Coverage Policy Manual
Policy #: 2009040
Category: Pharmacy
Initiated: August 2017
Last Review: July 2022
  Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma

Description:
Radioimmunotherapy  (RIT) involves the administration of an antibody linked to a radioisotope, targeted to a specific cell type. Ibritumomab (Zevalin) is a radioimmunoconjugates that target cell surface CD20 found on normal B lymphocytes and more than 90% of B-cell non-Hodgkin lymphomas (NHL). CD20-based radioimmunotherapy for NHL is similar to the anti-CD20 monoclonal antibody rituximab, which is widely used against B-cell malignancies, however, 90Y-ibritumomab tiuxetan uses a monoclonal anti-CD20 antibody to deliver beta-emitting yttium-90.
  
Radioimmunotherapy offers several advantages over external-beam irradiation in the treatment of NHL, a relatively radiosensitive disease (Emmanouilides, 2007). Radioimmunotherapy is given intravenously and, therefore, normal tissues overlying the tumor are spared significant radiation exposure. Radioimmunotherapy provides systemic radiation treatment to known as well as unsuspected tumor cells and a ”bystander effect” may be observed, since the radiation emitted from the isotopes is deposited over several cell diameters with poorly perfused or non-antigen-expressing cells within a tumor mass suffering the cytotoxic radiation effect.
 
Low-grade or indolent lymphomas usually present with advanced stage disease, and are not considered curable with current treatments, including chemotherapy. The disease course is usually prolonged, with a median survival of 7–10 years, and is characterized by initial response to chemotherapy, multiple relapses and increasing resistance to treatment. In addition, approximately 60% of patients may transform to a more aggressive type of lymphoma. Although rituximab is widely used in the treatment of B-cell NHL, not all patients respond, and a certain number of patients eventually develop resistance to the drug, necessitating additional treatments after rituximab.
 
A review article summarizes the various approaches to using radioimmunotherapy in non-Hodgkin lymphoma, including in newly diagnosed disease as well as in patients with recurrent B-cell lymphoma, in combination with chemotherapy or other monoclonal antibodies, with hematopoietic stem-cell transplant, as well as the use of pretargeting strategies to minimize toxicity and the simultaneous targeting of multiple B-cell antigens (Palanca-Wessels, 2010).
 
Regulatory Status
 
Ibritumomab tiuxetan (e.g., Zevalin®) was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular or transformed B-cell NHL, including patients with rituximab-refractory follicular non-Hodgkin lymphoma. In March 2008, the indication for transformed B-cell NHL was removed. In September 2009, FDA approved ibritumomab tiuxetan (e.g., Zevalin®) for consolidation therapy in previously untreated follicular NHL in patients who achieve a partial (PR) or complete response (CR) to first-line chemotherapy. Current FDA-approved indications are 1) relapsed or refractory, low-grade or follicular B-cell NHL and 2) previously untreated follicular NHL in patients who achieve a PR or CR to first-line chemotherapy (Spectrum, 2013).
 
Tositumomab (e.g., Bexxar®) was FDA-approved in June 2003 for rituximab-refractory follicular. On February 20, 2014, GlaxoSmithKline discontinued the manufacture and sale of tositumomab (e.g., Bexxar®) (GlaxoSmithKline, 2013).
   
 
 

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
 
Effective November 1, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single course of ibritumomab tiuxetan (e.g., Zevalin) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult patients with the following:
 
    • Follicular B-cell CD20 positive non-Hodgkin lymphoma when ALL of the following conditions are met (FDA, 2019; NCCN 2A):
        • Individual is age 18 years or older
        • Relapsed or refractory disease, or after initial therapy when individual demonstrates a partial or complete response.
        • Individual has adequate marrow reserve (cellularity >15%, <25% involvement of lymphoma, and platelets >100,000 109/L).
    • Other low-grade B-cel CD20 positive non-Hodgkin lymphoma (such as marginal zone or MALT lymphoma) when ALL of the following conditions are met (FDA, 2019):
        • Individual is age 18 years or older
        • Relapsed or refractory disease.
        • Individual has adequate marrow reserve (cellularity >15%, <25% involvement of lymphoma, and platelets >100,000 109/L).
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration:
 
Day 1: administer rituximab 250 mg/m2 IV
 
Day 7, 8, or 9: administer rituximab 250 mg/m2 IV
    • If platelets at least 150,000/mm3 within 4 hours after rituximab infusion, administer 0.4 mCi/kg (14.8 MBq per kg) Y-90 ibritumomab tiuxetan IV infusion.
    • If platelets 100,000 to 149,000/mm3 in relapsed or refractory patients: within 4 hours after rituximab infusion, administer 0.3 mCi/kg (11.1 MBq per kg) Y-90 ibritumomab tiuxetan IV infusion.
    • If platelets <100,000/mm3, DO NOT TREAT PATIENT
 
Maximum allowable dose of Y-90 Ibritumomab tiuxetan is 32.0 mCi (1184) MBq regardless of the patient’s body weight.
 
See FDA label for full dosage and administration guidelines.
 
