CAM 20305

Uses of Monoclonal Antibodies

Category:Prescription Drug   Last Reviewed:August 2019
Department(s):Medical Affairs   Next Review:August 2020
Original Date:August 2013    

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

Ofatumumab (Arzerra)

  • Compared with historical controls, ofatumumab has shown improved OS rates in patients with CLL that is refractory to fludarabine and alemtuzumab or who are ineligible for alemtuzumab due to bulky disease. 
  • A phase 3, randomized trial studied ofatumumab in patients with previously untreated CLL who had comorbidities and were not suitable for treatment with fludarabine. PFS was improved in patients who received ofatumumab plus chlorambucil compared with chlorambucil alone.
  • More data are needed on the use of ofatumumab for rituximab-refractory FL and for aggressive non-Hodgkin lymphoma (NHL). 

Obinutuzumab (Gazyva)

  • A phase 3, randomized trial showed substantially improved PFS in patients with previously untreated CLL who received obinutuzumab compared with those who received chlorambucil or rituximab plus chlorambucil. Preliminary analysis of OS showed increased survival with obinutuzumab compared with chlorambucil monotherapy, but not compared with rituximab combination therapy. 
  • A small phase 1/2 study of obinutuzumab monotherapy in relapsed/refractory CLL provides insufficient evidence to determine whether net health outcome is improved. Randomized trials are needed to show improved survival outcomes compared with current treatment regimens. 
  • Small phase 1 and 2 studies compared 2 doses of obinutuzumab in relapsed/refractory indolent and aggressive NHL, as monotherapy and in combination regimens. More data are needed to establish efficacy and safety of obinutuzumab for relapsed/refractory disease. 

Gemtuzumab (Mylotarg)
MYLOTARG 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

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 3 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.

Other Monoclonal Antibodies
Alemtuzumab (Campath®) is a recombinant, humanized, monoclonal antibody directed against the cell surface protein CD52, which is expressed on most normal and malignant B and T lymphocytes but not on hematopoietic stem cells. Therefore, alemtuzumab has the potential for broad application in treating Band T-cell malignancies. Its mechanism of action appears to involve complement-mediated cell lysis, antibody-dependent cellular toxicity and induction of apoptosis.

Gemtuzumab (Mylotarg®) is a recombinant, humanized monoclonal antibody directed against the CD33 antigen, which is expressed on the surface of leukemic blasts in more than 80% of patients with acute myeloid leukemia (AML) and by normal cells committed to the myeloid lineage. CD33 is not found on pluripotent hematopoietic stem cells. Leukemic blasts internalize CD33 antigen-antibody complexes, leading to DNA double-strand breaks and cell death.

This policy considers labeled and off-labeled indications for rituximab, ofatumumab, obinutuzumab, alemtuzumab and gemtuzumab in NHL and AML in the nonhematopoietic stem cell transplant setting.

Regulatory Status
On Oct. 26, 2009, FDA granted accelerated approval to ofatumumab (Arzerra®; Novartis) for treatment of patients with CLL refractory to fludarabine and alemtuzumab. Full approval was contingent on results of a phase 3 trial “intended to verify the clinical benefit of ofatumumab through demonstration of a clinically meaningful effect on progression-free survival.” 3 On April 17, 2014, FDA converted the accelerated approval to full approval and added the indication, “in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.”4,5 

Obinutuzumab (Gazyva; Genentech) is the first Breakthrough Therapy-designated drug to receive FDA approval, which was granted on Nov. 1, 2013. The approved indication is for treatment of patients with previously untreated CLL in combination with chlorambucil. 

Alemtuzumab (Campath®; Genzyme) was initially FDA-approved on May 7, 2001, for the treatment of previously treated patients with B-CLL who have failed fludarabine therapy. In September 2007, FDA expanded the approved labeling for alemtuzumab to include its use in previously untreated patients with B-CLL. The current FDA-approved indication for alemtuzumab is as single agent for treatment of B-CLL.6 On Sept. 4, 2012, Genzyme ceased all sales of Campath® and initiated the Campath Distribution Program.7 Although Campath® is no longer commercially available, the Campath Distribution Program “was developed to ensure continued access to Campath® for appropriate patients” (e.g., patients with CLL) free of charge. Alemtuzumab is commercially available as Lemtrada, which is FDA-approved for patients with relapsing forms of multiple sclerosis.8 

Policy
Rituximab
 Hycela
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. Non-Hodgkin’s Lymphoma (NHL): Rituxan is indicated for the treatment of patients with:  
      • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
      • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to Rituxan, in combination with chemotherapy, as single-agent maintenance therapy
      • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent after first-line CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy
      • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens
  2. Chronic Lymphocytic Leukemia (CLL): Rituxan is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.
  • Compendial Uses 
  1.  Hodgkin’s lymphoma, lymphocyte-predominant
  2.  Non-Hodgkin’s lymphoma
    • Acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma
    • Burkitt lymphoma
    • Castleman’s disease
    • Small lymphocytic lymphoma (SLL)
    • Marginal zone lymphomas (splenic, MALT)
    • Hairy cell leukemia, relapsed or refractory
    • Lymphoblastic lymphoma
    • Mantle cell lymphoma
    • Post-transplant lymphoproliferative disorder (PTLD)
    • Primary cutaneous B-cell lymphoma
    • Gastric MALT lympohoma
    • Nongastric MALT lymphoma
    • Splenic marginal zone lymphoma
  3. Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (LPL)
  4. Relapsed/refractory immune or idiopathic thrombocytopenic purpura (ITP)
  5. Autoimmune hemolytic anemia
  6. Thrombotic thrombocytopenic purpura 
  7. Myasthenia gravis, refractory 

