Medical Policies - Prescription Drugs


Rituxan (Rituximab)

Number:RX502.030

Effective Date:06-15-2018

Coverage:

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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

Rituxan® (Rituximab) may be considered medically necessary for the following U.S. Food and Drug Administration (FDA)-labeled and non-FDA-labeled indications:

FDA Labeled Indications (Oncologic)

Non-Hodgkin's Lymphoma (NHL)

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.

Previously untreated follicular, CD20-positive, B-cell NHL in combination with chemotherapy, and in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single agent maintenance therapy.

Non-progressing (including stable disease), low-grade (indolent), CD20-positive, B-cell NHL as a single agent, after first-line CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy.

Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or as maintenance therapy after treatment-induced remission.

Chronic Lymphocytic Leukemia (CLL)

In combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

Subcutaneous Rituximab (rituximab and hyaluronidase human [Rituxan Hycela])

Rituxan Hycela may be considered medically necessary to treat patients who have received at least one full dose of intravenous rituximab AND when meeting the oncologic indications as noted above.

FDA Labeled Indications (Non-oncologic)

Rheumatoid Arthritis (RA)

In combination with methotrexate to reduce signs and symptoms of 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.

Re-treatment with Rituxan in adult patients with moderately to severely-active RA may be considered medically necessary when the patient meets ALL the following criteria as documented in the medical record:

Patient has received an adequate response* to Rituxan; AND

An interval of no less than 24 weeks has passed since the previous dose of Rituxan.

*NOTE: Response is defined by criteria such as American College of Rheumatology (ACR) 20 or 1.2-point improvement on the Disease Activity Score on 28 joints (DAS28) OR symptomatic improvement as evidenced by a decrease in joint pain, joint swelling, etc.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

Indicated in adult patients in combination with glucocorticoids.

Non-FDA-Labeled Indications: (Oncologic and Non-oncologic)

Autoimmune hemolytic anemia (AIHA);

Any B-cell or other lymphoid malignancies that express CD-20 antigen, including but not limited to the following:

o Chronic lymphoid leukemia (CLL), in combination with fludarabine for first-line treatment,

o Chronic lymphoid leukemia (CLL), relapsed or refractory,

o AIDS-related B-cell lymphoma,

o Mantle cell lymphoma (MCL),

o Burkitt’s lymphoma,

o Marginal zone B-cell lymphoma, or

o Hairy cell leukemia, relapsed or refractory;

Evans syndrome, refractory to immunosuppressive therapy;

Graft-versus-host disease, chronic, steroid-refractory;

Hodgkin’s lymphoma;

Pemphigus vulgaris and other autoimmune blistering skin diseases, severe;

Post-transplant lymphoproliferative disorder (PTLD);

Thrombocytopenic purpura, (immune, thrombotic (TTP) or idiopathic [ITP]);

Waldenström’s macroglobulinemia;

Acute lymphocytic leukemia (ALL);

Minimal change disease (MCD) [also known as lipoid nephrosis or nil disease], refractory, steroid-dependent or steroid-resistant;

As a treatment option for sensitized renal transplant recipients for inhibition of antibody production;

Neuromyelitis optica;

Polymyositis; severe, refractory;

Rheumatoid arthritis, in combination with methotrexate, in patients with an inadequate response to methotrexate;

Systemic lupus erythematosus, refractory to immunosuppressive therapy;

Primary Sjögren’s syndrome;

Multicentric Castleman’s disease;

Relapsing-remitting multiple sclerosis;

Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis):

o First-line treatment in combination with corticosteroids for patients with severe (organ threatening) disease,

o Add-on therapy for treatment-refractory disease;

Factor inhibitors in patients with hemophilia who are refractory to conventional first-line treatments (e.g., immune tolerance induction, corticosteroids with or without cyclophosphamide), preferably as add-on therapy;

Add-on therapy for patients with hepatitis C virus (HCV)?associated cryoglobulinemic vasculitis who have:

o Active disease resistant to anti-viral drugs, or

o Severe or life-threatening cryoglobulinemic vasculitis;

The following pemphigoid diseases:

o Bullous pemphigoid,

o Mucous membrane pemphigoid, including ocular cicatricial pemphigoid, and epidermolysis bullosa acquisita;

Add-on therapy for lupus nephritis refractory to at least standard first-line treatment regimens;

Systemic sclerosis (scleroderma) in patients’ refractory to first-line treatment;

Idiopathic membranous nephropathy;

Myasthenia gravis, refractory.

Opsoclonus myoclonus ataxia syndrome (OMAS) that is refractory to steroids, chemotherapy and intravenous immunoglobulins (IVIG).

All other non-FDA labeled indications for Rituxan are considered experimental, investigational and/or unproven.

Description:

Rituximab (Rituxan) is a chimeric murine-human monoclonal antibody against the CD20 antigen on B lymphocytes. Rituximab lyses pre-B and B lymphocytes and is successfully used to treat B-cell lymphoma. Rituximab has been used with increased frequency for nononcologic indications, particularly autoimmune diseases thought to be B-cell mediated.

Regulatory Status

In November 1997, rituximab (Rituxan®; Genentech) was initially approved by the U.S. Food and Drug Administration (FDA) through the biologics license application process for the treatment of relapsed or refractory low-grade or follicular, CD20-positive, B-cell Non-Hodgkin's Lymphoma (NHL). Since 1997, rituximab has gained additional oncologic and nononcologic indications.

Intravenous rituximab is currently approved by the FDA for the following oncologic indications:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent;

Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy;

Nonprogressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens;

In combination with fludarabine and cyclophosphamide, for the treatment of patients with previously untreated and previously treated CD20-positive Chronic Lymphocytic Leukemia (CLL);

Treatment of B-cell CLL with monoclonal antibody therapy is used in patients with nonlocalized disease.

In June 2017, a subcutaneous form of rituximab with hyaluronidase human (Rituxan Hycela™; Genentech) was approved by the FDA through the regular approval process. The medication combines rituximab and hyaluronidase human. The human hyaluronidase was included to temporarily degrade the extracellular matrix and facilitate the absorption of larger volumes of rituximab. The FDA materials note that the product should only be administered by a health care professional. Rituxan Hycela™ is approved for the following indications in patients who have already received at least 1 full dose of intravenous rituximab:

Relapsed or refractory, follicular lymphoma (FL) as a single agent;

Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy;

Non-progressing (including stable disease), FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy;

Previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens;

Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC).”

Rationale:

This policy was originally created in 2007; this section of the current policy has been substantially revised and reformatted. A search of peer reviewed literature was conducted through January 2018 and is summarized below.

Oncologic Indications for Intravenous Rituximab (Rituxan)

Follicular Lymphoma

Previously Untreated Follicular Lymphoma

Several phase 3 trials have evaluated the efficacy of rituximab in combination with various chemotherapy regimens as first-line therapy for indolent non-Hodgkin lymphoma (NHL) or follicular lymphoma (FL). One narrative review summarized the effect on complete remission (CR) of adding rituximab to several different chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin [Adriamycin], vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisone), and others. It reported that the addition of rituximab resulted in significantly greater complete remission (CR; 41%-79% for rituximab-containing regimens vs 10%-63% for regimens without rituximab; p<0.005), and greater overall response rates (81%-96% vs 57%-90%, respectively; p<0.05). (9) The addition of rituximab to first- or second-line therapy with different chemotherapy regimens has shown variable results in improvement of overall survival (OS) in phase 3 trials. (200) However, a 2006 meta-analysis of OS data from 4 trials (total N=1015 patients) showed significantly improved OS when rituximab was added to chemotherapy compared with chemotherapy alone (hazard ratio [HR] for death, 0.57; 95% confidence interval [CI], 0.43 to 0.77).

Hiddemann et al. (2005) reported the results of front-line therapy in advanced-stage FL in 428 patients randomized to CHOP alone or rituximab plus CHOP (R-CHOP). (201) Patients who received R-CHOP had significantly prolonged time-to-treatment failure (p<0.001), higher overall response rate (96% vs 90%, p=0.011), and prolonged duration of remission (p=0.001). Additional follow-up in a subset of the original study group (patients age ≥60 years) showed a 4-year progression-free survival (PFS) advantage of R-CHOP over CHOP (62.2% vs 27.9%; p<0.001) and 4-year OS (90% vs 81%; p=0.039), all respectively.

Marcus et al. (2005) randomized previously untreated patients with advanced-stage FL to CVP (n=159) or rituximab plus CVP (R-CVP; n=162). (202) Overall response and CR rates were 81% and 41%, respectively, in the R-CVP arm vs 57% and 10%, respectively, in the CVP arm (p<0.001). After a median follow-up of 30 months, patients who received R-CVP had a median time to progression of 32 months vs 15 months for CVP only (p<0.001). Median time-to-treatment failure was 27 months for R-CVP vs 7 months for CVP (p<0.001). A 2007 update of the study at a median follow-up of 53 months showed improved OS in the R-CVP arm, with estimated 4-year OS of 83% vs 77% in the CVP arm (p=0.029). (203)

Relapsed and Refractory FL

Efficacy of rituximab as monotherapy in patients with relapsed or refractory low-grade FL has been examined in multicenter studies, (204-210) as summarized in a 2010 review article. (211) Most studies included patients with low-grade FL, and most patients had stage III or IV disease. When specified, the median duration of follow-up ranged from 173 days to 1.5 years. Across studies, baseline characteristics were: median patient age, 50 to 58 years; percent male, 34% to 63%; and the median number(s) of previous treatments, 2 (2 studies), 3 (3 studies), or 4 (1 study). Overall response rates were 38% to 48% after 4 weeks of rituximab therapy and 57% after 8 weeks of therapy. CR rates ranged from 3% to 17%. The median duration of response ranged from 5.9 to 17.8 months, and median time to progression was 8.1 to 16.3 months after 4 weeks of therapy. The median duration of response and median time to progression had not yet been reached after median follow-ups of 13.4 and 19.4 months, respectively, in patients who received 8 weeks of rituximab therapy. (211)

Maintenance Therapy

In 2017, Vidal et al. published an individual patient meta-analysis of studies on rituximab maintenance therapy in patients with previously treated or previously untreated FL. (212) The analysis included data from 7 RCTs comparing rituximab maintenance therapy with observation-only after induction. The primary endpoint of the analysis was OS, defined as the time from randomization until death. PFS and adverse events were secondary end points. The 7 trials included 2317 patients; 2 patients were excluded due to lack of data on outcome measures. The median follow-up was 6 years. A total of 209 (18.3%) of 1145 patients in the rituximab maintenance group died during follow-up compared with 246 (21.0%) of 1170 patients in the observation group. The difference between groups was statistically significant, favoring rituximab maintenance (HR=0.79; 95% CI, 0.66 to 0.96). PFS was significantly higher in the rituximab maintenance group compared with observation (HR=0.57; 95% CI, 0.51 to 0.64; p<0.001). Rates of grade 3 or 4 infection were significantly higher in the rituximab maintenance group than the observation group (HR=1.27; 95% CI, 1.112 to 1.45) and other adverse events were rarely reported.

Representative trials for FL are described below:

Previously Untreated FL

Salles et al. (2011) reported the results of a phase 3 RCT (the PRIMA study) conducted in 223 centers in 25 countries. (213) PRIMA assessed the potential benefit of 2 years of rituximab maintenance therapy after first-line treatment in patients with FL needing systemic therapy. A total of 1217 patients received 1 of 3 nonrandomized induction regimens comprising rituximab and chemotherapy; 1019 patients who had a partial response (PR) or CR were randomized to 2 years of rituximab maintenance therapy (n=505) or observation (n=513). The primary end point was PFS. After a median follow-up of 36 months, PFS was 74.9% (95% CI, 70.9% to 78.9%) in the rituximab maintenance group and 57.6% (95% CI, 53.2% to 62.0%) in the observation group (HR=0.55; 95% CI, 0.44 to 0.68; p<0.001). Two years after randomization, 71.5% of patients in the rituximab maintenance group were in CR vs 52.2% in the observation group (p=0.001). More patients with PR at the time of randomization converted to CR after 2 years in the rituximab maintenance group (52%) compared with those in the observation group (30%; estimated difference, 22.2%; 95% CI, 11.2% to 33.3%; p=0.001). Risks, such as starting a new antilymphoma treatment or a new chemotherapy or even death, were significantly reduced in the rituximab maintenance group. Grade 3 and 4 adverse events were recorded in 24% of patients in the rituximab maintenance group and in 17% in the observation group, with infections being the most common adverse event. OS did not differ significantly between groups; however, because longer follow- up was needed to show any possible effect of rituximab maintenance on OS, the authors planned to follow these patients. Moreover, the authors concluded that 2 years of rituximab maintenance therapy significantly prolonged PFS, delayed the time to the next antilymphoma treatment or chemotherapy, and improved the quality of response in patients with previously untreated FL responsive to first-line rituximab plus chemotherapy.

Long-term results of a different phase 3 RCT (E1496) were reported by Barta et al. in 2016. (214) The trial included patients with stage III or IV small lymphocytic, follicular small cleaved or follicular mixed small cleaved and large cell lymphoma. To be eligible, patients needed to have measurable disease, and an Eastern Cooperative Oncology Group Performance Status score of less than 2; moreover, patients could not have had previous lymphoma-directed therapy. After induction therapy with CVP, patients were randomized to 2 years of rituximab maintenance therapy (n=158) or observation-only (n=155). The primary end point was PFS. After a median follow-up of 11.5 years, PFS was significantly longer in the rituximab maintenance group (4.8 years) than the observational-only group (1.3 years; p<0.001). OS did not differ significantly between groups.

Relapsed or Refractory FL

In 2006, van Oers et al. evaluated the role of rituximab in both induction and maintenance of relapsed or refractory FL. (215) They randomized 465 patients to induction with 6 cycles of CHOP vs R-CHOP, with a second randomization of patients in CR or PR to rituximab maintenance or observation. Rituximab induction therapy yielded statistically significant improvement in overall response (85.1% vs 72.3%; p<0.001), CR (29.5% vs 15.6%; p<0.001), and median PFS from first randomization (33.1 months vs 20.2 months; p<0.001). Rituximab maintenance resulted in a median PFS from second randomization of 51.5 months vs 14.9 months with observation (HR=0.40; p<0.001). Rituximab maintenance also improved OS from second randomization with 3-year OS of 85% with rituximab vs 77% with observation (p=0.011). In 2010, van Oers et al. reported long-term outcomes in this same patient population with a median follow-up of 6 years. (216) Maintenance therapy with rituximab improved PFS compared with observation (median, 3.7 years vs 1.3 years, respectively; HR=0.55; p<0.001), both after CHOP induction (HR=0.37; p<0.001) and R-CHOP induction (HR=0.69; p=0.003). Five-year OS was 74% in the rituximab maintenance arm and 64% in the observation arm (p=0.07). Rituximab maintenance was associated with a significant increase in grade 3 and 4 infections (9.7% vs 2.4% respectively; p=0.01). The authors concluded that rituximab maintenance therapy in relapsed or resistant FL led to superior PFS and that, although improvement in OS was not statistically significant, this may have been due to an unbalanced use of rituximab in postprotocol salvage treatment; after disease progression, rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance.

Subsection Summary: Rituximab for Follicular Lymphoma

For first-line therapy, RCTs have shown that the addition of rituximab to front-line chemotherapy improves response rates and OS. For relapsed and refractory disease, multicenter studies have supported the efficacy of rituximab as monotherapy. For maintenance therapy, RCTs and an individual patient meta- analysis of RCT data have shown improved OS and PFS in patients with previously untreated and previously treated FL.

Diffuse Large B-Cell Lymphoma (DLBCL)

Previously Untreated DLBCL

The use of rituximab with a CHOP or CHOP-like regimens has been more effective than chemotherapy alone as first-line treatment in patients with advanced-stage DLBCL and mantle cell lymphoma (MCL) in several phase 3 trials.

In 2010, Coiffier et al. reported long-term outcomes of a randomized trial (LNH-98.5) involving 399 elderly patients (age range, 60-80 years) with previously untreated DLBCL who were randomized to 8 cycles of classical CHOP or R-CHOP. (217) Median follow-up was 10 years. Ten-year PFS was 36.5% (95% CI, 29.7% to 43.3%) with R-CHOP compared with 20% (95% CI, 14.6% to 26.2%) with CHOP only. Median OS was 8.4 years (95% CI, 5.4 to not reached) in the R-CHOP arm and 3.5 years (95% CI, 2.2 to 5.5 years) in the CHOP arm (p<0.001).

In 2008, Pfreundschuh et al. reported on an RCT of 1222 elderly patients (age range, 61-80 years) with aggressive CD20-positive NHL to 6 or 8 cycles of CHOP (at 2-week intervals [CHOP-14]), with or without rituximab, and showed significant improvements in event-free survival (EFS), PFS, and OS in patients receiving R-CHOP vs CHOP. (218) Three-year OS rates were 67.7% (95% CI, 62.0% to 73.5%) for 6 cycles of CHOP-14, 66.0% (95% CI, 60.1% to 71.9%) for 8 cycles of CHOP-14, 78.1% (95% CI, 73.2% to 83.0%) for 6 cycles of R-CHOP-14, and 72.5% (95% CI, 67.1% to 77.9%) for 8 cycles of R-CHOP-14. OS improved only after 6 cycles of R-CHOP-14 (relative risk, 0.63; 95% CI, 0.46 to 0.85; p=0.003). The authors concluded that six cycles of R-CHOP was the preferred treatment for elderly patients.

In 2006, Habermann et al. reported a 2-stage, randomized trial of 632 patients ages 60 years or older who had untreated DLBCL. (219) Patients were randomized to CHOP or R-CHOP, and 415 responders underwent a second randomization to maintenance therapy with rituximab or observation. The 3-year failure-free survival (FFS) rates were 53% for R-CHOP and 46% for CHOP induction (HR=0.78; 95% CI, 0.61 to 0.99; p=0.04). The 2-year FFS rates after the second randomization for maintenance were 76% for rituximab vs 61% for observation (p=0.009). A significant difference in the effect of rituximab maintenance therapy was seen by type of induction therapy received, with maintenance rituximab significantly prolonging FFS after CHOP (HR=0.45; 95% CI, 0.29 to 0.71; p<0.001) but not after R-CHOP (HR=0.93; 95% CI, 0.53 to 1.66; p=0.81). A secondary analysis evaluated the effect of induction therapy without maintenance rituximab. R-CHOP alone showed a significant decrease in the risk of treatment failure compared with CHOP (HR=0.64; 95% CI, 0.47 to 0.85; p=0.003), with an estimated 3-year FFS rate of 52% for R-CHOP and 39% for CHOP. Survival also was longer after R-CHOP induction alone, with an estimated 3-year OS rate of 67% for R-CHOP vs 58% for CHOP (HR=0.72; 95% CI, 0.52 to 1.00; p=0.05).

Jaeger et al. (2015) conducted an international, open-label RCT in 683 adults (median age, 58 years) with previously untreated CD20-positive, aggressive NHL. (220) Patients with DLBCL (n=662) or grade IIIb FL (n=21) were randomized 1:1 to rituximab maintenance therapy after first (confirmed or unconfirmed) complete remission or to observation for 2 years. Patients completed first-line therapy (8 infusions of rituximab [375 mg/m2] plus 4-8 cycles of CHOP-like chemotherapy) 12 to 14 weeks before the trial started. For patients randomized to rituximab maintenance, rituximab 375 mg/m2 was administered every 2 months. Assessments of both groups occurred every 8 weeks. The primary outcome was EFS by intention-to-treat analysis, with events defined as progressive disease, death from any cause, initiation of new anticancer treatment, secondary malignancy, or unacceptable toxicity. PFS and OS were also assessed. At median follow-up of 45 months, the estimated 3-year EFS rate was 80.1% in the rituximab maintenance group vs 76.5% in the observation group (HR=0.79; 95% CI, 0.57 to 1.08; p=0.143). Similarly, in intention-to-treat analysis, 3-year PFS and 3-year OS estimates did not differ statistically between treatment groups.

Aviles et al. (2015) conducted an RCT of rituximab consolidation therapy in 325 adults (median age, 63 years) with previously untreated, advanced-stage DLBCL and poor prognostic factors, who were in CR after dose-dense chemotherapy (CHOP-14). (221) Patients were randomized 1:1 to rituximab consolidation or observation. Assessments occurred every 3 months for 2 years, then every 6 months for 2 years, and then annually until relapse, death, or last follow-up. At median follow-up of 43 months, the estimated 5- year PFS rate was 51% in the rituximab consolidation group vs 53% in the observation group (p=0.8). Similarly, the estimated 5-year OS rate did not differ statistically between groups (65% vs 66%, respectively; p=0.78).

Maintenance Therapy for DLBCL

In 2017, Zhou et al. published a meta-analysis of studies on rituximab maintenance therapy for patients with DLBCL. (222) Five RCTs with at least 10 patients per study arm were identified and included in the meta- analysis. A meta-analysis of 4 trials that reported on OS did not find a statistically significant difference between the rituximab maintenance and observation groups (HR=0.66; 95% CI, 0.27 to 1.29; I2=0%). Two studies reported PFS and one reported FFS; these outcomes were combined in analysis. A meta-analysis of the 3 trials found a significantly higher PFS in the rituximab maintenance group compared with the control group (HR=0.72; 95% CI, 0.54 to 0.94). There was moderate heterogeneity among the 3 trials in the PFS analysis (I2=41%). In a sensitivity analysis, heterogeneity was low when 1 of the 3 trials was excluded and the PFS remained significantly higher in the rituximab maintenance group (HR=0.62; 95% CI, 0.48 to 0.81).

Subsection Summary: Rituximab for Diffuse Large B-Cell Lymphoma

For first-line therapy, RCTs have shown that the addition of rituximab to chemotherapy improves response rates. For maintenance therapy, a meta-analysis of three trials found significantly higher PFS with rituximab than observation-only.

Mantle Cell Lymphoma (MCL)

Previously Untreated MCL

In 2005, Romaguera et al. published a prospective phase 2 study of 97 patients who had newly diagnosed MCL and received rituximab plus hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate-cytarabine. (223) Among 97 assessable patients, the response rate was 97% with a CR or unconfirmed CR rate of 87%. At a median follow-up of 40 months, the 3-year FFS rate was 64% and the OS rate was 82%. Patients 65 years of age or younger had a 3-year FFS rate of 73%. Toxicity was significant and FFS shorter in patients older than 65 years of age. A 2017 update of this patient population, with median follow-up of 4.8 years, reported 5-year FFS rate of 48% and OS rate of 65%. (224)

In 2005, Lenz et al. published results of a prospective, randomized trial of 122 patients with previously untreated advanced-stage MCL that compared CHOP chemotherapy alone with R-CHOP. (225) R-CHOP (vs CHOP chemotherapy alone) was superior in terms of overall response (94% vs 75%; p=0.005), CR (34% vs 7%; p<0.001), and time-to-treatment failure (median, 21 months vs 14 months; p=0.013), all respectively. However, no differences were observed in PFS or OS between the two groups.

