Rituxan received U. S. Food and Drug Administration (FDA) approval on November 26, 1997 for the treatment of non-Hodgkin’s lymphoma (NHL) based on three pivotal trials. In data pooled from four studies looking at treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL, the overall response rate was an average of 45%, and complete response rate was an average of 8.3%. In three studies looking at rituximab as first-line treatment in patients with diffuse large B-cell, CD20-positive, haloperidol decanoate (HLD) in combination with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or other anthracycline-based chemotherapy regimens, the median progression-free or event-free survival was three years and the overall two year survival was an average of 79%.
In the main clinical study of 166 patients with advanced low-grade or slow-growing NHL, tumors shrunk by at least one-half in 48 percent of the patients who completed the treatment with 6 % having complete remissions. All of these patients had received at least one other form of chemotherapy before the clinical trial. The positive results have been long-lasting, with half of the patients who responded staying in remission for more than 11 months.
On February 10, 2006, the FDA granted approval to rituximab for use in the first-line treatment of patients with diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. The approval was based on efficacy and safety data from three randomized, controlled, multicenter studies of Rituxan in combination with CHOP or other anthracycline-based chemotherapy induction regimens in 1,854 previously untreated (first-line) patients with diffuse large B-cell lymphoma (DLBCL). In each study, hazard ratios for the time-to-event comparison, as well as the overall survival benefit, favored the Rituxan-containing arms. Results were generally consistent across subgroups, including age, gender and disease prognostic variables. With two years of follow-up, more patients were alive in the Rituxan-containing versus control arms for each study. In one of the studies with five years of follow-up, the GELA trial, R-CHOP improved overall survival by 47 percent compared to CHOP alone (a hazard ratio of 0.68, which is equivalent to a 32 percent decrease in the risk of death).
On September 29, 2006, the FDA granted approval to rituximab for use in the first-line treatment of patients with low grade or follicular B-cell, CD20-positive non-Hodgkin’s lymphoma. One approval was for the use of rituximab combined with CVP chemotherapy; the second is for use of rituximab following CVP chemotherapy. The FDA approval of Rituxan as a first-line treatment in previously-untreated patients with follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy is based on data from a Phase III, randomized, controlled study of 322 patients. The study evaluated the first-line use of Rituxan in combination with CVP chemotherapy (R-CVP) versus CVP chemotherapy alone. All patients received up to eight three-week cycles of CVP chemotherapy. Patients in the R-CVP arm received Rituxan 375 mg/m on Day 1 of each treatment cycle. The FDA approval of Rituxan for the treatment of low-grade, CD20-positive, B-cell NHL in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy, is based on a Phase III, randomized, controlled Eastern Cooperative Oncology Group study of 322 patients. Study participants received Rituxan 375 mg/² given in four weekly infusions, every six months for up to 16 doses, or observation. Rituxan reduced the risk of disease progression, relapse or death by more than 50 percent over observation (hazard ratio estimate in the range of 0.36 - 0.49).
Autoimmune Hemolytic Anemia
Evidence favors efficacy. Responses to rituximab have occurred in small, open-label single-arm clinical trials in adult and pediatric patients with either previously untreated or refractory, varied types of severe autoimmune hemolytic anemia (AIHA). Rituximab was effective in the treatment of AIHA reported in a case series of four infants failing first line steroid therapy. Small, open-label, single-arm, published clinical trials have resulted in responses to rituximab in adult patients with either previously untreated or refractory, idiopathic or secondary, cold agglutinin AIHA or AIHA of chronic lymphoid leukemia (CLL) and in refractory AIHA with various associated features in pediatric patients. Additional small, open-label, single-arm, unpublished clinical trials have resulted in responses in adult patients with warm agglutinin AIHA. An unpublished summary of case reports in adult patients with a variety of types of AIHA reported a response rate of 72% in 92 patients.
Combination Bendamustine, Mitoxantrone, and Rituximab therapy elicited a high response (95%) in a cohort of lymphoma patients in which 18 of 20 had stage IV disease. Monotherapy with rituximab showed moderate activity in mantle-cell lymphoma and immunocytoma but only limited activity in small B-cell lymphocytic lymphoma in a single phase II study (n=120). An overall response rate of 65% (27% complete response) was noted in patients with indolent non- Hodgkin's lymphoma (n=62).
