Uses of Monoclonal Antibodies - CAM 20305

Description
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).

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 patientswho 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.

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.

Background
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.

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
In 2009, ofatumumab (Arzerra^®; Novartis) was approved by FDA through the accelerated approval process for treatment of patients with CLL refractory to fludarabine and alemtuzumab. As of August 2016, Arzerra^® is approved for the following indications:⁴

“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 for the treatment of patients with relapsed CLL”
“for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL.”
“for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.”⁵

In 2013, obinutuzumab (Gazyva™; Genentech) was approved by FDA through the breakthrough therapy designation process for treatment of patients with previously untreated CLL in combination with chlorambucil. In February 2016, the drug was approved, in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of patients with FL who relapsed or are refractory to a rituximab-containing regimen.⁶

In November 2018, Truxima (rituximab-abbs; Celltrion) was approved by the FDA as a biosimilar of rituximab for the treatment of Non-Hodgkin’s Lymphoma.

Policy
Ofatumumab

FDA-Approved Indications
1. 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
  - extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL.
  - Refractory to fludarabine and alemtuzumab.
2. Compendial Uses
  - Initial treatment of CLL in combination with chlorambucil
  - Relapsed or refractory CLL
  - Small lymphocytic lymphoma (SLL) (managed in the same manner as CLL)
  - Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma

Obinutuzumab
The indications below including FDA-approved indications and compendial uses are considered a covered benefit provided that all the approval criteria are met and the member has no exclusions to the prescribed therapy.

FDA-Approved Indications
1. Chronic lymphocytic leukemia (CLL) Gazyva, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated CLL.
2. Follicular lymphoma Gazyva, in combination with bendamustine followed by Gazyva monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen.
3. Gazyva, in combination with chemotherapy followed by Gazyva monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, Ill or IV follicular lymphoma
Compendial Uses
1. Chronic lymphocytic leukemia
  - Therapy for those who are unable to tolerate purine analogs in combination with chlorambucil
  - Therapy for relapsed or refractory disease　
2. Small lymphocytic lymphoma (SLL) (managed in the same manner as CLL)
3. Gastric MALT lymphoma, recurrent or progressivedisease
4. Non-gastric MALT lymphoma, refractory or progressivedisease
5. Nodal and splenic marginal zone lymphoma, refractory or progressive disease
6. Primary cutaneous B-cell lymphomas: primary cutaneous marginal zone or follicle center lymphoma

MYLOTARG gemtuzumab ozogamicin
Is a CD33-directed antibody-drug conjugate indicated for:

treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults.
treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older .

Compendial Use:

Mylotarg is indicated in high risk patients with acute promyelocytic leukemia (APL)

All other indications are considered experimental/investigational and are not a covered benefit.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

Benefit Application
BlueCard/National Account Issues
State or federal mandates regarding off-label uses of drugs approved by the FDA may supersede this policy. Off-label uses for rituximab (Rituxan^®) and alemtuzumab (Campath^®) are from the American Hospital Formulary Service (AHFS) Drug Information. There are no off-label uses currently listed in the AHFS Drug Information for gemtuzumab ozogamicin (Mylotarg^®).

Rationale
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 function, including 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 one 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.

Intravenous Rituximab (Rituxan)
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 question addressed in this evidence review is: Do on-label and off-label uses of monoclonal antibodies for the treatment f NHL improve the net health outcome?

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

Patients
The relevant population of interest is individuals with NHL.

Interventions
The therapy being considered is IV rituximab 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 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. Patients with NHL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient or outpatient clinical setting.

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 [F]-fluorodesoxyglucose PET scanning to guide treatment of aggressive B-cell lymphomas (Table 2). In the process of this assessment, investigators evaluated the effectiveness of 6 vs the standard 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 R-CHOP. The results of the trial showed that 8 cycles of R-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

Outcome	DLBCL		PMBCL		FL grade 3
	6 x R	8 x R	6 x R	8 x R	6 x R	8 x R
No. of patients	292	252	22	15	21	14
Complete remission^a	186/271(68.6)	174/234 (74.4)	12/22 (54.6)	8/15 (53.3)	15/21 (71.4)	8/11 (72.7)
2-Year PFS^b	77.5 (72.2 – 81.9)	80.9 (75.4 – 85.3)	100	93.3 (61.3 – 99.0)	100	85.7 (53.9 – 96.2)
2-Year OS^b	87.4 (82.9 – 90.7)	88.9 (84.2 – 92.2)	100	93 (61.3 – 99.0)	100	100