Ibritumomab tiuxetan is a radiopharmaceutical and should be used only by physicians and other professionals qualified by training and experienced in th e safe use and handling of radionuclides.
 
Only administer Rituximab/Ibritumomab tiuxetan in facilities where immediate access to resuscitative measures is available.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Ibritumomab tiuxetan does not meet primary coverage criteria that there be scientific evidence of effectiveness when:
 
    • The above criteria are not met and for all other indications
    • Given as a repeat course of treatment
    • Used as a part of a pre-transplant conditioning regimen
 
For members with contracts without primary coverage criteria the use of ibritumomab tiuxetan is considered investigational.  
 
Investigational services are exclusions in most member benefit certificate of coverage.
 
*Due to the hematologic effects associated with the use of these agents (i.e., cytopenias), it is recommended that they not be used in patients with more than 25% bone marrow involvement by lymphoma and/or in patients with impaired bone marrow reserve (i.e., a platelet count less than 100,000/mm3 or a neutrophil count less than 1,500/mm3).
 
 
Effective July 2021 to October 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single course of ibritumomab tiuxetan (Zevalin) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult patients with the following:
 
    • Follicular B-cell CD20 positive non-Hodgkin lymphoma when ALL of the following conditions are met:
        • Individual is age 18 years or older
        • Relapsed or refractory disease, or after initial therapy when individual demonstrates a partial or complete response.
        • Individual has adequate marrow reserve (cellularity >15%, <25% involvement of lymphoma, and platelets >100,000 109/L).
    • Other low-grade B-cel CD20 positive non-Hodgkin lymphoma (such as marginal zone or MALT lymphoma) when ALL of the following conditions are met:
        • Individual is age 18 years or older
        • Relapsed or refractory disease.
        • Individual has adequate marrow reserve (cellularity >15%, <25% involvement of lymphoma, and platelets >100,000 109/L).
 
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
 
Dosage and Administration:
 
Day 1: administer rituximab 250 mg/m2 IV
 
Day 7, 8, or 9: administer rituximab 250 mg/m2 IV
    • If platelets at least 150,000/mm3 within 4 hours after rituximab infusion, administer 0.4 mCi/kg (14.8 MBq per kg) Y-90 ibritumomab tiuxetan IV infusion.
    • If platelets 100,000 to 149,000/mm3 in relapsed or refractory patients: within 4 hours after rituximab infusion, administer 0.3 mCi/kg (11.1 MBq per kg) Y-90 ibritumomab tiuxetan IV infusion.
    • If platelets <100,000/mm3, DO NOT TREAT PATIENT
 
Maximum allowable dose of Y-90 Ibritumomab tiuxetan is 32.0 mCi (1184) MBq regardless of the patient’s body weight.
 
See FDA label for full dosage and administration guidelines.
 
Ibritumomab tiuxetan (Zevalin) is a radiopharmaceutical and should be used only
by physicians and other professionals qualified by training and experienced in the safe use and handling of radionuclides.
 
Only administer Rituxan/Zevalin in facilities where immediate access to resuscitative measures is available.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Ibritumomab tiuxetan (Zevalin) does not meet primary coverage criteria that there be scientific evidence of effectiveness when:
 
    • The above criteria are not met and for all other indications
    • Given as a repeat course of treatment
    • Used as a part of a pre-transplant conditioning regimen
 
For members with contracts without primary coverage criteria the use of ibritumomab tiuxetan (Zevalin) is considered investigational.  
 
Investigational services are exclusions in most member benefit certificate of coverage.
 
*Due to the hematologic effects associated with the use of these agents (i.e., cytopenias), it is recommended that they not be used in patients with more than 25% bone marrow involvement by lymphoma and/or in patients with impaired bone marrow reserve (i.e., a platelet count less than 100,000/mm3 or a neutrophil count less than 1,500/mm3).
 
 
Effective June 2014 June 2021
 
Labeled Indications
 
A single course of ibritumomab tiuxetan (Zevalin®) used for the treatment of patients with relapsed or refractory CD-20-positive low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma, including patients with rituximab refractory follicular non-Hodgkin lymphoma, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Off-Label Indications
The use of ibritumomab tiuxetan (Zevalin®) for the initial treatment of follicular lymphoma   meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients who are unable to tolerate standard chemotherapy, e.g. elderly or frail patients.
 
The use of  ibritumomab tiuxetan (Zevalin®) for consolidation after chemotherapy for CD20-positive follicular non-Hodgkin lymphoma  in patients who achieve a partial or complete response meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
The use of ibritumomab tiuxetan (Zevalin®) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation in non-Hodgkin lymphoma patients does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without Primary Coverage Criteria the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation is considered investigational.  Investigational services are exclusions in the member benefit certificate of coverage.
 
 
*Due to the hematologic effects associated with the use of these agents (i.e., cytopenias), it is recommended that they not be used in patients with more than 25% bone marrow involvement by lymphoma and/or in patients with impaired bone marrow reserve (i.e., a platelet count less than 100,000/mm3 or a neutrophil count less than 1,500/mm3).
 