Chronic lymphoid leukemia (CLL)
Rituximab has demonstrated activity in combination with fludarabine, and with fludarabine and cyclophosphamide (FC) in the first line treatment of CLL. The current NCCN guidelines list purine analog +/- rituximab as a treatment option in patients with CLL.
Two international phase III studies presented December 2008 at the American Society of Hematology meeting in San Francisco demonstrated that advanced CLL patients who received Rituxan in addition to standard chemotherapy with FC had outcomes far better than those patients who received FC alone. The first study included 817 previously untreated advanced CLL patients whose mean age was 61 years. They were randomized to receive six 28-day courses of either FC or Fludarabine, Cyclophosphamide and Rituximab (FCR) group . After a median follow up of 25.5 months, the complete response rate in the FCR group was 52 %, compared with 27% in the fludarabine-cyclophosphamide (FC) group. Progression-free survival was also higher in the Fludarabine, Cyclophosphamide and Rituximab (FCR) group, with 76.6 % progression-free after two years versus 62.3 % in the FC arm. In the second study, 552 patients (mean age 63 years) with relapsed or refractory CLL were randomized to receive six 28-day courses of FC or FCR. Most of these patients had previously been treated with single-agent alkylator therapy, a purine analog therapy, or combination chemotherapy. Those in the FCR group had a median of 30.6 months without disease progression, compared with 20.6 months in the FC group. Complete response in the FCR group was nearly twice that of the FC group, 24% versus 13%. While the overall response with rituximab was better in both studies, negative side effects were more common in the patients who received the drug, including diminished leukocytes and neutrophils. The incidence of these side effects was associated with age, sex, renal function, and the patient's relative health. "While these studies clearly indicate that rituximab improves both response and progression-free survival when combined with FC, they do not address whether the addition of cyclophosphamide to fludarabine should become the standard chemotherapy platform for the treatment of CLL," cautioned Dr. Wyndham Wilson, head of the Lymphoma Therapeutics Section in the National Cancer Institute's Center for Cancer Research. "The increased toxicity associated with cyclophosphamide requires that physicians weigh the risks and benefits of FCR versus RF."
Evans syndrome, refractory to immunosuppressive therapy
Rituximab appears to effectively treat pediatric patients with refractory Evans syndrome based upon small, prospective, single-arm trials and case reports. Rituximab significantly improved platelet count in pediatric patients with severe immune thrombocytopenia purpura (ITP) (n=30) or Evans syndrome (n=6) in a prospective, open-label, single-arm trial. Rituximab was effective in treating refractory autoimmune hemolytic anemia (AIHA) in children with Evans syndrome (n=5) based upon a prospective, open-label, single-arm clinical trial. Rituximab was associated with remission of refractory Evans syndrome in a 3.5 year old male with vitiligo based upon a brief case report.
Chronic Graft Versus Host Disease (CGVHD)
The use of rituximab in the treatment of refractory CGVHD has been documented in multiple case series with mixed results. In one case series, eight patients with extensive CGVHD were treated with the standard course of rituximab. Four of these patients (50%) responded to rituximab therapy whereas the other four patients (50%) were nonresponders. In the largest series of 21 patients with steroid-refractory CGHVD, the overall response was 70% and included two patients who experienced a complete remission. In these patients, rituximab facilitated a statistically significant reduction in the median dose of steroid use from 40mg/day to 10mg/day (p<0.001). A steroid-sparing effect was therefore demonstrated in patients with CGVHD. Effective for cutaneous and musculoskeletal graft-versus-host disease (GVHD) in a phase I/II study.
Hodgkin’s disease, CD20-positive, as a monotherapy
In a phase 2, open-label study, patients (n=22) with lymphocyte-predominant Hodgkin disease (LPHD) treated with rituximab had an overall response rate (ORR) of 100%; although, the median freedom from progression in these patients was only 10.2 months. In a multicenter, phase 2, open-label study (n=14), patients with CD20-positive (CD20+), relapsed or progressive Hodgkin lymphoma treated with rituximab had an overall response rate (ORR) of 86%.
Pemphigus Vulgaris (PV)
A single cycle of intravenous rituximab was efficacious in treating severe pemphigus vulgaris, allowing for large decreases in concomitant corticosteroid doses in a prospective, open-label study (n=21). Combination treatment with intravenous (IV) rituximab and IV immune globulin resulted in rapid resolution of lesions and clinical remission in patients with refractory and prolonged pemphigus vulgaris in a prospective, open-label study (n=11).