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.⁶ 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 (cyclophosphamide, doxorubicin [Adriamycin], vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisone), and others. It reported that the addition of rituximab resulted in significantly greater (41% – 79% for rituximab-containing regimens vs 10% – 63% for regimens without rituximab; p < 0.005), and greater overall response rates (81% – 96% vs 57% – 90%, respectively; p < 0.05).⁷

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).⁸Patients who received R-CHOP had significantly prolonged time-to-treatment failure (p < 0.001), higher overall response rate (96% vs 90%, p = 0.011), and prolonged duration of remission (p = 0.001). Additional follow-up in a subset of the original study group (patients age ³60 years) showed a 4-year progression-free survival (PFS) advantage of R-CHOP over CHOP (62.2% vs 27.9%; p < 0.001) and 4-year OS advantage (90% vs 81%; p = 0.039), all respectively.

Marcus et al. (2005) randomized previously untreated patients with advanced-stage FL to cyclophosphamide, vincristine, and prednisone (CVP) (n = 159) or rituximab plus CVP (R-CVP; n = 162).⁹ 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 < 0.001). After a median follow-up of 30 months, patients who received R-CVP had a median time to progression of 32 months vs 15 months for CVP only (p < 0.001). Median time-to-treatment failure was 27 months for R-CVP vs7 months for CVP (p < 0.001). 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% vs 77% in the CVP arm (p = 0.029).¹⁰

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,^{11,12,13,14,15,16,}¹⁷ as summarized in Keating (2010).¹⁸ 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.¹⁸

Maintenance Therapy for Follicular Lymphoma
Vidal et al. (2017) published an individual patient meta-analysis of studies on rituximab maintenance therapy in patients with previously treated or previously untreated FL.¹⁹ The analysis included data from 7 RCTs comparing rituximab maintenance therapy with observation-only after induction. The primary end point of the analysis was OS, defined as the time from randomization to death. PFS and adverse events were secondary end points. The 7 trials included 2317 patients; 2 patients were excluded due to lack of data on outcome measures. The median follow-up was 6 years. A total of 209 (18.3%) of 1145 patients in the rituximab maintenance group died during follow-up compared with 246 (21.0%) of 1170 patients in the observation group. The difference between groups was statistically significant, favoring rituximab maintenance (HR = 0.79; 95% CI, 0.66 to 0.96). PFS was significantly higher in the rituximab maintenance group compared with observation (HR = 0.57; 95% CI, 0.51 to 0.64; p < 0.001). Rates of grade 3 or 4 infection were significantly higher in the rituximab maintenance group than the observation group (HR = 1.27; 95% CI, 1.112 to 1.45), and other adverse events were rarely reported.

Maintenance Therapy for Previously Untreated Follicular Lymphoma
Long-term results of a different phase 3 RCT (E1496) were reported by Barta et al. (2016).²⁰ The trial included patients with stage III or IV small lymphocytic, follicular small cleaved or follicular mixed small cleaved and large cell lymphoma. To be eligible, patients needed to have measurable disease, and an Eastern Cooperative Oncology Group Performance Status score of less than 2; moreover, patients could not have had previous lymphoma-directed therapy. After induction therapy with CVP, patients were randomized to 2 years of rituximab maintenance therapy (n = 158) or observation-only (n = 155). The primary end point was PFS. After a median follow-up of 11.5 years, PFS was significantly longer in the rituximab maintenance group (4.8 years) than the observational-only group (1.3 years; p < 0.001). OS did not differ significantly between groups.