Ofatumumab  

  • FDA-Aprroved 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.
  •  Compendial Uses
    1. Initial treatment of CLL in combination with chlorambucil
    2. Relapsed or refractory CLL
    3. Small lymphocytic lymphoma (SLL) (managed in the same manner as CLL)
    4. 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 wiht acute promyelocytic leukemia (APL)

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

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
RITUXIMAB (RITUXAN)
Follicular Lymphoma
First-Line Treatment of Follicular Lymphoma
Several phase 3 trials have evaluated the efficacy of rituximab in combination with various chemotherapy regimens as first-line therapy for indolent non-Hodgkin lymphoma (NHL) or follicular lymphoma (FL). One narrative review summarized the effect on complete remission (CR) of adding rituximab to several different chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin [Adriamycin], vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisone), and others. It reported that the addition of rituximab resulted in significantly greater complete remission (CR; 41%-79% for rituximab-containing regimens vs 10%-63% for regimens without rituximab; p<0.005), and greater overall response rates (81%-96% vs 57%-90%, respectively; p<0.05).7 The addition of rituximab to first- or second-line therapy with different chemotherapy regimens has shown variable results in improvement of overall survival (OS) in phase 3 trials.7 However, a 2006 meta-analysis of OS data from 4 trials (total N=1,015 patients) showed significantly improved OS when rituximab was added to chemotherapy compared with chemotherapy alone (hazard ratio [HR] for death, 0.57; 95% confidence interval [CI], 0.43 to 0.77).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).8 Patients who received R-CHOP had significantly prolonged time-to-treatment failure (p<0.001), higher overall response rate (96% vs 90%, p=0.011), and prolonged duration of remission (p=0.001). Additional follow-up in a subset of the original study group (patients age ≥60 years) showed a 4-year progression-free survival (PFS) advantage of R-CHOP over CHOP (62.2% vs 27.9%; p<0.001) and 4-year OS (90% vs 81%; p=0.039), all respectively.

Marcus et al. (2005) randomly assigned previously untreated patients with advanced-stage FL to 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 versus 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 versus 15 months for CVP only (p<0.001). Median time-to-treatment failure was 27 months for R-CVP versus 7 months for CVP (p<0.001). An update of the study at a median follow-up of 53 months showed improved OS in the R-CVP arm, with estimated 4-year OS of 83% versus 77% in the CVP arm (p=0.029).10 

Relapsed and Refractory FL
Efficacy of rituximab as monotherapy in patients with relapsed or refractory low-grade FL has been examined in multicenter studies,11-17 as summarized in a 2010 review article.18 Most studies included patients with low-grade FL, and most patients had stage 3 or 4 disease. When specified, 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 median number of previous treatments, 2 (2 studies), 3 (3 studies), or 4 (1 study). Overall response rates were 38% to 48% after 4 weeks of rituximab therapy and 57% after 8 weeks of therapy. CR rates ranged from 3% to 17%. 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. 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 in Previously Untreated FL
Salles et al. (2011) reported the results of a phase 3 randomized controlled trial (RCT; the PRIMA study) conducted in 223 centers in 25 countries.19 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 1,217 patients received 1 of 3 nonrandomized induction regimens comprising rituximab and chemotherapy; 1,019 patients who had a partial response (PR) or CR were randomly assigned to receive 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 versus 52.2% in the observation group (p=0.001). More patients with PR at the time of randomization converted to CR after 2 years in the rituximab maintenance group (52%) compared with those in the observation group (30%; estimated difference, 22.2%; 95% CI, 11.2% to 33.3%; p=0.001). Risk of starting a new antilymphoma treatment or a new chemotherapy or death was significantly reduced in the rituximab maintenance group. Grade 3 and 4 adverse events were recorded in 24% of patients in the rituximab maintenance group and in 17% in the observation group, with infections being the most common adverse event. OS did not differ significantly between groups; however, because longer follow-up was needed to show any possible effect of rituximab maintenance on OS, the authors planned to follow these patients. They concluded that 2 years of rituximab maintenance therapy significantly prolonged PFS, delayed the time to the next antilymphoma treatment or chemotherapy, and improved the quality of response in patients with previously untreated FL responsive to first-line rituximab plus chemotherapy.

Recent editorials have discussed an alternative to maintenance rituximab in patients with rituximab-responsive, low tumor burden FL20,21 Two trials compared maintenance rituximab with a watch-and-wait, treat-at-progression strategy and found no difference in PFS or OS.22,23 However, patients who received maintenance therapy sustained their first disease remission longer, and median response durations for patients in the watch-and-wait groups progressively declined, from 34 months after induction to 12 months after second retreatment. Low tumor burden FL was defined as "no mass measuring greater than 7 cm, fewer than 3 masses measuring more than 3 cm, no systemic or B symptoms, no splenomegaly measuring greater than 16 cm, no organ compromise, no leukemic phase greater than 5,000/mL circulating lymphocytes, and no cytopenias."20

Maintenance Therapy in Relapsed FL
In 2006, van Oers et al. evaluated the role of rituximab in both induction and maintenance of relapsed or refractory FL.24 They randomized 465 patients to induction with 6 cycles of CHOP versus R-CHOP, with a second randomization of patients in CR or PR to rituximab maintenance or observation. Rituximab induction therapy yielded statistically significant improvement in overall response (85.1% vs 72.3%; p<0.001), CR (29.5% vs 15.6%; p<0.001), and median PFS from first randomization (33.1 months vs 20.2 months; p<0.001). Rituximab maintenance resulted in a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR=0.40; p<0.001). Rituximab maintenance also improved OS from second randomization with 3-year OS of 85% with rituximab versus 77% with observation (p=0.011). In 2010, van Oers et al. reported long-term outcomes in this same patient population with a median follow-up of 6 years.25 Maintenance therapy with rituximab improved PFS compared with observation (median, 3.7 years vs 1.3 years, respectively; HR=0.55; p<0.001), both after CHOP induction (HR=0.37; p<0.001) and R-CHOP induction (HR=0.69; p=0.003). Five-year OS was 74% in the rituximab maintenance arm and 64% in the observation arm (p=0.07). Rituximab maintenance was associated with a significant increase in grade 3 and grade 4 infections (9.7% vs 2.4% respectively; p=0.01). The authors concluded that rituximab maintenance therapy in relapsed or resistant FL led to superior PFS and that, although improvement in OS was not statistically significant, this may have been due to an unbalanced use of rituximab in postprotocol salvage treatment; after disease progression, rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance.