Relapsed or Refractory MCL

In 2004, Forstpointner et al. published results of a prospective, randomized, open-label multicenter phase 3 trial comparing the use of fludarabine, cyclophosphamide, and mitoxantrone (FCM), with and without rituximab, in patients with relapsed and refractory follicular and MCL. (226) Fifty-two patients had MCL, and the group that received FCM plus rituximab (R-FCM) had a superior overall response rate (58%) compared with the FCM group (46%; p=0.282). Significantly longer OS was observed in the R-FCM group, with median OS not reached at 2 years, compared with an estimated median OS of 11 months for the FCM group (p=0.004). At 2 years, estimated OS in the R-FCM arm was 65% compared with 35% in the FCM arm.

Subsection Summary: Rituximab for Mantle Cell Lymphoma (MCL)

For first-line therapy, an RCT demonstrated that the addition of rituximab to chemotherapy improved response rates and time-to-treatment failure. For relapsed or r2r3eefractory disease, an RCT has shown that the addition of rituximab to chemotherapy resulted in improved response rates and OS.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a disease of older individuals and tends to have a prolonged course. Generally, it is treated conservatively, and often treatment is initiated only when a patient becomes symptomatic as the disease progresses. Treatment is variable and depends on age and other risk factors, including certain molecular abnormalities. Because CLL is generally considered incurable, the aim of treatment is to induce CR, including eliminating minimal residual disease in the bone marrow. Minimal residual disease usually is evaluated by sensitive testing methods, which include flow cytometry or polymerase chain reaction; patients who are free of minimal residual disease after treatment have longer remission duration and survival. (227)

Current chemotherapy options for CLL include alkylating agents such as chlorambucil or cyclophosphamide (which when used as single agents have shown CR rates <10%) and purine analogues such as fludarabine (with single-agent CR rates of 20%). The combination of an alkylating agent and fludarabine improves the CR to 40%. (228)

A 2012 Cochrane review compared monoclonal anti-CD20 antibodies with no further treatment or with other anti-leukemic therapies for treatment of CLL, irrespective of disease status. (229) Both previously treated and chemotherapy-naive patients were included, and all trials included were randomized and open-label. Three RCTs (total N=1421 patients) assessed the efficacy of rituximab plus chemotherapy compared with chemotherapy alone, and a meta-analysis found a statistically significant OS and PFS advantage for patients who received rituximab. Although there were more grade 3 and 4 adverse events in the rituximab arm, treatment-related mortality did not differ statistically between groups. Two RCTs (n=177 patients) evaluated rituximab and alemtuzumab; neither study reported PFS or OS. There was no statistically significant difference between arms for CR rate or treatment-related mortality; however, more serious adverse events occurred in the alemtuzumab arm.

Previously Untreated CLL

In 2010, Hallek et al. reported results of a randomized, open-label, multicenter phase 3 trial (CLL8 trial), (230) with longer term follow-up reported in 2016. (231) Treatment-naive patients with CLL were randomized to receive fludarabine (F) and cyclophosphamide (C) with (n=408) or without (n=409) rituximab in 190 centers in 11 countries. At 3 years after randomization, 65% of patients in the chemoimmunotherapy group were free of progression vs 45% in the chemotherapy-only group (HR=0.56; 95% CI, 0.46 to 0.69; p<0.001), and 87% were alive vs 83%, respectively (HR=0.67; 95% CI, 0.48 to 0.92; p=0.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (34% vs 21%, p<0.001) and leukopenia (24% vs 12%, p<0.001); other adverse events, including severe infections, did not increase. Treatment-related deaths occurred in 2% vs 3% of patients in the chemoimmunotherapy and chemotherapy-only groups, respectively. With follow-up at a median of 5.9 years after randomization, median PFS was 56.8 months in the chemoimmunotherapy group and 32.9 months in the chemotherapy-alone group (HR=0.59; 95% CI, 0.50 to 0.69; p<0.001). Median OS was not reached for the chemoimmunotherapy group, which was significantly longer than the median OS of 86.0 months for the chemotherapy-alone group (HR=0.68; 95% CI, 0.54 to 0.89; p=0.001).

Relapsed or Refractory CLL

The randomized, open-label multicenter phase 3 REACH trial (2010) examined the efficacy of adding rituximab to fludarabine and cyclophosphamide (FCR) in patients with relapsed or refractory CLL. (232) Patients were eligible if they had received 1 prior line of chemotherapy, were fludarabine sensitive, and had not received prior therapy with rituximab. Patients were randomized to receive FCR (n=276) or FC-only (fludarabine and cyclophosphamide only) (n=276). The primary end point was PFS, with a median follow-up of 25 months. Median PFS was significantly prolonged in the FCR group (30.6 months) vs the FC-only group (20.6 months; HR=0.65; p<0.001). Overall response rate, CR, and duration of overall response (HR=0.69; 95% CI, 0.50 to 0.96) also were significantly higher in the FCR group. Median time to new treatment also was significantly longer in patients receiving rituximab (not reached vs 34.3 months; HR=0.65; 95% CI, 0.49 to 0.86; p<0.01).

In 2011, Badoux et al. reported the final analysis of an open-label phase 2 study of 284 patients with relapsed CLL treated with FCR. (233) All patients had active, progressive CLL. The study included patients in second and subsequent relapses and those previously treated with rituximab or FC combination. The median patient age was 60 years, and the median number of prior treatments was 2 (range, 1-10). The primary objective was to improve the CR rate compared with historical controls treated with FC as salvage therapy (n=114). Secondary outcomes included OS and PFS, calculated from the first day of therapy. Of 284 patient, 280 (99%) were evaluable for response; 30% achieved CR, 14% achieved nodular partial remission, defined as patients who are otherwise in CR but had lymphoid nodules identified in bone marrow, and 30% achieved partial remission, for an overall response rate of 74%. When analyzed by prior therapy, patients with 3 or fewer prior therapies had significantly higher CR or nodular partial remission rates than those who received 4 or more prior regimens (52% vs 4%, respectively; p<0.001). The estimated median PFS was 20.9 months (95% CI, 18.8 to 27.6 months) for the entire cohort. Estimated median PFS for patients achieving CR was 60 months compared with 38 months for patients achieving nodular partial remission (p=0.076) and 15 months for those achieving partial remission (p<0.001). Estimated median OS for all patients was 46.7 months (95% CI, 41.2 to 53.4 months) and 100 months for patients who achieved CR or nodular partial remission. Compared with FC-treated patients in the historical cohort, patients receiving FCR had longer PFS (21 months vs 11 months, respectively; p<0.001) and longer OS (47 months vs 21 months, respectively; p<0.001). Subgroup analysis showed that the following patients had superior outcomes with FCR: those with up to 3 prior treatments, fludarabine-sensitive patients regardless of prior rituximab exposure, and patients without chromosome 17 abnormalities.

Maintenance Therapy for CLL

Maintenance therapy with rituximab was compared with observation from the AGMT CLL8a Mabtenance RCT (see CLL8 trial described in the Previously Untreated CLL section). (234) This multicenter open-label trial included patients who had a CR or PR to first- or second-line rituximab-containing chemoimmunotherapy.

Patients were randomized to rituximab (n=134) or observation (n=129) every 3 months for 2 years or until progression. PFS was significantly longer with rituximab maintenance (47.0 months) than with observation (35.5 months; HR=0.50; 95% CI, 0.33 to 0.75; p<0.001). A higher percentage of patients in the rituximab maintenance group converted from PR to CR (8/60 [13%]) compared with observation (1/55 [2%], p=0.033). There was no significant difference between groups in OS. Grade 3 and 4 neutropenia occurred in 28 (21%) of patients in the rituximab group and in 14 (11%) of patients in the observation group.

Subsection Summary: Rituximab for Chronic Lymphocytic Leukemia

For first-line therapy, RCTs have shown improved PFS and OS with the addition of rituximab to chemotherapy. For relapsed or refractory disease, 1 RCT has shown prolonged PFS in CLL, and a phase 2 open-label study has shown improved PFS and OS compared with a historical cohort. For maintenance therapy, 1 RCT has shown improved PFS, and higher conversion to CR, but no difference in OS compared with observation. Adverse events were higher with rituximab.

Burkitt Lymphoma

In 2016, Ribrag et al. reported on an open-label, phase 3 RCT that compared rituximab (4 infusions) plus chemotherapy (n=128) with chemotherapy alone (n=129) for the treatment of Burkitt lymphoma. (235) At a median follow-up of 38 months, patients in the rituximab group had better 3-year EFS (75%; 95% CI, 66% to 82%) than the chemotherapy-alone group (62%; 95% CI, 53% to 70%; p=0.024; HR=0.59; 95% CI, 0.38 to 0.94; p=0.025). OS was also better with rituximab (83%; 95% CI, 75% to 88%) than without rituximab (70%; 95% CI, 62% to 78%). There were no significant differences in adverse events between groups.

Subsection Summary: Rituximab for Burkitt Lymphoma

For first-line therapy, 1 RCT has shown an increase in EFS and OS with the addition of rituximab to chemotherapy.

Post-transplant Lymphoproliferative Disorders

Post-transplant lymphoproliferative disorders (PTLD) are characterized by lymphoid proliferations that occur in patients receiving immunosuppressive therapy after solid organ or allogeneic cell transplantation. Most PTLDs are B-cell proliferations that develop 12 to 24 months after transplant, with Epstein-Barr virus (EBV) detected in up to 70% of cases. EBV-negative PTLD typically has a later onset (>24 months after transplant). Risk factors for PTLD after solid organ transplant include EBV mismatch (positive donor/negative recipient), augmented immunosuppression (e.g., with antilymphocyte antibodies), and type of organ transplant (incidence ranges from ≈1% in kidney recipients to ≈10% in small bowel or multiorgan recipients). The World Health Organization has defined four categories of PTLD: 1) early lesions (reactive plasmacytic hyperplasia and infectious mononucleosis-like); 2) polymorphic PTLD; 3) monomorphic B-cell and T-cell PTLD; and 4) Hodgkin lymphoma (HL) and HL-like PTLD. (236) Early lesions and some polymorphic lesions may be found incidentally; more advanced disease (e.g., monomorphic PTLD) typically presents with bulky, extranodal lymphadenopathy. Nonhealing ulcers of the gastrointestinal tract, bowel perforation, or pulmonary manifestations can occur. A primary goal of treatment is to save the transplanted organ. (237-240)

Reduction of immunosuppression is the first step in treating PTLD. Several studies have investigated rituximab for patients who have an inadequate response to reduction in immunosuppression (see Table 1). Overall response rates were 59% to 90%. Two retrospective comparative studies showed that PFS and OS were increased with rituximab-containing regimens, including monotherapy, compared with rituximab-free regimens, (241) and that chemotherapy added to rituximab did not improve PFS and OS, (242) although both studies were small (N=80 and 35, respectively).

Table 1. Studies of Rituximab Chemoimmunotherapy for PTLD After Solid Organ Transplant (241-248)

Study

N

Patients

Treatment

Results

Trappe et al. (2012)

59

CD20-pos patients with PTLD (HL, polymorphic, monomorphic) unresponsive to RI

Rituximab 375 mg/m2 weekly x 4 wk (median, 4 doses) followed by 4 cycles of CHOP (median, 4 cycles)

CR=68% PR=22%

Evens et al. (2010)

(retrospective)

80

EBV-pos, -neg, or unknown PTLD after RI; median time from transplant to PTLD, 48 mo

Rituximab ± chemotherapy (various regimens; n=59)

Rituximab-free regimens (n=21)

3-y PFS=70%

3-y OS=73%

3-y PFS=21%

3-y OS=33%

González-Barca et al. (2007)

38b

PTLD after RI

Rituximab 375 mg/m2 weekly x 4 wk, repeated x1 in patients not achieving CR

CR=61% PR=18%

 

Study

N

Patients

Treatment

Results

Choquet et al. (2006)

46

B-cell PTLD unresponsive to RI

Rituximab 375 mg/m2 weekly x 4 wk

CR=26%

1-y OS=67%

Elstrom et al. (2006)

(retrospective)

35

PTLD unresponsive to or relapsed after RI

Rituximab 375 mg/m2 weekly x 4 wk (n=22)

CHOP chemotherapy ± rituximab up to 6 cycles (n=23)

CR=59% PR=9%

OSa=31 mo

CR=57% PR=17%

OSa=42 mo

Blaes et al. (2005)

11

CD20-pos patients with PTLD (HL, polymorphic) after RI; median time from transplant to PTLD, 9 mo

Rituximab 375 mg/m2weekly x 4 wk, repeated every 6 mo for 2 y in responding patients

CR=55% PR=9%

OSa=14 mo

Oertel et al. (2005)

17

PTLD (HL, HL-like,

polymorphic)

Rituximab 375 mg/m2 weekly x 4 wk

CR=53% PR=6%

OSa=37 mo

CHOP: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 to maximum 2 mg, plus prednisone 100 mg/d x 5 d, repeated every 21 d as tolerated; CR: complete response; EBV: Epstein-Barr virus; HL:

Hodgkin lymphoma; neg: negative; OS: overall survival; pos: positive; PFS: progression-free survival; PR: partial response; PTLD: post-transplant lymphoproliferative disorders; RI: reduction in immunosuppression.

a Median.

b Assessable patients.

Subsection Summary: Rituximab for Post-transplant Lymphoproliferative Disorders

For first-line therapy, two retrospective comparative studies have shown improved PFS and OS in patients receiving rituximab-containing regimens, including monotherapy, compared with rituximab-free regimens. This evidence is sufficient to demonstrate improved health outcomes in patients with PTLD but an inadequate response to reduction in immunosuppression, particularly because treatment options for these patients are limited.

Subcutaneous Rituximab (Rituxan Hycela) (oncologic indications only)

The subcutaneous product includes Rituxan (as does the intravenous (IV) rituximab product) and hyaluronidase human to facilitate absorption. Controlled studies are needed comparing IV Rituxan with subcutaneous Rituxan to determine whether the subcutaneous product is superior, inferior, or noninferior to the IV product in terms of both safety and efficacy,

Follicular Lymphoma

A phase 3 open-label RCT evaluated subcutaneous rituximab for treating FL (SABRINA). Stage 1 findings were published by Davies et al. in 2014 (248) and stage 2 findings were published by Davies et al. in 2017. (249) The study included 127 adults with previously untreated histologically confirmed CD20-positive FL requiring treatment. Patients needed to have an Eastern Cooperative Oncology Group Performance Status score of 0 or 1 and a life expectancy of at least 6 months. Patients were randomized to IV rituximab plus chemotherapy (n=64) or subcutaneous rituximab plus chemotherapy (n=63). Patients in the subcutaneous rituximab group received 1 cycle of IV rituximab prior to receiving subcutaneous rituximab.

Stage 1 assessed the pharmacokinetic noninferiority of subcutaneous rituximab. The primary end-point of stage 1 was the rituximab serum trough concentration at induction cycle 7. Assessable samples were available for 48 (75%) patients in the IV rituximab group and 54 (86%) of the subcutaneous rituximab group. Subcutaneous rituximab was found to be noninferior to IV rituximab since the serum trough concentration exceeded the prespecified margin. Patients were followed for a median of 9 months. The overall rate of adverse events and the rate of grade 3 or 4 adverse events were similar in the 2 groups. However, administration-related adverse events were higher in the subcutaneous rituximab group (50%) than in the IV rituximab group (32%).

After pharmacokinetic noninferiority was confirmed in stage 1, patient recruitment resumed, and an additional 282 patients were enrolled. The primary end point for stage 2 was the overall response rate, confirmed or unconfirmed CR and PR at the end of induction. The study protocol specified combining efficacy data from both stages. In stages 1 and 2 combined, 410 patients were enrolled, 205 were randomized to IV rituximab plus chemotherapy and 205 to subcutaneous rituximab plus chemotherapy. The primary outcome analysis was intention-to- treat. A total of 347 patients in the intention-to-treat population had a CR or PR at the end of induction, 174 (84.9%) in the IV rituximab group and 173 (84.4%) in the subcutaneous rituximab group. The rate of CR was the same in both groups (32.2%). The authors did not report a prespecified noninferiority margin for efficacy, but a nearly identical response rate indicates similar efficacy. As in stage 1, the overall rate of adverse events and the rate of grade 3 or 4 adverse events were similar in the 2 groups. Neutropenia was the most common adverse events of grade 3 or higher in both groups, affecting 34% in the IV rituximab arm and 37% in the subcutaneous rituximab arm. Also, as in stage 1, there were more administration-related adverse events in the subcutaneous rituximab arm (48%) than in the IV rituximab arm (35%); these were mainly grade 1 or 2 injection-site reactions.

In 2017, Rummel et al. published a crossover RCT comparing subcutaneous and IV rituximab in patients with previously untreated DLBCL or FL; the focus of the study was patient preference for mode of administration. (250) The trial included 740 patients, 63% had DLBCL and 37% had FL. All patients received 1 cycle of IV rituximab. Patients were then randomized to each of 2 treatments, in random order: 3 cycles of subcutaneous rituximab 1400 mg followed by 4 cycles of IV rituximab (arm A) or 3 cycles of IV rituximab followed by 4 cycles of subcutaneous rituximab (arm B). The primary outcome was overall patient preference for IV or subcutaneous rituximab assessed with a Patient Preference Questionnaire administered at cycles 6 and 8 that rated preference on a 3-point scale (very strong, fairly strong, not very strong). Safety and efficacy were included as secondary outcomes. Patients in both study arms preferred subcutaneous rituximab to IV rituximab (81% to 79% at cycle 6, 84% to 77% at cycle 8). In addition, 68% to 73% at cycle 6 and 71% to 76% at cycle 8 stated a very strong or fairly strong preference for subcutaneous rituximab. The most commonly stated reasons for preferring subcutaneous rituximab were “requires less time in the clinic” (68%-69%), “feels more comfortable during administration” (37%), and “feels less emotionally distressing” (28%-29%). The rates of CR (confirmed or unconfirmed) were 51% in arm A and 52% in arm B. Among patients with DLBCL (n=385), the rate of confirmed or unconfirmed CR was 56%. Both groups received multiple cycles of IV rituximab and subcutaneous rituximab, so the study is could not compare the efficacy of the 2 modes of administration.

Data on subcutaneous rituximab were also reported in the Rituxan Hycela product label. (197) The MabEASE study was an RCT in patients with previously untreated CD20-positive DLBCL comparing subcutaneous rituximab (n=369) with IV rituximab (n=203), both in combination with CHOP. As of August 2017, findings of MabEASE had not been published in a peer-review journal. A total of 82% of patients completed the 8-cycle intervention. The primary outcome, investigator-assessed complete response rate (confirmed or unconfirmed) at the end of combination treatment, was 179 (47%) in the subcutaneous rituximab group and 82 (42%) of 195 in the IV rituximab group. The difference in response rates was not statistically significant (4.9%; 95% CI, -3.6% to 13.5%). Survival outcomes were reported as secondary end points and did not differ significantly between groups. the overall survival rate was 17% in the subcutaneous rituximab group and 15% in the IV rituximab group (HR=1.22; 95% CI, 0.85 to 1.73). The progression-free survival rate was 27% in the subcutaneous rituximab group and 23% in the IV rituximab group (HR=1.08; 95% CI, 0.70 to 1.68). In terms of safety, the incidence of adverse events, grade 3 or 4 adverse events, and administration- related adverse events were similar in both groups. Ninety-one patients died during the study, 16% in each group. Of these, 44 patients (8% in the subcutaneous rituximab group and 5% in the IV rituximab group) died due to adverse reactions to treatment.

Chronic Lymphocytic Leukemia

A phase 1b open-label trial evaluated subcutaneous rituximab for treating CLL (SAWYER). Assouline et al. published stage 1 findings in 2015 (251) and stage 2 findings were published by Assouline et al. in 2016. (252) The trial included patients with previously untreated CD20-positive CLL (Binet stage A, B, or C). Stage 1 was a dose-finding study with 59 patients, 55 of whom completed the course of treatment. All patients received IV rituximab plus fludarabine and cyclophosphamide in cycle 1, IV rituximab in cycles 2, 3, and 4, and IV rituximab plus fludarabine and cyclophosphamide in cycle 5. In cycle 6, patients received a fixed dose of subcutaneous rituximab. The first patients received a dose of 1870 mg (n=22) and subsequent patients received 1400 mg (n=16) or 1600 mg (n=17). The primary objective of stage 1 was to identify a dose of subcutaneous rituximab that produced a serum trough concentration similar to that obtained during the initial treatment with IV rituximab. In the analysis, the investigators identified the optimal dose of subcutaneous rituximab as between 1400 mg and 1650 mg. SAWYER stage 2 was an open-label noninferiority RCT. A total of 176 patients with previously untreated CLL were randomized to IV rituximab (n=88) or subcutaneous rituximab (n=88) plus fludarabine and cyclophosphamide for up to 6 cycles. Patients in the subcutaneous rituximab group received 1 cycle of IV rituximab prior to receiving subcutaneous rituximab. The primary end point was the rituximab serum trough concentration at cycle 5. Tumor response was included as an exploratory secondary outcome. The pharmacokinetic analysis population included 134 (76%) of the randomized patients; the remainder were excluded because they withdrew from the trial or appropriate samples were not available. Subcutaneous rituximab was found to be noninferior to IV rituximab because the serum trough concentration exceeded the prespecified margin. Adverse events were reported in 82 (96%) of the subcutaneous rituximab group and in 81 (91%) of 89 of the IV rituximab group. The most common adverse events were neutropenia and nausea. More patients in the subcutaneous rituximab group had adverse events related to injection-site pain or reactions (e.g., erythema, pyrexia). More patients in the IV rituximab group had vascular adverse events (i.e., hypotension, hypertension). In an exploratory analysis of tumor response in the intention-to-treat population (n=176) 3 months after treatment, 75 (85%) in the subcutaneous rituximab group and 71 (81%) patients in the IV rituximab group had an overall response and 23 (26%) patients in the subcutaneous rituximab group and 29 (33%) patients in the IV rituximab group had a CR. The authors noted that the study was not powered to detect differences in efficacy between the groups.

Section Summary: Subcutaneous Rituximab

RCTs have evaluated subcutaneous rituximab in patients with previously untreated FL, DLBCL, and CLL. The studies found that subcutaneous rituximab was noninferior to IV rituximab in its pharmacokinetics, specifically serum trough concentration. The trials had response rates as primary or secondary outcomes, and all found that response rates were similar for subcutaneous rituximab and IV rituximab. Not all of the trials were powered to detect differences in response rates.