Effective Prior to June 2014
 
Labeled Indications
A single course of tositumomab (Bexxar®) used for the treatment of antigen CD20-positive, follicular, non-Hodgkin lymphoma, with or without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
A single course of ibritumomab tiuxetan (Zevalin®) used for the treatment of patients with relapsed or refractory CD-20-positive low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma, including patients with rituximab refractory follicular non-Hodgkin lymphoma, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Off-Label Indications
The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for the initial treatment of NHL  meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients who are unable to tolerate standard chemotherapy, e.g. elderly or frail patients.
 
The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for consolidation after chemotherapy in non-Hodgkin lymphoma patients who achieve a partial or complete response meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation in non-Hodgkin lymphoma patients does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without Primary Coverage Criteria the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation is considered investigational.  Investigational services are exclusions in the member benefit certificate of coverage.
 
*Due to the hematologic effects associated with the use of these agents (i.e., cytopenias), it is recommended that they not be used in patients with more than 25% bone marrow involvement by lymphoma and/or in patients with impaired bone marrow reserve (i.e., a platelet count less than 100,000/mm3 or a neutrophil count less than 1,500/mm3).
 
Effective October 2009 to August 2010
 
A single course of tositumomab (Bexxar®) used for the treatment of antigen CD20-positive, follicular, non-Hodgkin lymphoma, with or without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
 A single course of ibritumomab tiuxetan (Zevalin®) used for the treatment of patients with relapsed or refractory CD-20-positive low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma, including patients with rituximab refractory follicular non-Hodgkin lymphoma, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for the initial treatment of NHL does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for consolidation after chemotherapy or as part of a preparatory regimen prior to hematopoietic stem-cell transplantation does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without Primary Coverage Criteria, the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for the initial treatment of NHL or for consolidation after chemotherapy or as part of a preparatory regimen prior to hematopoietic stem-cell transplantation is considered investigational.  Investigational services are an exclusion in the member benefit certificate of coverage.
 
*Due to the hematologic effects associated with the use of these agents (i.e., cytopenias), it is recommended that they not be used in patients with more than 25% bone marrow involvement by lymphoma and/or in patients with impaired bone marrow reserve (i.e., a platelet count less than 100,000/mm3 or a neutrophil count less than 1,500/mm3).
 
 

Rationale:
Relapsed/Refractory Low-Grade non-Hodgkin lymphoma (NHL)
Three studies led to FDA approval of ibritumomab tiuxetan (Zevalin®). Study 1 was a single-arm study with 54 patients with relapsed follicular lymphoma refractory to rituximab (Witzig, 2002). Seventy-four percent of patients had bulky disease, and 67% had documented resistance to last chemotherapy. Seventeen of the patients had a brief response to rituximab (lasting less than 6 months), and 37 had no response. Overall response rate (ORR), the primary efficacy endpoint, was 74%, with a complete response rate (CR) of 15%. Secondary endpoints were time to disease progression and duration of response (DR). Median time to progression (TTP) for responders to ibritumomab was 8.7 months (range, 1.7–25.9 months). In the patients who had a brief response to rituximab, the response rate to ibritumomab was 88%, with a median DR of 11.5 months.
 
Study 2 was a randomized, controlled trial comparing therapy with ibritumomab to rituximab in 143 patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL (Witzig, 2002). Patients either received a single dose of ibritumomab (n=73) after pretreatment with 2 doses of rituximab, or rituximab weekly for 4 doses (n=70). ORR for the ibritumomab group was 80% versus 56% for the rituximab group (p=0.002), and CR was 30% versus 16%, respectively. No statistical difference was seen between the ibritumomab and rituximab groups for median DR or TTP.
 
Study 3 was a single-arm study involving 30 patients with relapsed or refractory low-grade, follicular or transformed B-cell NHL who had mild thrombocytopenia, and less than 25% bone marrow involvement by lymphoma. Objective, durable clinical responses were observed: ORR 67% (95% CI: 48–85%) and 11.8 months median DR (range, 4–17 months).
 
Two studies led to FDA approval of tositumomab (Bexxar®). A prospective, multicenter phase II study evaluated 131I tositumomab in 40 patients with indolent, follicular large-cell or transformed B-cell lymphoma with progressive disease after rituximab (Horning, 2005). Thirty-five patients were rituximab nonresponders or had a less than 6-month response, and 5 had a rituximab response (i.e., longer than 6 months). The median number of prior chemotherapy regimens per patient was 4 (range, 1–11), and 58% of patients were considered refractory to last chemotherapy. ORR to tositumomab was 65% and CR was 38%, which were not significantly associated with prior rituximab response. With a median follow-up of 39 months, median progression-free survival (PFS) was 10.4 months for all patients, and 24.5 months for confirmed responders to the tositumomab. PFS for 15 confirmed CR patients was not reached, with an estimated 3-year PFS of 73%. At the time of publication, 12 patients continued in response (11 CR, 1 PR) from 3–4.6 years after therapy.
 