Studies on Maintenance Therapy of Previously Untreated and Relapsed FL
In 2010, Martinelli et al. reported long-term follow-up of an RCT that compared induction therapy with single-agent rituximab with or without prolonged rituximab maintenance therapy in patients with FL.26 Patient population consisted of those who had received prior chemotherapy (n=138) and those who were chemotherapy-naive (n=64). All patients received single-agent rituximab, and those who did not progress were randomly assigned to no further treatment (observation arm) or 4 additional doses of rituximab given at 2-month intervals. Median follow-up was 9.5 years, with all living patients observed for at least 5 years. Median event-free survival (EFS) for the observation versus maintenance groups was 13 months versus 24 months, respectively (p<0.001). Among previously untreated patients, at 8-year follow-up, 45% (n=38) of those who received rituximab maintenance treatment after responding to rituximab induction were still without event compared with 22% in the observation group. The authors concluded that single-agent rituximab and prolonged maintenance therapy with rituximab could result in long-term remission, particularly in patients who had received no previous treatment and responded to rituximab induction.

In 2009, Vidal et al. published a systematic review and meta-analysis of RCTs to evaluate the effect of maintenance rituximab on OS of patients with FL.27 (The review did not include the previously discussed 2010 Martinelli study.) The largest study included in the systematic review is outlined in detail in the Maintenance Therapy in Relapsed FL section.24 Five studies (total N=1,143 patients) that compared rituximab maintenance therapy with observation or treatment at relapse (no maintenance) were selected. One study included only patients with previously untreated FL, 3 included patients with relapsed FL, and 1 included both previously untreated and relapsed FL. In 3 trials, patients were randomly assigned to type of induction therapy and subsequently underwent a second randomization to maintenance therapy or observation. The other 2 trials comprised patients treated with the same induction therapy who were then randomized to maintenance therapy or observation. Data for 985 patients were available for the meta-analysis of OS. Patients with refractory or relapsed FL had a clear survival benefit with maintenance rituximab therapy compared with patients in the observation group (4 trials; HR of death, 0.58; 95% CI, 0.42 to 0.79). Among previously untreated patients, the survival benefit was not statistically significant (2 trials; HR of death, 0.68; 95% CI, 0.37 to 1.25). Grade 3 or 4 adverse effects were reported in 3 trials and were more common in rituximab maintenance arms (pooled relative risk [RR], 1.52; 95% CI, 1.00 to 2.30).

Subsection Summary: Rituximab for Follicular Lymphoma
For first-line therapy, RCTs have shown that the addition of rituximab to front-line chemotherapy improves response rates and OS. For relapsed and refractory disease, multicenter studies have supported the efficacy of rituximab as monotherapy. For maintenance therapy, RCTs have shown improved PFS and OS with rituximab, both in patients with previously untreated and previously treated FL.

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

In 2010, Coiffier et al. reported long-term outcomes of a randomized trial (LNH-98.5) involving 399 elderly patients (age range, 60-80 years) with previously untreated DLBCL who were randomized to 8 cycles of classical CHOP or R-CHOP.28 Median follow-up was 10 years. Ten-year PFS was 36.5% (95% CI, 29.7% to 43.3%) with R-CHOP compared with 20% (95% CI, 14.6% to 26.2%) with CHOP only. Median OS was 8.4 years (95% CI, 5.4 to not reached) in the R-CHOP arm and 3.5 years (95% CI, 2.2 to 5.5 years) in the CHOP arm (p<0.001).

In 2008, Pfreundschuh et al. reported on an RCT of 1,222 elderly patients (age range, 61-80 years) with aggressive CD20+ NHL to 6 or 8 cycles of CHOP (at 2-week intervals [CHOP-14]), with or without rituximab, and showed significant improvements in EFS, PFS, and OS in patients receiving R-CHOP versus CHOP.29 Three-year OS was 67.7% (95% CI, 62.0% to 73.5%) for 6 cycles of CHOP-14, 66.0% (95% CI, 60.1% to 71.9%) for 8 cycles of CHOP-14, 78.1% (95% CI, 73.2% to 83.0%) for 6 cycles of R-CHOP-14, and 72.5% (95% CI, 67.1% to 77.9%) for 8 cycles of R-CHOP-14. OS improved only after 6 cycles of R-CHOP-14 (RR=0.63; 95% CI, 0.46 to 0.85; p=0.003). The authors concluded that 6 cycles of R-CHOP was the preferred treatment for elderly patients.

In 2006, Habermann et al. reported a 2-stage, randomized trial of 632 patients ages 60 years or older who had untreated DLBCL.30 Patients were randomized to CHOP or R-CHOP, and 415 responders underwent a second randomization to maintenance therapy with rituximab or observation. Three-year failure-free survival (FFS) was 53% for R-CHOP and 46% for CHOP induction (HR=0.78; 95% CI, 0.61 to 0.99; p=0.04). Two-year FFS rate after the second randomization for maintenance was 76% for rituximab versus 61% for observation (p=0.009). A significant difference in the effect of rituximab maintenance therapy was seen by type of induction therapy received, with maintenance rituximab significantly prolonging FFS after CHOP (HR=0.45; 95% CI, 0.29 to 0.71; p<0.001) but not after R-CHOP (HR=0.93; 95% CI, 0.53 to 1.66; p=0.81). A secondary analysis evaluated the effect of induction therapy without maintenance rituximab. R-CHOP alone showed a significant decrease in the risk of treatment failure compared with CHOP (HR=0.64; 95% CI, 0.47 to 0.85; p=0.003), with an estimated 3-year FFS rate of 52% for R-CHOP and 39% for CHOP. Survival also was longer after R-CHOP induction alone, with estimated 3-year OS of 67% for R-CHOP versus 58% for CHOP (HR=0.72; 95% CI, 0.52 to 1.00; p=0.05).