Nononcologic Uses of Rituximab

Rheumatoid Arthritis

The FDA approval of rituximab for RA was based on 4 placebo-controlled, randomized trials. Three trials enrolled adults (≥18 years of age) with moderately to severely active RA (defined as ≥8 swollen and ≥8 tender joints) who had a previous inadequate response to at least 1 TNF inhibitor. In the REFLEX trial, patients who received a single course of rituximab with concomitant methotrexate (MTX) had statistically significant and clinically meaningful improvements in disease activity at 24 weeks (as assessed by 20%, 50%, and 70% improvements in American College of Rheumatology [ACR] response criteria [ACR20, ACR50, ACR70, respectively]) compared with patients who received placebo. (3) On radiographic examination, progression of joint space narrowing and erosion at 48 and 96 weeks was less in patients who received rituximab: At 48 weeks, 60% of rituximab-treated patients had no progression of structural damage compared with 46% of placebo-treated patients; 87% of rituximab-treated patients who had no progression at 48 weeks also had no progression at 96 weeks. In the SUNRISE trial (2010), patients who received 2 courses of rituximab approximately 6 months apart had improved outcomes at 48 weeks (as assessed by ACR20) compared with those who received only 1 course of rituximab. (4) A third trial showed statistically significant and clinically meaningful improvements in physical function at 24 and 48 weeks in patients who received an initial course of rituximab 500 mg or 1000 mg compared with patients who received placebo. Radiographic responses were not assessed. (1,5)

A fourth randomized controlled trial (RCT; IMAGE) compared rituximab 500 mg with 1000 mg dosing in MTX-naive patients. (6) All patients received MTX. Patients who had active disease at 24 weeks could receive another course of rituximab at their assigned dose. At 48 weeks, the proportion of patients achieving clinically meaningful responses (ACR20, ACR50, ACR70) was similar in both rituximab groups and greater than placebo. However, compared with placebo, a statistically significant (67%) reduction in joint space narrowing and erosion was observed in the rituximab 1000-mg group only. (1)

Only studies have confirmed improvements in ACR20, ACR50, and ACR70 in patients treated with rituximab plus MTX compared with placebo plus MTX (summarized by Thaler et al. [2012] (1). Keystone et al. (2012) reported 5-year follow-up of the pivotal REFLEX trial. (7) Patients initially randomized to the placebo arm could receive rituximab in an observational extension study. In 400 patients who received 1 course of rituximab, ACR20, ACR50, and ACR70 responses were 62%, 31%, and 13%, respectively. In 91 patients who received 5 courses of rituximab, responses were 70%, 42%, and 22%, respectively. In 184 patients who had baseline and 5-year radiographs available, progression of joint damage over 5 years was less in rituximab-treated than in placebo-treated patients, although this difference was not statistically significant. Adverse event rates were generally stable over 5 years of follow-up. A 2015 Cochrane review of 8 studies (total N=2720 patients) also concluded that rituximab (labeled dosing) in combination with MTX improved multiple outcomes including ACR50, disease activity, physical function, x-ray progression, and quality of life (physical and mental). (8) Reviewers also noted fewer discontinuations among patients taking rituximab plus MTX compared with MTX alone—2 fewer per 100 after 2 years.

Observational studies conducted within registries including patients cared for in usual clinical practice have suggested that, after failure with at least 1 TNF inhibitor, rituximab may be more effective than an alternative TNF inhibitor. Emery et al. (2015) followed 1110 patients in a prospective international observational study (SWITCH-RA) in which patients stopping a single TNF inhibitor received a different TNF inhibitor or rituximab. (9) In the 728 patients with complete data allowing analysis, among patients discontinuing the initial TNF inhibitor for lack of efficacy, at 6 months rituximab treatment was accompanied by greater improvement in a modified Disease Activity Score (DAS28 score) (excluding global health assessment owing to missing baseline data, -1.7 vs -1.3). In 2017, Harrold et al. reported on 667 patients in the U.S. Coronna Registry with active RA who were treated with rituximab after receiving at least 1 TNF. (10) A total of 78% of patients continued taking rituximab for 1 year; the remainder switched to a different biologic. Overall, the Clinical Disease Activity Index (CDAI) improved from baseline to 1 year, with a median improvement of 8 points. Moreover, 30.4% of patients achieved CDAI low disease activity or remission (defined as CDAI ≤10) at 1 year. Other outcomes (e.g., global assessment, pain, fatigue) also improved at 1 year. Although the observational data are consistent, the lack of randomization limits definitive conclusions.

Section Summary: Rheumatoid Arthritis

Four RCTs have established the efficacy of rituximab in combination with MTX for patients with RA who had an inadequate response to 1 or more TNF inhibitors. Subsequent publications have confirmed this finding. A 5-year extension study reported sustained improvements in clinical and radiographic outcomes in patients who received at least 1 course of rituximab compared with placebo, although differences in progression of structural damage were not statistically significant. Observational studies have suggested switching to rituximab after failing 1 TNF inhibitor may be more efficacious than switching to another TNF inhibitor. Evidence for the use of rituximab in TNF inhibitor-naive patients is lacking. For patients with an inadequate response to MTX and contraindications to TNF inhibitor therapy, rituximab may be a reasonable option. In the 5-year extension study, adverse event rates were generally stable over time.

Antineutrophil Cytoplasmic Antibody?Associated Vasculitides (Granulomatosis with Polyangiitis [Wegener Granulomatosis] and Microscopic Polyangiitis)

Granulomatosis with polyangiitis (GPA; Wegener granulomatosis), microscopic polyangiitis (MPA), and Churg-Strauss syndrome are classified as antineutrophil cytoplasmic antibody (ANCA)?associated vasculitides because most patients with generalized disease have antibodies against proteinase 3 (PR3) or myeloperoxidase (MPO), enzymes found in neutrophil granulocytes. (11) Each vasculitis can be distinguished by the predominant type of immunofluorescence staining pattern (antibody) present, e.g., cytoplasmic ANCA (anti-PR3) in GPA and perinuclear ANCA (anti-MPO) in MPA. These vasculitides are also considered pauci-immune because, unlike immune complex vasculitides, they are not characterized by immune complex deposition. (12) ANCA-associated vasculitides affect small-to-medium-size blood vessels, particularly in the respiratory tract and kidneys; the characteristic kidney lesion is pauci-immune focal and segmental necrotizing and crescentic glomerulonephritis. (13) Limited vasculitis may respond to MTX plus glucocorticoids; standard treatment for more severe disease is cyclophosphamide plus glucocorticoids. Finally, these conditions are uncommon. The prevalence of GPA in the United States is estimated at 32 per million and MPA 2.9 per million. (14) Rituximab is FDA-approved in combination with glucocorticoids for the treatment of adults with GPA and MPA. The FDA’s approval of rituximab for GPA and MPA was based on 1 active-controlled randomized trial, the Rituximab in ANCA-Associated Vasculitis (RAVE) noninferiority trial. (11) Patients 15 years of age or older who had severe (Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis [BVAS/GPA] ≥3 [scores range, 0-63, with higher scores indicating more active disease], with at least 1 major item) GPA (n=151) or MPA (n=48) were enrolled. Patients with Churg-Strauss syndrome, considered by the authors to be a mimicker of ANCA-associated vasculitis, were excluded. Patients with severe alveolar hemorrhage or severe kidney disease (serum creatinine, >4 mg/dL) also were excluded. Approximately half of patients had newly diagnosed disease and half had relapsing disease, with mean disease duration of approximately 6 years. Patients were randomized to rituximab 375 mg/m2 weekly for 4 weeks (remission induction phase) followed by oral placebo beginning at 3 to 6 months (maintenance phase; n=99), or cyclophosphamide 2 mg/kg orally daily for 3 to 6 months (remission induction) followed by oral azathioprine daily beginning at 3 to 6 months (maintenance phase; n=98). All patients received 1 to 3 pulse doses of parenteral methylprednisolone 1000 mg followed by prednisone 1 mg/kg orally daily. Patients who achieved remission tapered and discontinued prednisone by month 5. The primary end point was complete remission at 6 months, defined as BVAS/GPA of 0 off prednisone. The prespecified noninferiority margin was a treatment difference of -20 percentage points (rituximab group minus cyclophosphamide group). At 6 months, 63% of patients in the rituximab group and 52% of patients in the cyclophosphamide group achieved complete remission, for a treatment difference of 11 percentage points (95% CI, -3 to 24), which exceeded the noninferiority margin. The incidence of adverse events was similar between treatment groups, with grade 2 or higher leukopenia more common in the cyclophosphamide group (10% vs 3% rituximab) and hospitalizations due to disease or treatment more common in the rituximab group (8% vs 2% cyclophosphamide).

Specks et al. (2013) published 18-month follow-up results to RAVE. (15) Patient blinding was maintained throughout the follow-up period. Among rituximab-treated patients, 47% achieved and maintained complete remission to 12 months, and 39% maintained complete remission to 18 months. In the cyclophosphamide/azathioprine group, 38% achieved and maintained complete remission through 12 months, and 32% maintained complete remission through 18 months. Treatment differences at 12 and 18 months (9 percentage points [95% CI, -5 to 22] at 12 months, 7 percentage points [95% CI, -7 to 20] at 18 months) exceeded the noninferiority threshold (-20 percentage points) but did not demonstrate superiority.

A subsequent analysis (2014) examined treatment and outcomes of 26 patients from the RAVE trial experiencing severe relapses suggesting rituximab may be safely used. (16) Relapses treated with rituximab were accompanied by remission rates of 87% (n=15, rituximab arm of trial) and 91% (n=11, cyclophosphamide plus azathioprine arm of trial). Although the sample was derived from the RAVE trial, the study was observational, with limited implications.

Jones et al. (2010) conducted an open-label RCT (RITUXVAS) to compare first-line induction regimens in 44 patients who had newly diagnosed ANCA-associated vasculitis with renal involvement (50% GPA, 36% MPA, 14% renal-limited vasculitis). (17) Renal involvement was defined as necrotizing glomerulonephritis on biopsy, or red-cell casts or hematuria (≥30 red cells per high-power field) on urinalysis. Median baseline glomerular filtration rate was 18 mL/min; 9 patients were dialysis-dependent (glomerular filtration rate, 0). Patients were randomized 3:1 to rituximab 375 mg/m2 weekly for 4 weeks plus intravenous (IV) cyclophosphamide 15 mg/kg with the first and third rituximab infusions, or IV cyclophosphamide for 3 to 6 months followed by azathioprine. Both groups received 1 dose of IV methylprednisolone 1 g and oral corticosteroid 1 mg/kg daily reducing to 5 mg daily at the end of 6 months. Primary outcomes were sustained remission (BVAS of 0 for ≥6 months) and incidence of severe adverse events at 12 months. No patients were lost to follow-up. At 12 months, between-group differences in primary outcomes were not statistically significant. Twenty-five (76%) patients in the rituximab group and 9 (82%) patients in the control group had a sustained remission (p=0.68). Serious adverse events occurred in 14 (42%) patients in the rituximab group and 4 (36%) patients in the control group (p=0.77); 2 (6%) patients, both in the rituximab group developed cancer (malignant melanoma, breast cancer). Among secondary outcomes, median time to remission was 90 days (interquartile range [IQR], 79-112 days) in the rituximab group and 94 days (IQR, 91-100 days) in the control group (p=0.87). At 12 months, median increase from baseline glomerular filtration rate was 19 mL/min in the rituximab group and 15 mL/min in the control group (p=0.14). Six of 8 dialysis-dependent patients randomized to rituximab had a sustained remission, five of whom no longer required dialysis; one dialysis-dependent randomized to control died soon after study entry. Eighteen percent of patients in each group had serious infections, and 18% in each group died. At 24 months, 6 (18%) of 33 patients in the rituximab group and 3 (27%) of 11 patients in the control group had died. (18)

Given the substantial relapse rate (50% through 5 years (19) with maintenance therapy (typically MTX or azathioprine and glucocorticoids), the potential role for rituximab maintenance has been examined. The MAINRITSAN trial (2014) included 87 patients with GPA, 23 with MPA, and 5 having only renal involvement of ANCA-associated vasculitis. (20) All were in complete remission following cyclophosphamide plus glucocorticoid treatment. Patients were randomized to rituximab or azathioprine regimens through 22 months with the primary end point (major relapse) assessed at 28 months. Major relapse was more frequent with azathioprine (n=17 [29%]) than rituximab (n=3 [5%]), but with considerable uncertainty (hazard ratio [HR], 6.61; 95% CI, 1.56 to 27.96). Similar rates of severe adverse events were observed with either treatment. Although trial results suggested rituximab maintenance superior, limitations include the small number of participants and tapering azathioprine dose between months 12 and 22. The Rituximab Vasculitis Maintenance Study (NCT01697267), which has a projected completion date of December 2019, may resolve some of these uncertainties.

Section Summary: Antineutrophil Cytoplasmic Antibody?Associated Vasculitides

One double-blind, double-dummy RCT demonstrated the noninferiority of rituximab to cyclophosphamide in patients with newly diagnosed or relapsing severe GPA (formerly called Wegener granulomatosis) or MPA. Both treatments were administered in combination with glucocorticoids. More patients who received a single course of rituximab maintained complete remission for 12 and 18 months compared with patients who continued azathioprine maintenance therapy, although these differences were not statistically significant. An open-label RCT in patients with newly diagnosed ANCA (GPA or MPA)-associated nephropathy showed no difference in sustained remission or serious adverse events at 12 months in patients treated with or without a rituximab-containing induction regimen. One trial found rituximab of similar efficacy in maintaining remission compared with an azathioprine regimen.

Autoimmune Blood Disorders

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) comprises direct Coombs-positive anemias, such as warm (80% of AIHA) and cold autoantibody types, and drug-induced AIHA. Warm AIHA is mediated by warm-reactive antibodies, primarily immunoglobulin G (IgG), that react optimally with human red blood cells in vitro at 37°C (98.6°F). Cold-reactive antibodies, primarily IgM, react maximally at 4° (39°F). Cold AIHA, in turn, comprises cold agglutinin syndrome and paroxysmal cold hemoglobinuria. Warm and cold AIHA may be idiopathic (primary) or secondary, e.g., to lymphoma or lymphoproliferative disorders. Corticosteroids are first-line treatment in warm AIHA but less effective in cold AIHA. (21,22)

Warm AIHA:

A 2011 systematic review of treatments for idiopathic warm AIHA in adults identified 3 studies (case series) of rituximab treatment for refractory disease (total N=42 patients). (23) Overall response rate (ORR) was 93% (complete response, 43%; partial response, 50%). One study (2009) reported relapse in 2 (15%) of 13 responders and severe sepsis in 1 (4%) of 27 rituximab-treated patients with a mean follow- up of 21 months. (24) Reviewers recommended rituximab 375 mg/m2 weekly for 4 weeks or splenectomy for relapsed or refractory warm AIHA (level 2 recommendation [evidence suggests that benefits and risks are finely balanced or uncertain] based on level C evidence [case series]).

Subsequently, 2 RCTs have been published in patients with newly diagnosed warm AIHA. Birgens et al. (2013) published a multicenter RCT of first-line rituximab in newly diagnosed patients with idiopathic or secondary warm AIHA. (25) Patients were randomized to rituximab (375 mg/m2 weekly for 4 weeks) plus short-course (2 weeks followed by taper) prednisolone (n=32) or prednisolone alone (n=32). At 12 months, ORR was 75% in the rituximab group and 36% in the control group (p=0.003). At 36 months, 70% of rituximab responders and 45% of control responders maintained complete or partial response (p=0.02). Serious adverse events occurred in 9 (28%) of 32 rituximab-treated patients and 5 (17%) of 32 controls (p=0.12). These events included 5 serious infections in the rituximab group and 2 serious infections in controls (p=0.16). In 2017, Michel et al. randomized 32 patients with warm AIHI that was diagnosed and treated no more than 6 weeks previously to rituximab (n=16) or placebo (n=16). (26) Patients received 2 infusions, 2 weeks apart (i.e., days 1 and 15 after randomization), prior to which all patients were treated with methylprednisolone. The primary outcome was the overall response rate (partial and complete responses) at 1 year. In an intention-to-treat analysis at 1 year, overall response rates were 75% (95% CI, 47.6% to 92.7%) in the rituximab group and 31% (11% to 58.7%) in the placebo group; the difference between groups was statistically significant (p=0.032). Eleven of 12 patients who responded in the rituximab group had a complete response and all 5 patients in the placebo group who responded had a complete response. Serious adverse events occurred in 4 patients in the rituximab group and 7 patients in the placebo group. Serious infections occurred in 2 patients in the rituximab group and 6 patients in the placebo group (p=0.39). Patients were followed for 2 years, at which time 6 patients in the placebo group and none in the rituximab group had died (p=0.017).

Cold Agglutinin Syndrome

In a 2008 review of cold AIHA, Petz identified 11 case reports and case series of rituximab in cold agglutinin syndrome. (22) In 2 case series (total N=47 patients), ORR was 62%. The median duration of response in 20 responders was 11 months, and no serious adverse events were reported in 20 rituximab- treated patients. Based on this evidence, Petz suggested rituximab as a treatment option for cold agglutinin syndrome, along with avoidance of cold and immunosuppressive drugs.

Systematic Reviews: Warm or Cold AIHI

Reynaud et al. (2015) conducted a meta-analysis of 21 observational studies (total N=409 patients). (27) The pooled ORR was 73% (95% CI, 64% to 81%; 20 studies) with considerable heterogeneity (I2=60%); complete response rate was 37% (95% CI, 26% to 49%; 20 studies), also accompanied by substantial heterogeneity (I2=72%). There was evidence of publication bias in the pooled ORR but not the complete response. In cold agglutinin syndrome, the pooled ORR was 57% (95% CI, 47% to 99%; 6 studies). For warm AIHI, the pooled ORR was 79% (95% CI, 60% to 90%; 11 studies). These results supported the previously cited literature, with heterogeneity suggesting the potential to identify predictors of response (explored by the authors) using individual-level data. The potential publication bias suggests the pooled response rate (at least ORR) is biased upward.

Paroxysmal Cold Hemoglobinuria

Due to the generally self-limiting course and excellent prognosis of paroxysmal cold hemoglobinuria, rituximab is not considered a treatment option.

Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disorder with no known cause, although it can co-occur with other autoimmune diseases. Corticosteroids, intravenous immunoglobulins (IVIG), or anti-Rho(D) immunoglobulin are standard initial treatments. However, relapses are common within the first year, and splenectomy is often required. Rituximab has been investigated to delay or avoid splenectomy. (28,29)

Auger et al. (2012) conducted a meta-analysis of studies evaluating rituximab before splenectomy in adults with ITP. (28) Literature was searched through May 2011; 15 retrospective or prospective observational studies and 4 RCTs were included (total N=368 nonsplenectomized patients). Publication bias was not detected. Thirteen studies dosed rituximab at 375 mg/m2 weekly for 4 weeks; 6 studies used alternative regimens. Concomitant medications were not described. Median follow-up was 9 months (range, 2.3-65 months). Pooled ORR (platelet count, >50x109/L) was 57% (95% CI, 48% to 65%; I2=49%; 20 studies), and 57% (95% CI, 35% to 76%; I2=79%) at 1 year (6 studies). In separate analyses, complete response rate (defined as platelet count either >150x109/L or >100x109/L) was 41% (95% CI, 33% to 50%; I2=51%; 19 studies) and 40% (95% CI, 31% to 49%; I2=0%) at 1 year (5 studies). In 36 responding patients, mean time to response and median duration of response were 6.3 weeks (95% CI, 2.8 to 9.9 weeks) and 49 weeks (range, 17-60 weeks), respectively. Adverse events and meta-analysis of RCT control arms were not reported.

Liang et al. (2012) conducted a systematic review of studies of rituximab for ITP in children. (30) Literature was searched through December 2011, and 30 case series or case reports were included (total N=370 patients). Publication bias was not detected. Median patient age was 8 years (range, 6 months to 19 years). Thirty-nine (11%) patients have had splenectomy. The most common rituximab dose (in 47% of patients) was 375 mg/m2 weekly for 4 doses; concomitant medications were not described. Pooled ORR (platelet count, ≥30x109/L with at least doubling of the platelet count, a standard response criterion) was 68% (95% CI, 58% to 77%; I2=68%), and pooled complete response (platelet count, ≥100x109/L) was 39% (95% CI, 30% to 49%; I2=57%). Median time to response was 3.0 weeks (IQR, 1.0-3.6 weeks) in 40 responders, and median duration of response was 12.8 months (IQR, 4.5-25.1 months). The incidence of grade 3 or 4 infection and grade 3 or 4 immediate hypersensitivity reaction or serum sickness was 4% each.

Two RCTs published after these systematic reviews examined rituximab in adults with newly diagnosed ITP. Gudbrandsdottir et al. (2013) randomized 133 patients with newly diagnosed ITP to rituximab 375 mg/m2 weekly for 4 weeks plus dexamethasone 40 mg daily for 4 days (n=62) or dexamethasone alone (n=72). (31) Patients had baseline platelet counts of 25x109/L or less, or 50x109/L or less with bleeding symptoms. Median follow-up was 2.5 years. ORR (platelets count ≥50x109/L) sustained at 6 months was 58% in the rituximab group and 37% in the control group (p=0.02); at 12 months, sustained response rates were 53% and 33%, respectively (p<0.05). Among responders, the median time to rescue treatment was not reached in the rituximab group and 7.4 months in the control group (p=0.007). The median platelet count at the time of rescue treatment was 15x109/L (IQR, 7-24 x109/L). Time to relapse also was longer in the rituximab group (p=0.03). Serious adverse events occurred more commonly in the rituximab group (26%) than in the control group (11%; p=0.04). Because the authors reported numbers of adverse events rather than patients who experienced adverse events, incidences could not be calculated.

Arnold et al. (2012) reported on a feasibility study of rituximab in nonsplenectomized adults with newly diagnosed (47%) or relapsed (53%) ITP. (29) Sixty patients were randomized to rituximab 375 mg/m2 weekly for 4 weeks (n=33) or placebo (n=27), both administered in combination with standard treatments (most commonly prednisone, dexamethasone, and IVIG). The primary efficacy outcome was a composite of any platelet count less than 50x109/L, significant bleeding, or rescue treatment once standard treatment was stopped. At 6 months, the between-group difference of the composite end point was not statistically significant (64% rituximab vs 78% placebo; relative risk, 0.81; 95% CI, 0.59 to 1.11). Differences in overall (platelet count, ≥30x109/L) or complete (platelet count, ≥100x109/L) response were not statistically significant at 6 or 12 months. Significant bleeding events occurred less commonly in the rituximab group (25%) than in the control group (35%). The number of infections (any grade) and serious adverse events were comparable between groups. Because numbers of adverse events rather than patients who experienced adverse events were reported, incidences could not be calculated.

Despite lack of clarity in the long-term durability of response, trials have suggested that there is a potential initial benefit from rituximab in untreated patients; however, in practice rituximab is generally reserved for treatment failures. Ghanima et al. (2015) reported results from a multicenter, double-blind, placebo-controlled, randomized trial of rituximab as second-line therapy in adult ITP (the RITP trial). (32)

Glucocorticoid-unresponsive patients (112 randomized, 3 refused treatment) were included from 14 centers in Norway, Tunisia, and France. Participants were unsplenectomized adults with platelet counts below 30x109/L and had failed to respond to glucocorticoids or relapsed during dose tapering or after stopping. Patients were randomized to infusions of rituximab or saline (placebo); glucocorticoids were continued but tapered to maintain platelet counts (>20x106/L). The initially specified primary end point was splenectomy within 1.5 years, but because of approval of thrombopoietin receptor agonists, it was revised to “treatment failure” defined by splenectomy after week 12 or meeting criteria for a splenectomy. The study was powered to detect a reduction in primary end point occurrence from 70% to 40% or a hazard ratio of 2.57, with a potential 20% dropout rate. Overall response was defined as a platelet count of 30x109/L or higher and complete response as a platelet count of 100x109/L or higher 4 weeks after drug administration (a doubling of platelet count was also required). Through 1.5 years, overall response was observed in 81% and 73% of the rituximab and placebo arms respectively (p=0.15), and complete response in 58% and 50% (p=0.12). Treatment failure occurred in 46% receiving rituximab and in 52% of the placebo arm (HR=0.89; 95% CI, 0.55 to 1.45; p=0.65). Splenectomies were performed in 8 (15%) receiving rituximab arm 14 (26%) receiving placebo (p=0.12). However, rituximab-treated patients experienced a longer median time to relapse (36 weeks vs 7 weeks). One or more bleeding episodes occurred in 21 (38%) and 27 (50%) of the rituximab and placebo arms, respectively, but more severe episodes were observed with rituximab. Finally, the cumulative steroid dose did not differ between treatment arms (p=0.33).