Kaminiski et al investigated the efficacy and safety of tositumomab in 60 patients with chemotherapy-refractory low-grade or transformed NHL and compared the efficacy to the patients’ last chemotherapy regimen (Kaminski, 2001).  Patients who had been treated with at least 2 chemotherapy regimens without response or who had progressed within 6 months after their last regimen were given a single course of iodine I 131 tositumomab. Patients had received a median of 4 prior chemotherapy regimens. A CR or PR was observed in 65% of patients with tositumomab versus 28% after their last chemotherapy regimen. Median DR was 6.5 months with tositumomab versus 3.4 months with the last chemotherapy regimen. Three percent of patients had a CR after last chemotherapy versus 20% after tositumomab. The median DR for CR was 6.1 months after the last chemotherapy, and had not been reached with follow-up of longer than 47 months after tositumomab.
 
The results of these studies were supported by demonstration of durable objective responses in 3 single-arm studies, with a total of 130 patients. In these studies, patients with rituximab-naive follicular non-Hodgkin lymphoma with or without transformation were evaluated for efficacy.  All patients had relapsed following, or were refractory to, chemotherapy. The overall response rates to tositumomab ranged from 49% to 64%, and the median durations of response ranged from 13 to 16 months. Due to small sample sizes in these supportive studies, the 95% confidence intervals for the median durations of response were wide.
 
Initial Therapy of Low-Grade NHL
Kaminski et al. reported the results of a phase II, single-center, open-label study that involved 76 consecutive patients with previously untreated, stage III/IV follicular lymphoma between June 1996 and April 1999 (Kaminski, 2005).  Patients received as initial therapy a single course of treatment with 131I-tositumomab. Median patient age was 49 years (range: 23–69) and the median time from the diagnosis of lymphoma to treatment was 8 months. Any response was observed in 95% of patients with a CR in 75%. Five-year PFS for all patients was estimated at 59% and, for patients who achieved a CR, 5-year PFS was 77%. Seventy percent of the patients who had a CR remained in CR for 4.3-7.7 years after treatment. The authors concluded that their results compared favorably with the best published results of studies of any type of initial therapy, including rituximab alone, intensive chemotherapy or chemotherapy combined with rituximab.
 
Consolidation Therapy
A multicenter phase II study with 8-year follow-up data assessed the safety and efficacy of a first-line combination of CVP chemotherapy and radioimmunotherapy (Link, 2010).  The study included 30 patients from 3 sites in the U.S. between July 2000 and June 2001 with CD-20-positive untreated stage III/IV or bulky stage II low-grade follicular lymphoma. Patients were treated with 6 cycles of CVP and then one cycle of radioimmunotherapy (tositumomab and 131I-tositumomab [Bexxar]) was initiated with 56 days after day 1 of the sixth cycle of CVP. All of the patients completed therapy as planned and therapy was well tolerated. Median follow-up of living patients was 8.4 years. After the 6 cycles of CVP, the complete remission (CR) rate was 53%. After completion of radioimmunotherapy, the overall response rate was 100%, and the CR rate was 93%. Median duration of response was not reached. Progression-free survival at 2 and 5 years was 76% and 56%, respectively and 2- and 5-year overall survival rates were 96% and 83%, respectively. Median OS was not reached. Strengths of the study included the prospective evaluation of a defined treatment regimen in a well-defined cohort of patients and 8 years of follow-up of safety and efficacy in 100% of enrolled patients. Concerns are that contemporary oncology practice includes an IV bolus of cyclophosphamide, whereas this study used oral cyclophosphamide. Also, none of the patients in this study received rituximab, which is commonly used in patients with follicular lymphoma.
 
A phase III, randomized, international trial involving 414 patients from 77 centers investigated the use of ibritumomab in advanced follicular lymphoma in first remission (Morschhauser, 2008). Patients received a variety of induction chemotherapy regimens and then were randomly assigned to consolidation with radioimmunotherapy or no consolidation. Patient characteristics were well balanced between the 2 treatment groups.
 
After a median follow-up of 3.5 years, consolidation with ibritumomab significantly prolonged median progression-free survival. Median PFS was also significantly prolonged regardless of whether patients achieved PR or CR. After ibritumomab consolidation, 77% of patients in PR after induction therapy converted to CR, for a final CR rate of 87%. The study had some weaknesses, including the multiplicity of induction regimens among patients, and with the relatively short follow-up, no overall survival difference was observed between the two groups (Press, 2006). In addition, the administration of rituximab with each induction cycle has become the usual treatment of follicular lymphoma, however, only 15% of the patients in the Morschhauser study (Morschhauser, 2008) received rituximab as part of their induction therapy, and in this subgroup a statistically significant improvement in PFS in favor of ibritumomab consolidation was not seen (Press, 2006).  
 
Jacobs et al. reported the results of a phase II, nonrandomized study which enrolled 60 patients with stage II to IV symptomatic or bulky follicular lymphoma from a single institution between March 2004 and February 2007 (Jacobs, 2008). Patients received 3 cycles of CHOP-rituximab (CHOP-R), followed by consolidation with RIT and then extended rituximab consisting of 4 additional weekly treatments. Fifty-five patients completed the protocol therapy. Median patient age was 57 years (range: 27-78). Median follow-up was 19.7 months (range 0.26-35.9 months). For the patients who completed the protocol therapy, the CR rate after CHOP-R (by CT and PET imaging) was 44% and 67%, respectively. After radioimmunotherapy, the CR rate was 89% and 96% by CT and PET, respectively. For patients who completed the therapy, 2-year PFS and OS were 78.4% and 100%.
 