Salles et al. (2011) reported the results of the phase 3 PRIMA RCT conducted in 223 centers in 25 countries.²¹ PRIMA assessed the potential benefit of 2 years of rituximab maintenance therapy after first-line treatment in patients with FL needing systemic therapy. A total of 1217 patients received 1 of 3 nonrandomized induction regimens comprising rituximab and chemotherapy; 1019 patients who had a partial response (PR) or CR were randomized to 2 years of rituximab maintenance therapy (n = 505) or observation (n = 513). The primary end point was PFS. After a median follow-up of 36 months, PFS was 74.9% (95% CI, 70.9% to 78.9%) in the rituximab maintenance group and 57.6% (95% CI, 53.2% to 62.0%) in the observation group (HR = 0.55; 95% CI, 0.44 to 0.68; p < 0.001). Two years after randomization, 71.5% of patients in the rituximab maintenance group were in CR vs 52.2% in the observation group (p = 0.001). More patients with PR at the time of randomization converted to CR after 2 years in the rituximab maintenance group (52%) than those in the observation group (30%; estimated difference, 22.2%; 95% CI, 11.2% to 33.3%; p = 0.001). Risks, such as starting a new 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).²² 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 (hazard ratio, 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.²³ They randomized 465 patients to induction with 6 cycles of CHOP vs R-CHOP, with a second randomization of patients in CR or PR to rituximab maintenance or observation. Rituximab induction therapy yielded statistically significant improvement in overall response (85.1% vs 72.3%; p<0.001), CR (29.5% vs 15.6%; p<0.001), and median PFS from first randomization (33.1 months vs 20.2 months; p < 0.001) vs CHOP, respectively. Rituximab maintenance resulted in a median PFS from second randomization of 51.5 months vs 14.9 months with observation (HR = 0.40; p < 0.001). Rituximab maintenance also improved 3-year OS from second randomization (85% with rituximab vs 77% with observation; p = 0.011).

Van Oers et al. (2010) reported long-term outcomes in this same patient population with a median follow-up of 6 years.²⁴ Maintenance therapy with rituximab improved PFS compared with observation (median, 3.7 years vs 1.3 years, respectively; HR = 0.55; p < 0.001), both after CHOP induction (HR = 0.37; p < 0.001) and R-CHOP induction (HR = 0.69; p = 0.003). The 5-year OS rate was 74% in the rituximab maintenance arm and 64% in the observation arm (p = 0.07). Rituximab maintenance was associated with a significant increase in grade 3 and 4 infections (9.7% vs 2.4% respectively; p = 0.01). The 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: 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 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).²⁵ The 5-year relapse-free survival rate was 81% for R-CHOP and 76% for CHOP (p = 0.28); the 5-year OS rate was 93% and 91% (p = 0.53) for R-CHOP and CHOP, respectively. There was no significant difference in safety between the 2 groups at 1-year follow-up (p > 0.05). 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).²⁶ 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 = 0.8). Similarly, the estimated 5-year OS rates did not differ statistically between groups (65% vs 66%, respectively; p = 0.78).

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.²⁷ 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<0.001).

Habermann et al. (2006) reported on a 2-stage, randomized trial of 632 patients ages 60 years or older who had untreated DLBCL.²⁸ Patients were randomized to CHOP or R-CHOP, and 415 responders underwent a second randomization to maintenance therapy with rituximab or observation. The 3-year failure-free survival (FFS) rates were 53% for R-CHOP and 46% for CHOP induction (HR = 0.78; 95% CI, 0.61 to 0.99; p = 0.04). The 2-year FFS rates after the second randomization for maintenance were 76% for rituximab vs 61% for observation (p = 0.009). A secondary analysis evaluated the effect of induction therapy without maintenance rituximab. R-CHOP alone showed a significant decrease in the risk of treatment failure compared with CHOP (HR = 0.64; 95% CI, 0.47 to 0.85; p = 0.003), with an estimated 3-year FFS rate of 52% for R-CHOP and 39% for CHOP. Survival also was longer after R-CHOP induction alone, with an estimated 3-year OS rate of 67% for R-CHOP and 58% for CHOP (HR = 0.72; 95% CI, 0.52 to 1.00; p = 0.05).

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.²⁹ 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: 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.

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.³⁰ 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 = 0.143). 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 vs CHOP.³¹ 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 = 0.003). The trialists concluded that 6 cycles of R-CHOP was the preferred treatment for elderly patients.

Subsection Summary: 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.

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.³² 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%.³³

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.³⁴ R-CHOP (vs CHOP chemotherapy alone) was superior in terms of overall response (94% vs 75%; p = 0.005), CR (34% vs 7%; p < 0.001), and time-to-treatment failure (median, 21 months vs 14 months; p = 0.013), all respectively. However, no differences were observed in PFS or OS between the 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.³⁵ Fifty-two patients had MCL, and the group that received FCM plus rituximab (R-FCM) had a superior overall response rate (58%) compared with the FCM group (46%; p = 0.282). Significantly longer OS was observed in the R-FCM group, with median OS not reached at 2 years, compared with an estimated median OS of 11 months for the FCM group (p = 0.004). At 2 years, estimated OS in the R-FCM arm was 65% compared with 35% in the FCM arm.