The well-conducted RITP trial failed to demonstrate improved outcomes with rituximab as second-line therapy in adults with ITP, despite generally more favorable outcomes with rituximab in the trial. In context, splenectomy achieves sustained response in 60% to 70% of patients. Here, 24% of rituximab- treated and 14% of placebo-treated patients experienced sustained responses. The results did not support the use of rituximab in this setting.

Subsection Summary: Idiopathic Thrombocytopenic Purpura

Two systematic reviews in ITP of primarily observational studies (1 in children [median age, 8 years], 1 in adults) and 2 RCTs in adults investigated mostly nonsplenectomized patients. Overall and complete response rates were approximately 57% and 40%, respectively, in adults, and 68% and 39% in children. Median response durations were approximately 1 year.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition characterized by microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia leading to end-organ ischemia and infarction (commonly brain, heart, kidneys). (33) TTP is due to an acquired (95% of cases) or congenital (5% of cases) deficiency of the von Willebrand factor?cleaving protease, ADAMTS13. In 38% to 95% of cases of idiopathic TTP, anti-ADAMTS13 neutralizing antibodies are present. (34) When ADAMTS13 is absent or depleted, large uncleaved von Willebrand factor multimers aggregate in high shear areas of the microvasculature, leading to thrombotic microangiopathy. (35) The main treatment for TTP is plasma exchange (PE) and corticosteroids. Refractory TTP, defined as progression of clinical symptoms during PE therapy, occurs in 10% to 20% of acquired TTP cases. (36) For these patients, increased PE and/or addition of cyclosporine are current treatment options. (35) The evidence for use of rituximab in TTP is comprised of a single phase 2 cohort study and several case series. All studies enrolled patients with acquired (i.e., anti-ADAMTS13 antibody-positive) TTP.

Acute Refractory or Relapsed TTP

Scully et al. (2011) conducted a phase 2, multicenter, nonrandomized cohort in England. (37) Forty patients with anti-ADAMTS13 antibody-positive, new-onset (85%) or acute relapsed (15%) TTP were enrolled and compared with an age-, sex-, and ethnicity-matched historical control group of 40 patients. Enrolled patients received rituximab 375 mg/m2 weekly for 4 weeks; 3 patients died, and 1 withdrew before receiving all 4 doses of rituximab. All patients and historical controls received PE at admission and then daily (or twice daily for new or progressive neurologic or cardiac symptoms; protocol maximum of 8 infusions) until remission, defined as sustained platelet count (>15x109/L) for 2 consecutive days; corticosteroid (typically IV methylprednisolone 1 g/d) was given for 3 days. The primary efficacy outcome was the number of PE treatments to remission. Forty enrolled patients received a median of 16.5 (range, 4-34) PE treatments compared with 18 (range, 6-92) treatments in the historical control group (p=0.5). Among secondary outcomes, there was no statistical difference between groups in the number of hospital admission days, but among patients who relapsed (4 in the rituximab group, 21 in the control group), median time to relapse (defined as readmission with thrombocytopenia <150x109/L 30 days after discharge from an acute episode) was longer in rituximab-treated patients (27 months; range, 17-31 months) than in historical controls (18 months; range, 3-60 months). However, follow-up for rituximab and control groups was 12 and 49 months, respectively. Both incidence of infections and serious adverse events were similar between groups.

In 2007, Scully et al. reported a multicenter cohort study of 25 patients who had anti-ADAMTS13 antibody-positive acute relapsing (56%) or acute refractory (44%) TTP. (38) Patients received methylprednisolone daily for 3 days, daily PE until sustained platelet count (as previously defined), and rituximab 375 mg/m2 immediately after PE weekly for 4 weeks. All 25 patients achieved clinical remission (defined as cessation of PE, sustained platelet count, and absence of clinical disease) within 1 to 3 weeks of treatment. During median follow-up of 10 months (range, 1-33 months), there were no relapses and no infectious complications.

This study was 1 of 15 case series and 16 case reports (total n=100 patients) included in a systematic review by Tun et al. (2012) of immune-mediated, relapsed or refractory TTP treated with rituximab. (33) Studies of secondary TTP and empirical rituximab treatment were excluded. In all studies, rituximab was dosed at 375 mg/m2 weekly for a median of 4 doses (range, 1-8 doses). Ninety-eight (98%) patients achieved complete response, defined as platelet recovery, lack of TTP-related symptoms, and no evidence of microangiopathic hemolytic anemia lasting more than 30 days. Two (2%) patients were considered nonresponders. During median follow-up of 13 months (range, 1-97 months), 9% of patients who achieved complete response relapsed. Anti-ADAMTS13 antibody positivity and severe ADAMTS13 deficiency (enzyme activity, <10%) predicted response to rituximab (positive predictive value, 99% for both). Serious rituximab-related adverse events occurred in 3 (3%) patients: acute biventricular cardiogenic shock, sacral abscess, and abdominal abscess.

Froissart et al. (2012) conducted a single-arm trial in 22 adults with acute (n=6) or relapsed (n=16) TTP refractory to therapeutic PE. (34) Rituximab was administered in 4 infusions over 15 days. Patients were enrolled from a registry in the Reference Network for Thrombotic Microangiopathies (France). Outcomes were compared with a historical control group of 57 consecutive patients (from the same registry, all ADAMTS13-deficient) treated with vincristine with or without cyclophosphamide. Both current patients and historical controls were treated using defined protocols. There was 1 (4.5%) death in the rituximab group and 4 (7.0%) in 57 historical controls. Platelet count recovery (>150x109/L) was observed in the 21 survivors (100%) vs 78% of historical controls; by day 35, all rituximab survivors had platelet count recovery versus 78% of controls, with shorter time to recovery in the rituximab group. No relapses were observed in rituximab-treated patients in the first year following treatment while 5 patients in the control group relapsed (p=0.34). Adverse effects of rituximab were not recorded during follow-up. Implications of these results are limited primarily by a small sample size, lack of randomization, and treatment dates (historical controls treated between 2000 and 2005 vs rituximab group between 2005 and 2008). That said, the results are consistent with others suggesting potential benefit in refractory and relapsed TTP.

Section Summary: Autoimmune Blood Disorders

Evidence for rituximab in AIHA comprises a small number of patients with primary (idiopathic) and secondary disease. For warm AIHA, 2 RCTs found higher response rates with rituximab than with a control condition in patients with previously untreated disease. Serious adverse events were higher with rituximab than corticosteroids (1 RCT) but lower than placebo (the other RCT). For cold agglutinin syndrome, which generally has a poorer response than warm AIHA to first-line corticosteroids, a response rate of 62% was reported. A meta-analysis including 21 studies estimated a pooled ORR at 79% in warm AIHI and 57% in cold agglutinin syndrome, but the potential for publication bias suggested these estimates biased upward. As a potential glucocorticoid-sparing agent in warm AIHA and effective treatment for cold agglutinin syndrome, rituximab may improve health outcomes. Rituximab is not considered a treatment option for paroxysmal cold hemoglobinuria.

Two systematic reviews in ITP of primarily observational studies (1 in children [median age, 8 years], 1 in adults) and 2 RCTs in adults investigated mostly nonsplenectomized patients. Overall and complete response rates were approximately 57% and 40%, respectively, in adults, and 68% and 39% in children. Median response durations were approximately 1 year. Adverse event reporting was inconsistent; serious infections and hypersensitivity reactions occurred in 4% of 370 children included in the systematic review. A placebo-controlled randomized trial evaluating rituximab as second-line therapy did not demonstrate benefit compared with placebo.

Studies of rituximab in TTP have enrolled patients with acquired (anti-ADAMTS13 antibody-positive) TTP. One small phase 2 nonrandomized cohort trial in patients with new-onset or relapsed TTP showed no difference compared with historical controls in the number of PE treatments needed to achieve remission. For patients with relapsed or refractory TTP, observational studies (case reports, case series) reported remission in 98% of rituximab-treated patients with a median follow-up of 10 months. A nonrandomized trial found rituximab-treated patients had shorter duration of treatment and fewer 1-year relapses than historical controls. This evidence suggests that, despite a small (3%) risk of serious adverse events with rituximab, some patients treated with PE who have relapsed or refractory disease may benefit from the addition of rituximab. Because progressive disease is potentially life-threatening and because relapsed and refractory patients have few alternative treatment options, rituximab may be considered medically necessary in this setting. A single case series of rituximab prophylaxis for recurrent disease provides insufficient evidence for the use of rituximab in this setting.

Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis)

Churg-Strauss syndrome, also called eosinophilic granulomatosis with polyangiitis (EGPA), is an ANCA- associated vasculitis characterized by peripheral and tissue eosinophilia, frequently affecting the lungs, in patients with asthma. (39) The disease is uncommon, with an estimated prevalence of 11 to 14 per million adults. Eosinophilic infiltration of the heart, lungs, and kidneys can lead to ventricular dysfunction, pulmonary hemorrhage, and renal failure, respectively; cardiac involvement is the leading cause of early death. Treatment recommendations are based primarily on studies in other ANCA-associated vasculitides (GPA and MPA). Corticosteroids are used with or without cyclophosphamide, depending on disease severity. Azathioprine or MTX may be used as steroid-sparing agents. Because of its demonstrated efficacy in GPA and MPA, rituximab has been used in patients with EGPA syndrome refractory to conventional immunosuppressant therapy. (40)

A small number of case series has been reported, and three identified as full publications summarized here. Thiel et al. (2013) reported a case series of 9 treatment-refractory patients who received rituximab add-on therapy. (41) All patients responded (1 complete response [BVAS=0 for ≥3 months and stable prednisone dose ≤7.5 mg daily], 8 partial remissions [BVAS >0]) after 1 cycle of rituximab with no relapses in 9 months of follow-up. Three patients who received preemptive retreatment (i.e., not in response to relapse) were relapse-free for a median follow-up of 3 years. Five (55%) of 9 patients had minor respiratory infections. One patient who received a second (preemptive) course of rituximab developed a testicular seminoma 12 months after the first cycle (6 months after the second cycle). Muñoz et al. (2015) reported results from 27 rituximab-treated EGPA patients with refractory (n=20), relapsed (n=5), and newly diagnosed (n=2) disease. (42) Adverse events included infections (n=2), bronchospasm (n=2), and seminoma (n=1). Mohammad et al. (2016) identified 20 men and 21 women treated with rituximab between 2003 and 2013 at 4 vasculitis centers-15 (37%) with refractory, 21 (51%) with relapsing, and 5 (12%) with new-onset EGPA. (43) At 1 year, remission was observed in 49% and partial response in 39%; 31 adverse events occurred, including 6 severe infections requiring hospitalization. Novikov et al. (2016) reported data of 6 patients with moderately severe or severe relapsing disease refractory to conventional immunosuppression. (44) A primary end point was complete or partial remission within 3 to 6 months after rituximab administration. The median duration of follow-up after the first rituximab dose was 10 months. All patients rapidly responded to rituximab treatment (e.g., disappearance of lung infiltrates, improvement of asthmatic symptoms, at least partial recovery of motor and sensory function). Within 3 to 6 months, complete (4/6) or partial (2/6) remission was achieved in all patients.

Section Summary: Churg-Strauss Syndrome

Evidence for rituximab in Churg-Strauss syndrome comprises case series primarily in treatment-refractory patients. Response and remission rates were generally high. Treatment-related adverse events—some severe—have been reported. Because little is known about treatment options for patients’ refractory to conventional immunosuppressants, and because rituximab has demonstrated efficacy in other ANCA-associated vasculitides (GPA and MPA), rituximab has been considered for use an add-on therapy in patients with treatment-refractory Churg-Strauss syndrome.

Factor Inhibitors in Hemophilia

Hemophilia is a coagulopathy characterized by reduced, absent, or nonfunctioning clotting factor VIII (FVIII) (hemophilia A) or, less commonly, factor IX (hemophilia B). Treatment comprises replacement therapy with the missing or deficient clotting factor. Over time, antibodies to infused clotting factor develop in 20% to 30% of patients with severe hemophilia A and 2% to 5% of patients with hemophilia B. (45) If left untreated, antibody inhibitors eventually render replacement therapy ineffective. Immune tolerance induction (ITI) is recommended first-line treatment of factor inhibitors in hemophilia. (46) ITI comprises increasing the dose and frequency of factor infusions until inhibitor is undetectable and FVIII levels normalize. Success rate is low (25%), and associated risks (e.g., anaphylaxis, irreversible nephrotic syndrome) are significant. Other regimens incorporate immunosuppressive drugs. Rituximab has been investigated as an alternative to ITI or for patients who are nonresponsive to ITI.

Hemophilia is generally considered a genetic disorder, but acquired hemophilia A is a rare autoimmune disease caused by acquired auto-antibodies against FVIII. Underlying medical conditions, such as autoimmune diseases, solid tumors, lymphoproliferative malignancies, or pregnancy, can be identified in approximately half of patients. Immunosuppressive therapy with corticosteroids alone or in combination with cyclophosphamide is recommended for first-line inhibitor eradication. Rituximab has been studied as second-line treatment in this setting. (47)

Congenital Hemophilia

Collins et al. (2013) reviewed the literature on rituximab for treatment of factor inhibitors in congenital hemophilia. (46) Several case reports in patients who failed conventional ITI reported mixed responses. A cohort study of 15 patients’ refractory to first-line ITI showed improved response when rituximab was added to ITI rather used as monotherapy. But durable responses were uncommon (14%). In case reports and case series, rituximab has been added to ITI in patients with hemophilia B with mixed results.

In 2008, Franchini et al. published a systematic review of rituximab in congenital hemophilia with inhibitors. (48) A literature search identified 29 studies (case reports, case series; total N=49 patients). In most reports, rituximab was given after failure of several courses of conventional ITI. Half of the studies administered rituximab in combination with ITI or other immunosuppressive treatment (e.g., plasmapheresis, immunoadsorption, immunosuppressive drugs), and half administered rituximab monotherapy. Analysis of individual patient data showed complete remission in 53% of patients. No serious rituximab-related adverse events were reported. In multivariate analysis, coadministration with FVIII, ITI was statistically associated with response (HR=4.7; 95% CI, 1.6 to 13.7; p=0.005), although the confidence interval was wide, suggesting instability of the effect estimate, likely due to small numbers.

Laros-van Gorkom et al. (2014) conducted a systematic review of immunosuppressants in congenital hemophilia. (49) Only case reports and cohort studies were identified. Cyclophosphamide (46 children, 39 adults) and rituximab (42 children, 23 patients) were the most commonly used drugs, with overall success rates of 40% to 44% and 40% to 63%, respectively. Three infections were reported with cyclophosphamide (three severe sepsis) and six with rituximab.

Leissinger et al. (2014) reported results from a phase 2 trial of rituximab monotherapy to decrease amnestic FVIII antibody levels in patients with congenital hemophilia A. (50) Investigators planned to attain a sample size of 50, but, due to low accrual, closed enrollment after 16 patients (data and safety monitoring board decision). Four weekly doses of rituximab (375 mg/m2) were administered. A major response was seen in 3 (18.8%) patients, and 1 had a minor response through 22 weeks; 11 participants experienced serious adverse events. The authors concluded: “Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.”

Acquired Hemophilia A

Huth-Kuhne et al. (2009) reviewed the literature on rituximab for inhibitor eradication in acquired hemophilia A. (47) Uncontrolled studies and case reports usually administered rituximab in combination with other immunosuppressive treatments. Remission rates in 43 rituximab-treated patients (half first-line therapy, half second-line therapy) and 44 control patients treated with cyclophosphamide and corticosteroids (all first-line) were comparable.

Section Summary: Factor Inhibitors in Hemophilia

Rituximab for factor inhibitor eradication in congenital hemophilia and acquired hemophilia A has been studied in a small number of patients, primarily in case reports and cohort studies. In ITI-refractory patients with congenital hemophilia and factor inhibitor, remission rates between 40% and 63% have been reported in patients who received rituximab alone or in combination with continued ITI. A comparative study in acquired hemophilia A did not find improved response rates in patients treated with rituximab alone or in combination compared with standard cyclophosphamide plus cyclosporine.

Evidence does not support rituximab as an alternative to standard treatments for factor inhibitor eradication (i.e., ITI in congenital hemophilia and immunosuppression with cyclophosphamide and corticosteroids in acquired hemophilia A). However, the evidence does suggest that patients who are refractory to these first-line treatments may benefit from rituximab without an increase in adverse events. Combination regimens may be preferred. Given the lack of treatment options in refractory patients and the serious, possibly fatal, outcomes if factor inhibitors are not eradicated, rituximab may be considered in this setting.

Hepatitis C Virus?Associated Cryoglobulinemic Vasculitis

Of 3 types of cryoglobulinemia, type 2 and type 3 may be called “mixed” due to the clonal expansion of more than 1 immunoglobulin class, commonly IgM and IgG. (Type 1, in contrast, is characterized by a single monoclonal immunoglobulin.) Eighty percent of mixed cryoglobulinemic vasculitis is associated with chronic hepatitis C virus (HCV) infection. Treatment of the underlying infection to achieve sustained viral response is the treatment of choice. For patients who do not achieve sustained viral response, corticosteroids and cytotoxic agents are alternative treatment options but may exacerbate underlying liver disease. (51,52)

In 2013, Dammacco et al. (52) and Puéchal and Guillevin (53) published reviews of HCV-associated cryoglobulinemic vasculitis. Previous treatment recommendations, (54) recently published RCTs, (55,56) and heterogeneous nonrandomized studies (that varied by design, HCV genotype, previous treatment, rituximab dose, concomitant therapy) (total N=377 patients) reported response rates of approximately 80%, and led the reviewers to draw the following conclusions (52,53):

The choice of most suitable treatment for a given patient is based on the level of disease activity and the extent and severity of organ involvement.

o For patients with mild-to-moderate disease activity, antiviral therapy is recommended as first- line treatment.

o For patients with active disease that is resistant to antiviral agents, and for patients with severe (e.g., leg ulcers, glomerulonephritis, peripheral neuropathy) or life-threatening cryoglobulinemic vasculitis, the addition of rituximab (or other B-cell-depleting monoclonal antibody) may slow or halt disease progression.

o Pegylated interferon alfa may exacerbate some clinical features of cryoglobulinemic vasculitis, such as skin ulcers and peripheral neuropathy.

o When rituximab is added, plasmapheresis and immunosuppressive therapy also should be added.

Optimal rituximab dosing for vasculitis has not been determined. Most patients in studies received 4 weekly infusions of 375 mg/m2.

One-gram dosing of rituximab may precipitate cryoglobulin and rituximab.

HCV load, which does not appear to be associated with detectable adverse effects on the liver or with HCV reactivation, may increase during rituximab therapy.

Viral load and liver function tests should be monitored at regular intervals during rituximab treatment.

Visentini et al. (2015) reported results from a phase 2 trial (EUDRACT) addressing rituximab dosing in mixed cryoglobulinemia. (57) Fifty-two patients with HCV-associated disease, either not eligible or intolerant of antivirals, were treated with low-dose rituximab (250 mg/m2x2). Response was evaluated at 3, 6, and 12 months and then compared with historical results from 19 published studies. Complete or partial response was observed in 81% of patients by 3 months compared with 86% in 208 patients in prior studies treated with high-dose rituximab (375 mg/m2x4). Adverse events attributed to treatment were identified in 11.5% of patients compared with 19.9% in the high-dose studies. The investigators suggested this low-dose regimen may have similar efficacy to a high-dose regime.

Section Summary: Hepatitis C Virus?Associated Cryoglobulinemic Vasculitis

Recent reviews have summarized the literature on rituximab for the treatment of HCV-associated cryoglobulinemic vasculitis. Across 2 RCTs and many observational studies (total N=377 patients), the median overall response was approximately 80%. However, these studies were done before the advent of several new HCV antiviral drugs and pegylated interferon?free drug regimens. More effective antiviral treatments should improve outcomes (e.g., virologic and immunologic responses, cure rate) of both HCV and associated vasculitis. However, for patients with antiviral-resistant active disease or with severe or life-threatening cryoglobulinemic vasculitis, rituximab in combination with current treatments may improve health outcomes. Viral load and liver function tests should be monitored during rituximab treatment. A phase 2 trial has suggested low-dose rituximab may have similar efficacy as high-dose treatment with and fewer adverse events.

Mixed Connective Tissue Disease

Mixed connective tissue disease (MCTD) has various features of systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis (PM/DM), and RA in the presence of increased anti- ribonucleoprotein (anti-RNP) antibodies. (58) Although some have questioned whether MCTD is a distinct entity, associated human leukocyte antigen (HLA) class 2 alleles (HLA-DR4 and -DR1) are distinct from those associated with SLE, systemic sclerosis, and PM/DM. The most common clinical presentation— Raynaud syndrome, arthralgias, swollen hands, sausage-like fingers, and muscle weakness—appear in 90% of patients. More serious organ involvement can lead to pulmonary arterial hypertension, glomerulonephritis, gastrointestinal bleeding, and severe central nervous system involvement. Common treatments include corticosteroids and cyclophosphamide.

The evidence for rituximab to treat MCTD consists of small case series. A 2011 case series was a retrospective cohort study of 65 pediatric patients who had various autoimmune disorders. (59) Mean age at disease onset was 11 years; mean disease duration before rituximab treatment was 3 years. Patients were treated with rituximab and followed for at least 6 months. Five patients were considered to have a MCTD-two unclassified, one Sjögren syndrome, and two MCTD. One patient with MCTD died 3 months after starting rituximab, and this death was attributed to disease progression. Of the four remaining patients with a MCTD disorder, three attained partial remission, and one had disease progression. Adverse infusion-related events were reported in 12 (18%) of 65 patients but were not reported separately by disease type.

A 2016 multicenter case series by Lepri et al. included a total of 44 patients with connective tissue disorders related to interstitial lung disease, six of whom had MCTD. (60) Patients received treatment with rituximab. In addition, they were treated with disease-modifying antirheumatic drugs (DMARDs) or immunosuppressants. The primary outcome, change in forced vital capacity at 1 year, did not change significantly from baseline to 1 year in the MCTD group (mean, 64.5% at baseline; 63.0% at 1 year; p=0.6). There was a small, nonstatistically significant change in forced vital capacity at 2 years (mean, 61%; p=0.80). Adverse events were not reported separately for the subset of patients with MCTD.

Section Summary: Mixed Connective Tissue Disease

Data from 2 case series with 6 or fewer patients with MCTD; each is insufficient to determine the efficacy and safety of rituximab for the treatment of MCTD. In one of the series, 3 of 5 patients with MCTD achieved partial remission with rituximab; in the other, which focused on MCTD related to interstitial lung disease, there was no significant change in forced vital capacity at 1 or 2 years after initiating rituximab.