Press et al. reported the results of a phase II trial conducted from 1999-2000 assessing the efficacy of consolidation therapy with tositumomab/iodine I-131 tositumomab after 6 cycles of CHOP chemotherapy in 90 patients with previously untreated advanced-stage follicular lymphoma (Press, 2008). Median patient age was 50 years (range: 23-84). Eighty-four patients had sufficient documentation available to assess response, 98% of which had objective remissions, including 74% with CR and 24% with PR. Tositumomab/iodine I-131 tositumomab improved the CR rate from 39% after 6 cycles of CHOP to 69%. After a median follow-up of 5.1 years, the estimated 5-year OS rate was 87% and the PFS was 67%. The 5-year OS and PFS were each 23% better (absolute difference) than the corresponding figures for patients previously treated on SWOG protocols with CHOP only.
 
Leonard et al. assessed the safety and efficacy of a regimen consisting of 3 cycles of fludarabine followed by consolidation with iodine I-131 tositumomab in patients with previously untreated follicular lymphoma. (Leonard, 2005) The study, which was an open-label, prospective, phase II trial, was conducted between August 1998 and June 1999. Median patient age was 49 years (range: 25-82). Thirty-eight patients were enrolled, and 35 completed both fludarabine and iodine I-131 tositumomab therapy, and were assessable for response. After 3 cycles of fludarabine, the overall response rate was 89% with 9% of patients attaining a CR, 80% a PR and 11% having stable disease. After completion of tositumomab and iodine I 131 tositumomab, the response rate was 100% with 86% CR. After a median follow-up of 58 months, the median PFS had not been reached (95% CI, 27 months to not reached). Five-year estimated PFS rate was 60%.
 
A recent review article summarizes the data on the use of radioimmunotherapy in non-Hodgkin lymphoma as consolidation therapy (Morschhauser, 2009).
 
As Part of a Preparatory Regimen Prior to Hematopoietic Stem-Cell Transplantation (HSCT)
High-dose chemotherapy with autologous stem-cell transplant in eligible patients with chemotherapy sensitive, relapsed NHL, leads to prolonged PFS, although some patients eventually relapse. Also, HSCT has limited success in chemotherapy-refractory disease, and because of its highly toxic nature is unsuitable for elderly patients (Gisselbrecht, 2009). Therefore, there is interest in evaluating new treatment regimens to improve outcomes with HSCT in NHL without increasing the toxicity level of existing regimens.
 
A recent review article summarizes the trials that have been conducted using radioimmunotherapy in the stem cell transplantation setting, either as high-dose myeloablative RIT with or without chemotherapy, as standard-dose nonmyeloablative radioimmunotherapy in combination with high-dose chemotherapy or as part of a reduced-intensity conditioning regimen for allogeneic transplantation (RIC-allogeneic HSCT) (Gisselbrecht, 2009).  
 
Several trials have suggested that incorporating radioimmunotherapy as part of the conditioning regimen may improve disease control while adding negligible toxicity. Reports investigating radioimmunotherapy in combination with high-dose regimens in patients with chemotherapy-refractory disease have demonstrated overall survival rates of 55% at 38 months (range: 27-60 months) (Vose, 2005) and 87% at 30 months (range: 22-48 months) (Devizzi, 2008), as compared to historical controls with chemotherapy-refractory disease with an estimated 3-year survival rate of less than 20% with standard high-dose chemotherapy and autologous hematopoietic stem-cell transplant (Gisselbrecht, 2009).  
 
Preliminary data suggest that radioimmunotherapy in combination with RIC-allogeneic HSCT may improve clinical outcomes, with better disease eradication and decreased disease recurrence while maintaining the low toxicity of the reduced-intensity conditioning (Gisselbrecht, 2009).  A small pilot trial evaluated 12 patients with chemotherapy-refractory NHL who were treated with a fludarabine-based regimen in combination with 90Y-ibritumomab tiuxetan (Shimoni, 2008). Median patient age was 54 years. Eighty-three percent of patients achieved a partial or complete remission, and at a median follow-up of 21 months, the actuarial 2-year PFS and OS were 33%. Three patients relapsed (2-year cumulative incidence of relapse was 25%.
 
2012 Update
A search of the MEDLINE database through September 2012 did not reveal any new information that would prompt a change in the coverage statement.
  