Post-transplant lymphoproliferative disorder (PTLD)
Rituximab has been effective in the treatment of post-transplant lymphoproliferative disease including Epstein-Barr virus lymphoma. Oertel et al. (10) 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/m² 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, nine patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in one patient, minor remission in two patients, no change in three patients and one patient experienced progressive disease. Two patients relapsed, at intervals three and five months after obtaining complete remission. The investigators concluded that rituximab proved well tolerated and effective in the treatment of PTLD.
Thrombocytopenic purpura, immune or idiopathic (ITP)
Overall response rates of 35% to 52% in patients with ITP. Effective in severe refractory immune-mediated thrombocytopenia associated with chronic graft-versus-host disease in a single case report.
Waldenstrom Macroglobulinemia (WM)
Rituximab monotherapy (1-8 cycles) has shown efficacy in limited studies. In one single case report Rituxan was effective in treating polyneuropathy associated with WM. Rituximab is being used increasingly in the management of WM patients because of its positive treatment responses, acceptable toxicity and lack of therapy-associated myelosuppression and myelodysplasia. Data are insufficient to determine whether rituximab should be considered the first line treatment for WM. Current studies include combining rituximab with either an alkylating agent or a purine nucleoside analog, or both an alkylating agent and a purine nucleoside analog. Other studies are underway that will compare outcomes of patients receiving rituximab as a first line therapy as compared to patients previously treated with chemotherapy and then treated with rituximab upon relapse. The NCCN guidelines for treatment of WM include rituximab as an option, but note that long-term results are unknown and the use of rituximab alone is discouraged for those with M-protein > 5g/dL.
A systematic review and meta-analysis of five randomized trials (between 1998 and 2004) was conducted by an international group of researchers. The researchers compared survival of 1,143 patients with follicular lymphoma (relapsed or was refractory to treatment), who received rituximab maintenance therapy with that of patients who did not receive maintenance therapy. In one trial, patients in the control group were given rituximab when their disease relapsed; in the other four trials, treatment at relapse in the control arm was not part of the studies and no information was provided on the use of subsequent rituximab. Survival data were available for 985 patients with follicular lymphoma. In the pooled analysis of all five trials, patients who were treated with rituximab maintenance therapy had better overall survival than those who did not. The trials were also analyzed separately according to the type of control group (that is, whether or not rituximab was given at relapse to patients who had not received maintenance rituximab). Among patients in the four trials in which the control group did not receive rituximab at relapse, patients who received rituximab maintenance lived significantly longer than those who did not. Among patients in the single trial in which the control group did receive rituximab at relapse, survival was not improved in those who received rituximab maintenance treatment. However, this trial was too small to show whether one treatment approach was superior to the other. In the overall analysis, a survival benefit of maintenance rituximab appeared to be restricted to patients with previously treated (that is, refractory or relapsed) follicular lymphoma; no such benefit was seen in patients who had not received previous treatment for follicular lymphoma. Patients treated with rituximab maintenance therapy developed more severe infections and other adverse effects than patients in the control group. The five studies used a variety of induction therapy regimens--chemotherapy alone (one trial), rituximab alone (two trials), and chemotherapy with or without rituximab (one trial). The use of different induction regimens could have reduced the comparability of the trials. In addition, three of the five trials were stopped earlier than initially planned, which could have inflated the estimates of treatment benefit. Finally, only one of the trials compared maintenance rituximab with rituximab given at relapse.
In a 2009 article from the National Cancer Institute, Wyndham Wilson, M.D., head of the Lymphoma Therapeutics Section of the National Cancer Institute's Center for Cancer Research, noted the analysis mentioned above confirms the value of rituximab in extending the lives of patients with follicular lymphoma. However, Dr. Wilson notes it does not answer the question of whether patients treated with maintenance rituximab live longer than patients who receive rituximab when their disease relapses. "We know that patients with follicular lymphoma benefit from treatment with rituximab," says Wilson. "But we cannot conclude from this analysis that maintenance therapy is the optimal approach to administering rituximab." The current standard of care in the United States is to treat patients with follicular lymphoma with rituximab when their disease relapses after initial chemotherapy, and notes the findings of this analysis do not justify changing that standard.