Subsection Summary: Rituximab for Mantle Cell Lymphoma
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.

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.³⁶

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.³⁷ Both previously treated and chemotherapy-naive patients were included, and all selected trials were randomized and open-label. Three RCTs (total N = 1421 patients) assessed the efficacy of rituximab plus chemotherapy compared with chemotherapy alone, and a meta-analysis found a statistically significant OS and PFS advantage for patients who received rituximab. Although there were more grade 3 and 4 adverse events in the rituximab arm, treatment-related mortality did not differ statistically between groups. Two RCTs (n = 177 patients) evaluated rituximab and 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
In their randomized phase 3 trial, Shanafelt et al. (2019) compared efficacy of treatment with ibrutinib plus rituximab with standard chemoimmunotherapy for patients with previously untreated CLL.³⁸ Investigators randomly assigned 529 patients ≤ 70 years of age to 1 of 2 groups: group 1 (n = 354) received either 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; hazard ratio [HR] for progression or death, 0.35; 95% CI, 0.22 to 0.56; p < .001). Ibrutinib-rituximab was also superior to chemoimmunotherapy for overall survival (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%) vs the chemoimmunotherapy group (20.3%). Although the ibrutinib-rituximab regimen is superior for PFS and overall survival at 3 years in CLL patients aged ≤ 70 years, there is potential for long-term toxic effects and an increased risk of developing drug resistance with indefinite use of ibrutinib therapy.

Hallek et al. (2010) reported on the results of a randomized, open-label, multicenter phase 3 trial (CLL8 trial),³⁹ with longer term follow-up reported in 2016.⁴⁰ 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 vs 45% in the chemotherapy-only group (HR = 0.56; 95% CI, 0.46 to 0.69; p < 0.001), and 87% were alive vs 83%, respectively (HR = 0.67; 95% CI, 0.48 to 0.92; p = 0.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (34% vs 21%, p < 0.001) and leukopenia (24% vs 12%, p < 0.001); other adverse events, including severe infections, did not increase. Treatment-related deaths occurred in 2% vs 3% of patients in the chemoimmunotherapy and chemotherapy-only groups, respectively. With follow-up at a median of 5.9 years after randomization, median PFS was 56.8 months in the chemoimmunotherapy group and 32.9 months in the chemotherapy-alone group (HR = 0.59; 95% CI, 0.50 to 0.69; p < 0.001). Median OS was not reached for the chemoimmunotherapy group, which was significantly longer than the median OS of 86.0 months for the chemotherapy-alone group (HR = 0.68; 95% CI, 0.54 to 0.89; p = 0.001).

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).⁴¹ 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 < 0.001). The estimated median PFS was 20.9 months (95% CI, 18.8 to 27.6 months) for the entire cohort. Estimated median PFS for patients achieving CR was 60 months compared with 38 months for patients achieving nodular partial remission (p = 0.076) and 15 months for those achieving partial remission (p < 0.001). Estimated median OS for all patients was 46.7 months (95% CI, 41.2 to 53.4 months) and 100 months for patients who achieved CR or nodular partial remission. Compared with FC-treated patients in the historical cohort, patients receiving FCR had longer PFS (21 months vs 11 months, respectively; p < 0.001) and longer OS (47 months vs 21 months, respectively; p < 0.001). Subgroup analysis showed that the following patients had superior outcomes with FCR: those with up to 3 prior treatments, fludarabine-sensitive patients regardless of prior rituximab exposure, and patients without chromosome 17 abnormalities.

The randomized, open-label multicenter phase 3 REACH trial (2010) evaluated the efficacy of treating patients with relapsed or refractory CLL with FCR.⁴² 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) vs the FC-only group (20.6 months; HR = 0.65; p < 0.001). Overall response rate, CR, and duration of overall response (HR = 0.69; 95% CI, 0.50 to 0.96) also were significantly higher in the FCR group. Median time to new treatment also was significantly longer in patients receiving rituximab (not reached vs 34.3 months; HR = 0.65; 95% CI, 0.49 to 0.86; p < 0.01).