2014 Update
 
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Scholz et al (2013) reported the results of a Phase 2, multicenter, open label study of 59 patients enrolled between June 2007 and June 2010, age 50 years or older (median age, 66 years; range, 51-83), and had untreated, stage II (extended)–IV follicular lymphoma (Scholz, 2013). Patients received rituximab plus a single dose of 90Y-ibritumomab tiuxetan. At 6 months after treatment, ORR was 87% (56% confirmed or unconfirmed CR plus 31% PR). Thirteen patients were positive for the t(14;18) translocation before treatment and obtained a CR; of these, 11 were tested after treatment, and 1 remained translocation positive. (This patient received rituximab consolidation per the study protocol.) After a median follow-up of 31 months, median PFS was 26 months (95% CI, 18 to 34), and median overall survival (OS) was not reached. Of
26 patients who attained a CR lasting 12 months or longer, 23 (88%) remained relapse-free at the time of publication; of the remaining 33 patients, 22 (67%) relapsed. The authors noted that the observed median PFS was less than that observed with first-line rituximab-chemotherapy regimens (32 months or more than 34 months in other studies). Grade 3 or higher thrombocytopenia occurred in 48% of patients,
1 of whom required a platelet transfusion. No cases of myelodysplastic syndrome or acute myeloid leukemia were observed.
 
In 2014, 2 European studies of ibritumomab tiuxetan for untreated disease were reported. Ibatici et al administered rituximab plus single-dose ibritumomab tiuxetan to 50 patients with primarily indolent disease in several centers in Italy (Ibatici, 2014. Patients had untreated, low-grade, stage II “bulky” or stage III-IV follicular lymphoma. Median patient age was 60 years (interquartile range, 50-67). Approximately 67% of patients did not meet criteria for immediate treatment. At treatment completion, 47 patients (94%) achieved an objective response, and 43 (86%) achieved CR; 21 (45%) of 47 patients subsequently relapsed or progressed. After a median follow-up of 39 months, median PFS and OS had not been reached. Estimated 3-year PFS and OS were 63% and 90%, respectively. Grade 3-4 thrombocytopenia and neutropenia occurred in 30% and 26% of patients, respectively.
 
Illidge et al administered rituximab and 2 doses of ibritumomab tiuxetan to 74 patients in several centers across Europe (Illidge, 2014). Patients had previously untreated, grade 1-3a, stage I (3%)-IV (43%) follicular lymphoma. Median age was 61 years (range, 28-80). All patients met criteria for immediate treatment.
Patients with more than 20% bone marrow involvement (18%) received rituximab induction. At 3 months,
94% of patients achieved an objective response, 58% achieved confirmed or unconfirmed CR, and 36% achieved PR. After a median follow-up of 37 months, median PFS was 40 months, and median OS had not been reached. Estimated 3-year PFS and OS were 58% and 95%, respectively. Grade 3-4 thrombocytopenia and neutropenia occurred in 56% and 36% of patients, respectively.
 
A 2012 meta-analysis pooled results from studies (including those reviewed next) of previously untreated patients with follicular lymphoma who received induction therapy, with or without rituximab, followed by
RIT consolidation (total N=779) (Rose, 2012). Pooled CR and ORRs were 96% and 83%, respectively. Pooled
PFS at 2 and 5 years was 77% and 58%, respectively, and pooled OS at 2 and 5 years was 94% and 90%, respectively. The meta-analysis had several limitations: 1) Statistical heterogeneity was significant for all outcomes except 2-year OS; 2) included studies varied in design, patient characteristics (eg, sex distribution, lymphoma grade, presence of bulky disease, baseline serum lactate dehydrogenase), induction chemotherapy regimen, and radioimmunotherapy consolidation therapy (ie, both ibritumomab tiuxetan and tositumomab were used); 3) median patient age (range, 49-57 years) was younger than the typical patient with follicular lymphoma; and 4) there was evidence of publication bias. The authors assert nonetheless that these pooled results provide “a baseline estimate of the general effect of radioimmunotherapy consolidation after chemotherapy induction.”
 
In 2014, Provencio et al published a study of 30 patients with follicular lymphoma who received ibritumomab tiuxetan consolidation after induction with CHOP-R (4 cycles) and CHOP (2 cycles) (Provencio, 2014).
ORR after consolidation was 93%. Of 18 patients with PR after induction, 11 (61%) achieved CR after consolidation. At 26 months of follow-up, mean PFS and OS had not been reached. Grade 3-4 thrombocytopenia and neutropenia occurred in 46% and 56% of patients, respectively.
 
On the matter of Consolidation Therapy for Aggressive CD20-positive B-cell NHL in Remission data from an abstract cited by Smith et al (Kluin. 2011) (subsequently published in 2012 (Kluin, 2012) raise the possibility that median PFS duration for patients with mantle-cell lymphoma may be substantially longer with rituximab maintenance (56 months) than TTF (34 months) after RIT consolidation as postremission therapy. Thus, direct comparative studies are needed.
 
Autologous transplants. Several studies have suggested that incorporating RIT as part of the conditioning regimen may improve disease control while adding minimal toxicity. Reports investigating RIT in combination with high-dose regimens in patients with chemotherapy-refractory disease have demonstrated OS rates of 87% at 30 months (range, 22-48), (34) 55% at 38 months (range, 27-60), (Vose, 2005) and 73% at 60 months (Devizzi, 2013).
 