Jaeger et al. (2015) conducted an international, open-label RCT in 683 adults (median age, 58 years) with previously untreated CD20+, aggressive NHL.31 Patients with DLBCL (n=662) or grade 3b FL (n=21) were randomized 1:1 to rituximab maintenance therapy after first (confirmed or unconfirmed) complete remission or to observation for 2 years. Patients completed first-line therapy (8 infusions of rituximab [375 mg/m2] plus 4-8 cycles of CHOP-like chemotherapy) 12 to 14 weeks before trial start. For patients randomized to rituximab maintenance, rituximab 375 mg/m2 was administered every 2 months. Assessments of both groups occurred every 8 weeks. The primary outcome was EFS by intention-to-treat analysis, with events defined as progressive disease, death from any cause, initiation of new anticancer treatment, secondary malignancy, or unacceptable toxicity. PFS and OS also were assessed. At median follow-up of 45 months, estimated 3-year EFS was 80.1% in the rituximab maintenance group versus 76.5% in the observation group (HR=0.79; 95% CI, 0.57 to 1.08; p=0.143). Similarly, in intention-to-treat analysis, 3-year PFS and 3-year OS estimates did not differ statistically between treatment groups.  

Aviles et al. (2015) conducted an RCT of rituximab consolidation therapy in 325 adults (median age, 63 years) with previously untreated, advanced-stage DLBCL and poor prognostic factors, who were in CR after dose-dense chemotherapy (CHOP-14).32 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, estimated 5-year PFS was 51% in the rituximab consolidation group versus 53% in the observation group (p=0.8). Similarly, estimated 5-year OS did not differ statistically between groups (65% vs 66%, respectively; p=0.78).

Maintenance Therapy for DLBCL
The NHL13 RCT compared rituximab maintenance (n=338) or observation (n=345) for patients with DLBCL in first remission.31 At a median follow-up of 45 months, no significant differences were observed between the groups for EFS, PFS, or OS.

Subsection Summary: Rituximab for Diffuse Large B-Cell Lymphoma
For first-line therapy, RCTs have shown that the addition of rituximab to front-line chemotherapy improves response rates. For consolidation or maintenance therapy, randomized trials have not shown benefit of rituximab in patients with DLBCL in first CR.

Mantle Cell Lymphoma
Previously Untreated MCL
In 2005, Romaguera et al. published a prospective phase 2 study of 97 patients who had newly diagnosed MCL and received rituximab plus hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) alternating with high-dose methotrexate-cytarabine.33 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, 3-year FFS was 64% and OS was 82%. Patients 65 years of age or younger had 3-year FFS of 73%. Toxicity was significant and FFS shorter in patients older than 65 years of age. An update of this patient population, with median follow-up of 4.8 years, reported 5-year FFS of 48% and OS of 65%.34

In 2005, Lenz et al. published results of a prospective, randomized trial of 122 patients with previously untreated advanced-stage MCL that compared CHOP chemotherapy alone to R-CHOP.35 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.36  

Relapsed or Refractory MCL
In 2004, Forstpointner et al. published results of a prospective, randomized, open-label multicenter phase 3 trial comparing the use of fludarabine, cyclophosphamide, and mitoxantrone (FCM), with and without rituximab, in patients with relapsed and refractory follicular and MCL.36 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 showed that the addition of rituximab to chemotherapy improved response rates and time-to-treatment failure. For relapsed or refractory disease, an RCT has shown that the addition of rituximab to chemotherapy resulted in improved response rates and OS.

Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a disease of older individuals and tends to have a prolonged course. Generally, it is treated conservatively, and often treatment is initiated only when a patient becomes symptomatic as the disease progresses. Treatment is variable and depends on age and other risk factors, including certain molecular abnormalities. Because CLL is generally considered incurable, the aim of treatment is to induce CR, including eliminating minimal residual disease in the bone marrow. Minimal residual disease usually is evaluated by sensitive testing methods, which include flow cytometry or polymerase chain reaction; patients who are free of minimal residual disease after treatment have longer remission duration and survival.37 

Current chemotherapy options for CLL include alkylating agents such as chlorambucil or cyclophosphamide (which when used as single agents have shown CR rates <10%) and purine analogs such as fludarabine (with single-agent CR rates of 20%). The combination of an alkylating agent and fludarabine improves the CR to 40%.38 

A 2012 Cochrane review compared monoclonal anti-CD20 antibodies with no further treatment or with other anti-leukemic therapies for treatment of CLL, irrespective of disease status.39 Both previously treated and chemotherapy-naive patients were included, and all trials included were randomized and open-label. Three RCTs (n=1,421) assessed the efficacy of rituximab plus chemotherapy compared with chemotherapy alone, and a meta-analysis found a statistically significant OS and PFS advantage for patients who received rituximab. Although there were more grade 3 and 4 adverse events in the rituximab arm, treatment-related mortality did not differ statistically between groups. Two RCTs (n=177 patients) evaluated rituximab and alemtuzumab; neither study reported PFS or OS. There was no statistically significant difference between arms for CR rate or treatment-related mortality; however, more serious adverse events occurred in the alemtuzumab arm.