Maintenance Therapy for Chronic Lymphocytic Leukemia
Maintenance therapy with rituximab was compared with observation from the AGMT CLL8a Maintenance RCT (see CLL8 trial described in the Previously Untreated CLL section).⁴³ This multicenter open-label trial included patients who had a CR or PR to first- or second-line rituximab-containing chemoimmunotherapy. Patients were randomized to rituximab (n = 134) or observation (n = 129) every 3 months for 2 years or until progression. PFS was significantly longer with rituximab maintenance (47.0 months) than with observation (35.5 months; HR = 0.50; 95% CI, 0.33 to 0.75; p < 0.001). A higher percentage of patients in the rituximab maintenance group converted from PR to CR (8/60 [13%]) compared with observation (1/55 [2%], p = 0.033). There was no significant difference between groups in OS. Grade 3 and 4 neutropenia occurred in 28 (21%) of patients in the rituximab group and in 14 (11%) of patients in the observation group.

Subsection Summary: Rituximab for Chronic Lymphocytic Leukemia
For first-line therapy, RCTs have shown improved PFS and OS with the addition of rituximab to chemotherapy. For 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; a randomized, phase 3 study showed worse PFS and OS, but improved adverse event rates, compared with oral ibrutinib. 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.

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.⁴⁴ At a median follow-up of 38 months, patients in the rituximab group had better 3-year EFS (75%; 95% CI, 66% to 82%) than the chemotherapy-alone group (62%; 95% CI, 53% to 70%; p = 0.024; HR = 0.59; 95% CI, 0.38 to 0.94; p = 0.025). OS was also better with rituximab (83%; 95% CI, 75% to 88%) than without rituximab (70%; 95% CI, 62% to 78%). There were no significant differences in adverse events between groups.

Subsection Summary: Rituximab for Burkitt Lymphoma
For first-line therapy, 1 RCT has shown an increase in EFS and OS with the addition of rituximab to chemotherapy.

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 (e.g., 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.⁴⁵ 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.^46,47,48,49

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,⁵⁰ and that chemotherapy added to rituximab did not improve PFS and OS,⁵¹ although both studies were small (N = 80 and 35, respectively).

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

Study	N	Patients	Treatment	Results, %
				CR	PR	OS	PFS
Phase 2 studies
Trappe et al. (2012)⁵²	59	CD20-positive patients with PTLD (HL, polymorphic, monomorphic) unresponsive to RI	Rituximab 375 mg/m² weekly x 4 wk (median, 4 doses) followed by 4 cycles of CHOP (median, 4 cycles)	68	22
González-Barca et al. (2007)⁵³	38^b	PTLD after RI	Rituximab 375 mg/m² weekly x 4 wk, repeated x 1 in patients not achieving CR	61	18
Choquet et al. (2006)⁵⁴	46	B-cell PTLD unresponsive to RI	Rituximab 375 mg/m² weekly x 4 wk	26		67^b
Blaes et al. (2005)⁵⁵	11	CD20-positive patients with PTLD (HL, polymorphic) after RI; median time from transplant to PTLD, 9 mo	Rituximab 375 mg/m² weekly x 4 wk, repeated every 6 mo for 2 y in responding patients	55	9	14 mo^c
Oertel et al. (2005)⁵⁶	17	PTLD (HL, HL-like, polymorphic)	Rituximab 375 mg/m² weekly x 4 wk	53	6	37 mo^c
Retrospective studies
Evens et al. (2010)⁵⁰	80	EBV-positive, -negative, or unknown PTLD after RI; median time from transplant to PTLD, 48 mo	Rituximab ± chemotherapy (n = 59) Rituximab-free regimens (n = 21)			73^a 33^a	70^a 21^a
Elstrom et al. (2006)⁵¹	35	PTLD unresponsive to or relapsed after RI	Rituximab 375 mg/m² weekly x 4 wk (n = 22) CHOP chemotherapy ± rituximab up to 6 cycles (n = 23)	59 57	9 17	31 mo^c 42 mo^c

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: 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.

Subcutaneous Rituximab (Rituxan Hycela)
The subcutaneous product includes Rituxan (as does the IV rituximab product) and hyaluronidase human to facilitate absorption.

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 monoclonal antibodies 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. Patients with NHL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient clinical setting.

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. Patients with NHL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient 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.

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)⁵⁷ and stage 2 findings were also published by Davies et al. (2017).⁵⁸ 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 event and the rate of grade 3 or 4 adverse events were similar in both groups. Neutropenia was the most common adverse events of grade 3 or higher in both groups, affecting 34% in the IV rituximab arm and 37% in the subcutaneous rituximab arm. Also, as in stage 1, there were more administration-related adverse events in the subcutaneous rituximab arm (48%) than in the IV rituximab arm (35%); they were mainly grade 1 or 2 injection-site reactions.