Hochster et al. presented study data from “Maintenance Rituximab after Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival (PFS) in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study”. The authors note, “This study provides the first phase III data (to our knowledge) in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS, to a far greater extent than achieved by any prior strategy and with minimal toxicity. Patients who achieved complete response (CR), partial response (PR), or stable disease after induction chemotherapy were randomly assigned to rituximab maintenance (375 mg/² once per week for 4 consecutive weeks every 6 months for a maximum of 2 years) versus observation. With up to 16 infusions of rituximab, PFS as calculated from the time of random assignment was prolonged by 36 months. PFS results were similar for the follicular lymphoma subset of patients. The three-year overall survival (OS) for all evaluable patients was 92% versus 86% (maintenance v observation) at borderline significance. For follicular NHL patients, these data were 91% versus 86%. The authors note “In extrapolating our study results to current practice, several points should be considered. First, indolent lymphoma has a variable clinical course and patients with favorable status and low tumor burden were under-represented in our study. Although such patients had longer PFS with moderate response (MR), the OS in the observation arm was 99% at 2 years, a figure that will be difficult to improve on. In fact, none of the published rituximab plus chemotherapy studies included asymptomatic patients with favorable status, for whom watchful waiting remains an option as well as ongoing investigational trials. Second, although our results establish definitive benefit for MR after CVP in untreated patients, they do not address the benefit of MR after combined rituximab plus chemotherapy. The question whether rituximab maintenance (RM) in first remission is as effective after rituximab-chemotherapy induction as after chemotherapy-only induction (as was shown in the EORTC study) in relapsed patients remains to be answered. The authors note that observations from this study inform the design of future studies.
The role of maintenance rituximab in B-cell malignancies other than follicular lymphoma has just started to be evaluated.
Chronic Lymphocytic Leukemia (CLL)
The safety and effectiveness of Rituxan were evaluated in two randomized multicenter open-label studies comparing FC alone or in combination with Rituxan for up to six cycles in patients with previously untreated CLL or previously treated CLL. Patients received fludarabine 25 mg/m²/day and cyclophosphamide 250 mg/²/day on days 1, 2 and 3 of each cycle, with or without Rituxan. In both studies, seventy-one percent of CLL patients received six cycles and 90% received at least three cycles of Rituxan-based therapy.
The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators or an independent review committee. The investigator assessed results were supportive of those.
Maintenance Therapy / Follicular Lymphoma (FL)
Randomized studies have failed to show a survival benefit with maintenance rituximab. Different dosing schedules were used in the available studies reviewed and no data are available for the optimal dosing schedule of maintenance therapy and the recommended duration of this treatment. In addition, toxicities associated with maintenance rituximab may include an increase in grade 3 or grade 4 infections as well as less common consequences such as progressive multifocal leukoencephalopathy, and it is not known if maintenance therapy may compromise response to subsequent therapies.
No published studies in follicular lymphoma involve maintenance that follows the current standard of chemoimmunotherapy as the initial approach to the disease. Although evidence exists for the improved progression-free survival with the use of maintenance therapy for FL, the benefit in terms of overall survival is still controversial.
2011 Update -Maintenance Therapy / Follicular Lymphoma (8, 9, 12, 31)
The 2011 FDA approval of rituximab maintenance therapy was based on the international phase III PRIMA trial, which involved 1,200 patients. Those in the trial who responded to initial treatment with rituximab and chemotherapy, and who continued to receive rituximab every two months for the next two years, had a 46 percent improvement in progression-free survival compared with patients who did not receive the maintenance therapy. After two years, 82 percent of patients in the maintenance therapy arm compared with 66 percent of patients in the control arm were still alive with no progression of their disease.
The PRIMA study demonstrated that continuing rituximab administration every two months for two years in patients who responded to initial treatment with rituximab plus chemotherapy, improved the likelihood of them living without their disease worsening (progression-free survival or PFS) compared to those who stopped treatment.
A search of peer reviewed literature was conducted through March 2013. Use of Rituxan as monotherapy or in conjunction with various chemotherapy agents and/or other monoclonal antibodies as noted in this medical policy is based on scientific literature from the FDA, clinical trial data, Drugdex compendia, and NCCN Clinical Practice Guidelines in Oncology™ (NCCN).