Multicentric Castleman Disease

Castleman disease (angiofollicular lymph node hyperplasia) is a rare lymphoproliferative disorder associated with human herpes virus?8 infection. Prevalence is increased among HIV-infected patients and associated with Kaposi sarcoma. Progression to lymphoma and mortality is high in these patients. Castleman disease has two distinct forms with characteristic findings on histologic examination: unicentric or localized (hyaline vascular histology), and multicentric (plasma cell infiltrate). The clinical presentation typically involves lymphadenopathy and multiorgan involvement with an aggressive course. In HIV-non- infected patients, multicentric Castleman disease typically presents after age 70 years. (61) For HIV-infected patients, current guidelines suggest IV ganciclovir or oral valganciclovir for treatment of multicentric Castleman disease based on level C evidence. Rituximab is considered an alternative therapy. (62) Other treatments include combination chemotherapy and tocilizumab, a monoclonal anti-interleukin 6 antibody.

In 2012, Reid et al. reviewed the literature on rituximab in patients with HIV-related lymphoma and multicentric Castleman disease. (63) They identified 1 prospective and 2 retrospective cohort studies of patients with multicentric Castleman disease who were treated with rituximab (total N=69 patients). In the prospective study (N=21), median follow-up was 12 months (range, 1-49 months), and estimated 2-year overall survival (OS) was 95%. Of 11 patients who had Kaposi sarcoma at baseline, progression occurred in 4 (36%). No grade 3 or 4 adverse events were reported. One retrospective study compared the incidence of subsequent non-Hodgkin lymphoma (NHL) in 33 rituximab-treated patients with the incidence in non-rituximab-treated patients. All rituximab-treated patients had received first-line chemotherapy (etoposide, vinblastine, anthracyclines). Three-year NHL incidence was 0.04% in the rituximab group compared with 23% in non-rituximab-treated patients. Median OS rates were 15.7 years and 5.2 years in the rituximab and control groups, respectively. Kaposi sarcoma recurred in 4 (27%) of 11 patients. Mild-to-moderate infections occurred in 27% of rituximab-treated patients.

Gerard et al. (2012) reported on a prospective cohort of 113 HIV-infected patients who had multicentric Castleman disease. (64) The authors compared the incidence of subsequent NHL in rituximab-treated (n=48) with that in non-rituximab-treated (n=65) patients. At a mean follow-up of 4.2 years, annual NHL incidence was 0.004% (4.2 per 1000 person-years) in the rituximab group and 7% (69.6 per 1000 person- years) in the control group (HR=0.09; 95% CI, 0.01 to 0.70). Two- and 5-year OS rates were 93% (95% CI, 80% to 98%) and 90% (95% CI, 76% to 96%), respectively, in the rituximab group, and 68% (95% CI, 54% to 79%) and 47% (95% CI, 32% to 61%), respectively, in the control group. Ten Kaposi sarcoma exacerbations and 1 newly diagnosed Kaposi sarcoma were observed in 9 patients after rituximab therapy. Among 36 rituximab responders, multicentric Castleman disease recurred in 8 (22%) after a median of 10.5 months.

In 2011, Hoffmann et al. retrospectively reviewed 23 rituximab-treated and 29 non-rituximab-treated HIV- infected patients who had multicentric Castleman disease. (65) At a mean follow-up of 2.3 years, the mean estimated OS was not reached in the rituximab group, and was 5.1 years in the control group (p=0.03). An earlier systematic review (2008) identified 25 case series and case reports of HIV-infected patients with multicentric Castleman disease (total N=84 patients, 20 [24%] pre-HAART, 64 [76%] post-HAART). (61) Seven (9%) of 75 patients for whom treatment data were available received rituximab as first-line (n=2) or second-line (n=5) therapy. Complete responses occurred in 5 (81%) patients.

One 2011 case report of rituximab in multicentric Castleman disease in an HIV-uninfected patient was identified. (66) Complete remission was achieved after 4 cycles of rituximab and followed by 4 months of corticosteroid maintenance therapy. Recurrence was not detected during more than 4 years of follow-up.

Section Summary: Multicentric Castleman Disease

Evidence for rituximab in multicentric Castleman disease comes almost exclusively from the HIV literature, which reflects the epidemiology of the disease. Prospective and retrospective cohort studies have reported markedly reduced incidence of subsequent NHL and substantially improved OS rates (≥93% at 2 years in 2 studies; 90% at 5 years in 1 study) in rituximab-treated patients compared with non- rituximab-treated unmatched controls. Progression or emergence of Kaposi sarcoma is an associated risk of rituximab treatment, with Kaposi sarcoma recurrence in approximately 30% of patients. No studies comparing rituximab with currently suggested first-line treatment with ganciclovir or valganciclovir were identified. However, given the low-quality evidence supporting this recommendation and aggressive course of multicentric Castleman disease, effective treatment with rituximab may outweigh its associated risks. Therefore, rituximab may be considered for multicentric Castleman disease in the first- or second- line setting.

Multiple Sclerosis

A 2013 Cochrane review by He et al. (67) identified 1 RCT of rituximab in relapsing-remitting multiple sclerosis (RRMS). (68) The phase 2, double-blind, placebo-controlled HERMES trial (2008)68 enrolled 104 adults (age range, 18-55 years) with RRMS, at least 1 relapse during the preceding year, and an Expanded Disability Status Scale (EDSS) score of 0 to 5.0 (median, 2.5, indicating mild disability) at trial entry. Patients were randomized 2:1 to 2 doses of IV rituximab 1000 mg 2 weeks apart or placebo. The primary efficacy end point was the total number of gadolinium-enhancing lesions on serial T1-weighted magnetic resonance imaging (MRI) brain scans (markers of acute inflammatory changes) at weeks 12, 16, 20, and 24. Planned follow-up was 48 weeks; 92% of patients completed 24 weeks of follow-up while 76% completed 48 weeks. Withdrawals were greater in the placebo group (40% vs 16% in the rituximab group). Patients who withdrew without having a relapse were considered to be relapse-free. The primary end point showed a statistically significant reduction in the rituximab group (p<0.001) as did the number of new gadolinium-enhancing lesions over the same interval (p<0.001). Fewer patients in the rituximab group than in the placebo group relapsed within 24 weeks (34% vs 15% placebo; p=0.02) and at 48 weeks (20% vs 40% placebo; p=0.04). Annualized relapse rates differed statistically at week 24 (0.4 [90% CI, 0.2 to 0.6] for rituximab vs 0.8 [90% CI, 0.5 to 1.3] for placebo), but not at week 48 (0.4 [90% CI, 0.2 to 0.6] for rituximab vs 0.7 [90% CI, 0.5 to 1.1] for placebo). Disability progression was not assessed. More patients in the rituximab group (78%) than in the placebo group (40%) had adverse events within 24 hours after the first infusion (e.g., chills, headache, nausea, pyrexia). Most (93%) were mild or moderate. The most common infection-associated adverse events (>10% in the rituximab group) were nasopharyngitis (20% vs 17% placebo), upper respiratory tract infections (19% vs 17%), urinary tract infections (15% vs 9%), and sinusitis (13% vs 9%). Study limitations included a high and disproportionate number of withdrawals, lack of sensitivity analyses, and short duration of follow-up. Lack of a disability progression outcome (e.g., change in EDSS) would be considered a shortcoming in light of evidence that MRI changes and relapse rates are poor predictors of long-term disability. (69,70)

Castillo-Trivino et al. (2013) reviewed studies of rituximab for relapsing and progressive forms of multiple sclerosis (MS). (71) They identified 4 studies, including the HERMES trial in patients with RRMS, a second RCT which was conducted in patients with primary-progressive MS (PPMS) (72) and 2 small cohort studies in RRMS (n=56 patients). (73,74) The RCT, known as the OLYMPUS trial, was double-blind, placebo-and enrolled 439 adults (age range, 18-65 years) with PPMS for at least 1 year who had EDSS scores ranging from 2.0 to 6.5 (median, 5.0 indicating moderate-to-severe disability with impairment of daily activities). Patients with a history of relapse were excluded. Patients were randomized 2:1 to 2 doses of IV rituximab 1000 mg 2 days apart every 6 months for 4 courses (8 doses). The primary end point was time to confirmed disease progression, defined as an increase in EDSS score of 1.0 point or more (≥0.5 points if baseline EDSS scores was >5.5 points) sustained for at least 12 weeks. Planned follow-up was 96 weeks for efficacy and 122 weeks for safety. Eighty-three percent of patients completed 96 weeks, and 77% completed 122 weeks of follow-up. Time to disease progression did not differ statistically between the rituximab and placebo groups (HR=0.77; 95% CI, 0.55 to 1.09; p=0.144). At 96 weeks, the increase in T2 lesion volume on MRI brain scan (a marker of past disease activity) was less in the rituximab group than in the placebo group (p<0.001). The incidence of grade 3 or higher adverse events was 40% in the rituximab group and 38% in the placebo group. Serious infections occurred in 5% and in less than 1% of the rituximab and placebo groups, respectively. Incidences of infusion-associated adverse events within 24 hours of the first dose were 67% and 23% in the rituximab and placebo groups, respectively. Most incidences were mild-to-moderate.

In 2016, Salzer et al. reported on 822 rituximab-treated MS patients in a Swedish registry. (75) Of these 557 patients had RRMS, 198 had secondary-progressive MS (SPMS), and 67 had PPMS. About 80% of patients had previously used other disease-modulated drugs, for about 20%, rituximab was their first disease-modulated drug. The mean follow-up was 23 months, and the mean duration of treatment with rituximab was 22 months. Patients were generally treated with a single IV infusion of rituximab 500 or 1000 mg every 6 to 12 months; in some cases, patients were given a higher dose after initial treatment (i.e., 1000 to 2000 mg, divided into 2 infusions). A total of 59 MS relapses were identified in the database, with annualized relapse rates of 0.044 for RRMS, 0.038 for SPMS, and 0.015 for PPMS. The median EDSS score remained the same in patients with RRMS (p=0.42), increased 0.5 points in patients with SPMS (p=0.20), and increased 1.0 points in patients with PPMS (p=0.25). At baseline, 26.2% of patients had contrast-enhancing lesions on MRI, and 4.6% of patients had contrast-enhancing lesions after treatment initiation. Contrast-enhancing lesions occurred most commonly in the first 6 months of treatment. Infusion reactions occurred in 7.8% of infusions. Of these, 159 adverse events were grade 1, 72 were grade 2, and 3 were grade 3. This study lacks a placebo or comparison group.

Section Summary: Multiple Sclerosis

Two RCTs have evaluated rituximab in patients with MS. One RCT in patients with RRMS showed improvements in MRI and clinical outcomes at 24-week follow-up. However, methodologic limitations restrict the conclusions that can be based on these data. The second RCT, which was well-designed and was conducted in patients with PPMS, demonstrated no effect of rituximab on disease progression. A large registry study found a relatively low rate of adverse events and relapses and little change in disability scores; this study lacks a comparison group.

Neuromyelitis Optica

Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disorder that selectively affects the spinal cord and optic nerves; clinical presentation is characterized by severe optic neuritis that can lead to blindness and transverse myelitis that can lead to paralysis. The clinical course typically is more severe than in MS, and often fatal, (76) and treatments may differ. (77,78) An autoantibody to aquaporin 4, a water channel found in high concentrations at the blood-brain barrier, is included in NMO diagnostic criteria. (79,80) Curative treatment does not currently exist; treatment goals are: relapse remission, relapse prevention, and symptom relief. (81) Immunosuppression with azathioprine or mycophenolate mofetil (MMF) is commonly used for relapse prevention. Rituximab is being studied for relapse prevention in NMO.

Several systematic reviews of the literature were identified. Most recently, in 2016, Damato et al. published a systematic review and meta-analysis of studies on rituximab treatment for patients with NMO. (82) Reviewers included controlled or uncontrolled studies with at least 2 patients. Forty-six uncontrolled studies (total N=438 patients) were identified and included in the review; there were no RCTs or other controlled studies. The review had 2 primary efficacy outcomes: the annualized relapse rates ratio and the EDSS score before and after treatment. A meta-analysis of 25 studies providing data on the annualized relapse rates ratio found a significant reduction after therapy. The pooled mean reduction after rituximab therapy was 0.79 (95% CI, -1.09 to -0.50). Eighteen studies were included in a meta-analysis of EDSS scores. There was a significant reduction in the EDSS score after treatment (mean reduction, 0.64; 95% CI, -1.18 to -0.10). Overall, adverse events were reported in 114 (26%) of 438 patients. The most common adverse events were infusion-related events (n=45 [10.3%]) and infections (n=40 [9.1%]). Seven (1.6%) patients died; it was not reported whether the deaths were likely to be treatment-related.

Previously, in 2012, Sato et al. published an evidence-based review NMO treatments. (83) Literature was searched through June 2011, and 10 case reports, case series, and retrospective reviews of rituximab treatment were identified. Studies generally showed reductions in annualized relapse rates (from 1.7 to 5.0 at baseline to 0 to 0.6 posttreatment) and improvements in EDSS scores, except in severely disabled patients (e.g., baseline EDSS score, 8.7) for whom neurologic damage may be irreversible. Dosing regimen was commonly 375 mg/m2 followed by 1000 mg biweekly for 2 weeks either as scheduled semi- annual maintenance doses or as-needed. Two of the largest series (total N=55 patients) had follow-up ranging between 19 and 24 months. In 1 study, disability stabilized or improved in 80% of patients; in the other, 70% of patients were relapse-free for 24 months. (84,85) Of 55 patients, 1 (1.8%) death due to septicemia occurred. No cases of posterior reversible encephalopathy syndrome were observed.

In a retrospective series of 90 patients with NMO and NMO spectrum disorders (seropositive for anti- aquaporin-4 IgG but lack other criteria for diagnosis) treated at 2 academic medical centers, Mealy et al. (2014) reported reductions in annualized relapse rate of 88% with rituximab, 87% with MMF, and 72% with azathioprine. (86) Failure rates were 33% with rituximab, 36% with MMF, and 53% with azathioprine. Most patients were previously treated (e.g., with prednisone, β-interferon, glatiramer acetate, and IVIG).

Torres et al. (2015) retrospectively identified 71 patients with NMO or related NMO spectrum disorder. (87) Telephone follow-up was used to ascertain disease status. Rituximab (n=32), azathioprine (n=22), mycophenolate (n=11), and cyclophosphamide (n=5) were given to 54 patients. Reported decreases in annualized relapse rates were: rituximab, 0.92; azathioprine, 0.36; mycophenolate, 0.67; and cyclophosphamide, 0.38. Corresponding adverse events rates by agents were: rituximab, 25%; azathioprine, 36%; mycophenolate, 36%; and cyclophosphamide, 80%.

Collongues et al. (2016) retrospectively analyzed the efficacy of rituximab as a maintenance therapy in 21 patients with refractory NMO. (88) After a mean follow-up of 31 months, 11 (52.3%) were relapse-free; the mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and the median EDSS score decreased from 5 to 3 (p=0.02).

Radaelli et al. (2016) reported on the results of a prospective observational study of 21 patients with NMO or NMO spectrum of disorders who underwent at least 1 cycle of rituximab and were followed for at least 2 years. (89) At a mean follow-up of 48 months, the annualized relapse rate decreased from 2.0 to 0.16 (p<0.01) and EDSS scores decreased from 5.5 to 4.0 (p<0.013). Twelve (57%) patients remained disease free during the follow-up period.

Section Summary: Neuromyelitis Optica

The evidence base for use of rituximab to prevent relapse in NMO is comprised of uncontrolled observational studies and systematic review. A 2016 systematic review of 46 uncontrolled studies found significant reductions in the relapse rate and EDSS score after beginning treatment with rituximab. In a retrospective review of 90 patients previously treated with MS treatments (e.g., β-interferon, glatiramer acetate), the efficacy of rituximab appeared comparable with that of azathioprine and MMF, considered first-line immunosuppressive drugs for NMO. A retrospect-prospective cohort has suggested rituximab as, or possibly more, effective than other agents in preventing relapse. Based on adverse events reported, the safety of rituximab in NMO appeared comparable to the safety in other patient populations.

Pemphigoid and Pemphigus Diseases

Pemphigoid diseases include 8 blistering disorders characterized by auto-antibodies directed against the epidermal basement membrane: bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA disease, epidermolysis bullosa acquisita, anti-laminin g1/anti-p200 pemphigoid, lichen planus pemphigoides, and pemphigoid with renal insufficiency. Pemphigus, in contrast, comprises 3 major forms characterized by auto-antibodies directed against epidermal cell junctions: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Both classes of disease are characterized by blisters and erosions; however, pemphigoid blisters are subepidermal and therefore tense, and pemphigus blisters are more superficial and therefore flaccid or often ruptured. Nikolsky sign—exfoliation and blister formation with skin friction—is negative in pemphigoid diseases and positive in pemphigus. (90)

In 2009, Peterson and Chang reviewed the literature on rituximab for autoantibody-mediated blistering skin diseases. (91) Literature was searched through August 2007, and 71 patients in case series and case reports were identified. Patients had both pemphigoid diseases (4 epidermolysis bullosa acquisita, 1 bullous pemphigoid) and pemphigus diseases (52 pemphigus vulgaris, including 1 pemphigus vegetans, a localized form of pemphigus vulgaris, 9 pemphigus foliaceus, and 5 paraneoplastic pemphigus). Fifteen (21%) of 71 patients received rituximab monotherapy; 56 (79%) received concomitant systemic corticosteroids, immunosuppressive drugs, and/or IVIG. Overall, 49 (69%) patients had a complete response, 18 (25%) had a partial response, and 4 (6%) had progressive disease (2 patients with paraneoplastic pemphigus, 1 with pemphigus foliaceus, and 1 with pemphigus vegetans). Of 6 deaths associated with rituximab, 4 occurred in patients with paraneoplastic pemphigus, which typically is resistant to conventional treatment if the primary tumor is not eradicated. One death occurred in a patient with pemphigus vulgaris who developed pneumonia, 1 death occurred in a patient with bullous pemphigoid and graft-versus-host disease (GVHD) who developed sepsis. Infections (pneumonia and infective arthritis) also were reported in two other patients with pemphigus vulgaris who received rituximab in combination with corticosteroids and immunosuppressive drugs. Overall incidence of infections was 7%. Noninfectious adverse events were atrial fibrillation, congestive heart failure, and deep venous thrombosis. Of 52 patients with pemphigus vulgaris, 25 (48%) received rituximab monotherapy or combination therapy with IVIG; all 25 patients responded to treatment with no adverse events reported.

Pemphigoid Diseases

Schmidt and Zillikens (2013) reviewed the clinical presentation, diagnostic workup, and treatment options for pemphigoid diseases. (90) They found evidence for rituximab in refractory bullous pemphigoid in combination with first-line treatments, such as topical or oral corticosteroid and some immunosuppressive drugs (level C evidence, based on small case series, case reports, and expert opinion); refractory mucous membrane pemphigoid in combination with immunosuppressive drugs, such as dapsone and/or sulfasalazine (level B evidence, based on poor-quality controlled trials and large case series); and refractory epidermolysis bullosa acquisita in combination with systemic corticosteroids (level C evidence).

Shetty and Ahmed (2013) reviewed the literature on rituximab for treatment of refractory bullous pemphigoid. (92) Sixteen patients (1 case series, 8 case reports), including 4 children, (mean age, 6.4 years; range, 5 months to 14 years) were identified. Fourteen (88%) patients received IV rituximab 375 mg/m2 weekly for 4 doses, and 2 (12%) patients received 1000 mg every other week for 2 doses. All patients received concomitant immunosuppressive therapy and/or IVIG. Mean follow-up was 15.6 months (range, 1-36 months). Eleven (69%) of 16 patients had a complete response, 1 (6%) had a partial response, 1 (6%) had no response, and 3 (19%) died. Deaths were due to sepsis in 2 (1 child) patients and cardiac adverse events. Three (19%) patients had serious infections.

Shetty and Ahmed (2013) also reviewed the literature on rituximab for the treatment of refractory mucous membrane pemphigoid. (93) Studies that dosed rituximab at 375 mg/m2 weekly for 4 weeks were included. Twenty-eight patients (1 case series, 6 case reports) were identified. Median follow-up ranged from 9 to 31 months. All patients received concomitant immunosuppressive and/or immunoadsorbent therapy. Twenty (71%) of 28 patients had a complete response, 3 (11%) had a partial response, 2 (7%) were nonresponders, and 1 (4%) patient who had progression of disease leading to blindness was considered a treatment failure. One patient died from infection (pyelonephritis and tuberculosis). Approximately half of patients received a second rituximab cycle because of relapse or lack of response.

Foster et al. (2010) reported a retrospective comparative study of 12 patients who had refractory mucous membrane pemphigoid of the eye (ocular cicatricial pemphigoid), 10 of whom were blind in 1 eye. (94) Six patients received rituximab 375 mg/m2 weekly for 8 weeks plus IVIG, and 6 patients received immunosuppressive therapy (cyclophosphamide or infliximab) plus IVIG. At the median follow-up of 11 months, visual acuity was preserved, and no progression of disease observed in the rituximab group. By contrast, all 6 control patients progressed to blindness in both eyes. No adverse events were observed in the rituximab group.

Pemphigus Diseases Refractory to First-Line Treatment

Cianchini et al. (2012) reported on 42 patients who had refractory pemphigus vulgaris with severe mucous or mucocutaneous involvement (n=37) or pemphigus foliaceus (n=5). (95) Patients received rituximab 1000 mg/m2 every 2 weeks for 2 doses plus corticosteroids only; IVIG or immunosuppressive drugs were not given. At the median follow-up of 26.5 months (range, 12-51 months), 36 (86%) of 42 patients achieved a complete response and discontinued steroids within 6 months. Six (14%) patients had a partial response and achieved complete response after an additional infusion of IV rituximab 500 mg. Twenty (48%) patients relapsed (time to relapse, 8-64 months), each of whom received an additional infusion of IV rituximab 500 mg and achieved a complete response. No serious adverse events were observed.

Heelan et al. (2014) conducted a retrospective cohort study of patients with refractory pemphigus vulgaris (n=84) and pemphigus foliaceus (n=8). (96) Using a fixed-dose protocol (rituximab 1 g days 1 and 15, 500 mg every 6 months as indicated), complete remission was observed in 82 (89%) patients. Serious adverse events were not reported.

Maley et al. (2016) retrospectively analyzed 49 patients with mucous membrane pemphigoid who had more than 6 months of follow-up after the initiation of therapy with rituximab (n=24) or with conventional immunosuppression (n=25). (97) One hundred percent of the rituximab group achieved disease control compared with 40% of the conventional group, at a mean time to disease control of 10.17 months and 37.7 months, respectively. Adverse events were seen in 33% of patients after rituximab compared with 48% of patients in the conventional group.

Newly Diagnosed Pemphigus Diseases

The evidence on rituximab as part of first-line combination treatment for pemphigus consists of several small case series and 1 RCT. Case series had sample sizes ranging from 5 to 10 patients each with untreated pemphigus. (98-101) The series generally found rituximab, along with corticosteroids to be beneficial in terms of response and remission rates; however, the studies lack a comparison group with first-line corticosteroids alone. In a series by Anandan et al. (2017), 10 patients with previously untreated pemphigus and 10 patients with pemphigus refractory to first-line therapy were treated with rituximab. After treatment, 13 of the 20 patients attained remission for 3 to 22 month. Seven patients relapsed during the study, six of whom had been treated previously, and one of whom was taking rituximab as first-line therapy.