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.³ 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.⁶⁰ 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 findings⁶¹ and stage 2 findings were also published by Assouline et al. (2016).⁶² 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 (e.g., erythema, pyrexia). More patients in the IV rituximab group had vascular adverse events (i.e., hypotension, hypertension). In an exploratory analysis of tumor response in the intention-to-treat population (n = 176) 3 months after treatment, 75 (85%) in the subcutaneous rituximab group and 71 (81%) patients in the IV rituximab group had an overall response, and 23 (26%) patients in the subcutaneous rituximab group and 29 (33%) patients in the IV rituximab group had a CR. The 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.

Ofatumumab (Arzerra)
Clinical Context and Test 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 question addressed in this evidence review is: Do on-label and off-label uses of monoclonal antibodies 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 ofatumumab alone or combined with chemotherapy. Patients with NHL are actively managed by oncologists, radiation oncologists, and hematologists in an inpatient clinical setting.

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
Follicular Lymphoma
Czuczman et al. (2012) reported on the use of ofatumumab as monotherapy in rituximab-refractory FL.⁶³ 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.

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).⁶⁴ 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).⁶⁵ 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.

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.⁶⁶ 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 = 0.677) or OS (HR = 1.0; 95% CI, 0.66 to 1.53; p = 0.567). 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.⁶⁷ 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 ³2 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.⁶⁸

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).⁶⁹ 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 = 0.003). 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 < 0.001). 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 = 0.14).

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.⁷⁰ 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 = 0.27). 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 = 0.019). 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.⁷¹ 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 = 0.173). 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.⁷²Treatment continued until disease progression or the patient withdrew from the trial (unacceptable side effects orother 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<0.001). However, there was no significant difference between the treatment arms in OS (HR = 0.85; 95% CI, 0.52 to 1.37; p = 0.49). 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.⁷³ 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: 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)
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.

Obinutuzumab (Gazyva)
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 question addressed in this evidence review is: Do on-label and off-label uses of monoclonal antibodies 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 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.

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
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.⁷⁴ 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 = 0.001); the 3-year OS rates were 94% and 92.1% (HR = 0.75; 95% CI, 0.49 to 1.17; p = 0.21) 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.⁵ 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 < 0.001). 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.⁷⁵ 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 one rituximab-containing regimen.⁷⁶ 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.⁷⁷ 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<0.001). Thus, PFS was significantly longer with obinutuzumab combined with bendamustine.

Chronic Lymphocytic Leukemia
First-Line Therapy for Previously Untreated Chronic Lymphocytic Leukemia
The FDA’s approval of obinutuzumab (also known as GA101) was based on an open-label, phase 3 RCT, CLL11.⁷⁸ CLL11 was conducted at 155 centers in 24 countries. Adults (≥ 18 years of age) with previously untreated, CD20-positive CLL with coexisting medical conditions (e.g., 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.⁷⁹ The primary end point was PFS. Only results comparing obinutuzumab combination therapy with chlorambucil monotherapy were considered by FDA for approval.⁸⁰ 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 < 0.001). 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 = 0.002), 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 = 0.001), 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.⁸¹

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.⁸² 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)
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. Randomized trials are needed to show improved survival outcomes compared with current treatment regimens.

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

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 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.

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 a meaningful 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 a meaningful 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; 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.

Practice Guidelines and Position Statements
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 NHL.^83,^79,^84,85

Subcutaneous Rituximab in Combination With Hyaluronidase Human
NCCN guidelines state:

B-cell lymphomas including diffuse large B-cell lymphoma, and follicular lymphoma: “Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of intravenous rituximab. The substitution cannot be made for rituximab used in combination with ibritumomab tiuxetan.”⁸³

Chronic Lymphocytic Leukemia: “Rituximab and hyaluronidase human injection for subcutaneous use may be used in patients who have received at least 1 full dose of a rituximab product by intravenous route.”⁷⁹

Obinutuzumab for Follicular Lymphoma (Grade 1 – 2)
In 2020, NCCN guidelines for B-cell lymphomas were updated to add lenalidomide + obinutuzumab as a category 2B, other recommended option for first line therapy for FL (grade 1 – 2). Obinutuzumab monotherapy and lenalidomide + obinutuzumab were added as category 2A, other recommended regimens for second-line and subsequent therapy.⁸³

