immunosuppression.  With multi-organ involvement, the anti-viral therapy may be limited due to severity of renal disease, treatment failure, side effects or contraindications.  On the other hand, immunosuppressive therapy may be poorly tolerated or ineffective.  Thus, new treatment options such as rituximab have been proposed as a rescue therapy. These researchers reviewed the literature to evaluate the current evidence in treating HCV-related refractory mixed CG.  There have been many published case series and case reports on the use of rituximab in the treatment of HCV-related CG. However, there has been no randomized controlled trial. In the literature, there have been 60 patients with CG treated with rituximab. The male to female ratio was 14:46. A total of 53 patients were HCV-positive; 46 had mixed type II CG, 7 had type III CG, and for 7 the type was not specified.  Twenty-five patients had renal involvement ranging from proteinuria, to nephrotic syndrome, to nephritic syndrome, to chronic kidney disease.  Eight patients had had a renal transplant and were on immunosuppression. Most patients responded to rituximab, with only 17 of 60 patients relapsing, and 8 of 17 of those were re-challenged with rituximab with a good response. Total follow-up period varied between 3 and 31 months. The authors concluded that rituximab is a suitable rescue therapy in refractory CG associated with HCV.  There is evidence supporting the use of rituximab as first-line therapy, as opposed to the proposals of others who would strongly recommend anti-viral therapy.  However, a prospective, randomized, controlled trial is needed to assess the safety and effectiveness of rituximab compared with current standard therapy, which includes anti-viral therapy, immunosuppression, as well as plasmapheresis.

In a phase II, double-blind, 48-week clinical trial involving 104 patients with relapsing–remitting multiple sclerosis, Hauser, et al. (2008) assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24.  Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse. As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (p < 0.001) and of total new gadolinium-enhancing lesions over the same period (p < 0.001); and these results were sustained for 48 weeks (p < 0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% versus 34.3%, p = 0.02) and week 48 (20.3% versus 40.0%, p = 0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups. The authors concluded that a single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. However, the authors noted that this phase II study was not designed to evaluate long-term safety or to detect uncommon adverse events. They stated that the safety and effectiveness of rituximab for the treatment of multiple sclerosis need to be validated by larger and longer-term controlled studies.  MacFarland (2008) noted that a phase II clinical trial leaves many questions unanswered including the duration of the treatment effect, the effect of progression of disability, and most importantly the types of adverse events that may occur at low frequency. Issues of long-term safety of rituximab must still be addressed, given reports to the FDA of progressive multifocal leukoencephalopathy in patients with lupus who were treated with rituximab.

Genentech, Inc. (South San Francisco, CA) reported that a Phase II/III randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy, safety and tolerability of four courses of rituximab for primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period. A total of 439 patients were randomized 2:1 to receive either four treatment courses of rituximab 6 months apart or placebo.  MRI evaluations were conducted at baseline, weeks 6, 48, 96 and 122. The incidence of overall adverse events was comparable between rituximab and placebo treatment groups. Serious adverse events were 16.4% in the rituximab arm versus 13.6% in the placebo arm, with an incidence of serious infections of 4.5% compared with < 1.0% respectively.  Infectious events (10%) reported in either group included upper respiratory and urinary tract infections.  Most infectious events in the rituximab arm were reported as mild to moderate in severity, though events of greater severity were reported more frequently in patients receiving rituximab. There were more infusion-related reactions with rituximab, the majority of which were mild to moderate in severity (Genentech, 2008).

The largest published study of rituximab for SLE (Ng, et al., 2007) examined its efficacy in combination with cyclophosphamide and glucocorticoids in 90 patients with systemic lupus erythematosus refractory to conventional treatment.  Following rituximab infusion patients were followed for from 3 to 40 months; a "meaningful" decrease in disease activity was noted in 80%, infusions were well tolerated in 90% of patients, but adverse events (ascribed to hypersensitivity to the chimeric antibody) occurred in 10%.

In December 2006, the FDA learned that two patients who were treated with rituximab for systemic lupus erythematosus developed progressive multifocal leukoencephalopathy (PML), a fatal viral infection of the central nervous system (FDA, 2007). This side effect has been reported in patients as late as 12 months after their last dose of rituximab. The FDA stated that SLE is not an approved indication for rituximab. A black box warning was added to the labeling of rituximab stating that JC virus infection resulting in PML and death has been reported in patients treated with rituximab. 

Genentech, Inc. reported that the EXPLORER study, a phase II/III randomized, double-blind, placebo-controlled, multi-center study of rituximab for SLE, did not meet its primary endpoint defined as the proportion of rituximab treated patients who achieved a major clinical response or partial clinical response measured by BILAG, a lupus activity response index, compared to placebo at 52 weeks.  A total of 257 patients were randomized 2:1 to receive rituximab plus prednisone or placebo plus prednisone in two infusions 15 days apart. Patients were retreated 6 months later with the same regimen. Patients were evaluated for efficacy every four weeks for 52 weeks. The majority of patients are being monitored to week 78.  The study also did not meet any of the six secondary endpoints, including: time adjusted area-under-the-curve minus baseline of BILAG score over 52 weeks; proportion of patients who achieve a major clinical response, and proportion of patients who achieve a partial clinical response (including major clinical response) at week 52; proportion of patients who achieve BILAG C or better in all domains at week 24; time to moderate or severe flare over 52 weeks; change in SLE Expanded Health Survey physical function score from baseline at week 52; and proportion of subjects who achieve a major clinical response with 10 mg prednisone per day from weeks 24 to 52 (Genentech, 2008).

The LUNAR study, an ongoing placebo-controlled phase III trial, is evaluating rituximab in patients with active lupus nephritis.  Results of this study are not expected until sometime in 2009.

The FDA-approved labeling for Rituxan includes black box warnings about fatal infusion reactions with rituximab. The labeling states that rituximab administration can result in serious, including fatal reactions, and that deaths within 24 hours of infusion have occurred. The labeling states that approximately 80% of fatal infusion reactions occurred in association with the first infusion. The labeling states that patients should be carefully monitored during infusion, and that rituximab infusions should be discontinued and medical treatment provided for grade 3 or 4 infusion reactions.

The FDA-approved labeling for Rituxan also includes a black box warning about tumor lysis syndrome (TLS). The labeling states that acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) patients with rituximab.

The labeling also includes black box warnings about severe, including fatal, mucocutaneous reactions in patients receiving rituximab treatment. The labeling warns that JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death has been reported in patients treated with rituximab.

Appendix

According to the FDA-approved labeling for Rituxan, rituximab for rheumatoid arthritis is given as two-1000 mg IV infusions separated by 2 weeks. The labeling states that additional courses of treatment should not occur more frequently than every 16-24 weeks. Glucocorticoids administered as methylprednisolone 100 mg IV or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions.