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Medical Policy

Policy Num:       05.001.016
Policy Name:    Uses of Monoclonal Antibodies for the Treatment of Non-Hodgkin Lymphoma

Policy ID:          [05.001.016]  [Ar / B / M+ / P+]  [2.03.05]

Last Review:     December 4, 2024
Next Review:     Policy Archived 

Related Policies;

05.001.029 - Nononcologic Uses of Rituximab

     Uses of Monoclonal Antibodies for the Treatment of Non-Hodgkin Lymphoma

Summary

Description

Monoclonal antibodies targeted to cancer-associated antigens have been approved by the U.S. Food and Drug Administration (FDA) for various uses in oncology. In some cases, these agents are used in settings outside of the approved label (ie, off-label use). This evidence review is limited to 3 CD20 antigen-directed monoclonal antibodies (rituximab, ofatumumab, and obinutuzumab) used for patients with non-Hodgkin lymphoma. Ibritumomab (Zevalin), which combines a CD20-directed antibody with a radioactive agent, and monoclonal antibodies that target other antigens besides CD20, are not addressed here.

Summary of Evidence

Intravenous Rituximab (Rituxan)

For individuals who have non-Hodgkin lymphoma (NHL) who receive intravenous rituximab alone or combined with chemotherapy, the evidence includes randomized controlled trials (RCTs) and nonrandomized comparative studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Randomized trials have shown that the addition of rituximab to front-line chemotherapy has resulted in improved response rates and survival in follicular lymphoma (FL) and diffuse large B-cell lymphoma. A number of multicenter studies have demonstrated the efficacy of rituximab as monotherapy in relapsed and refractory FL. Randomized trials of rituximab maintenance therapy have shown improved progression-free survival (PFS) in patients with previously untreated FL and improved PFS and overall survival in patients with previously treated FL. One study of diffuse large B-cell lymphoma showed improved PFS and overall survival in patients receiving rituximab-containing regimens, including monotherapy, compared with rituximab-free regimens. For maintenance therapy, a meta-analysis of 3 RCTs found significantly higher PFS with rituximab than a control condition. For first-line therapy, RCTs have shown that the addition of rituximab to front-line chemotherapy improves response rates. RCTs have shown that the addition of rituximab to chemotherapy has improved response rates and time-to-treatment failure in newly diagnosed mantle cell lymphoma and improved overall survival in relapsed or refractory disease. RCTs have also shown improved PFS and overall survival with the addition of rituximab to chemotherapy in previously untreated chronic lymphocytic leukemia (CLL). One RCT showed prolonged PFS in relapsed or refractory CLL, and a phase 2 open-label study showed improved PFS and overall survival. One RCT showed better event-free survival and overall survival in patients with Burkitt lymphoma when combined with chemotherapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Subcutaneous Rituximab (Rituxan Hycela)

For individuals who have NHL who receive subcutaneous rituximab following at least 1 full dose of intravenous rituximab, the evidence includes RCTs in patients with FL, diffuse large B-cell lymphoma, and CLL. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. The published RCTs focused on patients with previously untreated disease. They found that subcutaneous rituximab was noninferior to intravenous rituximab in its pharmacokinetics, specifically serum trough concentration. The trials had response rates as primary or secondary outcomes, and each trial found that response rates were similar with subcutaneous rituximab and intravenous rituximab. According to the FDA product label, the study findings were applicable to select patients with previously treated FL and CLL. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Ofatumumab (Arzerra)

For individuals who have NHL who receive ofatumumab alone or combined with chemotherapy, the evidence includes RCTs and nonrandomized comparative studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Ofatumumab has been shown to improve PFS when used as first-line therapy and to treat relapsed and refractory CLL under certain conditions. Based on a phase 3 RCT (COMPLEMENT 1), ofatumumab improved PFS for first-line therapy in previously untreated CLL for patients who were not candidates for treatment with fludarabine. In another phase 3 RCT (COMPLEMENT 2), ofatumumab improved PFS when combined with fludarabine and cyclophosphamide to treat relapsed CLL. Ofatumumab also improved PFS for treatment of CLL refractory to fludarabine or alemtuzumab, based on response rates in CLL treatment-resistant groups. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Obinutuzumab (Gazyva)

For individuals who have NHL who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Obinutuzumab was approved by the FDA for the treatment of FL in patients who have relapsed or are refractory to a rituximab-containing regimen (in combination with bendamustine) or in adults with previously-untreated stage II bulky, III, or IV FL (in combination with chemotherapy; the drug was also approved for use in combination with chlorambucil for previously untreated CLL. These indications are based on positive results in phase 3 trials that compared combination therapy with monotherapy. A phase 3 RCT in patients with previously untreated CLL demonstrated superior PFS with the combination of obinutuzumab and venetoclax, with or without ibrutinib, compared with rituximab and venetoclax or rituximab-based chemoimmunotherapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to evaluate the efficacy of on-label and off-label uses of monoclonal antibodies for the treatment of non-Hodgkin lymphoma improves the net health outcome.

Policy Statements

Intravenous Rituximab

Intravenous rituximab (Rituxan) may be considered medically necessary to treat patients with non-Hodgkin lymphoma (NHL) for the following U.S. Food and Drug Administration (FDA) labeled indications:

Follicular lymphoma (FL):

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

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

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

Diffuse large B-cell lymphoma (DLBCL):

• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or other anthracycline-based chemotherapy regimens

Chronic lymphocytic leukemia (CLL):

• Previously untreated and previously treated CD20-positive CLL in combination with FC (fludarabine and cyclophosphamide)

Intravenous rituximab (Rituxan) may be considered medically necessary to treat patients with NHL for the following off-label indications:

Mantle cell lymphoma:

First-line therapy in combination with one of guideline-based chemotherapy regimens.

Maintenance therapy until progression or intolerance.

Burkitt lymphoma:

• First-line therapy

Posttransplant lymphoproliferative disorders:

• For patients who have had an inadequate response to reduction of immunosuppression or are not candidates for reduction of immunosuppression

Subcutaneous Rituximab

Subcutaneous rituximab (Rituxan) may be considered medically necessary to treat patients with non-Hodgkin lymphoma (NHL) for the following FDA labeled indications:

Subcutaneous rituximab (rituximab and hyaluronidase human) [Rituxan Hycela]) may be considered medically necessary to treat patients with NHL who have received at least one full dose of intravenous rituximab for the following FDA labeled indications:

Follicular lymphoma (FL):

• 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.

• Relapsed or refractory FL as a single agent.

Diffuse large B-cell lymphoma (DLBCL):

• Previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline based-chemotherapy regimens.

Chronic lymphocytic leukemia (CLL):

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

Ofatumumab

Intravenous ofatumumab (Arzerra) may be considered medically necessary to treat patients with NHL for the following FDA labeled indications:

Chronic lymphocytic leukemia (CLL):

• In combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate

• In combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with relapsed CLL

• For extended treatment of patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL

• For the treatment of patients with CLL refractory to fludarabine and alemtuzumab

Ofatumumab (Arzerra) is considered investigational as maintenance therapy in patients with CLL.

Ofatumumab (Arzerra) is considered investigational for the treatment of malignancies other than CLL.

Obinutuzumab

Intravenous obinutuzumab (Gazyva) may be considered medically necessary to treat patients with NHL for the following FDA labeled indications:

Follicular lymphoma (FL):

• In combination with chemotherapy followed by obinutuzumab monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV FL.

• In combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of patients with FL who relapsed after, or are refractory to, a rituximab-containing regimen.

Chronic lymphocytic leukemia (CLL):

• In combination with chlorambucil, for the treatment of patients with previously untreated CLL.

Obinutuzumab (Gazyva) is considered investigational for relapsed or refractory CLL.

Policy Guidelines

Coding

Please see the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates regarding off-label uses of drugs approved by the Food and Drug Administration may supersede this policy. Off-label uses of rituximab (Rituxan) are from the AHFS Drug Information, as well as recent studies. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Triple-S Salud Preferred Drugs Determination 

For all FDA approved indications first treatment of choice will be biosimilars Truxima and Ruxience.

In order to consider any other rituximab agents, patients must have:

• documented previous use and therapeutic failure to biosimilars Truxima and Ruxience
• intolerance or contraindication to biosimilars Truxima and Ruxience.

Background

Monoclonal antibodies targeted to cancer-associated antigens have been approved by the U.S. Food and Drug Administration for various uses in oncology. In some cases, these agents are used in settings outside of the approved label (i.e., off-label use).

C20-Directed Cytolytic Antibodies

CD20 is a cell surface antigen expressed on pre-B and mature-B lymphocytes. More than 90% of malignant B-cells in non-Hodgkin lymphoma (NHL) express CD20.^1, CD20-directed cytolytic antibodies mediate cell lysis by (1) antibody-dependent cell-mediated cytotoxicity, (2) complement-dependent cytotoxicity, and (3) induction of intracellular death signaling pathways (apoptosis). All three CD20-directed cytolytic antibodies carry black box warnings for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.

•         Rituximab (Rituxan) is a chimeric murine-human monoclonal antibody. In addition to inducing B-cell lysis, rituximab sensitizes B cells to the cytotoxic effects of chemotherapy. Rituximab also carries black box warnings for serious, potentially fatal, infusion reactions and severe mucocutaneous reactions.

•         Ofatumumab (Arzerra) is a fully human monoclonal antibody produced in a recombinant murine cell line. Ofatumumab targets an epitope that differs from the binding location of rituximab.^2, In chronic lymphocytic leukemia (CLL), B cells underexpress CD20; unlike rituximab, which depends on CD20 expression for complement-dependent cytotoxicity, ofatumumab does not appear to depend on antigen intensity.

•         Obinutuzumab (Gazyva) is a humanized monoclonal antibody produced in Chinese hamster ovary cell culture. In addition to the cytolytic mechanisms described earlier, obinutuzumab induces antibody-dependent cellular phagocytosis.

This review considers labeled and off-labeled indications for rituximab, ofatumumab, and obinutuzumab, in NHL in the nonhematopoietic cell transplant setting.

Regulatory Status

U.S. Food and Drug Administration (FDA) labeled indications for rituximab, ofatumumab, and obinutuzumab in patients with NHL are shown in Table 1. Rituximab, ofatumumab, and obinutuzumab all carry black box warnings for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.

A number of biosimilars of rituximab have been FDA approved for the treatment of NHL: Truxima in 2018, Ruxience in 2019, and Riabni in 2020 (See Table 1).

Table 1. FDA Labeled Indications for Monoclonal Antibodies for Non-Hodgkin Lymphoma

    CLL: chronic lymphocytic leukemia; DLBCL: Diffuse large B-cell lymphoma; FDA: U.S. Food and Drug Administration; FL: follicular lymphoma; NHL: non-Hodgkin lymphoma. Source: Drugs@FDA2 

RATIONALE

This evidence review was created in August 2001 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 23,2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population reference No. 1

Intravenous Rituximab (Rituxan) 

for Non-Hodgkin Lymphoma

Clinical Context and Therapy Purpose

The purpose of intravenous (IV) rituximab alone or combined with chemotherapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with non-Hodgkin lymphoma (NHL).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NHL.

Interventions

The therapy being considered is IV rituximab alone or combined with chemotherapy. 

Comparators

The following therapies are currently being used to treat NHL: standard chemotherapy regimens. Treatment of patients with NHL can also include radiotherapy, stem cell transplantation, and medications that stimulate bone marrow growth. .

Outcomes

The general outcomes of interest are overall survival (OS), change in disease status, quality of life, and treatment-related mobility. Interval follow-up over 1 to 12 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

First-Line Therapy for Previously Untreated B-Cell Lymphomas

Hüttmann et al (2018) reported the results of the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial, which assessed the ability of [¹⁸F]-fluorodeoxyglucose positron emission tomography (PET) scanning to guide treatment of aggressive B-cell lymphomas (Table 2).^3, In the process of this assessment, investigators evaluated the effectiveness of 6 versus the European standard of 8 doses of rituximab in patients receiving CHOP (CHOP consists of cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP is CHOP plus rituximab). Investigators combined randomized and nonrandomized patients with B cell lymphomas and a negative interim scan into 3 groups with these conditions: diffuse large B cell lymphoma (n=544), primary mediastinal B cell lymphoma (n=37), and follicular lymphoma (FL) grade 3 (n=35). Each group was split into 2 subgroups that received either 6 or 8 doses of rituximab with CHOP. The results of the trial showed that 8 cycles of rituximab with CHOP did not result in better outcomes than 6 cycles in patients with aggressive B cell lymphomas. The results are summarized in Table 2.

Table 2. Remission and Survival Rates in PETAL Trial at Median 52-Month Follow-Up

    Table adapted from Hüttmann et al (2018). DLBCL: diffuse large B cell lymphoma; FL: follicular lymphoma; PFS: progression-free survival; PMBCL: primary mediastinal B cell lymphoma; R: rituximab.  a Number of patients responding/total number of patients reaching the end-of-treatment evaluation (%). b Kaplan-Meier estimate of percentage of patients surviving after 3 years (95% CI).

Follicular Lymphoma

First-Line Therapy for 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 NHL or FL.^3, A narrative review by Cvetkovic and Perry (2006) summarized the effect on complete remission (CR) of adding rituximab to several different chemotherapy regimens, including CHOP, CVP (cyclophosphamide, vincristine, prednisone), and others. It reported that the addition of rituximab resulted in significantly greater CR rates (41%-79% for rituximab-containing regimens vs 10%-63% for regimens without rituximab; p<.005), and greater overall response rates (81%-96% vs 57%-90%, respectively; p<.05).^4,

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).^5, Patients who received R-CHOP had significantly prolonged time-to-treatment failure (p<.001), higher overall response rate (96% vs 90%, p=.011), and prolonged duration of remission (p=.001). Additional follow-up in a subset of the original study group (patients age ³60 years) showed a 4-year progression-free survival (PFS) advantage of R-CHOP over CHOP (62.2% vs 27.9%; p<.001) and 4-year OS advantage (90% vs 81%; p=.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).^6, Overall response and CR rates were 81% and 41%, respectively, in the R-CVP arm and 57% and 10%, respectively, in the CVP arm (p<.001). After a median follow-up of 30 months, patients who received R-CVP had a median time to progression of 32 months versus 15 months for CVP only (p<.001). Median time-to-treatment failure was 27 months for R-CVP versus 7 months for CVP (p<.001). In an update of this study at a median follow-up of 53 months, Turturro (2007) showed improved OS in the R-CVP arm, with the estimated 4-year OS rate of 83% versus 77% in the CVP arm (p=.029).^7,

Second-Line Therapy for Relapsed and Refractory Follicular Lymphoma

The efficacy of rituximab as monotherapy in patients with relapsed or refractory low-grade FL has been examined in multicenter studies,^{8,9,10,11,12,13,14,} as summarized in Keating (2010).^15, 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 to 4 (6 studies). Overall response rates were 38% to 48% after 4 weeks of rituximab therapy and 57% after 8 weeks of chemotherapy. 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.^15,

Maintenance Therapy for Follicular Lymphoma

Long-term results of a different phase 3 RCT (E1496) were reported by Barta et al (2016).^17, 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<.001). OS did not differ significantly between groups.

Salles et al (2011) reported the results of the phase 3 Primary RItuximab and MAintenance (PRIMA) RCT conducted in 223 centers in 25 countries.^18, 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<.001). Two years after randomization, 71.5% of patients in the rituximab maintenance group were in CR versus 52.2% in the observation group (p=.001). More patients with PR at the time of randomization converted to CR after 2 years in the rituximab maintenance group (52%) than those in the observation group (30%; estimated difference, 22.2%; 95% CI, 11.2% to 33.3%; p=.001). Risks, such as starting a new anti-lymphoma 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 trialists planned to follow these patients. Moreover, the trialists concluded that 2 years of rituximab maintenance therapy significantly prolonged PFS, delayed the time to the next anti-lymphoma treatment or chemotherapy, and improved the quality of response in patients with previously untreated FL responsive to first-line rituximab plus chemotherapy. Final results of PRIMA were published in 2020, with a median duration of follow-up of 9.0 years (range 0.0 to 11.5 years).^19, Results were consistent with the primary analysis: Median PFS was 10.5 years in patients in the rituximab maintenance arm, compared to 4.1 years in the observation group (HR, 0.61; 95% CI 0.52 to 0.73; p<.001). There was no difference in OS between groups (HR , 1.04; 95% CI, 0.77 to 1.40; p=.80).

Maintenance Therapy for Relapsed or Refractory Follicular Lymphoma

Van Oers et al (2006) evaluated the role of rituximab in both induction and maintenance of relapsed or refractory FL.^20, They randomized 465 patients to induction with 6 cycles of CHOP versus 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<.001), CR (29.5% vs 15.6%; p<.001), and median PFS from first randomization (33.1 months vs 20.2 months; p<.001) versus CHOP, respectively. Rituximab maintenance resulted in a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; p<.001). Rituximab maintenance also improved 3-year OS from second randomization (85% with rituximab vs 77% with observation; p=.011).

Van Oers et al (2010) reported long-term outcomes in this same patient population with a median follow-up of 6 years.^21, Maintenance therapy with rituximab improved PFS compared with observation (median, 3.7 years vs 1.3 years, respectively; HR, 0.55; p<.001), both after CHOP induction (HR, 0.37; p<.001) and R-CHOP induction (HR, 0.69; p=.003). The 5-year OS rate was 74% in the rituximab maintenance arm and 64% in the observation arm (p=.07). Rituximab maintenance was associated with a significant increase in grade 3 and 4 infections (9.7% vs 2.4% respectively; p=.01). The trialists 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 might have been due to an unbalanced use of rituximab in post-protocol 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: Intravenous 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 second-line treatment of 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

First-Line Therapy for Previously Untreated Diffuse Large B-Cell Lymphoma

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 diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) in several phase 3 trials.

Hu et al (2017) published an RCT comparing R-CHOP with CHOP. One hundred thirty-four patients with DLBCL were randomized to the 2 groups (CHOP=68; R-CHOP=66).^22, The 5-year relapse-free survival rate was 81% for R-CHOP and 76% for CHOP (p=.28); the 5-year OS rate was 93% and 91% (p=.53) for R-CHOP and CHOP, respectively. There was no significant difference in safety between the 2 groups at 1-year follow-up (p>.05). Trial limitations were single-center data, homogeneity in patient ethnicity (Uyghur), and variation in investigators’ experience levels.

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).^23, 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 and 53% in the observation group (p=.8). Similarly, the estimated 5-year OS rates did not differ statistically between groups (65% vs 66%, respectively; p=.78).

Coiffier et al (2010) 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.^24, Median follow-up was 10 years. The 10-year PFS rate 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<.001).

Habermann et al (2006) reported on a 2-stage, randomized trial of 632 patients ages 60 years or older who had untreated DLBCL.^25, 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=.04). The 2-year FFS rates after the second randomization for maintenance were 76% for rituximab versus 61% for observation (p=.009). 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=.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 and 58% for CHOP (HR, 0.72; 95% CI, 0.52 to 1.00; p=.05).

Maintenance Therapy for Diffuse Large B-Cell Lymphoma

Zhou et al (2017) published a meta-analysis assessing studies on rituximab maintenance therapy for patients with DLBCL.^26, 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 1 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: Intravenous 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 3 trials found significantly higher PFS with rituximab than observation-only.

Intravenous Rituximab for CD20-Positive Non-Hodgkin Lymphoma

Jaeger et al (2015) conducted an international, open-label RCT in 683 adults (median age, 58 years) with previously untreated CD20-positive, aggressive NHL.^27, Patients with DLBCL (n=662) or grade IIIb FL (n=21) were randomized 1:1 to rituximab maintenance therapy after first (confirmed or unconfirmed) CR 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 event-free survival (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 and 76.5% in the observation group (HR, 0.79; 95% CI, 0.57 to 1.08; p=.143). Similarly, in intention-to-treat analysis, 3-year PFS and 3-year OS estimates did not differ statistically between treatment groups.

Pfreundschuh et al (2008) reported on an RCT of 1222 elderly patients (age range, 61-80 years) who had aggressive CD20-positive NHL and treatment with 6 or 8 cycles of CHOP (at 2-week intervals), with or without rituximab, and showed significant improvements in EFS, PFS, and OS in patients receiving R-CHOP versus CHOP.^28, Three-year OS rates were 67.7% (95% CI, 62.0% to 73.5%) for 6 cycles of CHOP, 66.0% (95% CI, 60.1% to 71.9%) for 8 cycles of CHOP, 78.1% (95% CI, 73.2% to 83.0%) for 6 cycles of R-CHOP, 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 (relative risk, 0.63; 95% CI, 0.46 to 0.85; p=.003). The trialists concluded that 6 cycles of R-CHOP was the preferred treatment for elderly patients.

Subsection Summary: Intravenous Rituximab for CD20-Positive Non-Hodgkin Lymphoma

For first-line therapy, 1 RCT showed that the addition of rituximab to chemotherapy improved response rates. For maintenance therapy, 1 RCT found that rituximab maintenance after first remission did not significantly alter the outcome of patients with CD20-positive, aggressive NHL.

Intravenous Rituximab for Mantle Cell Lymphoma

First-Line Therapy for Previously Untreated Mantle Cell Lymphoma

Romaguera et al (2005) 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.^29, 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. In an update of this patient population, with median follow-up of 4.8 years, Fayad et al (2017) reported 5-year FFS rate of 48% and OS rate of 65%.^30,

Lenz et al (2005) published the results of a prospective, randomized trial of 122 patients with previously untreated advanced-stage MCL that compared CHOP chemotherapy alone with R-CHOP.^31, R-CHOP (vs CHOP chemotherapy alone) was superior in terms of overall response (94% vs 75%; p=.005), CR (34% vs 7%; p<.001), and time-to-treatment failure (median, 21 months vs 14 months; p=.013), all respectively. However, no differences were observed in PFS or OS between the 2 groups.

Second-Line Therapy for Relapsed or Refractory Mantle Cell Lymphoma

Forstpointner et al (2004) 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.^32, 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=.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=.004). At 2 years, estimated OS in the R-FCM arm was 65% compared with 35% in the FCM arm.

Subsection Summary: Intravenous Rituximab for Mantle Cell Lymphoma

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

Intravenous Rituximab for 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.^33,

A Cochrane review by Bauer et al (2012) compared monoclonal anti-CD20 antibodies with no further treatment or with other anti-leukemic therapies for treatment of CLL, irrespective of disease status.^34, Both previously treated and chemotherapy-naive patients were included, and all selected trials were randomized and open-label. Three RCTs ( N=1421 ) 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 ) evaluated rituximab and another monoclonal antibody, 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.

First-Line Therapy for Previously Untreated Chronic Lymphocytic Leukemia

The phase 3 GAIA-CLL13 RCT, described in detail in the Obinutuzumab for Chronic Lymphocytic Leukemia section (First-Line Therapy for Previously Untreated Chronic Lymphocytic Leukemia subsection) below, indicated that the combination of venetoclax and rituximab did not produce superior rates of undetectable minimal residual disease or PFS compared with rituximab-based chemoimmunotherapy in relatively fit patients with previously-untreated CLL.^35,

In their randomized phase 3 E1912 trial, Shanafelt et al (2019) compared efficacy of treatment with ibrutinib plus rituximab with standard chemoimmunotherapy for patients with previously untreated CLL.^36, Investigators randomly assigned 529 patients ≤70 years of age to 1 of 2 groups: group 1 (n=354) received ibrutinib and rituximab for 6 cycles (following a single cycle of ibrutinib alone), then only ibrutinib until disease progression; group 2 (n=175) received 6 cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. PFS at the median follow-up of 33.6 months favored the ibrutinib-rituximab combination over chemoimmunotherapy (89.4% vs 72.9% at 3 years; HR for progression or death, 0.35; 95% CI, 0.22 to 0.56; p<.001). Ibrutinib-rituximab was also superior to chemoimmunotherapy for OS (98.8% vs 91.5% at 3 y; HR for death, 0.17; 95% CI, 0.05 to 0.54; p<.001). The occurrence of adverse events of grade 3 or higher was similar in the 2 groups (80.1% for ibrutinib-rituximab; 79.7% for chemoimmunotherapy). However, infectious complications of grade 3 or higher were fewer in the ibrutinib-rituximab group (10.5%) versus the chemoimmunotherapy group (20.3%). Updated analysis of E1912 data with median follow-up of 70 months confirmed PFS (HR, 0.37; 95% CI, 0.27 to 0.51) and OS benefit (HR, 0.47; 95% CI, 0.25 to 0.89) in patients assigned to ibrutinib and rituximab compared with those assigned to chemoimmunotherapy.^37, Grade 3 or higher treatment-related adverse events were reported in 73.0% and 83.5% of ibrutinib-rituximab and chemoimmunotherapy recipients, respectively; among these, arthralgias, hypertension, and cardiac adverse events (including atrial fibrillation and several other reported cardiac toxicities) were more frequently reported with ibrutinib-rituximab, whereas anemia, hemolysis, lymphopenia, neutropenia, thrombocytopenia, and infection (primary febrile neutropenia) were more frequently reported with chemoimmunotherapy.

Hallek et al (2010) reported on the results of a randomized, open-label, multicenter phase 3 trial (CLL8 trial),^38, with longer term follow-up reported in 2016.^39, Treatment-naive patients with CLL were randomized to receive fludarabine (F) and cyclophosphamide (C) with (n=408) or without (n=409) rituximab at 190 centers in 11 countries. At 3 years after randomization, 65% of patients in the chemoimmunotherapy group were free of progression versus 45% in the chemotherapy-only group (HR, 0.56; 95% CI, 0.46 to 0.69; p<.001), and 87% were alive versus 83%, respectively (HR, 0.67; 95% CI, 0.48 to 0.92; p=.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (34% vs 21%, p<.001) and leukopenia (24% vs 12%, p<.001); other adverse events, including severe infections, did not increase. Treatment-related deaths occurred in 2% versus 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<.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=.001).

Second-Line Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia

Badoux et al (2011) reported on the final analysis of an open-label phase 2 study of 284 patients with relapsed CLL treated with FC plus rituximab (FCR).^40, 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. Of the 284 patients, 280 (99%) were evaluable for response; 30% achieved CR, 14% achieved nodular partial response (defined as patients who were 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 (52%) than those who received 4 or more prior regimens (4%; p<.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=.076) and 15 months for those achieving partial remission (p<.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<.001) and longer OS (47 months vs 21 months, respectively; p<.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.

The randomized, open-label multicenter phase 3 REACH trial (2010) evaluated the efficacy of treating patients with relapsed or refractory CLL with FCR.^41, 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 FCR (n=276) or FC-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) versus the FC-only group (20.6 months; HR, 0.65; p<.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<.01).

Maintenance Therapy for Chronic Lymphocytic Leukemia

Maintenance therapy with rituximab was compared with observation from the Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT) CLL8a Mabtenance RCT (see CLL8 trial described in the Previously Untreated CLL section).^42, 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<.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=.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: Intravenous Rituximab for Chronic Lymphocytic Leukemia

For first-line therapy, RCTs have shown improved PFS and OS with the addition of rituximab to chemotherapy. For second-line therapy to treat 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.

Intravenous Rituximab for Burkitt Lymphoma

Ribrag et al (2016) reported on an open-label, phase 3 RCT that compared rituximab (4 infusions) plus chemotherapy (n=128) with chemotherapy alone (n=129) for previously untreated Burkitt lymphoma.^43, 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=.024; HR, 0.59; 95% CI, 0.38 to 0.94; p=.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: Intravenous 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.

Intravenous Rituximab for Posttransplant Lymphoproliferative Disorders

Posttransplant 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 detected in up to 70% of cases. Epstein-Barr virus-negative PTLD typically has a later onset (>24 months after transplant). Risk factors for PTLD after solid organ transplant include Epstein-Barr virus mismatch (positive donor/negative recipient), augmented immunosuppression (eg, with antilymphocyte antibodies), and type of organ transplant (incidence range, »1% in kidney recipients to »10% in small bowel or multiorgan recipients). The World Health Organization has defined 4 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 and Hodgkin lymphoma-like PTLD.^44, Early lesions and some polymorphic lesions may be found incidentally; more advanced disease (eg, 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.^45,46,47,48,

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 3). 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,^49, and that chemotherapy added to rituximab did not improve PFS and OS,^50, although both studies were small (N=80 and 35, respectively).

Table 3. Studies of Rituximab Chemoimmunotherapy for PTLD After Solid Organ Transplant

    CHOP: cyclophosphamide, doxorubicin, vincristine, plus prednisone; CR: complete response; EBV: Epstein-Barr virus; HL: Hodgkin lymphoma; OS: overall survival; PFS: progression-free survival; PR: partial response; PTLD: posttransplant lymphoproliferative disorders; RI: reduction in immunosuppression. a 3 year rate. b 1 year rate. c Median.