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
Intravenous rituximab
NCT01516580	Intergroup Trial for Children or Adolescents With B-Cell Non Hodgkin Lymphoma or B-Acute Leukemia: Evaluation of Rituximab Efficacy and Safety in High Risk Patients - Phase III Trial	482	Dec 2021
NCT01996865^a	A Phase 3B Randomized Study of Lenalidomide (CC-5013) Plus Rituximab Maintenance Therapy Followed by Lenalidomide Single-Agent Maintenance Versus Rituximab Maintenance in Subjects With Relapsed/Refractory Follicular, Marginal Zone or Mantle Cell Lymphoma	500	Jul 2024
Subcutaneous rituximab
NCT02303119^a	A Randomized Phase III Trial Evaluating Two Strategies of Rituximab Administration for the Treatment of First Line/Low Tumor Burden Follicular Lymphoma (Follicular Lymphoma IV/SC Rituximab Therapy)	202	Jan 2021
NCT01808599	Phase II Study of Chlorambucil and Subcutaneous Rituximab in Patients With Extranodal MALT Lymphoma	112	Sep 2028
Ofatumumab
NCT01077518^a	A Randomized, Open Label Study of Ofatumumab and Bendamustine Combination Therapy Compared With Bendamustine Monotherapy in Indolent B-cell Non-Hodgkin's Lymphoma Unresponsive to Rituximab or a Rituximab-Containing Regimen During or Within Six Months of Treatment	346	Dec 2024
Obinutuzumab
NCT01332968^a	A Multicentre, Phase III, Open Label, Randomized Study in Previously Untreated Patients With Advanced Indolent Non-Hodgkin's Lymphoma Evaluating the Benefit of GA101 (RO5072759) Plus Chemotherapy Compared to Rituximab Plus + Chemotherapy Followed by GA101 or Rituximab Maintenance Therapy in Responders	1401	Apr 2021
NCT03269669	Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma	150	Dec 2022

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. Nov 15 2004; 104(10): 3064-71. PMID 15284112
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Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. Nov 14 2012; 11: CD008079. PMID 23152253
Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. Aug 01 2019; 381(5): 432-443. PMID 31365801
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Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. Mar 17 2011; 117(11): 3016-24. PMID 21245487
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Harris N, Swerdlow S, Frizzera G, et al. Post transplant lymphoproliferative disorders. In: Swerdlow S, Campo E, Harris N, eds. Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC Press; 2008:342-349.
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Jagadeesh D, Woda BA, Draper J, et al. Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol. Mar 2012; 13(1): 122-36. PMID 22241590
Nassi L, Gaidano G. II. Challenges in the management of post-transplant lymphoproliferative disorder. Hematol Oncol. Jun 2015; 33 Suppl 1: 96-9. PMID 26062065
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Evens AM, David KA, Helenowski I, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. Feb 20 2010; 28(6): 1038-46. PMID 20085936
Elstrom RL, Andreadis C, Aqui NA, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant. Mar 2006; 6(3): 569-76. PMID 16468968
Trappe R, Oertel S, Leblond V, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. Feb 2012; 13(2): 196-206. PMID 22173060
Gonzalez-Barca E, Domingo-Domenech E, Capote FJ, et al. Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease. Haematologica. Nov 2007; 92(11): 1489-94. PMID 18024397
Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood. Apr 15 2006; 107(8): 3053-7. PMID 16254143
Blaes AH, Peterson BA, Bartlett N, et al. Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial. Cancer. Oct 15 2005; 104(8): 1661-7. PMID 16149091
Oertel SH, Verschuuren E, Reinke P, et al. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. Dec 2005; 5(12): 2901-6. PMID 16303003
Davies A, Merli F, Mihaljevic B, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol. Mar 2014; 15(3): 343-52. PMID 24521993
Davies A, Merli F, Mihaljevic B, et al. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. Jun 2017; 4(6): e272-e282. PMID 28476440
Rummel M, Kim TM, Aversa F, et al. Preference for subcutaneous or intravenous administration of rituximab among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, crossover study (PrefMab). Ann Oncol. Apr 01 2017; 28(4): 836-842. PMID 28031173
Lugtenburg P, Avivi I, Berenschot H, et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. Nov 2017; 102(11): 1913-1922. PMID 28935843
Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. Nov 2015; 80(5): 1001-9. PMID 25900065
Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. Mar 2016; 3(3): e128-38. PMID 26947201
Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. Apr 19 2012; 119(16): 3698-704. PMID 22389254
Coiffier B, Radford J, Bosly A, et al. A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma. Br J Haematol. Nov 2013; 163(3): 334-42. PMID 24032456
Matasar MJ, Czuczman MS, Rodriguez MA, et al. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. Jul 25 2013; 122(4): 499-506. PMID 23692856
Wu Y, Wang Y, Gu Y, et al. Safety and efficacy of Ofatumumab in chronic lymphocytic leukemia: a systematic review and meta-analysis. Hematology. Dec 2017; 22(10): 578-584. PMID 28580841
Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. May 09 2015; 385(9980): 1873-83. PMID 25882396
Hillmen P, Janssens A, Babu KG, et al. Health-related quality of life and patient-reported outcomes of ofatumumab plus chlorambucil versus chlorambucil monotherapy in the COMPLEMENT 1 trial of patients with previously untreated CLL. Acta Oncol. Sep 2016; 55(9-10): 1115-1120. PMID 27494089
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Coding Section