Previously Untreated CLL
In 2010, Hallek et al. reported results of a randomized, open-label, multicenter phase 3 trial (CLL8 trial),40 with longer term follow-up reported in 2016.41 Treatment-naive patients with CLL were randomized to receive fludarabine (F) and cyclophosphamide (C) with (n=408) or without (n=409) rituximab in 190 centers in 11 countries. At 3 years after randomization, 65% of patients in the chemoimmunotherapy group were free of progression versus 45% in the chemotherapy-only group (HR=0.56; 95% CI, 0.46 to 0.69; p<0.001), and 87% were alive versus 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% versus 3% of patients in the chemoimmunotherapy and chemotherapy only groups, respectively. With follow-up at a median of 5.9 years after randomization, median PFS was 56.8 months in the chemoimmunotherapy group and 32.9 months in the chemotherapy-alone group (HR=0.59; 95% CI, 0.50 to 0.69; p<0.001). Median OS was not reached for the chemoimmunotherapy group, which was significantly longer than the median OS of 86.0 months for the chemotherapy-alone group (HR=0.68; 95% CI, 0.54 to 0.89; p=0.001).

Relapsed or Refractory CLL
The randomized, open-label multicenter phase 3 REACH trial (2011) examined the efficacy of adding rituximab to FC (FCR) in patients with relapsed or refractory CLL.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 receive FCR (n=276) or FC only (n=276). The primary end point was PFS, with a median follow-up of 25 months. Median PFS was significantly prolonged in the FCR group (30.6 months) versus the FC-only group (20.6 months; HR=0.65; p<0.001). Overall response rate, CR, and duration of overall response (HR=0.69; 95% CI, 0.50 to 0.96) also were significantly higher in the FCR group. Median time to new treatment also was significantly longer in patients receiving rituximab (not reached vs 34.3 months; HR=0.65; 95% CI, 0.49 to 0.86; p<0.01).

In 2011, Badoux et al. reported the final analysis of an open-label phase 2 study of 284 patients with relapsed CLL treated with FCR.43 All patients had active, progressive CLL. The study included patients in second and subsequent relapses and those previously treated with rituximab or FC combination. Median patient age was 60 years, and median number of prior treatments was 2 (range, 1-10). The primary objective was to improve the CR rate compared with historical controls treated with FC as salvage therapy (n=114). Secondary outcomes included OS and PFS, calculated from the first day of therapy. Of 284 patient, 280 (99%) were evaluable for response; 30% achieved CR, 14% achieved nodular partial remission (PR), defined as patients who are otherwise in CR but had lymphoid nodules identified in bone marrow, and 30% achieved PR, 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 PR rates than those who received 4 or more prior regimens (52% vs 4%, respectively; p<0.001). 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 PR (p=0.076) and 15 months for those achieving PR (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 PR. Compared with FC-treated patients in the historical cohort, patients receiving FCR had longer PFS (21 months vs 11 months, respectively; p<0.001) and longer OS (47 months vs 21 months, respectively; p<0.001). Subgroup analysis showed that the following patients had superior outcomes with FCR: those with up to 3 prior treatments, fludarabine-sensitive patients regardless of prior rituximab exposure, and patients without chromosome 17 abnormalities.

Maintenance Therapy for CLL
Maintenance therapy with rituximab was compared with observation from the AGMT CLL8a Mabtenance RCT (see CLL8 trial described in the Previously Untreated CLL section).44 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 to observation (1/55 [2%], p=0.033). There was no significant difference between groups in OS. Grade 3 and 4 neutropenia occurred in 28 (21%) of patients in the rituximab group and in 14 (11%) of patients in the observation group.

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

Burkitt Lymphoma
In 2016, Ribrag et al. report an open-label, phase 3 RCT that compared rituximab (4 infusions) plus chemotherapy (n=128) to chemotherapy alone (n=129) for the treatment of Burkitt lymphoma.45 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%) compared to no rituximab (70%; 95% CI, 62% to 78%). There were no significant differences in adverse events between groups.  

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

Post-transplant Lymphoproliferative Disorders
Post-transplant lymphoproliferative disorders (PTLD) are characterized by lymphoid proliferations that occur in patients receiving immunosuppressive therapy after solid organ or allogeneic cell transplantation. Most PTLDs are B-cell proliferations that develop 12 to 24 months after transplant, with Epstein-Barr virus (EBV) detected in up to 70% of cases. EBV-negative PTLD typically has a later onset (>24 months after transplant). Risk factors for PTLD after solid organ transplant include EBV mismatch (positive donor/negative recipient), augmented immunosuppression (e.g., with antilymphocyte antibodies), and type of organ transplant (incidence ranges from ≈1% in kidney recipients to ≈10% in small bowel or multiorgan recipients). The World Health Organization has defined 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 (HL) and HL-like PTLD.46 Early lesions and some polymorphic lesions may be found incidentally; more advanced disease (e.g., monomorphic PTLD) typically presents with bulky, extranodal lymphadenopathy. Nonhealing ulcers of the gastrointestinal tract, bowel perforation, or pulmonary manifestations can occur. A primary goal of treatment is to save the transplanted organ.47-50 

Reduction of immunosuppression is the first step in treating PTLD. Several studies have investigated rituximab for patients who have an inadequate response to reduction in immunosuppression (see Table 1). Overall response rates were 59% to 90%. Two retrospective comparative studies showed that PFS and OS were increased with rituximab-containing regimens, including monotherapy, compared with rituximab-free regimens,51 and that chemotherapy added to rituximab did not improve PFS and OS,52 although both studies were small (N=80 and 35, respectively). 

 Table 1. Studies of Rituximab Chemoimmunotherapy for PTLD After Solid Organ Transplant

Study

N

Patients

Treatment

Results

Trappe (2012)53

59

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

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

CR=68%
PR=22%

Evens (2010)51 (retrospective)

80

 

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

 

Rituximab ± chemotherapy (various regimens; n=59)

 

Rituximab-free regimens (n=21)

3-y PFS=70%
>3-y OS=73%

3-y PFS=21%
3-y OS=33%

González-Barca (2007)54

38b

PTLD after RI

 

Rituximab 375 mg/m2 weekly × 4 wk, repeated × 1 in patients not achieving CR

CR=61%
PR=18%

Choquet (2006)55

46

B-cell PTLD unresponsive to RI

Rituximab 375 mg/m2 weekly × 4 wk

CR=26%
1-y OS=67%

Elstrom (2006)52 (retrospective)

35

PTLD unresponsive to or relapsed after RI

  • Rituximab 375 mg/m2 weekly ×4 wk (n=22)
  • CHOP chemotherapy ± rituximab up to 6 cycles (n=23)

CR=59%
PR=9%
OSa =31 mo
CR=57% 
PR=17%
OSa=42 mo

 Blaes (2005)56

11 

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

Rituximab 375 mg/m2 weekly  ×  4 wk, repeated every 6 mo for 2 y in responding patients

CR=55%
PR=9%
OSa=14 mo

 Oertel (2005)57

17

PTLD (HL, HL-like, polymorphic)

 Rituximab 375 mg/m2 weekly x 4 wk

CR=53%
PR=6%
OSa=37 mo

CHOP: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 to maximum 2 mg, plus prednisone 100 mg/d x 5 d, repeated every 21 d as tolerated; CR: complete response; EBV: Epstein-Barr virus; HL: Hodgkin lymphoma; neg: negative; OS: overall survival; pos: positive; PFS: progression-free survival; PR: partial response; PTLD: posttransplant lymphoproliferative disorders; RI: reduction in immunosuppression.
a Median.
b Assessable patients.  

Subsection Summary: Rituximab for Post-transplant 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: Rituximab (Rituxan)
Studies have examined efficacy of rituximab, alone or in combination with chemotherapy, for first line therapy, relapsed/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, mantel cell lymphoma, CLL, Burkitt Lymphoma, and PTLD, A benefit of rituximab for relapsed/refractory disease has been shown for FL, mantel cell lymphoma, and CLL. For maintenance therapy, rituximab has shown improved outcomes in patients who have FL, but not for DLBCL or CLL, due to absence of a difference in OS and a higher incidence of adverse effects.

OFATUMUMAB (ARZERRA)
Follicular Lymphoma
Czuczman et al. (2012) reported on the use of ofatumumab as monotherapy in rituximab-refractory FL.58 Median age of these patients was 61 years, and 47% had high-risk Follicular Lymphoma International Prognostic Index scores. Sixty-five percent were chemotherapy-refractory, and the median number of prior therapies was 4. Overall response rate was 13% and 10% for 2 different doses of ofatumumab; among 27 patients refractory to rituximab monotherapy, 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 1,000 mg doses) to 81 patients with DLBCL who were transplant ineligible (n=56) or had relapsed or progressed after transplant (n=25).59 Overall response rate was 11% (2% CR, 9% PR), 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 ifosfamide, carboplatin, and etoposide or dexamethasone, cytarabine, and cisplatin to 61 transplant-eligible patients with relapsed or primary refractory, aggressive NHL (77% DLBCL, 20% transformed FL, 3% grade 3B FL).60 All patients received rituximab-containing primary treatment regimens. For 59 CD20-positive patients, 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
Previously Untreated CLL
U.S. Food and Drug Administration (FDA) approval of Arzerra for previously untreated CLL was based on an open-label, phase 3 RCT, COMPLEMENT 1.61 COMPLEMENT 1 enrolled 447 patients (median age, 69 years) considered by the investigator to be unsuitable for fludarabine-based chemotherapy (e.g., due to advanced age or comorbidities; 72% of patients had >2 comorbidities). Patients were randomized to receive ofatumumab plus chlorambucil or chlorambucil alone for at least three 28-day cycles and, at most, 12 cycles. Median PFS by blinded independent review (the primary end point) was 22 months in the ofatumumab group versus 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 reactions in the ofatumumab group were infusion reactions (10%) and neutropenia (26% vs 14% chlorambucil). Health-related quality of life (HRQOL) did not differ significantly between the 2 arms during or following treatment.62

Relapsed or Refractory CLL
FDA approval of Arzerra for the treatment of patients with relapsed CLL was based on an RCT comparing chemoimmunotherapy with ofatumumab plus fludarabine and cyclophosphamide (n=183) to chemotherapy plus fludarabine and cyclophosphamide (n=182).3 PFS assessed by an independent review committee 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). The overall response rate with ofatumumab chemoimmunotherapy was 84% (95% CI, 77% to 89%) compared to 68% (95% CI, 60% to 74%; p<0.001) for chemotherapy.

In 2010, Wierda et al. reported a planned interim analysis of patients treated with ofatumumab monotherapy who had either fludarabine- or alemtuzumab-refractory (FA-ref) CLL or were ineligible for alemtuzumab treatment.63 Overall response rates (primary end point) were 58% (99% CI, 40% to 74%) and 47% (99% CI, 32% to 62%) in the FA-ref and fludarabine refractory (BF-ref) groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. In the FA-ref group, median PFS and OS were 5.7 months (95% CI, 4.5 to 8.0 months) and 13.7 months (95% CI, 9.4 to not reached), respectively, and 5.9 months (95% CI, 4.9 to 6.4 months) and 15.4 months (95% CI, 10.2 to 20.2 months) in the BF-ref group, respectively. Adverse events were more common during treatment and included infusion reactions and infections; more were primarily grade 1 or 2 events.

Maintenance Therapy for CLL
In 2015, van Oers et al. reported the interim analysis of the PROLONG trial, an open-label multicenter (130 centers) phase 3 RCT that compared ofatumumab maintenance therapy (1,000 mg every 8 weeks for up to 2 years) to observation for patients in remission after reinduction for relapsed CLL.64 Treatment continued until disease progression or the patient withdrew from the study (unacceptable side effects or other reasons). At the planned interim analysis, PFS was significantly improved in the ofatumumab arm (29.4 months; 95% CI, 26.2 to 34.2 months) compared to 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 HRQOL were observed. 

Subsection Summary: Chronic Lymphocytic Leukemia
A phase 3 RCT found improved PFS with ofatumumab plus chlorambucil compared to 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 to historical controls in patients with CLL refractory to fludarabine and alemtuzumab or who are ineligible for alemtuzumab due to bulky disease. 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. This evidence does not support an improvement in the net health outcome for use of ofatumumab as maintenance therapy for CLL.

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.

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 use of ofatumumab as maintenance therapy.

Other
The evidence is insufficient to evaluate the efficacy of ofatumumab in the treatment of malignancies other than CLL.

OBINUTUZUMAB (GAZYVA)
Follicular Lymphoma
Relapsed or Refractory FL
Gazyva 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.4 The pivotal phase 3 trial (GADOLIN) was an open-label multicenter trial of 321 patients randomized to receive either 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 (PFS HR=0.48; 95% CI, 0.34 to 0.68; p<0.001). Median OS had not been reached in either arm at a median of 24 months of observation time.

Relapsed or Refractory NHL
The 2016 publication of the phase 3 trial (GADOLIN) described above for relapsed or refractory FL contained 396 patients with NHL.65 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).

Chronic Lymphocytic Leukemia
Previously Untreated CLL
FDA approval of obinutuzumab (also known as GA101) was based on 1 open-label, phase 3 RCT, CLL11.66 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) enrolled. Patients were randomized 2:2:1 to receive 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.67 The primary end point was PFS. Only results comparing obinutuzumab combination therapy with chlorambucil monotherapy were considered by FDA for approval.68 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.68 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 2015 follow-up report 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 to 28.8% (34/118) in the chlorambucil monotherapy arm.69

Relapsed or Refractory CLL
Cartron et al. (2014) published results of the open-label, phase 1/2 GAUGIN study of obinutuzumab monotherapy for relapsed/refractory CLL.70 Phase 1 (n=13) was a dose-finding study. Phase 2 (n=20) administered a fixed dose of obinutuzumab (1,000 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. A phase 3 RCT showed substantially improved PFS in patients with previously untreated CLL who received obinutuzumab compared with those who received chlorambucil or rituximab plus chlorambucil. Preliminary analysis of OS showed increased survival with obinutuzumab compared with chlorambucil monotherapy, but not compared with rituximab combination therapy. A small phase 1/2 study of obinutuzumab monotherapy in relapsed or refractory CLL provided insufficient evidence to determine whether net health outcome is improved. Randomized trials are needed to show improved survival outcomes compared with current treatment regimens. Small phase 1 and 2 studies have compared 2 doses of obinutuzumab in relapsed or refractory indolent and aggressive NHL, as monotherapy and in combination regimens. More data are needed to establish the efficacy and safety of obinutuzumab for relapsed/refractory CLL.

SUMMARY OF EVIDENCE
Rituximab (Rituxan)
For individuals who have non-Hodgkin lymphoma who receive rituximab alone or combined with chemotherapy, the evidence includes randomized controlled trials (RCTs) and nonrandomized comparative studies. Relevant outcomes are overall survival, disease-free survival, change in disease status, and quality of life. Randomized trials have shown that the addition of rituximab to front-line chemotherapy has resulted in improved response rates and survival in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The efficacy of rituximab as monotherapy in relapsed and refractory FL has been shown in multicenter studies. Randomized trials have shown improved progression-free survival (PFS) and overall survival with the use of rituximab as maintenance therapy, both in patients with previously untreated and previously treated FL. One study of DLBCL showed improved PFS and overall survival in patients receiving rituximab-containing regimens, including monotherapy, compared with rituximab-free regimens. Randomized trials 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. Randomized trials have also shown improved PFS and overall survival with the addition of rituximab to chemotherapy in previously untreated chronic lymphocytic leukemia (CLL). One randomized trial 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.

Ofatumumab (Arzerra)
For individuals who have non-Hodgkin lymphoma who receive ofatumumab alone or combined with chemotherapy, the evidence includes RCTs and nonrandomized comparative studies. Relevant outcomes are overall survival, disease-free survival, change in disease status, and quality of life. 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 in patients not candidates for treatment with fludarabine. In another phase 3 RCT, 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 non-Hodgkin lymphoma who receive obinutuzumab alone or combined with chemotherapy, the evidence includes RCTs. Relevant outcomes are overall survival, disease-free survival, change in disease status, and quality of life. Obinutuzumab was approved by the U.S. Food and Drug Administration for the treatment of FL in patients who have relapsed or are refractory to a rituximab-containing regimen and 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 to 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
Rituximab
The National Comprehensive Cancer Network (NCCN) guidelines (v.3.2016) recommend rituximab for the following indications for non-Hodgkin lymphoma (see Table 2).71

Table 2. NCCN Guidelines on Treatment Regimens Including Rituximab for NHL 

NHL Type

Therapy

Category

FL, grade 1-2

First line with bendamustine

1

 

 First line, with multiagent chemotherapy       

1

 

 First line, monotherapy

2A

 

 First line, with lenalidomide

3

 

 Second line, monotherapy

2A

 

 Second line, with fludarabine

2A

 

 Second line, with multiagent chemotherapy

2A

FL, grade 1-2, elderly or infirm

First line, monotherapy

2A

 

 First line, with single-agent alkylators

2A

FL, grade 1-2, consolidation or extended dosing

First line, monotherapy

1

 

 Second line, monotherapy

1

 

Aggressive induction, with multiagent chemotherapy 

2A

 