Other studies on RIT as part of conditioning for autologous HSCT reported since the 2011 update are phase 2 studies that lack controls for comparison. These include:
  • A 2011 study (N=11) of RIT followed by HDC and autologous HSCT for consolidation of a first remission after R-CHOP in patients with DLBCL; (Han, 2011)
  • A 2011 study (N=7) of RIT to consolidate PRs after HDC plus autologous HSCT; Ria, 2011
  • A 2012 study (N=40) of RIT plus BEAM followed by autologous HSCT for a mixed group of patients with DLBCL who were in a chemosensitive relapse, refractory to standard dose induction, or in a high-risk first remission; (Vose, 2012)  and
  • A 2014 study (N=30) of ibritumomab tiuxetan plus high-dose BEAM followed by autologous HSCT in patients with refractory de novo (n=22) or transformed (n=8) DLBCL. (Briones, 2014).
 
Taken together, the available data are insufficient to determine whether inclusion of RIT in preparative regimens is superior to alternative regimens for conditioning before autologous HSCT.
 
Ongoing Clinical Trials
 
Ongoing trials sponsored by U.S. government agencies (eg, National Cancer Institute) or conducted by
U.S. cooperative clinical trials groups include:
    • A multicenter, open label RCT to compare consolidation therapy with ibritumomab tiuxetan versus autologous stem cell transplant in patients with follicular lymphoma in complete or partial remission after second- or third-line chemotherapy with rituximab (NCT01827605).
    • A multicenter, open label RCT to compare BEAM to ibritumomab tiuxetan-BEAM as the conditioning regimen before autologous stem-cell transplant in patients with diffuse large B-cell lymphoma (NCT00491491).
    • A multicenter, open label RCT to compare standard versus response-driven maintenance in patients with advanced-stage follicular lymphoma (NCT02063685). Patients randomized to the response-driven arm who responds to induction therapy and all patients with stable or progressive disease will be divided into risk groups based on fluorodeoxyglucose (FDG)-PET results. Patients at high risk (positive FDG-PET) will receive intensified maintenance with ibritumomab tiuxetan and rituximab.
    • A multicenter, open label RCT to compare sequential ibritumomab tiuxetan versus observation in patients 60 years of age or older who have newly diagnosed diffuse large B-cell lymphoma in PET-negative complete remission after R-CHOP or R-CHOP-like induction (NCT01510184).
    •  A multicenter, open label RCT to compare ibritumomab tiuxetan consolidation with observation in patients with diffuse large B-cell lymphoma who achieved complete remission with CHOP-R (NCT00322218). The current recruitment status of this trial is listed as unknown on ClinicalTrials.gov.
 
National Comprehensive Cancer Network (NCCN) Guidelines
NCCN practice guidelines (v. 2.2013) (NCCN, 2014) recommend radioimmunotherapy:
  • Follicular lymphoma (These guidelines apply to patients with histological grade 1 or 2 follicular lymphoma; grade 3 follicular lymphoma is commonly treated like diffuse large B-cell lymphoma.)
    • As first-line therapy for elderly or infirm if other first-line therapies are not tolerable (category 2A)
    • Following chemotherapy or chemoimmunotherapy induction as first-line consolidation  (category 1, but full impact of induction regimen containing rituximab on RIT consolidation is unknown)
    • As second-line and subsequent therapy (category 1)
    • For histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma, either after multiple prior therapies, or after minimal or no prior chemotherapy if initial treatment for transformed disease yields only aPR, no response, or progressive disease (category 2A).
  • Primary Cutaneous Diffuse Large B-cell Lymphoma, leg type
      • As secondary therapy for generalized (skin-only) disease (stage T3) that either has relapsed or only partially responded to initial therapy (category 2A).
 
NCCN guidelines do not list radioimmunotherapy among its recommended primary or secondary
treatments for any other type of B-cell NHL (eg, de novo diffuse large B-cell or mantle cell lymphomas)
(NCCN, 2014).
 
2015 Update
A literature search conducted through June 2015 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
Consolidation Therapy for Aggressive CD20-Positive B-Cell NHL in Remission
Hohloch et al (2014) reported on 215 patients enrolled in an international RIT registry who had DLBCL and received RIT, primarily ibritumomab tiuxetan (Hohloch, 2014). Patients varied by age (range, 17-88 years), disease stage, and number and types of previous therapies. Whether DLBCL was de novo or transformed was not reported. The majority of patients received RIT as consolidation after rituximab-containing first-line therapy (26%). At median follow-up of 11.5 months, 1- and 2-year PFS was 60% and 49%, respectively, and 1- and 2-year OS was 69% and 56%, respectively, for the entire cohort. In patients receiving RIT in first-line therapy, 2-year PFS and OS were 55% and 74%, respectively.
 
Persky et al (2015) in the Southwest Oncology Group (SWOG) used ibritumomab tiuxetan consolidation in 46 patients with early-stage, high-risk, aggressive B-cell NHL (96% DLBCL) who received 3 cycles of CHOP plus involved field radiotherapy (IFRT) (Persky, 2015). Investigators used CHOP instead of R-CHOP due to data from some previous studies that rituximab may interfere with RIT. At median follow-up of 7.3 years, estimated 2-, 5-, and 7-year PFS was 89%, 82%, and 75%, respectively. Estimated 2-, 5-, and 7-year OS was 91%, 87%, and 82%, respectively. Results were slightly better than a previous SWOG study in similar patients who received R-CHOP plus IFRT without ibritumomab tiuxetan consolidation (5-year PFS=78%; 5-year OS=83%). No unexpected toxicities were observed; 2 patients (4%) discontinued treatment due to adverse events. An ongoing trial is testing R-CHOP plus involved field radiation followed
by consolidation RIT in early-stage DLBCL (NCT01359592).
 