The approved FDA indications remain as identified in the coverage position of this medical policy. (35)
The off-label cancer indications addressed on this MP are supported by current NCCN guidelines as well as the DrugDex compendia. The NCCN maintains a comprehensive set of guidelines documenting patient management recommendations for the malignancies that affect about 97% of all patients with cancer. They also address supportive care issues. The guidelines are developed and updated by 44 individual panels, composed of more than 800 clinicians and oncology researchers from the 21 NCCN member institutions and their affiliates. (38)
Autoimmune,immune-mediated dermatological and other conditions
Rituxan continues to be explored for therapeutic efficacy in a variety of autoimmune and immune-mediated dermatological conditions in which traditional therapy has failed or caused significant intolerance. Until further controlled clinical studies are performed to validate the safety and efficacy of rituximab therapy in dermatological disorders, information regarding the off-label usage of Rituxan will come from drug compendia reviews and other scientific case reports and cohort studies.
Although randomized, controlled clinical trials of rituximab for the treatment of steroid-resistant or steroid-dependent childhood idiopathic nephrotic syndrome (NS) are lacking, there is evidence for clinical benefit based on retrospective reviews and case series involving pediatric patients with refractory steroid-resistant NS (SRNS) or steroid-dependent NS (SDNS). A multicenter, retrospective, questionnaire-based chart review suggested that rituximab was beneficial for refractory, childhood idiopathic nephrotic syndrome.
- Rheumatoid arthritis, in combination with methotrexate, in patients with an inadequate response to methotrexate:
The addition of rituximab to methotrexate in patients with active rheumatoid arthritis despite methotrexate treatment significantly improved ACR20 (American College of Rheumatology) and ACR50 response rates at week 24 in a multicenter, randomized, double-blind, placebo-controlled, phase 3 study (SERENE; n=509).
An ACR20 response was achieved in 64% to 72% of patients with rheumatoid arthritis (RA) at 48 weeks after treatment with 1 of 3 rituximab regimens administered initially and at 24 weeks plus methotrexate, in the multicenter, randomized, double-blind, phase 3 MIRROR trial (n=346).
- Systemic lupus erythematosus, refractory to immunosuppressive therapy:
There was no difference in clinical response between rituximab and placebo in patients with moderate-to-severe extrarenal systemic lupus erythematosus receiving background immunosuppression and prednisone in a 52-week, multicenter, phase 2/3, randomized, double-blind, placebo-controlled (EXPLORER; n=257) trial However, preliminary evidence suggests that rituximab may be used adjunctively with immunosuppressive therapies to treat refractory systemic lupus erythematosus (SLE) in adult and pediatric patients.
Post marketing surveillance reported the deaths of two adult patients from progressive multifocal leukoencephalopathy (PML) while receiving rituximab for SLE. Rituximab improved disease severity in adult and pediatric patients with SLE who had failed or were intolerant of conventional immunosuppressive therapy based upon open-label trials and retrospective reviews. Rituximab improved systemic lupus activity measure (SLAM) index scores in adults with active disease who achieved complete B-cell depletion in an open-label, uncontrolled, dose-escalating phase I/II trial
- Neuromyelitis optica (NMO):
Therapy strategies using rituximab have been tested in NMO, with positive results in open label studies. Because NMO is a rare central nervous system (CNS) disorder with high early morbidity and mortality, there is no available evidence from randomized controlled trials. (36)
Rituxan has been studied in small numbers of people with polymyositis and dermatomyositis and shown to improve muscle strength, lung involvement and skin rash. For patients with polymyositis who are severe and other treatment options have failed Rituxan may be an option for therapy. (37).
- Prophylactic treatment option for sensitized kidney transplant recipients for inhibition of antibody production:
Rituximab has been used off label in desensitization protocols for incompatible kidney transplantation (ABO-incompatible or cross-match positive). Kidney transplantation is the preferred treatment modality for patients with ESRD because of improved patient survival and quality-of-life over dialysis Findings from preliminary studies suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor. These new protocols have improved transplant rates and outcomes for patients once considered un-transplantable or high risk for a poor outcome. Larger and longer trials will help to further evaluate the clinical efficacy and safety of this protocol.
- Multicentric Castleman's Disease
- Relapsing-remitting Multiple Sclerosis
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