Subsection Summary: Intravenous Rituximab for Posttransplant Lymphoproliferative Disorders

For first-line therapy, 2 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.

Section Summary: Intravenous Rituximab (Rituxan)

Studies have examined efficacy of rituximab, alone or in combination with chemotherapy, for first-line therapy, relapsed or refractory disease, and maintenance therapy for several types of NHL. Outcomes reported included OS, PFS, EFS, response rates, and time to failure. These studies have shown improved outcomes as first-line therapy in patients who have FL, DLBCL, MCL, CLL, Burkitt Lymphoma, and PTLD. A benefit of rituximab for relapsed or refractory disease has been shown for FL, MCL, and CLL. For maintenance therapy, rituximab has shown improved outcomes in patients who have FL, but not for DLBCL or CLL, due to the absence of a difference in OS and a higher incidence of adverse events.

Intravenous Rituximab (Rituxan)

For individuals who have non-Hodgkin lymphoma (NHL) who receive intravenous rituximab alone or combined with chemotherapy, the evidence includes randomized controlled trials (RCTs) and nonrandomized comparative studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Randomized trials have shown that the addition of rituximab to front-line chemotherapy has resulted in improved response rates and survival in FL and diffuse large B-cell lymphoma. A number of multicenter studies have demonstrated the efficacy of rituximab as monotherapy in relapsed and refractory follicular lymphoma (FL). Randomized trials of rituximab maintenance therapy have shown improved progression-free survival (PFS) in patients with previously untreated FL and improved PFS and overall survival in patients with previously treated FL. One study of diffuse large B-cell lymphoma showed improved PFS and overall survival in patients receiving rituximab-containing regimens, including monotherapy, compared with rituximab-free regimens. For maintenance therapy, a meta-analysis of 3 RCTs found significantly higher PFS with rituximab than a control condition. For first-line therapy, RCTs have shown that the addition of rituximab to front-line chemotherapy improves response rates. RCTs have shown that the addition of rituximab to chemotherapy has improved response rates and time-to-treatment failure in newly diagnosed mantle cell lymphoma and improved overall survival in relapsed or refractory disease. RCTs have also shown improved PFS and overall survival with the addition of rituximab to chemotherapy in previously untreated chronic lymphocytic leukemia (CLL). One RCT showed prolonged PFS in relapsed or refractory CLL, and a phase 2 open-label study showed improved PFS and overall survival. One RCT showed better event-free survival and overall survival in patients with Burkitt lymphoma when combined with chemotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population reference No. 2

Subcutaneous Rituximab (Rituxan Hycela)

Clinical Context and Therapy Purpose

The purpose of subcutaneous rituximab following at least 1 full dose of IV rituximab is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NHL.

The question addressed in this evidence review is: Do on-label and off-label uses of subcutaneous rituximab for the treatment of NHL improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NHL.

Interventions

The therapy being considered is subcutaneous rituximab after at least 1 full dose of IV rituximab. The subcutaneous product includes Rituxan (as does the IV rituximab product) and hyaluronidase human to facilitate absorption.

Comparators

The following therapy is currently being used to treat NHL: IV rituximab. Treatment of patients with NHL can include chemotherapy, radiotherapy, stem cell transplantation, and medications that stimulate bone marrow growth.

Outcomes

The general outcomes of interest are OS, change in disease status, quality of life, and treatment-related mobility. Interval follow-up of 1 to 12 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Controlled studies are needed comparing IV rituximab with subcutaneous rituximab to determine whether the subcutaneous product is superior, inferior, or noninferior to the IV product in terms of both safety and efficacy,

Review of Evidence

Subcutaneous Rituximab for Follicular Lymphoma

A phase 3 open-label RCT evaluated subcutaneous rituximab for treating FL (SABRINA). Stage 1 findings were published by Davies et al (2014)^56, and stage 2 findings were also published by Davies et al (2017).^57, 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 because 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 both 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 CR rate 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 both groups. Neutropenia was the most common adverse event 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%); they were mainly grade 1 or 2 injection-site reactions.

Cartron et al (2023) published results of a phase 3 trial comparing subcutaneous rituximab with IV rituximab in patients with previously untreated, histologically confirmed, CD20-positive, low-tumor burden FL.^58, Patients in the intervention group (n=100) were treated with IV rituximab (375 mg/m²) on day 1 followed by subcutaneous rituximab (1400 mg) on days 8, 15, and 22 as well as at month 3, month 5, month 7, and month 9. While the control group (n=102) received IV rituximab (375 mg/m²) on days 1, 8, 15, and 22. Four-year PFS was improved in the intervention group compared with control (58.1% vs 41.2%; HR, 0.585; 95% CI, 0.393 to 0.871; p=.0076). Adverse events were similar between groups. No conclusions can be drawn regarding comparative efficacy of subcutaneous rituximab and IV rituximab due to differences in regimens and doses, but the study does indicate efficacy for subcutaneous rituximab in FL.

Subcutaneous Rituximab for Diffuse Large B-Cell Lymphoma

Rummel et al (2017) 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.^59, 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 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 could not compare the efficacy of the 2 modes of administration.

Data on subcutaneous rituximab were also reported in the Rituxan Hycela product label.^60,The MabEASE study was an RCT evaluating patients with previously untreated CD20-positive DLBCL, which compared subcutaneous rituximab (n=369) with IV rituximab (n=203), both in combination with CHOP.^61, 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 OS 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 PFS 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, 5% in the IV rituximab group) died due to adverse reactions to treatment.

Subcutaneous Rituximab for Chronic Lymphocytic Leukemia

A phase 1b open-label trial evaluated subcutaneous rituximab for treating CLL (SAWYER). Assouline et al (2015) published stage 1 findings^62, and stage 2 findings were also published by Assouline et al (2016).^63, 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 treatment. All patients received IV FCR in cycle 1, IV rituximab in cycles 2, 3, and 4, and IV FCR 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 FCR (n=88) 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 (eg, erythema, pyrexia). More patients in the IV rituximab group had vascular adverse events (ie, 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 trialists noted that the study was not powered to detect differences in efficacy between the groups.

Section Summary: Subcutaneous Rituximab (Rituxan Hycela)

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.

Subcutaneous Rituximab (Rituxan Hycela)

For individuals who have NHL who receive subcutaneous rituximab following at least one full dose of intravenous rituximab, the evidence includes RCTs in patients with FL, diffuse large B-cell lymphoma, and CLL. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. The published RCTs focused on patients with previously untreated disease. They found that subcutaneous rituximab was noninferior to intravenous rituximab in its pharmacokinetics, specifically serum trough concentration. The trials had response rates as primary or secondary outcomes, and each trial found that response rates were similar with subcutaneous rituximab and intravenous rituximab. According to the Food and Drug Administration product label, the study findings were applicable to select patients with previously treated FL and CLL. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population reference No. 3

Ofatumumab (Arzerra) for Non-Hodgkin Lymphoma

Clinical Context and Test Purpose

Clinical Context and Therapy Purpose

The purpose of ofatumumab alone or combined with chemotherapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NHL.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NHL.

Interventions

The therapy being considered is ofatumumab alone or combined with chemotherapy.