In 2017, Joly et al. published an unblinded RCT (Ritux 3) comparing first-line treatment with corticosteroids plus rituximab compared with corticosteroids alone in patients with pemphigus. (102) The study included 91 adult patients with newly diagnosed pemphigus (clinical features suggestive of either pemphigus vulgaris or pemphigus foliaceus). One patient withdrew prior to randomization; 90 patients were included in the intention-to-treat analysis. Patients were randomized to corticosteroid treatment alone (i.e., an initial high dose of prednisone tapered over 12 to 18 months) or short-term corticosteroid treatment plus rituximab (i.e., an initial high dose of prednisone with rapid tapering over 3 to 6 months plus IV rituximab, 100 mg on days 1 and 14, and 500 mg at months 12 and 18). The primary end point was the proportion of patients who achieved complete response at month 24, defined as the absence of new or established lesions with the patients off corticosteroids for at least 2 months. At 24 months, 41 (89%) of 46 patients in the rituximab plus corticosteroid group and 15 (34%) of 44 patients in the corticosteroid-only group achieved a CR. The difference between groups was statistically significant (RR=2.61; 95% CI, 1.71 to 3.99; p<0.001). This degree of difference corresponded to a number needed to treat with initial combined treatment of 1.82 (95% CI, 1.39 to 2.60). Patients in the rituximab plus corticosteroid group took a significantly lower cumulative dose of corticosteroids during the study (6143 mg, SD=2166 mg) than the corticosteroid-only group (17,974 mg, standard deviation (SD)=7273 mg; p=0.001). Moreover, more grade 3 or 4 serious adverse events were reported in the corticosteroid-only group (53 events in 29 patients; mean, 1.20 events per patient) than the rituximab plus corticosteroid group (27 events in 16 patients; mean, 0.59 events per patient; p=0.002).

Section Summary: Pemphigoid and Pemphigus Diseases

Evidence for rituximab in pemphigoid diseases and pemphigus, refractory to first-line treatment is comprised of case reports, case series, retrospective cohort studies of patients with pemphigus, and a retrospective comparative study in ocular cicatricial pemphigoid. Patients were refractory to previous treatments, but most (75%-100%) responded to rituximab. Infections, including serious and fatal infections, were reported in 4% to 19% of patients, but adverse event reporting may have been incomplete. Only 3 of 8 pemphigoid diseases were examined in the literature: epidermolysis bullosa acquisita, bullous pemphigoid, and mucous membrane pemphigoid.

The evidence on first-line treatment with rituximab plus corticosteroids in patients with newly diagnosed pemphigus consists of an RCT and small case series. The RCT found that patients treated with rituximab plus short-term corticosteroids (3-6 months) had significantly better outcomes than those treated with long-term corticosteroid use. Outcomes included the complete response rate, cumulative dose of corticosteroids, and rate of grade 3 or 4 serious adverse events.

Primary Sjögren Syndrome

Sjögren syndrome is an autoimmune disorder characterized by lymphocytic infiltration and progressive destruction of the exocrine glands of the body, specifically the salivary and lacrimal glands, which cause xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Extraglandular disease leads to vaginal dryness, chronic bronchitis, and dry skin, and may affect the kidneys, blood vessels, liver, pancreas, peripheral nervous system (distal axonal sensorimotor neuropathy), and central nervous system. Sjögren syndrome often accompanies other autoimmune disorders, such as RA and lupus. The condition is most common in women older than 40 years. Treatment focuses on symptom relief; corticosteroids, immunosuppressive drugs, or IVIG may be prescribed for severe complications.

In 2010, Ramos-Casals et al. published a systematic review of treatments for primary Sjögren syndrome. (103) Literature was searched through April 2010, and 2 small RCTs (n=47 patients) plus several uncontrolled studies were identified. The RCTs compared rituximab with placebo for symptoms of xerostomia and fatigue. Statistically significant improvements in primary end points were not achieved with rituximab 1000 mg biweekly for 2 doses, although other symptoms (e.g., dry eye) showed significant improvements. Uncontrolled studies have shown improvements in extraglandular features, such as vasculitis, neuropathy, and glomerulonephritis.

In 2016, Souza et al. published a systematic review of RCTs published until December 2015 that included trials enrolling adults with established primary Sjögren syndrome diagnosis and that compared rituximab with other drugs or placebo as controls. (104) Four studies met eligibility criteria, three with low risk of bias and one with uncertain risk of bias. The total number of participants was 276 (145 rituximab, 131 placebo). Reviewers evaluated multiple outcomes such as lacrimal gland function, salivary gland function, fatigue improvement, and adverse events. They found no significant differences in the Schirmer test (the test determines whether the eye produces enough tears to keep it moist) between the groups at week 24. A significant difference between groups was reported for salivary flow rate. Reviewers concluded that treatment with a single rituximab course can improve salivary flow.

A 2014 blinded RCT by Devauchelle-Pensec et al. assigned 120 patients with primary Sjögren syndrome and at least 1 extraglandular manifestation to rituximab 1000 mg weekly for 2 doses or placebo, and assessed response in global disease, pain, fatigue, and dryness at 24 weeks. (105) Mean baseline European Sjögren’s Syndrome Disease Activity Index (ESSDAI) score was 10 (ESSDAI scoring range, 0 [no symptoms] to 49 [high disease activity]). Baseline corticosteroids (30% of patients) and MTX (20% of patients) were discontinued 4 weeks before trial entry. By prespecified response criteria (≥30 mm improvement in 2 of 4 symptom visual analog scales at week 24), a statistically significant between-group difference was not observed. A statistically significant difference in the proportion of responders was observed at 6 weeks and in reduction of fatigue at 6 and 16 weeks, both favoring rituximab. Serious infection occurred in 3% of rituximab-treated patients and 9% of controls, but overall serious adverse events occurred more commonly in rituximab-treated patients (21% vs 14% control). Infusion reactions occurred in 8% of rituximab-treated patients and 2% of controls.

In a 2013 nonrandomized study, Carubbi et al. compared rituximab (6 courses at 6-month intervals of rituximab 1000 mg biweekly for 2 doses; n=19) with conventional DMARDs (hydroxychloroquine, MTX, or cyclosporine; n=22) in patients with early-onset primary Sjögren syndrome. (106) A minimum ESSDAI score of 6 was required for study entry (median, 20; range, 6-41). Median disease duration was 14 month (range, 6-21 months). DMARDs and corticosteroids were discontinued at least 6 months before baseline, except for patients with severe extraglandular manifestations needing treatment continuation, with no change in dosage allowed. At 24 weeks, the mean reduction from baseline ESSDAI score was significantly greater with rituximab than with DMARD therapy, and this difference was maintained through 120 weeks of follow-up.

In 2012, Mekinian et al. published 2 registry studies of patients with primary Sjögren syndrome and involvement of the central (107) or peripheral nervous system. (108) Patients were drawn from the French Autoimmunity and Rituximab registry, a prospective cohort study of rituximab in autoimmune diseases. Of 11 patients with central nervous system involvement (e.g., MS-like symptoms [n=6], cognitive dysfunction [n=3]), only 1 patient with cyclophosphamide-refractory transverse myelitis reported improvement in the ability to walk, and 1 patient with anxiety and depression reported subjective improvement. Of 17 patients with peripheral nervous system involvement (sensorimotor neuropathy [n=11], sensory neuropathy [n=4], multineuritis [n=2]), physician-assessed neurologic improvements occurred in 11 (65%) patients at 3 months and persisted in 9 (53%) patients at 6 months. Statistically significant improvements in objective measures (Rankin Scale scoring range, a 0 [no symptoms] to 6 [dead]; ESSDAI) were observed at 3, 6, and 9 months. Physician-assessed improvements at 3 months and change in ESSDAI at 6 months were statistically greater in patients with cryoglobulinemia and/or vasculitis.

In 2013, Gottenberg et al. published an updated report of the French Autoimmunity and Rituximab registry. (109) Of 78 enrolled patients, 74 (95%) had systemic involvement of disease. At a median follow-up of 35 months, statistically significant reductions in corticosteroid usage and in ESSDAI scores were observed, and physician-assessed improvements after 1 cycle of rituximab were reported in 60% of patients. In contrast with the earlier studies by Mekinian et al., improvements in both central and peripheral neuropathy were observed. Half of patients required rituximab retreatment. Infusion reactions and delayed serum sickness-like disease leading to discontinuation of rituximab occurred in 5 (6%) patients. Three serious infections (1.3/100 patient-years) and 2 cancer-related deaths occurred.

Section Summary: Primary Sjögren Syndrome

Patients with primary Sjögren syndrome who require more than symptomatic treatment for severe glandular or extraglandular disease are generally treated with corticosteroids and immunosuppressive drugs. Rituximab has been studied in a small number of patients in randomized and nonrandomized trials and observational studies. The efficacy of rituximab was not consistently demonstrated. For example, a large randomized trial (n=120) showed no difference in response compared with placebo in patients who had disease onset less than 10 years prior, and a small nonrandomized trial (N=41) showed statistically significant differences in response compared with DMARDs in previously treated patients. Incidence of adverse events did not appear to be increased above that observed in other patient populations. Given the limited treatment options and potential serious outcomes, including death, for patients with refractory disease, rituximab has been considered for these patients.

Systemic Lupus Erythematosus

One RCT (EXPLORER) and several systematic reviews were identified. A 2014 systematic review (110) examined several biologics and included only 2 rituximab trials (EXPLORER, LUNAR), which are described next. Three systematic reviews that included the EXPLORER trial are summarized in Table 2. They are comprised of mostly prospective and retrospective cohort studies and case series. Most patients had refractory SLE. Rituximab dosing regimens and definitions of response, flare, and relapse varied across studies. Duxbury et al. (2013) observed that this heterogeneity contributed to the “discrepancy in the perceived efficacy of rituximab between controlled [studies, which generally reported lower response rates] and observational studies [which generally reported higher response rates].” (111)

Table 2. Systematic Reviews of Rituximab in Systemic Lupus Erythematosus (111-114)

Study

N/N

Follow-Up, mo

Efficacy

Serious Adverse Eventsa

Cobo-Ibanez et al. (2014)

25b (1 RCT)/1231

Range, 2-103

CR/PR: 64%-91%

TTR: 4-18 mo

Infections: 7%-13%

Duxbury et al. (2013)

30 (3 RCTsc)/1243

Range, 2-38

PR: 31%-38%

CR: 47%-57%

SAEs: 11.5%

Lan et al. (2012)

21 (2 RCTs)/1012

Median, 18.2

PR: 25%

CR: 33%

TTR: 3-44 mo

Allergic reactions: 10%

CR: complete response; N/N: no. of studies/no. of patients; PR: partial response; RCT: randomized controlled trial; SAE: serious adverse event; TTR: median time to relapse.

a In rituximab-treated patients.

b A post hoc analysis of the RCT is not counted as a separate study here.

c Included EXPLORER, LUNAR, and a 2010 Spanish-language RCT that found no difference between rituximab and cyclophosphamide in 19 patients with severe systemic lupus erythematosus.

The 2010 EXPLORER (Exploratory Phase 2/3 SLE Evaluation of Rituximab) double-blind, RCT enrolled patients with moderate-to-severe extrarenal lupus despite background immunosuppressive therapy. (115) Patients (N=257) were randomized 2:1 to IV rituximab 1000 mg at weeks 1, 3, 24, and 26 or placebo in combination with prednisolone and either azathioprine, MMF, or MTX. At 1-year follow-up, there was no statistically significant between-group difference in clinical response as defined by improvement in British Isles Lupus Assessment Group (BILAG) index (BILAG measures overall and organ-specific disease activity on a scale from A [severe] to E [unaffected]). Seventy percent of the rituximab group and 72% of the placebo group had no clinical response; major clinical response (improvement from BILAG A to BILAG C in all organs at 24 weeks and maintenance of this response without moderate or severe flare to week 52) was achieved by 12% and 16% of the rituximab and placebo groups, respectively. In prespecified subgroup analysis, African-American or Hispanic patients (n=96) who received rituximab achieved more major and partial responses (14% and 20%, respectively) compared with those in the placebo group (9% and 6%, respectively; p=0.041). However, because there was no correction for multiple comparisons, these results require replication. Safety and tolerability were similar in both groups. In 2011, the authors reported a post hoc analysis using alternative definitions of flare in the 72% (N=185) of patients who achieved low disease activity (BILAG C or better) at any point before week 52. (116) When mild (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent BILAG A flare and the mean annualized rate of BILAG A flares.

As suggested in a letter about this trial, the stringent end point used in EXPLORER-improvement to BILAG C in all organs-may have been unrealistic. (117) Based on observational data, rituximab appears to improve renal and musculoskeletal symptoms more than neurologic, cutaneous, and cytopenic symptoms in SLE patients; organ-specific improvements may have been informative end points. Similarly, change in corticosteroid dose may have demonstrated a steroid-sparing effect with rituximab. Additionally, possible differences in dosages of background immunosuppressive therapies (not reported) may have biased results.

Section Summary: Systemic Lupus Erythematosus

Evidence for rituximab in patients with refractory SLE comprises a large RCT that did not show improved response rates at 1 year with rituximab add-on therapy. Systematic reviews that included mostly cohort studies and case series of refractory patients generally reported higher response rates (25%-91% overall responses) than controlled studies. Rates of serious adverse events and severe adverse events, mostly infections and infusion or allergic reactions, were 7% to 13%.

Lupus Nephritis

Lupus nephritis (LN) is among the most serious complications of SLE. It occurs in approximately half of SLE patients and is associated with a poor prognosis. (118) Estimated 5-year survival among patients with International Society of Nephrology/Renal Pathology Society class IV (diffuse) LN is 80% and among all SLE patients, 86% (119); 5% to 10% of LN patients will progress to end-stage renal disease at 10 years. (120) Current treatment regimens include cyclophosphamide or MMF, both administered with corticosteroids. Response rates at 1 year are 50% to 80%, but they are often only partial responses. (118)

Evidence for the use of rituximab in LN includes a systematic review, an RCT, a registry study, and several case series and case reports. A 2013 systematic review of rituximab in refractory LN included 9 prospective comparative studies, 9 retrospective studies, and 8 case series and case reports (total N=300 patients). (121) Thirty-nine percent of patients had class IV nephritis, but 30% were unclassified. Rituximab dosing and use as alternative or add-on therapy (to cyclophosphamide, MMF, azathioprine, or MTX) varied across studies; the most common dosing regimen was 375 mg/m2 weekly for 4 weeks. Mean follow-up was 60 weeks (range, 12-120 weeks). Rituximab induced a complete, partial, or no response (using American College of Rheumatology and European League Against Rheumatism standard definitions in most studies) in 40%, 34%, and 26% of cases, respectively. Complete responses and any responses (complete or partial) were most frequent in patients with class III (focal) LN and least frequent in patients with class V (membranous) LN.

One of the RCTs identified in the systematic review previously described was the 2012 double-blind LUNAR (Lupus Nephritis Assessment with Rituximab) trial. (118) LUNAR was a randomized, double-blind, placebo-controlled phase 3 trial of rituximab plus MMF and corticosteroids as initial therapy for proliferative LN. The trial included 144 patients 16 to 75 years of age who had histologic evidence of class III or IV LN on biopsy within 12 months before randomization. Patients were randomized to IV rituximab 1000 mg at weeks 1, 3, 24, and 26 or placebo in combination with MMF and prednisone. The primary efficacy end point, superior overall (complete or partial response) renal response rate at 1 year with rituximab, was not reached (57% [26% CR, 31% partial response] in the rituximab group vs 46% [31% complete response, 15% partial response] in the placebo group; p=0.18). Incidence of serious adverse events did not differ statistically between groups. An accompanying editorial observed that the trial was powered to detect a 20% increase in complete renal response and a 5% increase in partial renal response; it was underpowered to detect a difference comprising mainly partial responses. (119)

In 2012, Diaz-Lagares et al. reported on pooled results from the UK-BIOGEAS Registry and published European studies. (122) The UK-BIOGEAS Registry was jointly developed in the U.K. and Spain to evaluate the use of rituximab in LN. Among a total of 164 patients (99 Registry patients, 65 patients in published studies), most (57%) had class IV LN. Rituximab was administered in combination with corticosteroids in 99% of patients and with immunosuppressive agents (cyclophosphamide or MMF) in 76% of patients. Half of patients were refractory to standard treatment, 42% were treated for disease flare, and 8% were treated at first presentation of LN. At 6 and 12 months, respectively, renal response rates (using standard definitions) were 27% and 30% for complete response, 40% and 37% for partial response, and 33% at both time points for no response. Overall (complete or partial) responses were more common in patients with class III LN than in patients with class IV or V LN (p=0.007 and 0.03, respectively). Two (1%) patients developed severe infusion reactions. Twenty (12%) patients had 21 infections, most commonly (n=7) respiratory infections. Six (4%) patients developed neutropenia (3 [2%] febrile neutropenia) after rituximab administration. Three (2%) patients developed posterior reversible leukoencephalopathy.

Section Summary: Lupus Nephritis

Evidence for rituximab in refractory LN includes an RCT that did not show improved ORRs at 1 year with rituximab add-on therapy; however, this trial may have been underpowered to show an improvement in partial responses. Summaries of noncomparative studies reported complete and partial response rates of 30% to 40% and approximately 35%, respectively, in patients with mostly refractory disease. Adverse events occurred in approximately 20% of patients. For some patients with refractory LN, add-on rituximab may improve health outcomes. However, because serious adverse events were observed in these patients (severe infections, febrile neutropenia, posterior reversible leukoencephalopathy), the risk-benefit profile of rituximab is improved when used after the failure of standard treatment regimens.

Systemic Sclerosis (Scleroderma)

Jordan et al. (2015) conducted a multicenter case-control study of patients with scleroderma enrolled in the European Scleroderma Trial and Research database. (123) Sixty-three rituximab-treated patients were matched with non-rituximab-treated controls on scleroderma subtype (diffuse or limited), baseline forced vital capacity, baseline Modified Rodnan Skin Score, disease duration, follow-up duration, and immunosuppressive therapy. Fifty-six percent of patients had severe diffuse scleroderma. The most frequent dose of IV rituximab was 1000 mg weekly for 2 weeks. Immunosuppressive therapies included prednisone, MTX, azathioprine, MMF, and cyclophosphamide. Median follow-up was 7 months (interquartile range (IQR), 4-9 months). Mean improvement in Modified Rodnan Skin Score was 24.0 percentage points in 25 rituximab- treated patients and 7.7 percentage points in matched controls (p=0.03). Treatment effect exceeded an anchor-based minimally important difference of 5.3 percentage points reported by Khanna et al. (2006). (124) Mean forced vital capacity increased 0.4 percentage points in 9 rituximab-treated patients and decreased 7.7 percentage points in matched controls (p=0.02). Mean (SD) improvement in diffusing capacity of carbon monoxide (DLCO) did not differ statistically between groups (3.7 percentage points in the rituximab group vs 6.2 percentage points in the control group; p=0.9). Infections occurred in 21% of rituximab- treated patients, and serum sickness/hypersensitivity reaction in 4%. The authors concluded: “Taken together, in this large, multicentre, observational trial using the European Scleroderma Trial and Research database, we could show beneficial effects of RTX [rituximab] on skin and lung fibrosis in patients with systemic sclerosis compared with matched-control systemic sclerosis patients without RTX treatment. These promising results need to be confirmed in phase III randomized-controlled trials.”

In 2011, Phumethum et al. reviewed the literature on biologic therapies to improve inflammatory arthritis, disability (as assessed by the Health Assessment Questionnaire Disability Index [HAQ-DI]), and skin symptoms in patients with systemic sclerosis. (125) Literature was searched in early 2010; 6 studies of rituximab (1 controlled trial [126], 3 cohort studies, 3 case reports; total N=39 patients) were identified. No study reported improvements in HAQ-DI score, and resolution of joint pain was reported in 1 patient. Improvements in skin score were observed in some rituximab-treated patients, but the effect size was smaller than in the control arm of the RCT. Incidences of infusion reactions and respiratory tract infections were 47% and 29%, respectively, in 1 study each. Reviewers concluded, “Adequately powered trials are needed to evaluate efficacy, and longitudinal studies are needed to evaluate long-term safety of these agents in SSc [systemic sclerosis].” Similar conclusions were reached by McQueen and Solanki (2015) (127) in a review that included studies identified by Phumethum (excluding case reports) and the Jordan observational result- “if RTX were to be used today, it should either be in the context of a clinical trial or in specialized centres to ensure that outcome data are carefully collected and available to the international rheumatology research community.”

Daoussis et al. (2010) assigned (by birth date) 14 patients with diffuse scleroderma to standard treatment plus 2 cycles of rituximab (375 mg/m2 weekly for 4 doses) 6 months apart (n=8) or standard treatment alone (n=6). (126) Assignments were unblinded. Standard treatments included prednisone, bosentan, MMF, and cyclophosphamide. Statistically significant improvements in pulmonary function tests, but not in skin symptoms, were observed with rituximab compared with control. At 1-year follow-up, median forced vital capacity increased 10.3 percentage points (IQR, 6.2-18.7) in the rituximab group and decreased 5.0 percentage points (IQR, 4.1-11.6; p=0.002) in the control group. Median DLCO increased 19.5 percentage points (IQR, 3.7-30.8) in the rituximab group and decreased 7.5 percentage points (IQR, 1.4-26.6) in the control group (p=0.023). Median improvement in Modified Rodnan Skin Score was 39.3 percentage points (IQR, 27.3-65.0) in the rituximab group and 20.8 percentage points (IQR, 10.8-39.3) in the control group (p=0.06).

Several case reports and case series have described improvements in pulmonary function or decline in rates of progression in patients with interstitial lung disease (128-131) and improvements in skin symptoms (131,132) with add-on rituximab (total N=25 patients). All but 1 treatment-naive patient were refractory to standard immunosuppressive therapy. Serious adverse events occurred in 7 (28%) patients, including 2 sepsis deaths. Two reports described benefit with rituximab cycles administered at 6-month intervals. (128,133) In a small retrospective study (2015) of 25 chronic connective tissue disease-associated interstitial lung disease, rituximab was not associated with changes in percent forced vital capacity change or corticosteroid-sparing effects. (134)

Section Summary: Systemic Sclerosis

Evidence for rituximab in treatment-refractory systemic sclerosis includes observational studies and 1 small, unblinded trial. Add-on rituximab generally improved skin symptoms and pulmonary function tests; adverse events, including sepsis deaths, occurred in 21% to 47% of patients. Long-term follow-up for efficacy and safety is limited. However, second-line treatment options are limited, and the consequences of progressive disease may be life-threatening.

Myasthenia Gravis

Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction resulting in varying degrees of muscular weakness. The normal communication of nerve impulses involves nerve endings releasing acetylcholine, a neurotransmitter at the neuromuscular junction, which normally binds with acetylcholine receptors that activate and result in a muscle contraction. For individuals with myasthenia gravis, this cholinergic communication is disrupted by antibodies.

In 2017, Tandan et al. published a systematic review of studies on rituximab treatment of myasthenia gravis. (135) Forty-seven articles were identified, of which 38 were case reports. Nineteen studies were case series with at least 2 patients; there were no controlled studies. Data on response to rituximab were available for 168 patients. Patients received a mean of 6.8 infusions of rituximab. The mean number of relapses after rituximab in 100 patients was 0.4. The mean quantitative myasthenia gravis score was 16.8 before rituximab treatment and 8.7 after treatment. Many of the publications did not report adverse events. With a median follow-up of 17 months, adverse events were identified in 15 (14%) of 105 patients who had available data.