Codes	Number	Description
CPT	96409- 96417	IV chemotherapy administration, code range
HCPCS	J9203	Injection, gemtuzumab ozogamicin, 0.1 mg
	J9301	Injection, obinutuzumab, 10 mg
	J9302	Injection, ofatumumab, 10 mg
	J9310	Injection, rituximab, 100 mg (deleted eff 1/1/19)
	J9311	Injection, rituximab 10 mg and hyaluronidase (eff 1/1/19)
	J9312	Injection, rituximab 10 mg (eff 1/1/19)
	C9042	Injection, bendamustine hydrochloride, (Belrapzo), 1 mg (code deleted eff 06/30/19)
	J9036	Injection, bendamustine hydrochloride, (Belrapzo), 1 mg (eff 7/1/19) Policy discusses bendeamustine used in conjunction with obinutuzumab
	Q5115	Injection, rituximab-abbs, biosimilar, 10 mg (eff 7/1/19)
ICD-10-CM	C82.90-C82.99	Follicular lymphoma code range
	C83.50-C83.59	Lymphoblastic (diffuse) lymphoma code range
	C83.70-C83.79	Burkitt lymphoma code range
	C85.1-C85.99	Non-Hodgkin lymphoma code range
	C91.10-C91.12	Chronic lymphocytic leukemia code range
	C92.00-C92.02C92.40-C92.42C92.50-C92.52C96.60-C92.62C92.A0-C92.A2	Acute myeloid leukemia code range
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services
	3E0330M, 3E0430M, 3E0530M, 3E0630M	Administration, physiological systems and anatomical regions, introduction, percutaneous, antineoplastic, monoclonal antibody, code by body part (peripheral vein, central vein, peripheral artery, central artery)
Type of service	Oncology
Place of service	Outpatient/inpatient

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

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2014 Forward

10/12/2022	Updating coding section. Adding code J9203. No other changes made.
08/23/2022	Annual review, no change to policy intent.
08/05/2021	Annual review, no change to policy intent. Updating rationale and references.
10/29/2020	Interim review to add the statement: BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.
08/18/2020	Annual review, removing rituximab as it is addressed in a separate policy. Otherwise, no change to policy intent.
08/01/2019	Annual review, updating description and adding compendial uses for Mylotarg and Rituxan Hycela. No other changes made.
08/27/2018	Annual review, updating title to mirror uses of medications in this policy. Removing Diffuse large B cell lymphoma as a compendial use for Rituxan. Adding 4 additional compendial uses for Rituxan. Updating Gazyva to expand coverage for follicular lymphoma and adding 5 new compendial uses. No other changes made.
11/27/2017	Interim review to update coding and information on Gemtuzumab as it has been reintroduced to the market.
08/30/2017	Annual review, updating policy verbiage to expand coverage of Gazyva, Arzerra and Rituxan. Also updating rationale and references.
08/02/2016	Annual review, no change to policy intent.
08/31/2015	Annual review, no change to policy intent. Updated title, background, description, rationale and references. Added coding. Rituximab continues to be addressed separately in CAM 060.
08/11/2014	Annual review. Updated verbiage to include ofatumemab, obinutuzumab and gemtuzumab criteria; background, description, FDA status, rationale and references.
04/01/2014	Removed information related to Rituximab as that drug will be separately addressed in CAM 060.

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Uses of Monoclonal Antibodies - CAM 20305