Comparators

Comparators of interest include standard chemotherapy regimens. Treatment of patients with NHL can also include radiotherapy, stem cell transplantation, and medications that stimulate bone marrow growth.

Outcomes

The general outcomes of interest are OS, change in disease status, quality of life, and treatment-related mobility. Follow-up through 36 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Ofatumumab for Follicular Lymphoma

Czuczman et al (2012) reported on the use of ofatumumab as monotherapy in rituximab-refractory FL.^64,The median age of these patients was 61 years, and 47% had high-risk Follicular Lymphoma International Prognostic Index scores; 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for 2 different doses of ofatumumab; among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. Median PFS was 5.8 months. Grade 3 or 4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. The authors concluded that ofatumumab was well-tolerated and modestly active in this heavily pretreated, rituximab-refractory patient population.

Ofatumumab for Diffuse Large B-Cell Lymphoma

Two single-arm studies have examined ofatumumab for DLBCL. Coiffier et al (2013) administered weekly doses of ofatumumab (300 mg for the first dose followed by seven 1000 mg doses) to 81 patients with DLBCL who were transplant ineligible (n=56) or had relapsed or progressed after transplant (n=25).^65, The overall response rate was 11% (CR, 2%; PR, 9%), median duration of response was 9.5 months, and median PFS was 2.6 months. Neutropenia was the most common grade 3 or 4 adverse event (11%). Grade 3 or 4 infusion reactions occurred in 5% of patients, and infections in 6%.

Matasar et al (2013) administered three 21-day cycles of ofatumumab in combination with chemotherapy to 61 transplant-eligible patients with relapsed or primary refractory, aggressive NHL (77% DLBCL, 20% transformed FL, 3% grade IIIB FL).^66, All patients received rituximab-containing primary treatment regimens. For 59 CD20-positive patients, the overall response rate was 61% (37% CR, 24% PR). Seventy-four percent of patients underwent stem cell mobilization, and 56% underwent stem cell transplant.

Ofatumumab for Chronic Lymphocytic Leukemia

Wu et al (2017) published a systematic review and meta-analysis investigating ofatumumab for patients with CLL. Thirteen studies 2314 total participants (range, 6-474 patients) were identified.^67, Of the 13 studies, 11 assessed ofatumumab for patients with refractory or relapsed CLL. When compared with non-ofatumumab treatments, no significant difference was found for PFS (HR, 0.88; 95% CI, 0.47 to 1.63; p=.677) or OS (HR, 1.0; 95% CI, 0.66 to 1.53; p=.567). In pooled toxicity analysis, ofatumumab showed an increased risk of infusion-related reactions but a decreased risk of thrombocytopenia and anemia compared with non-ofatumumab treatments.

First-Line Therapy for Previously Untreated Chronic Lymphocytic Leukemia

U.S. Food and Drug Administration (FDA) approval of ofatumumab for previously untreated CLL was based on the COMPLEMENT 1 open-label, phase 3 RCT.^68, COMPLEMENT 1 enrolled 447 patients (median age, 69 years) considered by investigators to be unsuitable for fludarabine-based chemotherapy (eg, due to advanced age or comorbidities; 72% of patients had ≥ 2 comorbidities). Patients were randomized to ofatumumab plus chlorambucil or chlorambucil alone for at least three 28-day cycles and, at most, 12 cycles. Median PFS, by a blinded independent review (the primary end point), was 22 months in the ofatumumab group and 13 months in the chlorambucil monotherapy group (HR, 0.57; 95% CI, 0.45 to 0.72). The most common grade 3 or higher adverse events in the ofatumumab group were infusion reactions (10%) and neutropenia (26% vs 14% chlorambucil). Health-related quality of life did not differ significantly between the 2 arms during or following treatment.^69,

Second-Line Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia

The FDA’s approval of ofatumumab for the treatment of patients with relapsed CLL was based on an RCT published by Robak et al (2017).^70, This open-label phase 3 trial (COMPLEMENT 2) compared chemoimmunotherapy with ofatumumab plus FC (n=183) to chemotherapy alone (n=182). The primary outcome was PFS, as assessed by an independent review committee. Median PFS was 28.9 months with chemoimmunotherapy and 18.8 months with chemotherapy alone (HR, 0.67; 95% CI, 0.51 to 0.88, p=.003). A secondary outcome was the overall response rate (again assessed by an independent review committee), which was found to be significantly higher in the ofatumumab chemoimmunotherapy group (84%) than in the group that did not receive ofatumumab (68%; p<.001). OS (another secondary outcome) did not differ significantly between groups. After a median follow-up of 34 months, median OS was 56.4 months in the ofatumumab chemoimmunotherapy group and 45.7 months in the chemotherapy-alone group (HR, 0.78; 95% CI, 0.56 to 1.00; p=.14).

Osterborg et al (2016) published an interim analysis of a phase 3 open-label RCT comparing ofatumumab to non-ofatumumab-containing therapy (physician’s choice) in patients with bulky fludarabine-refractory CLL.^71, Patients in this trial of off-label use of ofatumumab were randomized on a 2:1 basis to a standard length course of ofatumumab (n=79) or non-ofatumumab-containing therapy (n=43) or up to 24 weeks. The primary outcome (median PFS assessed by the independent review committee) was 5.4 months in the ofatumumab arm and 3.6 months in the non-ofatumumab-containing therapy arm; the difference between groups was not statistically significant (p=.27). Among the secondary outcomes, the overall response rate (as assessed by an independent review committee) was significantly higher in the ofatumumab arm (38%) than in the non-ofatumumab-containing therapy arm (16%; p=.019). Median OS did not differ significantly between groups (19.2 months in the ofatumumab arm vs 14.5 months in the non-ofatumumab-containing therapy arm, p=0.13). Five-year results from this trial were published in 2020 and were consistent with the interim analysis: OS was longer in the ofatumumab arm but the difference was not statistically significant.^72, Median OS was 19.2 months in the ofatumumab arm, compared to 14.5 months in the physicians’ choice arm (HR, 0.75; 95% CI, 0.48 to 1.17; p=.173). The overall response rate remained unchanged from the interim analysis.

Maintenance Therapy for Chronic Lymphocytic Leukemia

Randomized Controlled Trial

Van Oers et al (2015) reported on an interim analysis of the PROLONG trial, an open-label multicenter (130 centers) phase 3 RCT that compared ofatumumab maintenance therapy (1000 mg every 8 weeks for up to 2 years) with observation for patients in remission after reinduction for relapsed CLL.^73,Treatment continued until disease progression or the patient withdrew from the trial (unacceptable side effects or other reasons).At the planned interim analysis, PFS was significantly improved in the ofatumumab arm (29.4 months; 95% CI, 26.2 to 34.2 months) compared with the observation arm (15.2 months; 95% CI, 11.8 to 18.8 months; HR, 0.50; 95% CI, 0.38 to 0.66; p<.001). However, there was no significant difference between the treatment arms in OS (HR, 0.85; 95% CI, 0.52 to 1.37; p=.49). Maintenance therapy delayed the time to next treatment from a median of 31.1 months (95% CI, 21.6 to not reached) to 38.0 months (95% CI, 28.3 to not reached). Both the total number of adverse events and the number of grade 3 or higher adverse events were higher in the ofatumumab maintenance group. The most common adverse event was neutropenia (24% of 237 patients in the maintenance group vs 10% of 237 patients in the observation group). No clinically relevant differences in health-related quality of life were observed. The final analysis of PROLONG, published in 2019, confirmed the interim results.^74, At a median follow-up duration of 40.9 months, median PFS was 34.2 months and 16.9 months in the ofatumumab and the observation arms, respectively, (HR, 0.55; 95% CI, 0.43 to 0.70]; p<.0001). Overall survival was similar in both arms and median was not reached (HR 0.99; 95% CI 0.72 to 1.37)