A 2017 study by Hehir et al. (not included in the Tandan systematic review, described above [135]) was a prospective blinded nonrandomized comparative study in patients with anti-MuSK myasthenia gravis. (136) Twenty-four patients were treated with rituximab and 31 received standard care without rituximab treatment. The primary outcome was the Myasthenia Gravis Status and Treatment Intensity (MGSTI) score. MGSTI scores range from level 0 (complete stable remission; no immunotherapy) to level 6 (symptomatic and requiring hospitalization). The authors defined a beneficial clinical outcome as an MGSTI level of 2 or better. Level 2 was defined as having minimal manifestations/pharmacologic remissions with a low dose of dual therapy. A secondary outcome was an MGSTI level of 1 or better (minimal manifestations/pharmacologic remissions with a low dose of oral monotherapy). Fifty-eight percent of patients in the rituximab arm had a successful clinical outcome (i.e., MGSTI level of 2 or higher) compared with 16% of controls; the difference between groups was statistically significant (p=0.002). The median time to achieve an MGSTI level of 2 or better for patients in the rituximab arm was 54 months. In addition, 54% of patients in the rituximab arm achieved the more stringent outcome of MGSTI level of 1 or better at the final evaluation compared with 26% in the control arm (p=0.003).

Section Summary: Myasthenia Gravis

Evidence for rituximab in treatment-refractory myasthenia gravis is comprised of multiple small uncontrolled studies, a systematic review of uncontrolled studies, and a small controlled observational study. A systematic review of 47 small uncontrolled studies found a significant reduction in a myasthenia gravis symptom score after beginning rituximab treatment and a relatively low rate of adverse events. However, adverse event reports were not available for all patients. An uncontrolled observational study found significantly better clinical outcomes in patients with anti-MuSK myasthenia who were treated with rituximab compared with those who did not receive rituximab. Although there are no randomized studies, there is a nonrandomized comparative study and numerous series, summarized in a systematic review, reporting positive outcomes.

Idiopathic Membranous Nephropathy

Membranous nephropathy involves the abnormal thickening of the glomerular basement membrane and is a leading cause of nephrotic syndrome. Most membranous nephropathy cases occur from unknown causes, and secondary membranous nephropathy may result from other predisposing diseases, infection, or medical therapy. In many cases, conservative treatment with renin-angiotensin system blockade is provided. Immunomodulatory therapies (e.g., alkylating agents, calcineurin inhibitors, corticosteroids) are used to treat individuals who are unresponsive to conservative therapy. Rituximab has been evaluated in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens or those with a moderate risk of progression who have not previously received immunosuppressive therapy.

In a 2016 unblinded trial of 75 patients with persistent proteinuria (>3.5 g/d), patients were randomized to rituximab or no rituximab (38 patients). (137) At 6 months, there was no significant difference in the primary composite end point of complete (<500 mg/d) or partial (<3.5 g/d with ≥50% reduction vs baseline) remission of proteinuria between patients treated with (35%) or without rituximab (21%). The lack of benefit was attributed in part to the short duration of the trial. In a post-trial, observational phase that followed patients for an additional 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65% vs 34%). In addition, patients treated with rituximab had lower proteinuria (2195 mg/g vs 4701 mg/g) and higher serum albumin (3.2 g/dL vs 2.7 g/dL) levels. These findings are consistent with observational studies that have demonstrated a maximal reduction in proteinuria at 18 to 24 months after treatment with rituximab. (138,139) A 2016 multicentric prospective study in 34 patients with idiopathic membranous nephropathy and nephrotic syndrome received rituximab once (n=18) or twice (n=16). (140) Rituximab was the first-line therapy for 19 (56%) and the second-line for 15 (44%) patients. At 12 months, 5 (14.7%) patients achieved complete response, 10 (29.4%) partial, and 19 (55.8%) no response. Response occurred approximately 6 months later. At 24 months, the clinical situation was unchanged: 2 nonresponders achieved partial response and 2 responders relapsed. Authors concluded that low-dose rituximab resulted in remission in less than 50% of patients with idiopathic membranous nephropathy. Probably, higher doses and longer treatments are needed to induce and maintain a response. Large, RCTs are needed to determine the optimal schedule, dose, and long- term safety and efficacy.

Section Summary: Idiopathic Membranous Nephropathy

Evidence for rituximab in the treatment of idiopathic membranous nephropathy includes multiple observational studies and an RCT. Rituximab may have moderate benefit in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens or those with a moderate risk of progression who have not previously received immunosuppressive therapy.

Minimal Change Disease

Rituximab has been used to treat various glomerulopathies, including those associated with minimal change disease (adults and children). There are no randomized or controlled trials to support the use of rituximab for this indication. Observational studies have suggested that rituximab may be effective therapy in adults with frequently relapsing or glucocorticoid-dependent minimal change disease who have failed to attain a durable remission with cyclophosphamide or calcineurin inhibitors. (141-145) By contrast, rituximab does not appear to be effective in adults with glucocorticoid-resistant minimal change disease and therefore should be avoided in these patients. For example, Munyentwali et al. (2013) reported data of 17 adults with glucocorticoid-dependent minimal change disease who were treated with rituximab and had a mean follow-up of 29.5 months. (141) Remission was achieved in 11 patients after rituximab infusion (mean follow- up, 26.7 months), and 9 of these patients were able to discontinue all other immunosuppressive drugs. Six patients relapsed at least once after rituximab (mean time to relapse, 11.9 months), although other immunosuppressive therapies were successfully discontinued or reduced during this period.

Papakrivopoulou et al. (2016) reported data from a prospective study of 15 young adults with frequently relapsing or steroid-dependent, biopsy-proven minimal change disease who were treated with 2 doses of rituximab given 6 months apart. (146) All patients were in remission at the start of treatment and on a calcineurin inhibitor. A subset also received an additional dose 12 months later. Median steroid-free survival after rituximab treatment was 25 months (range, 4-34 months). Mean relapse frequency decreased from 2.60 to 0.4 (p<0.001). Thus, rituximab was effective at maintaining prolonged steroid-free remission and reducing relapse frequency in this group of patients.

Rituximab has been evaluated in 2 RCTs in children with nephrotic syndrome. In the first trial (2014), 48 children with frequently relapsing or with steroid-dependent (mean accumulated prednisolone dose, 18-19 mg/m2) nephrotic syndrome were randomized to rituximab (375 mg/m2) or placebo for 4 weeks. (147) At 1-year follow-up, the primary end point of median relapse-free duration was longer with rituximab (267 days) than with placebo (101 days). The relapse rate was lower in the rituximab group (1.54 vs 4.17 relapses per person-year), as was the daily prednisolone dose (8.4 mg/m2 vs 21 mg/m2). However, the effects were not maintained and, by the end of year 1, 17 (71%) of 24 patients who received rituximab relapsed compared with 23 (96%) of 24 who received placebo, and, by 19 months, all patients had relapsed. In the second trial (2015), prednisone alone was compared with prednisone plus single dose of rituximab. (148) At 3-month follow-up, proteinuria was 42% lower in the prednisone plus rituximab group. In addition, all but 1 patient in the prednisone-alone group relapsed within 6 months whereas the median time to relapse in the prednisone plus rituximab group was 18 months.

Section Summary: Minimal Change Disease

Evidence for rituximab in treatment of minimal change disease includes multiple observational studies in adults and 2 RCTs plus multiple observational studies in children. Rituximab may benefit in children with nephrotic syndrome associated with minimal change disease.

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. (255)

Waldenström’s Macroglobulinemia (WM) (255)

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.

Transplantation

Graft-Versus-Host Disease

Rituximab has been studied primarily for steroid-refractory chronic GVHD. Chronic GVHD, historically defined as occurring more than 100 days after transplant, (149) is the primary cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). (150) Approximately half of patients respond to first-line treatment (systemic corticosteroid with or without a calcineurin inhibitor), but treatment options for steroid-refractory disease are limited, and prognosis is poor.

In 2009, Kharfan-Dabaja published a systematic review and meta-analysis of 7 cohort studies (total N=111 patients) of rituximab in chronic GVHD. (151) Three studies were prospective, and four were retrospective. Pooled ORR was 66% (95% CI, 57% to 74%). Indication-specific response rates were 13% to 100% for skin, 0% to 83% for oral mucosa, 0% to 66% for liver, and 0% to 38% for lung. Common adverse events were infusion reactions or infectious complications.

In 2010, Kim et al. (152) published a multicenter, phase 2 cohort study of 37 patients with steroid-refractory chronic GVHD diagnosed according to National Institute of Health criteria. (153) Most transplants used myeloablative conditioning regimens (78%) and unrelated donor cells. Patients received rituximab 375 mg/m2 weekly for 4 weeks and then monthly for 4 months; 29 patients completed treatment (4 dropped out, 4 died), and 22 completed 8 additional months of follow-up (2 dropped out, 5 died). Thirty-two (86%) patients had any response (complete or partial) at any time during the study; median time to response was 29 days (range, 0-252 days). Twenty-one (57%) patients maintained response for 1 year, of whom 6 discontinued and 15 reduced steroid therapy. Response rates were higher for skin, oral mucosa, and musculoskeletal symptoms (response rates, 71%-100%) than for other organs (e.g., 9% for lung involvement). Most treatment failures were due to infectious complications or relapse of the primary disease.

Two studies examined prophylactic rituximab for the prevention of chronic GVHD after allo-HCT. Cutler et al. (2013) administered rituximab 375 mg/m2 at 100 days and 3, 6, 9, and 12 months after nonmyeloablative or myeloablative transplantation of HLA-matched related (48%) or unrelated (58%) donor cells (N=65). (154) The most common diagnoses were acute myeloid leukemia and myelodysplastic syndromes. Systemic immunosuppressants were tapered per institutional standards. Thirty-two (49%) patients received all 4 rituximab infusions (median, 3); most common reasons for not completing the treatment course were due to development of GVHD and relapse. All patients had at least 2 years of follow-up (median, 2 years). Cumulative incidence of chronic GVHD and of steroid-requiring chronic GVHD were 48% and 31%, respectively; in a contemporaneous control cohort of 68 patients who declined study participation, corresponding incidences were 60% (p=0.1 vs treatment cohort) and 49% (p=0.015), respectively. Estimated 4-year relapse (34%) and nonrelapse mortality (5%) may have been unreliable due to low patient numbers at follow-up, which were not reported. Two-year cumulative incidence of grade 3 or higher infections was 15%; 1 of 2 lethal infections was considered possibly related to rituximab.

Arai et al. (2012) administered rituximab 375 mg/m2 on posttransplantation days 56, 63, 70, and 77 to 35 patients who had high-risk chronic lymphocytic leukemia (n=22) or mantle cell lymphoma (n=13). (155) Patients received reduced-intensity conditioning with total lymphoid irradiation and antithymocyte globulin. Transplants were from matched related (n=19) or unrelated (n=16) donors. Systemic immunosuppressants were tapered and discontinued during rituximab treatment. Median follow-up for patients seen at the study center was 4 years. Incidence of acute GVHD was 6%, cumulative incidence of chronic GVHD was 20%, and nonrelapse mortality was 3%. Four-year OS was 73% for patients with chronic lymphocytic leukemia and 69% for patients with mantle cell lymphoma. Rituximab-related neutropenia (<500/µL) developed in 40% of patients, with febrile neutropenia and infection in 1 patient.

Fifteen (43%) patients had severe grade 3 infections within 1 year of transplant; none were fatal.

Section Summary: Graft-Versus-Host Disease

Rituximab for treatment of steroid-refractory chronic GVHD has been examined in cohort studies, which have shown responses in most patients, with sustained responses and steroid reductions or discontinuations in some. Because treatment options for patients with steroid-refractory GVHD are limited, rituximab may be considered in this setting. The evidence for rituximab prophylaxis for GVHD includes 2 small cohort studies, one of which contained a contemporaneous control group. Results suggest that rituximab may reduce the incidence of GVHD.

HLA Sensitization Pretransplant

Patients who are HLA-sensitized have broadly reactive alloantibodies (e.g., due to previous pregnancy, transfusion of blood or blood products, or transplantation). HLA-sensitized patients are difficult to match for donor organs because of high risks of hyperacute rejection and graft loss with cross-matched organs (i.e., positive for reactive antigens). Panel reactive antibody (PRA) assays define the level of HLA sensitization and are used to optimize identification of compatible donors. Some transplant centers employ desensitization protocols to overcome HLA sensitization. Protocols commonly use low-dose IVIG with PE or high-dose IVIG. (156)

Vo et al. (2014) planned to conduct a double-blind RCT of 90 HLA-sensitized, deceased donor, renal transplant recipients randomized to pretransplant desensitization with IVIG plus rituximab or IVIG plus placebo. (156) Of 15 patients enrolled, 13 underwent transplantation. However, after 5 serious events were observed in 7 patients randomized to placebo (antibody-mediated rejection [ABMR] in 3 patients, graft loss in 2 patients), the trial was halted. No ABMR or graft loss occurred in 6 rituximab-treated patients. Mean serum creatinine levels at 6 and 12 months were 1.7 mg/dL and 2.0 mg/dL, respectively, in 2 patients in the placebo group who had surviving allografts, and 1.1 mg/dL at both time points for patients who received rituximab. Although groups were similar at the time of transplantation for panel reactive antibody and donor-specific alloantibody levels, 1 (17%) of 6 patients randomized to rituximab had undergone previous transplant compared with 5 (70%) of 7 patients randomized to placebo.

This same group reported 3 other cohort studies of induction immunosuppression with rituximab plus IVIG in HLA-sensitized renal transplant recipients (total N≈200). (157-159) Patient and graft survival was 100% and 94% at 12 months; 95% and 84% at 24 months; and 95% and 88% (deceased donor transplants) at 48 months, all respectively. Mean serum creatinine levels at 12, 24, and 36 months were 1.5 mg/dL, 1.3 mg/dL, and 1.3 mg/dL, respectively. By comparison, estimated 3-year survival of a contemporaneous cohort of 3754 highly sensitized (PRA>80%) patients with end-stage renal disease who were wait-listed for transplants and remained on dialysis was 79%.

Opportunistic infection with polyomavirus BK (BKV) occurs in 10% to 20% of kidney transplants and can cause nephropathy, rejection, and graft dysfunction and failure. Barbosa et al. (2014) compared 2 cohorts of kidney transplant recipients (63% deceased donor) for posttransplant emergence of BKV. (160) One cohort (n=187) comprised HLA-sensitized patients who underwent pretransplant desensitization with IVIG plus rituximab; the other cohort (n=284) comprised non-HLA-sensitized patients. More patients in the desensitized group received lymphocyte-depleting immunosuppression induction (i.e., with antithymocyte globulin or alemtuzumab; 78%) than in the nondesensitized group (38%). At 2 years posttransplant, BKV viremia occurred in 20% of desensitized patients and 10% of nondesensitized patients. Patient survival, graft survival, and incidence of BKV-associated nephropathy did not differ statistically between groups.

Section Summary: HLA Sensitization Pretransplant

Several cohort studies in sensitized individuals have demonstrated good patient and graft survival with rituximab desensitization 3 years after transplant. An RCT comparing desensitization regimens with and without rituximab was terminated due to excess serious adverse events in the control arm, and 1 study reported no increase in PBK-associated nephropathy at 2-year follow-up. This evidence suggests that health outcomes are improved with rituximab desensitization regimens in sensitized renal transplant candidates.

Antibody-Mediated Rejection

Antibody-mediated injury to allografts comprises ABMR, ABMR without complement deposition, antibody- mediated endarteritis, and accelerated arteriosclerosis of allografts. (161) Induction immunosuppressive regimens initiated before, at the time of, or immediately after transplantation, mute T-cell responses to antigen presentation reduces acute rejection. (162) Induction regimens typically are combination high-dose immunosuppressive agents or anti-T-cell antibodies (e.g., antithymocyte globulin) plus lower dose immunosuppressive agents.

Induction to Prevent ABMR

Zhao et al. (2014) conducted a meta-analysis of rituximab-containing induction regimens in HLA- sensitized kidney transplant recipients. (163) Literature was searched through July 2013, and 7 comparative studies (total N=589 patients) were identified. Studies varied by design (retrospective or prospective), sample size (40-144 patients), induction regimens, rituximab dosing, and whether rituximab was add-on or alternative therapy. However, statistical heterogeneity was low. Overall study quality was very low; no prospective, randomized trials were included. In meta-analysis of 5 studies, acute ABMR occurred less in patients treated with rituximab (n=182) than in controls (n=212) (odds ratio [OR], 0.52; 95% CI, 0.28 to 0.98; p=0.04; I2=0%). Meta-analysis of 4 studies showed increased graft survival at 1 year in rituximab- treated patients (n=165) than in controls (n=183) (OR=3.02; 95% CI, 1.14 to 8.02; p=0.03; I2=18%).

Tyden et al. (2009) conducted a multicenter, double-blind, RCT comparing induction immunosuppressive regimens with and without rituximab in 136 kidney transplant recipients. (164) Patients were randomized to a single infusion of rituximab (n=68) or placebo (n=68) within 24 hours before transplantation. All patients also received steroids, tacrolimus, and MMF. At 6 months after transplant, there was no statistical between-group differences in treatment failures (10 rituximab, 14 placebo; p=0.348), rejection episodes (8 rituximab, 12 placebo; p=0.317), mean creatinine clearance (67 mL/min rituximab, 66 mL/min placebo), or incidence of infections. At 3-year follow-up, 8 (12%) of rituximab-treated patients and no placebo-treated patients had died (p=0.006). Deaths were due to fungal pneumonia and lung cancer in 1 patient each, and 6 cardiac arrests. Pretreatment history of cardiovascular disease was similar between groups.

Van den Hoogen et al. (2015) conducted an RCT of 280 renal transplant patients. (165) Participants were randomized to rituximab (375 mg/m2) or placebo during surgery; maintenance immunosuppression included tacrolimus, MMF, and glucocorticoids. Acute rejection at 6 months occurred in 16.7% (23/138) of rituximab-treated patients and 21.2% (30/142) in the placebo arm (p=0.25). Through 24 months there were similar rates of malignancies infections in both arms.

Treatment of ABMR in Solid Organ Transplantation

Roberts et al. (2012) conducted a systematic review of acute ABMR treatments in kidney transplant recipients. (166) Two published, low-quality studies of rituximab were identified (total N=78 patients). The studies used historical controls and were rated to be of very low quality. Most patients in both studies received deceased donor allografts. Graft failure occurred in 3 (8%) of 28 rituximab-treated patients and 14 (35%) of 40 controls.

Ravichandran et al. (2013) reported a retrospective case review of 33 cardiac recipients who had clinical suspicion of rejection (signs or symptoms of heart failure and/or hemodynamic compromise), complement component 4 staining on endomyocardial biopsy, and absence of grade 2R or greater cellular rejection. (167) Thirteen patients received rituximab, and 20 did not. Immunosuppressive regimens varied; all patients received steroids. All rituximab-treated (100%) patients and 80% of controls survived at least 1 week. At year 3, patient survival was 75% in the rituximab group and 29% in the control group (p=0.009). Infections and rehospitalizations occurred in 4 (31%) and 8 (65%) of 13 rituximab-treated patients and in 2 (10%) and 7 (35%) of 20 controls, respectively.

Zarkhin et al. (2008) reported on an open-label RCT of 20 consecutive pediatric patients (age range, 2-23 years; mean, 14 years) who had biopsy-proven acute rejection with infiltrating B-cell clusters after kidney transplant. (168) Patients were randomized to standard immunosuppressive treatment (pulse steroid and/or antithymocyte globulin; n=10) or standard treatment plus rituximab weekly for 4 doses (n=10). All patients completed rituximab dosing without serious adverse events through 12 months of follow-up. Statistically significant improvements in creatinine clearance were seen in the rituximab group compared with the control group at 6 and 12 months after treatment (p=0.026 for trend).

Sautenet et al. (2016) reported results of a phase 3 (N=38), multicenter, double-blind, placebo-controlled trial in biopsy-proven ABMR patients who were randomized to rituximab (n=19) or placebo (n=19) at day 5. (169) All patients received PE, IVIG, and corticosteroids. The primary end point was a composite of graft loss or no improvement in renal function at day 12. There was no difference in the proportion of patients achieving primary end point (53% for rituximab vs 58% for placebo; p>0.05). Authors acknowledged that the trial was underpowered to detect a significant difference between groups.

Section Summary: Antibody-Mediated Rejection

Evidence for rituximab induction to prevent acute ABMR includes a meta-analysis of five very low-quality trials and one RCT. Although the meta-analysis indicated reduced ABMR and improved graft survival compared with controls, trial quality was very low. One RCT demonstrated increased mortality in the rituximab group at three years of follow-up. A second RCT found no beneficial effect on biopsy-proven rejection. Rituximab has not been shown to improve health outcomes when used for induction immunosuppression in kidney transplant recipients. Small numbers of heart and kidney transplant recipients with ABMR have been treated with rituximab in comparative studies. Although observed improvements in outcomes would suggest potential benefit with rituximab, data are retrospective or from small prospective studies.

Pancreatic Islet Transplantation

Autoimmune destruction of insulin-secreting islet beta-cells causes type 1 diabetes (T1D). (170) ABMR after pancreatic transplantation is less common than cell-mediated rejection, but when it occurs, pancreatic islet cells appear to be particularly susceptible to injury. (171) Pancreatic islet transplantation is used in patients who have T1D complicated by recurrent severe hypoglycemic episodes, and insulin independence is restored in 44% of patients. (172) However, graft function commonly declines over time, which is thought to be due in part to allograft rejection.

Immunosuppression management after islet transplantation is not standardized. Use of rituximab in a patient with evidence of ABMR has been described in a single case report (2009). (173) Use of rituximab has been described in 4 patients who underwent pancreas transplantation and developed ABMR (i.e., graft dysfunction in the presence of anti-HLA antibodies with or without complement deposition on histopathologic staining). In a series of 18 patients reported by Torrealba et al. (2008), 1 received rituximab plus IV corticosteroid, IVIG, and plasmapheresis for ABMR after simultaneous pancreas and kidney transplantation. (174) This patient subsequently required chronic insulin therapy for blood glucose control. Three patients with T1D who underwent simultaneous pancreas and kidney transplantation and developed ABMR received single doses of rituximab 375 mg/m2 in combination with T-cell-directed therapies (thymoglobulin and daclizumab, an anti-CD25 monoclonal antibody) (175) or IVIG and plasmapheresis. (176) Two patients in the first group remained insulin-independent for 36 months and 12 months, respectively, and 1 patient in the second group remained insulin-independent for 10 months of follow-up.

Section Summary: Pancreatic Islet Transplantation

Comparative studies of rituximab for ABMR after pancreas transplantation were not identified. Dose-response studies and larger RCTs with longer follow-up and are needed to demonstrate improved health outcomes with rituximab treatment of ABMR.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines (v.4.2017) recommend rituximab for the following indications (see Table 3).