 Less aggressive induction, with bendamustine

2A

MCL, candidate for HDT/ASCR

First line, as maintenance

2A

MCL, not candidate for HDT/ASCR

First line, RCHOP with rituximab maintenance

1

DLBCL

First line, with multiagent chemotherapy

1

 

 First line, with multiagent chemotherapy

2B

 

 Second line, with multi-agent chemotherapy

2A

DLBCL, frail or elderly patients

First line, with multiagent chemotherapy

2A

Burkitt lymphoma

First line, with multiagent chemotherapy

2A

Second line, with multiagent chemotherapy

 Second line, with multiagent chemotherapy

2A

CLL/SLLa

First line, monotherapy

3

 

First line, with multiagent chemotherapy 

2A 

CLL/SLLa, age ≥65 or with comorbidities 

First line, with chlorambucil 

2A 

 CLL/SLLa, relapsed r refractory

With methylprednisone or chemotherapy 

2A 

ASCR: autologous stem cell rescue; CLL: chronic lymphocytic leukemia; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; HDT: high dose therapy; MCL: mantle cell lymphoma; NHL: non-Hodgkin lymphoma; SLL: small lymphocytic lymphoma.
a Without del(17p)/TP53 mutation.

Ofatumumab
NCCN guidelines (v.1.2017) recommend ofatumumab for the following indications (all category 2A) for CLL only (see Table 3).67

Table 3. NCCN Guidelines on Treatment Regimens Including Ofatumumab for CLL and SLL Without del(17p)/TP53 Muta

CLL and SLL

Therapy

Category

Frail with significant comorbidity

First line, with chlorambucil

2A

Age ≥65 y

First line, with chlorambucil

2A

Relapsed/refractory, with significant comorbidity or age ≥65 y

Monotherapy

2A

Relapsed/refractory, without significant comorbidity

Monotherapy

2A

Complete or partial response after relapsed or refractory therapy

Monotherapy

2B

CLL: chronic lymphocytic leukemia; SLL: small lymphocytic lymphoma.

Obinutuzumab
NCCN guidelines (v.1.2017) recommend obinutuzumab for the following indications (all category 2A) for CLL only (see Table 4).67

Table 4. NCCN Guidelines on Treatment Regimens Including Obinutuzumab for CLL and SLL Without del(17p)/TP53 Mutation

CLL and SLL

Therapy

Category

Frail with significant comorbidity

First line, with chlorambucil

1

Age ≥65 y

First line, with chlorambucil

1

Relapsed/refractory, with significant comorbidity or age ≥65 y

Monotherapy

2A

Relapsed/refractory, without significant comorbidity

Monotherapy

2A

CLL: chronic lymphocytic leukemia; SLL: small lymphocytic lymphoma.

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 5. 

Table 5. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing

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   600  Dec 2021 

NCT01595048

Intergroup Trial for Children or Adolescents With B-Cell NHL or B-AL: Evaluation of Rituximab Efficacy and Safety in High Risk Patients  640  Mar 2023 

NCT01996865a 

 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  Mar 2023 

Ofatumumab    

NCT01200589a 

Phase III Randomized, Open Label Study of Single Agent Ofatumumab vs Single Agent Rituximab in Follicular Lymphoma Relapsed After Rituximab-Containing Therapy 516  Jun 2019 

NCT01077518a

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  May 2022 

Obinutuzumab    

NCT01287741a 

A Phase III, Multicenter, Open-label Randomized Trial Comparing the Efficacy of GA101 (RO5072759) in Combination With CHOP (GCHOP) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients With CD20-positive Diffuse Large B-cell Lymphoma (DLBCL) 

1,418  May 2016 

NCT01659099a

Randomized Phase III Study Using a PET-driven Strategy and Comparing GA101 OR Rituximab Associated to a Chemotherapy Delivered Every 14 Days (ACVBP or CHOP) in DLBCL CD20+ Lymphoma Untreated Patients From 18 to 60 Presenting With 1 or More Adverse Prognostic Factors of the Age-adjusted IPI

 670  Feb 2019

NCT01332968a

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) + Chemotherapy Compared to Rituximab + Chemotherapy Followed by GA101 or Rituximab Maintenance Therapy in Responders 1,401   Mar 2017

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

References

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  43. 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):3016-3024. PMID 21245487
  44. Greil R, Obrtlikova P, Smolej L, et al. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. Jul 2016;3(7):e317-329. PMID 27374465
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Coding Section

Codes Number Description
CPT 96409-96417

IV chemotherapy administration, code range

ICD-9 Procedure

   

ICD-9 Diagnosis

200.10-200.18

Lymphosarcoma code range

 

202.00-202.08

Nodular lymphoma code range

 

202.80-202.88

Other lymphomas (including non-Hodgkin lymphoma not otherwise specified), coding range

 

204.10-204.12

Chronic lymphocytic leukemia code range

 

205.00-205.02

Acute myeloid leukemia code range

HCPCS

J9010

Injection, alemtuzumab, 10 mg

 

J2903 (effective 1/1/2018)

Injection, gemtuzumab ozogamicin, 0.1 mg 

 

J9300

Injection, gemtuzumab ozogamicin, 5 mg

 

J9301

Injection, obinutuzumab, 10 mg

 

J9302

Injection, ofatumumab, 10 mg

ICD-10-CM (effective 10/01/15)

C82.90-C82.99

Follicular lymphoma code range

 

C83.50-C83.59

Lymphoblastic (diffuse) lymphoma code range

 

C85.80-C85.89

Non-Hodgkin lymphoma code range

 

C91.10-C91.12

Chronic lymphocytic leukemia code range

 

C92.00-C92.02, C92.40-C92.42, C92.50-C92.52, C96.60-C92.62, C92.a0-C92.a2

Acute myeloid leukemia code range

ICD-10-PCS (effective 10/01/15)

 

ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for the initiation of this therapy.

 

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 

 

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 and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

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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