Subsection Summary: Ofatumumab for Chronic Lymphocytic Leukemia

A phase 3 RCT found improved PFS with ofatumumab plus chlorambucil compared with chlorambucil alone in patients with previously untreated CLL who had comorbidities and were unsuitable for treatment with fludarabine. A pivotal RCT found that PFS was improved by adding ofatumumab to fludarabine and cyclophosphamide to treat patients with relapsed CLL. In a case series, ofatumumab was shown to improve OS rates compared with historical controls in patients with CLL refractory to fludarabine. Finally, the phase 3 PROLONG trial showed a significant improvement in PFS when ofatumumab was used as maintenance therapy for CLL and a modest reduction in time to next treatment, but there was no difference in OS between groups, and there was an increase in grade 3 or higher adverse events.

Section Summary: Ofatumumab (Arzerra) for Non-Hodgkin Lymphoma

Follicular Lymphoma

More data are needed to evaluate the use of ofatumumab in patients with rituximab-refractory FL and aggressive NHL.

Diffuse Large B-Cell Lymphoma

More data are needed on the use of ofatumumab in patients with DLBCL.

Chronic Lymphocytic Leukemia

Chemoimmunotherapy with ofatumumab has been shown to improve PFS more than chemotherapy alone for first-line therapy and treatment of relapsed and refractory CLL under specified conditions. As a maintenance therapy, ofatumumab improved PFS but not OS and increased grade 3 or higher adverse events. A positive benefit to harm ratio has not been demonstrated for the use of ofatumumab as maintenance therapy.

Ofatumumab (Arzerra)

For individuals who have NHL who receive ofatumumab alone or combined with chemotherapy, the evidence includes RCTs and nonrandomized comparative studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Ofatumumab has been shown to improve PFS when used as first-line therapy and to treat relapsed and refractory CLL under certain conditions. Based on a phase 3 RCT (COMPLEMENT 1), ofatumumab improved PFS for first-line therapy in previously untreated CLL for patients who were not candidates for treatment with fludarabine. In another phase 3 RCT (COMPLEMENT 2), ofatumumab improved PFS when combined with fludarabine and cyclophosphamide to treat relapsed CLL. Ofatumumab also improved PFS for treatment of CLL refractory to fludarabine or alemtuzumab, based on response rates in CLL treatment-resistant groups. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population reference No. 4

Obinutuzumab (Gazyva) for Non-Hodgkin Lymphoma

Clinical Context and Test Purpose

The purpose of obinutuzumab alone or combined with chemotherapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NHL.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NHL

Interventions

The therapy being considered is obinutuzumab alone or combined with chemotherapy. Patients with NHL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient or outpatient clinical setting.

Comparators

The following therapy is currently being used to treat NHL: standard chemotherapy regimens. Patients with FL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient or outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, change in disease status, quality of life, and treatment-related mobility. Interval follow-up of 1 to 12 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Obinutuzumab for Follicular Lymphoma

First-Line Therapy for Previously Untreated Follicular Lymphoma

Marcus et al (2017) published a randomized study (GALLIUM trial) comparing obinutuzumab-based with rituximab-based chemotherapy as first-line treatment for FL.^75, Between 2011 and 2014, 1202 patients were randomized to the treatment groups. The estimated 3-year PFS rate was 80% for obinutuzumab and 73.3% for rituximab (HR, 0.66; 95% CI, 0.51 to 0.85; p=.001); the 3-year OS rates were 94% and 92.1% (HR, 0.75; 95% CI, 0.49 to 1.17; p=.21) for obinutuzumab and rituximab, respectively. The response rate for obinutuzumab was 88.5% and 86.9% for rituximab (95% CI, -2.1 to 5.5; p=.33), and grade 3, 4, and 5 adverse events occurred in 74.6% and 67.8% of the 2 groups, respectively. Trial limitation included nonrandomized assignment of chemotherapy agents.

Second-Line Therapy for Relapsed or Refractory Follicular Lymphoma

Obinutuzumab has been approved for use in combination with bendamustine for treatment of patients with FL who relapsed after, or who are refractory to, a rituximab-containing regimen.^76,The pivotal phase 3 trial (GADOLIN) was an open-label multicenter study of 321 patients randomized to bendamustine alone (n=166) or obinutuzumab plus bendamustine for 6 cycles. Following initial treatment, patients in the combination therapy arm who did not have disease progression continued receiving obinutuzumab monotherapy for 2 years. PFS, determined by an independent review committee, was reached at a median of 13.8 months in the bendamustine arm and not reached within a median of 21 months in the obinutuzumab plus bendamustine arm (HR=0.48; 95% CI, 0.34 to 0.68; p<.001). Median OS had not been reached in either arm at 24 months. More recent results from GADOLIN were published in 2018 and confirmed the PFS benefit shown in the primary analysis.^77, At a median follow-up of 31.8 months, PFS events had occurred in 115 patients in the obinutuzumab plus bendamustine arm (56.4%) and 146 in the monotherapy arm (69.9%). Median PFS was significantly longer in the combination arm (25.8 months; 95% CI, 19.5 to 41.1 months) than in the bendamustine monotherapy arm (14.1 months; 95% CI, 12.6 to 16.0 months), with a HR for progression or death of 0.57 (95% CI, 0.44 to 0.73; p<.001). There was also an OS benefit demonstrated in the combination treatment arm: 25.5% of patients in the combination arm and 34.9% in the monotherapy arm died (HR, 0.67; 95% CI, 0.47 to 0.96; p=.03).

Morschhauser et al (2019) published a single-arm, phase 2 study of obinutuzumab plus lenalidomide in 89 patients with relapsed or refractory FL previously treated with at least 1 rituximab-containing regimen.^78, Patients received induction treatment with lenalidomide plus obinutuzumab, followed by 1-year maintenance with lenalidomide plus obinutuzumab, and 1-year maintenance with obinutuzumab. The primary endpoint was overall response; PFS and OS were secondary endpoints. The primary endpoint was met with an overall response rate of 79% (38% achieved a complete response). At 2 years, PFS was 65% (95% CI 54% to 74%) and OS was 87% (95% CI 78% to 93%). Median PFS and OS were not reached. This regimen is not FDA approved for the treatment of relapsed or refractory FL, and RCTs are needed to establish the efficacy and safety of obinutuzumab plus lenalidomide compared to current treatments.

Second-Line Therapy for Relapsed or Refractory Non-Hodgkin Lymphoma

The 2016 publication of the phase 3 trial (GADOLIN) described above for relapsed or refractory FL assessed 396 patients with NHL.^79, The trial was stopped after a preplanned interim analysis. About 81% of patients had FL, 12% had marginal zone lymphoma, 7% had small lymphocytic leukemia, and 1 patient had Waldenström macroglobulinemia. Median follow-up was 21.9 months. As in the subgroup with FL (included in the FDA label), median PFS was not reached at the time of follow-up in the chemoimmunotherapy induction and obinutuzumab maintenance arm. In the bendamustine monotherapy arm, median PFS was 14.9 months (HR, 0.55; 95% CI, 0.40 to 0.74; p<.001). Thus, PFS was significantly longer with obinutuzumab combined with bendamustine.