Table 3. Guidelines on Treatment Regimens Including Rituximab for NHL (253)

NHL Type

Therapy

Category

FL, grade 1-2

First-line with bendamustine

1

 

First-line, with multiagent chemotherapy

1

 

First-line, monotherapy

2A

 

First-line, with lenalidomide

3

 

Second-line, monotherapy

2A

 

Second-line, with fludarabine

2A

 

Second-line, with multiagent chemotherapy

2A

 

Second-line consolidation or extended dosing, maintenance for 2 years

1

FL, grade 1-2, elderly or infirm

First-line, monotherapy

2A

 

First-line, with single-agent alkylators

2A

FL, grade 1-2, consolidation or extended dosing

First-line, monotherapy

1

 

Second-line, monotherapy

1

 

Aggressive induction, with multiagent chemotherapy

2A

 

Less aggressive induction, with bendamustine

2A

MCL, candidate for HDT/ASCR

First-line, as maintenance

2A

MCL, not candidate for HDT/ASCR

First-line, R-CHOP with rituximab maintenance

1

DLBCL

First-line, with multiagent chemotherapy

1

 

First-line, with multiagent chemotherapy

2B

 

Second-line, with multiagent chemotherapy

2A

DLBCL, frail or elderly patients

First-line, with multiagent chemotherapy

2A

Burkitt lymphoma

First-line, with multiagent chemotherapy

2A

 

Second-line, with multiagent chemotherapy

2A

CLL/SLLa

First-line, monotherapy

3

 

First-line, with multiagent chemotherapy

2A

CLL/SLLa, age >65 or with comorbidities

First-line, with chlorambucil

2A

CLL/SLLa, relapsed or refractory

With methylprednisone or chemotherapy

2A

ASCR: autologous stem cell rescue; CLL: chronic lymphocytic leukemia; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; HDT: high-dose therapy; MCL: mantle cell lymphoma; NHL: non-Hodgkin lymphoma; R-CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab; SLL: small lymphocytic lymphoma.

a Without del(17p)/TP53 variant.

NCCN guidelines (v.2.2018) recommend first-line treatment with rituximab for the following indications for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (see Table 4).

Table 4. Guidelines on Treatment Regimens Including First-Line Rituximab for CLL and SLL Without del(17p)/TP53 Variant (254)

CLL and SLL

Therapy

Category

Frail with significant comorbidity

Rituximab plus chlorambucil

2A

 

High-dose methylprednisone plus Rituximab

2B

 

Rituximab

3

Age ≥65 y

Monotherapy or with chlorambucil

2A

 

High-dose methylprednisone plus Rituximab

2A

Age <65 y without significant comorbidity

Rituximab, in combination with fludarabine and cyclophosphamide

1

 

Rituximab, in combination with fludarabine

2A

 

High-dose methylprednisone plus Rituximab

2A

American College of Rheumatology

Rheumatoid Arthritis

The American College of Rheumatology updated its evidence-based consensus guidelines on rheumatoid arthritis (RA) in 2015 and made the following recommendations (177):

If a patient has moderate (e.g., Clinical Disease Activity Index [CDAI] >10-22 or DAS28 [Disease Activity Score] ≥3.2 to ≤5.1) or high (e.g., CDAI >22 or DAS28 >5.1) disease activity after 3 months of MTX [methotrexate] monotherapy or disease-modifying antirheumatic drugs (DMARD) combination therapy, the panel recommended adding (Level A evidence, based on multiple randomized controlled trials) or switching (Level C evidence, based on expert consensus, case studies, or standard-of-care) to a tumor necrosis factor [TNF] inhibitor, abatacept, or rituximab as an alternative to DMARD combination therapy.

If a patient still has moderate or high disease activity after 3 months of TNF inhibitor therapy and this is due to a lack or loss of benefit, switching to another TNF inhibitor or a non-TNF biologic, such as rituximab (Level B evidence, based on a single randomized trial or nonrandomized studies), is recommended.

Reassessment after treatment with a non-TNF biologic, such as rituximab, is recommended at 6 months due to anticipation that a longer time to peak effect is needed for non-TNF biologics compared with TNF inhibitors.

Rituximab may be started or resumed in patients with RA who have a previously treated solid malignancy, including nonmelanoma skin cancer, within the last 5 years, or a previously-treated melanoma skin cancer or lymphoma (Level C recommendation, based on clinical trial extensions, observational data, and expert consensus).

The panel recommended vaccination with all killed (pneumococcal, influenza intramuscular, and hepatitis B), recombinant (human papillomavirus [HPV] vaccine for cervical cancer), and live attenuated (herpes zoster) vaccines before starting a DMARD or biologic agent.

o If not administered before starting a DMARD or biologic agent, pneumococcal (killed), influenza intramuscular (killed), hepatitis B (killed), and HPV (recombinant) vaccines should be administered to RA patients already taking a DMARD or biologic agent.

o Live attenuated vaccines (herpes zoster) are not recommended during therapy with biologic agents.

Lupus Nephritis

In 2012, the College published evidence-based consensus guidelines on the treatment of lupus nephritis. (191) A task force panel voted that, in some cases, rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both cyclophosphamide and mycophenolate mofetil (MMF) treatments (level C evidence, based on consensus, expert opinion, or case series).

National Institute for Health and Care Excellence

Rheumatoid Arthritis

In 2010, the National Institute for Health and Care Excellence issued a guidance on adalimumab, etanercept, infliximab, rituximab, and abatacept for the treatment of RA after the failure of a TNF inhibitor. (178) The recommendations involving rituximab include:

“Rituximab in combination with methotrexate is recommended as treatment for patients with severe active rheumatoid arthritis who have had an inadequate response to, or are intolerant of other disease-modifying anti-rheumatic drugs (DMARDs), including at least one tumour necrosis factor (TNF) inhibitor. Treatment with rituximab should be given no more frequently than every 6 months.

Treatment with rituximab in combination with methotrexate should be continued only if there is an adequate response…. An adequate response is defined as an improvement in disease activity score (DAS28) of 1.2 points or more.”

Antineutrophil Cytoplasmic Antibody?Associated Vasculitides

In 2014, the National Institute for Health and Care Excellence issued guidance rituximab in combination with glucocorticoids for treating antineutrophil cytoplasmic antibody-associated vasculitis. (182)

“Rituximab, in combination with glucocorticoids, is recommended as an option for inducing remission in adults with anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis (severely active granulomatosis with polyangiitis [Wegener's] and microscopic polyangiitis), only if:

Further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose, or

Cyclophosphamide is contraindicated or not tolerated, or

The person has not completed their family and treatment with cyclophosphamide may materially affect their fertility, or

The disease has remained active or progressed despite a course of cyclophosphamide lasting 3– 6months, or

The person has had uroepithelial malignancy.”

The guidance did not offer conclusions on maintenance therapy.

Multiple Sclerosis

In 2014, the Institute updated its guidance on the management of multiple sclerosis in primary and secondary care. (188) It does not include rituximab.

European League Against Rheumatism

Rheumatoid Arthritis

The European League Against Rheumatism’s (EULAR) 2013 recommendations for the management of RA with synthetic and biological DMARDs stated: “In patients responding insufficiently to MTX (methotrexate) and/or other conventional synthetic DMARD strategies, with or without glucocorticoids, biological DMARDs (TNF inhibitors, abatacept, or tocilizumab, and, under certain circumstances, rituximab) should be commenced with MTX.” (179) The “certain circumstances” are: recent history of lymphoma; latent tuberculosis (TB) and contraindications to chemoprophylaxis; living in a TB-endemic area; or previous demyelinating disease.

International Consensus Expert Group

Rheumatoid Arthritis

An international (mostly European) consensus group updated its evidence-based consensus statements in 2010 (180) and 2011. (181) The group supported consideration of rituximab when TNF inhibitors are not suitable (category D evidence) and in MTX-naive patients.

Kidney Diseases: Improving Global Outcomes (KDIGO)

Glomerulonephritis

In 2012, KDIGO published evidence-based consensus guidelines for glomerulonephritis. (13) Rituximab plus corticosteroid was recommended as an alternative first-line treatment (to cyclophosphamide plus corticosteroid) in patients who do not have severe disease or in whom cyclophosphamide is contraindicated (level 1 recommendation based on level B [moderate quality] evidence).

Hepatitis C Virus?Associated Cryoglobulinemic Vasculitis

In 2012, KDIGO published evidence-based consensus guidelines for glomerulonephritis. (13) Rituximab in combination with intravenous (IV) methylprednisolone and antiviral therapy is suggested as 1 of several treatment options (along with plasmapheresis or cyclophosphamide, also in combination with IV methylprednisolone and antiviral therapy) for patients with hepatitis C virus and mixed (immunoglobulin [Ig] G, IgM) cryoglobulinemia who have nephrotic proteinuria, progressive kidney disease, or an acute flare of cryoglobulinemia (level 2 suggestion based on level D [very low-quality] evidence).

Lupus Nephritis

Rituximab is suggested in the 2012 KDIGO guidelines, as one of several treatment options (along with IVIG and calcineurin inhibitors) for patients with lupus nephritis who have failed more than 1 first-line regimen (level 2 suggestion based on level D [very low-quality] evidence).

Kidney Transplant

In 2009, KDIGO published evidence-based consensus guidelines on the care of kidney transplant recipients. (162) Rituximab was discussed but not included in any recommendations. For treatment of acute rejection, it was noted that “the optimal protocol to treat acute humoral rejection remains to be determined,” and randomized controlled trials comparing safety and efficacy of various regimens were lacking. IVIG plus rituximab has been used to treat recurrent (posttransplant) hemolytic-uremic syndrome that is resistant to multiple courses of plasma exchange.

American Society of Hematology

Idiopathic Thrombocytopenic Purpura

In 2011, the American Society of Hematology published evidence-based guidelines for immune thrombocytopenia (ITP). (183) Rituximab was suggested in the following clinical scenarios (all grade 2 suggestions based on level C evidence [randomized controlled trials with serious flaws, weaker observational studies, or indirect evidence]):

“… children or adolescents with ITP who have significant ongoing bleeding despite treatment with IVIg [intravenous immunoglobulins], anti-D, or conventional doses of corticosteroids (Grade 2C).

“… as an alternative to splenectomy in children or adolescents with chronic ITP or in patients who do not respond favorably to splenectomy (Grade 2C).”

“…[adults with ITP] at risk of bleeding who have failed one line of therapy such as corticosteroid, IVIg, or splenectomy (Grade 2C).”

British Committee for Standards in Haematology

Thrombotic Thrombocytopenic Purpura

The British Committee for Standards in Haematology published evidence-based consensus guidelines for treatment of thrombotic thrombocytopenic purpura (TTP) and thrombotic microangiopathy in 2012. (35) Recommendations are included in Table 5.

Table 5. Recommendations on Treatment of Thrombotic Thrombocytopenic Purpura

Recommendations

LOE

SOR

In acute idiopathic TTP with neurological or cardiac pathology, which are associated with a high mortality, rituximab should be considered on admission, in conjunction with plasma exchange and corticosteroids

Ideally plasma exchange should be withheld for at least 4 hours after completing a rituximab infusion

1B

Strong

Increased plasma exchange and/or rituximab therapy are the agents of choice in refractory or relapsing disease

1B

Strong

In patients in remission who have a documented reduction of ADAMTS13 activity to <5%, elective therapy with rituximab can be considered

1B

Strong

In resistant HIV-related TTP, rituximab could be considered

2B

Weak

LOE: level of evidence; SOR: strength of recommendation; TTP: thrombotic thrombocytopenic purpura.

U.K. Haemophilia Centre Doctors Organization

Congenital Hemophilia

In 2013, U.K. Haemophilia Centre Doctors Organization updated its evidence-based consensus guidelines on the diagnosis and treatment of factor VIII (FVIII) and factor IX inhibitors in congenital hemophilia. (46) For patients undergoing ITI, rituximab was suggested as one of several strategies (along with FVIII dose increase; use of low-purity platelet-derived FVIII rather than recombinant FVIII; or discontinuation of ITI) if there is an inadequate decrease in inhibitor titer (≤20% reduction in 6 months). (Grade 2 [weak] recommendation based on level C [low-quality] evidence.)

International Consensus Expert Group

Acquired Hemophilia A

In 2009, an international group of experts in the management of acquired hemophilia published evidence- based consensus recommendations on the diagnosis and treatment of patients with acquired hemophilia A. (47) Rituximab alone or in combination with corticosteroids was suggested as second-line therapy if first- line inhibitor eradication therapy (with corticosteroids alone or in combination with cyclophosphamide) fails or is contraindicated. (Evidence grade not provided because all recommendations and suggestions were based on low-quality evidence.)

Physicians World Europe

An expert panel, coordinated by Physicians World Europe, conducted a systematic review on the management of acquired hemophilia A and published their results in 2010. (184) The panel recommended that patients receive immunosuppressive therapy immediately following diagnosis of acquired hemophilia A. If corticosteroid treatment does not induce remission, adding cyclophosphamide or rituximab is suggested, though rituximab is not currently approved for this indication.

Centers for Disease Control and Prevention et al.

Multicentric Castleman Disease

In 2013, the Centers for Disease Control and Prevention, National Institutes of Health, and other medical societies jointly updated evidence-based guidelines on the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. (62) Rituximab was recommended as an optional alternative therapy for multicentric Castleman disease; regimens with ganciclovir and valganciclovir were preferred. Guideline authors noted that patients treated with rituximab “may experience subsequent exacerbation or emergence of KS [Kaposi sarcoma].” (Level C [optional] recommendation based on level 2 evidence [1 or more nonrandomized trials or observational studies with long-term clinical outcomes].)

In 2013, the Centers for Disease Control and Prevention, the National Institutes of Health, and 3 other medical societies jointly published evidence-based guidelines on the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children. (185) Rituximab was not included among recommended treatments for multicentric Castleman disease.

American Academy of Neurology

Multiple Sclerosis

The American Academy of Neurology’s guidelines on disease-modifying therapies for multiple sclerosis (186) has not been reaffirmed since 2008. (187) It does not include rituximab.

National Multiple Sclerosis Society

The National Multiple Sclerosis Society does not include rituximab among its listed treatments for multiple sclerosis. (189)

Neuromyelitis Optica Study Group

Neuromyelitis Optica

In 2014, Neuromyelitis Optica Study Group published evidence-based consensus recommendations on the diagnosis and treatment of neuromyelitis optica. (81) Rituximab was recommended as first-line treatment, along with azathioprine, and as second-line treatment after azathioprine failure.

British Association of Dermatologists

Bullous Pemphigoid

In 2012, the British Association of Dermatologists published evidence-based guidelines on the management of bullous pemphigoid. (190) Rituximab received a level D recommendation based on level 3 evidence (case reports and case series).

European League Against Rheumatism et al.

In 2012, the European League Against Rheumatism and the European Renal Association European Dialysis and Transplant Association published joint evidence-based consensus recommendations on the management of pediatric and adult lupus nephritis. (192) For refractory disease (i.e., for patients not responding to cyclophosphamide [CYC] or MMF), treatment may be switched from MMF to CYC or from CYC to MMF, or rituximab may be added or given as monotherapy (category 4 evidence, based on expert committee reports or opinions and/or clinical experience of respected authorities).

British Committee for Standards in Haematology

Graft-Versus-Host Disease

In 2012, the British Committee published evidence-based consensus guidelines for the diagnosis and management of acute graft-versus-host disease (GVHD) (193) and chronic GVHD. (149) Due to insufficient evidence (case reports), the Committee did not recommend rituximab for acute GVHD. For chronic GVHD, the British Committee made 2 recommendations (the magnitude of benefit is less certain):

“Rituximab is suggested as a second line treatment in refractory cutaneous or musculoskeletal GvHD.” (Level 2B evidence, based on randomized trials with important limitations or strong evidence from observational studies)

“…rituximab may be considered as [a] third line treatment option in chronic GvHD involving other organs.” (Level 2C evidence, based on observational studies, case series or opinion).

Consensus Conference on Clinical Practice in Chronic GVHD

In 2011, Wolff et al. published evidence-based consensus guidelines on second-line treatment of chronic GVHD. (150) Rituximab was recommended as a reasonable second-line therapy of chronic GVHD, especially in patients with sclerodermatous, lichenoid cutaneous disease, and in autoantibody-mediated cytopenias (level C recommendation [evidence is insufficient to support for or against; use in greater than second-line treatment is justified] based on level II evidence [based on observational studies]). Evidence was insufficient to make dose recommendations.

International Society of Heart and Lung Transplantation

Solid Organ Transplant

In 2010, the International Society of Heart and Lung Transplantation published evidence-based consensus guidelines for the care of heart transplant recipients. (194) Rituximab was recommended for:

Desensitization therapy in human leukocyte antigen–sensitized heart transplant candidates (class 2b recommendation, usefulness/efficacy is less well-established; level C evidence, based on expert consensus);

In combination treatments for antibody-mediated rejection (class 2a recommendation, weight of evidence/opinion favors usefulness/efficacy; level C evidence).

Table 6. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

 

Warm autoimmune hemolytic anemia

 

NCT01181154a

Rituximab in Adult's Warm Auto-Immune Hemolytic Anemia: a Phase III, Double-bind, Randomised Placebo-controlled Trial

32

Jul 2016

(ongoing)

 

ANCA-associated vasculitis

 

NCT02433522

Comparison Between a Long Term and a Conventional Maintenance Treatment with Rituximab (MAINRITSAN3)

97

Jan 2019

 

NCT01697267

Rituximab Vasculitis Maintenance Study (RITZAREM)

190

Dec 2019

 
   
   
 

Acquired hemophilia

 

NCT01808911

Outcome of Acquired Hemophilia with Steroid Combined with Cyclophosphamide Versus Steroid Combined with Rituximab (CREHA Study)

164

Nov 2018

 

Pemphigoid and pemphigus diseases

 

NCT02383589a

A Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil (MMF) in Participants with Pemphigus Vulgaris (PV)

124

Sep 2019

 

Systemic sclerosis

 

NCT01748084

Rituximab in Systemic Sclerosis (RECOVER)

22

Mar 2017

(ongoing)

 

NCT01862926

A Randomized, Double Blind Controlled Trial Comparing Rituximab Against Intravenous Cyclophosphamide in Connective Tissue Disease Associated Interstitial Lung Disease

116

Nov 2020

 

Myasthenia gravis

 

NCT02950155

A Study Evaluating the Safety and Efficacy of Rituximab in Patients with Myasthenia Gravis (Rinomax)

60

Dec 2018

 

Idiopathic membranous nephropathy

 

NCT01508468

Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX)

80

Sep 2016

(ongoing)

 

NCT01180036

A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)

126

Oct 2017

(ongoing)

 

NCT01955187

Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy

106

Apr 2019

 

NCT03018535

Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO)

70

Dec 2019

 

Human leukocyte antigen sensitization pretransplant

 

NCT01095172 a

RituxiMab INDuction in Renal Transplantation

612

Oct 2023

                 

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

C9467, J9310, J9311, J9312

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

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93. Shetty S, Ahmed AR. Critical analysis of the use of rituximab in mucous membrane pemphigoid: a review of the literature. J Am Acad Dermatol. Mar 2013;68(3):499-506. PMID 23200198

94. Foster CS, Chang PY, Ahmed AR. Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report. Ophthalmology. May 2010;117(5):861-869. PMID 20045562

95. Cianchini G, Lupi F, Masini C, et al. Therapy with rituximab for autoimmune pemphigus: results from a single- center observational study on 42 cases with long-term follow-up. J Am Acad Dermatol. Oct 2012;67(4):617-622. PMID 22243765

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Policy History:

Date Reason
6/15/2018 Partial Update. The following indication added to the off-label medically necessary indications: opsoclonus myoclonus ataxia syndrome (OMAS) that is refractory to steroids, chemotherapy and intravenous immunoglobulins (IVIG).
3/15/2018 Document updated with literature review. Removal of wording “in treatment-refractory patients” for pemphigoid diseases. Medically necessary statement added for subcutaneous rituximab (Rituxan Hycela, rituximab and hyaluronidase human) in selected patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) who have received at least one full dose of intravenous rituximab. In addition, “as maintenance therapy after treatment-induced remission” added to coverage indication: “Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or as maintenance therapy after treatment-induced remission.” References and Rationale significantly revised.
4/15/2017 Document updated with literature review. The following were added to non-FDA-labeled indications listed in the coverage section: 1) idiopathic membranous nephropathy, and 2) myasthenia gravis, refractory.
3/15/2016 Document updated with literature review. The following was added to the non-FDA-labeled indications: 1) Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis): as first-line treatment in combination with corticosteroids for patients with severe (organ threatening) disease or add-on therapy for treatment-refractory disease; 2) Factor inhibitors in patients with hemophilia who are refractory to conventional first-line treatments (e.g., immune tolerance induction, corticosteroids with or without cyclophosphamide), preferably as add-on therapy; 3) Add-on therapy for patients with hepatitis C virus (HCV)?associated cryoglobulinemic vasculitis who have active disease resistant to anti-viral drugs; or severe or life-threatening cryoglobulinemic vasculitis; 4) The following pemphigoid diseases in treatment-refractory patients: bullous pemphigoid, mucous membrane pemphigoid, including ocular cicatricial pemphigoid, and epidermolysis bullosa acquisita; 5) Add-on therapy for lupus nephritis refractory to at least standard first-line treatment regimens; and 6) Systemic sclerosis (scleroderma) in patients refractory to first-line treatment.
2/1/2015 Reviewed. No changes.
7/15/2013 Document updated with literature review. The following FDA non-labeled indications were added as considered medically necessary 1) B-cell or other Lymphoid malignancies that express CD-20 antigen (including but not limited to chronic lymphoid leukemia (CLL), in combination with fludarabine for first-line treatment, chronic lymphoid leukemia (CLL), relapsed or refractory, AIDS-related B-cell lymphoma, mantle cell lymphoma (MCL), Burkett lymphoma, marginal Zone B-Cell lymphoma, Hairy Cell Leukemia, relapsed or refractory);2) Acute lymphocytic leukemia (ALL) (3) Minimal change disease (MCD) [also known as lipoid nephrosis or nil disease] refractory, steroid-dependent or steroid-resistant; (4) Sensitized kidney transplant recipients for inhibition of antibody production; (5) Neuromyelitis optica; (6) Polymyositis; severe, refractory; (7) Rheumatoid arthritis, in combination with methotrexate, in patients with an inadequate response to methotrexate; (8) Systemic lupus erythematosus, refractory to immunosuppressive therapy; (9) Primary Sjögren’s syndrome, (10) Pemphigus vulgaris was modified to include other autoimmune blistering skin diseases. The coverage for FDA labeled indications for treatment of rheumatoid arthritis and other chronic inflammatory conditions is unchanged, but was moved to this Medical Policy from RX501.051. Policy title changed from Rituxan (Rituximab) for Treatment of Cancer and Hematologic Conditions.
5/1/2011 Medical document updated with new FDA approved indication. A medically necessary statement was added for Rituxan as a single agent maintenance therapy for the indication of non-Hodgkin’s lymphoma for patients achieving a complete or partial response to Rituxan in combination with chemotherapy.
7/15/2010 Medical document updated with literature review. Added the following changes: 1) New FDA approved indication for Rituxan: Chronic Lymphocytic Leukemia (CLL) in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL. 2) Updated rationale on experimental, investigational and unproven coverage position pertaining to maintenance therapy.
2/1/2010 New medical document with literature review. Coverage position is conditional addressing FDA labeled and off-label indications.

Archived Document(s):

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