Obinutuzumab for Chronic Lymphocytic Leukemia

First-Line Therapy for Previously Untreated Chronic Lymphocytic Leukemia

In the randomized, open-label phase 3 GAIA-CLL13 trial, Eichhorst et al (2023) compared combinations of venetoclax and rituximab (n=237), venetoclax and obinutuzumab (n=229), venetoclax, obinutuzumab, and ibrutinib (n=231), and chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab [patients aged ≤65 years] or bendamustine and rituximab [patients aged >65 years]; n=229) in relatively fit patients with previously untreated CLL.^35, Patients assigned to chemoimmunotherapy received 6 cycles of treatment. Patients assigned to venetoclax-containing arms received 6 cycles of the assigned monoclonal antibody and 10 cycles of venetoclax (plus an initial 5-week venetoclax ramp-up phase, initiated 3 weeks after the first antibody dose); ibrutinib was initiated concomitantly with obinutuzumab in the venetoclax-obinutuzumab-ibrutinib arm, and continued for 15 to 36 cycles (with discontinuation after cycle 15 in patients meeting criteria for minimal residual disease negativity). The co-primary endpoints were the rate of undetectable minimal residual disease at month 15 and PFS, the latter of which was analyzed in an interim analysis which met prespecified criteria for early stopping and completion of the full analysis based on an alpha spending function with a p-value boundary of ≤.000393 for comparison of the venetoclax-obinutuzumab-ibrutinib and chemoimmunotherapy groups. At month 15, prespecified hierarchical testing indicated significantly more patients assigned to venetoclax-obinutuzumab (86.5%; 97.5% CI, 80.6 to 91.1) or venetoclax-obinutuzumab-ibrutinib (92.2%; 97.5% CI, 87.3 to 95.7) had undetectable minimal residual disease than those assigned to chemoimmunotherapy (52.0%; 97.5% CI, 44.4 to 59.5; p<.001 for both comparisons), whereas the proportion of patients with undetectable minimal residual disease in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2) was not significantly different from the chemoimmunotherapy group (p=.32). With median follow-up of 38.8 months, prespecified hierarchical testing indicated PFS was significantly prolonged in patients assigned to venetoclax-obinutuzumab (HR, 0.42; 97.5% CI, 0.26 to 0.68; p<.001) or venetoclax-obinutuzumab-ibrutinib (HR 0.32; 97.5% CI, 0.19 to 0.54; p<.001), but not those assigned to venetoclax-rituximab (HR, 0.79; 97.5% CI, 0.53 to 1.18; p=.18), compared with chemoimmunotherapy. Three-year OS rates were similar between groups (ranging from 95.0% to 96.5%). Grade 3 or 4 adverse events were reported in approximately 70% of venetoclax-rituximab recipients, 80% of venetoclax-obinutuzumab recipients, 80% of venetoclax-obinutuzumab-ibrutinib recipients, and 77% of chemoimmunotherapy recipients; early discontinuation due to adverse events occurred in 5.9% of venetoclax-rituximab recipients, 5.7% of venetoclax-obinutuzumab recipients, 12.6% of venetoclax-obinutuzumab-ibrutinib recipients, and 15.3% of chemoimmunotherapy recipients.

The FDA’s approval of obinutuzumab (also known as GA101) was based on an open-label, phase 3 RCT, CLL11.^80, CLL11 was conducted at 155 centers in 24 countries. Adults (≥18 years of age) with previously untreated, CD20-positive CLL with coexisting medical conditions (eg, creatinine clearance, 70-30 mL/min) were enrolled. Patients were randomized 2:2:1 to obinutuzumab plus chlorambucil (n=238), rituximab plus chlorambucil (n=233), or chlorambucil monotherapy (n=118). The National Comprehensive Cancer Network does not currently recommend chlorambucil monotherapy for first-line treatment of CLL.^81, The primary end point was PFS. Only results comparing obinutuzumab combination therapy with chlorambucil monotherapy were considered by FDA for approval.^82, Median PFS by independent review was 23 months in the obinutuzumab group and 11 months in the chlorambucil group (HR, 0.16; 95% CI, 0.11 to 0.24; p<.001). Investigator-assessed PFS was similar. OS was increased in the obinutuzumab group compared with the chlorambucil group (HR for death, 0.41; 95% CI, 0.23 to 0.74; p=.002), but OS data were not yet mature (medians had not been reached). The most common serious adverse event in CLL11 was infusion reaction (11%). A follow-up report by Goede et al (2015) confirmed the OS benefit for combination therapy (HR, 0.47; 95% CI, 0.29 to 0.76; p=.001), with deaths of 15.5% (37/238) of patients in the combination therapy arm compared with 28.8% (34/118) in the chlorambucil monotherapy arm.^83,

Second-Line Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia

Cartron et al (2014) published results of the open-label, phase 1/2 GAUGIN study of obinutuzumab monotherapy for relapsed or refractory CLL.^84, Phase 1 (n=13) was a dose-finding study. Phase 2 (n=20) administered a fixed dose of obinutuzumab (1000 mg IV) for 8 cycles total. Twelve (65%) patients received all doses. At median follow-up of 29 months, best overall response was 30% (CR, 5%; PR, 25%). Median PFS was 10.7 months.

Section Summary: Obinutuzumab (Gazyva) for Non-Hodgkin Lymphoma

A phase 3 RCT showed improved PFS in patients with FL who relapsed after, or were refractory to, a rituximab-containing regimen. Another phase 3 RCT showed substantially improved PFS in patients with previously untreated CLL who received obinutuzumab compared with those who received chlorambucil alone or rituximab plus chlorambucil. Preliminary analysis of OS has shown increased survival with obinutuzumab compared with chlorambucil monotherapy, but not compared with rituximab combination therapy. A phase 3 RCT showed improved PFS in patients with previously untreated CLL who received obinutuzumab and venetoclax, with or without ibrutinib, compared with rituximab and venetoclax or rituximab-based chemoimmunotherapy.

Additional data are needed to establish the efficacy and safety of obinutuzumab for relapsed/refractory CLL.

Obinutuzumab (Gazyva)

For individuals who have NHL who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Obinutuzumab was approved by the Food and Drug Administration for the treatment of FL in patients who have relapsed or are refractory to a rituximab-containing regimen; the drug was also approved for use in combination with chlorambucil for previously untreated CLL in combination with bendamustine. These indications are based on positive results in phase 3 trials that compared combination therapy with monotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

PRACTICE GUDELINES AND POSITION STATEMENTS

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) has published multiple guidelines for the treatment of the various types of non-Hodgkin lymphoma. These include recommendations for the appropriate use of monoclonal antibody therapy (rituximab, ofatumumab, and obinutuzumab) alone or in combination with chemotherapy for treatment of non-Hodgkin lymphoma. ^81,85,86,87,

U.S. Preventive Services Task Force Recommendations

Not applicable.

MEDICARE NATIONAL COVERAGE

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in August 2024 did not identify any ongoing or unpublished trials that would likely influence this review.

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