As Part of a Preparative Regimen Prior to Hematopoietic Stem Cell Transplantation
 
Autologous Transplants
In 2014, Kolstad et al in Scandinavia reported on 160 patients with untreated, stage II-IV mantle cell lymphoma who received high-dose BEAM conditioning before autologous HSCT.47 Patients without CR before transplant also received ibritumomab tiuxetan as part of the conditioning regimen. Survival curves for PFS and OS did not differ from those obtained in a previous study by this same group of similar patients who did not receive ibritumomab tiuxetan.
 
A 2014 meta-analysis48 of ibritumomab tiuxetan-BEAM conditioning regimens included 2 of the studies described above (Shimoni, 2012; Krishnan, 2012) along with 8 other single-arm studies presented primarily in abstract form (N=328). Pooled 2-year OS and PFS were 85% (n=328; I2=57%) and 67% (n=285; I2=24%), respectively.
 
Allogeneic Transplants
In 2015, Bouabdallah et al in France reported on a single-arm study of 30 patients with refractory or relapsed advanced NHL (DLBCL [47%], mantle cell lymphoma [20%], or low-grade lymphoma in transformation or relapsing after 2 or more chemotherapy regimens with or without autologous HSCT [33%]) (Bouabdallah, 2015). Median number of previous treatments was 3 (range, 2-4), all patients had received rituximab previously, and almost all patients (97%) had received autologous HSCT. Patients received fludarabine-based RIC with ibritumomab tiuxetan followed by allogeneic HSCT (67% matched related; 27% matched unrelated). By day 30, all patients experienced a sustained engraftment. At median follow-up of 32 months (range, 29-60), 2-year event-free and OS were both 80%. Sixteen patients experienced grade I-IV acute graft-versus-host disease, primarily affecting the skin. All patients had grade 4 neutropenia (median days to recovery: 17 [range, 12-22]), and 22 patients (73%) had grade 4 thrombocytopenia (median days to recovery: 11 [range, 6-16]).
 
As with autologous HSCT, these studies are insufficient to determine whether RIT in RIC regimens is superior to alternative RIC regimens for allogeneic HSCT. Results to date are from small, uncontrolled studies that do not permit efficacy and safety comparisons between RIC regimens that do and do not contain RIT.
 
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) updated their practice guidelines (v.2.2015)56 make the following recommendations for radioimmunotherapy in NHL:
 
    • Follicular lymphoma (These guidelines apply to patients with histological grade 1 or 2 follicular lymphoma; grade 3 follicular lymphoma is commonly treated like diffuse large B-cell lymphoma.)
        • As first-line therapy for elderly or infirm if other first-line therapies are not tolerable (category 2B)
        • Following chemotherapy or chemoimmunotherapy induction as first-line consolidation (category 2A, but full impact of induction regimen containing rituximab on RIT consolidation is unknown)
        • As second-line and subsequent therapy (category 1)
        • For histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma, either after multiple prior therapies, or after minimal or no prior chemotherapy if initial treatment for transformed disease yields only partial response, no response, or progressive disease (category 2A).
    • Primary Cutaneous Diffuse Large B-Cell Lymphoma, leg type
        • As secondary therapy for generalized (skin-only) disease (stage T3) that either has relapsed or only partially responded to initial therapy (category 2A).
 
July 2017
A literature search conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Bendamustine and rituximab (BR) has been established as a superior frontline therapy over R-CHOP in the treatment of follicular lymphoma (FL). Yttrium-90 Ibritumomab tiuxetan (90YIT) is an effective consolidation strategy after chemotherapy induction. This prospective, single-arm, multicenter, phase II trial evaluated the response rate, progression-free survival (PFS), and tolerability of BR followed by consolidation with 90YIT in patients with untreated FL.
 
The study included grade 1 to 3a FL patients aged 18 years, chemotherapy-naïve, and requiring treatment for stage II–IV disease. Study treatment included an initial rituximab treatment, followed by four cycles of BR. Patients were eligible for consolidation with 90YIT, 6 to 12 weeks after BR, if they obtained at least a partial response after induction had adequate count recovery and bone marrow infiltration
< 25%.
 
Thirty-nine patients were treated. Eighty-two percent had an intermediate or high-risk Follicular Lymphoma International Prognostic Index score, and 6 of 39 (15%) were grade 3a. The response rate was 94.8%, and the complete response (CR)/CR unconfirmed (CRu) rate was 77% in the intention-to-treat analysis. The conversion rate from PR to CR/Cru after 90YIT was 81%. After median follow-up of 45 months, the PFS was 0.71 (95% confidence interval, 0.57–0.89).
 
This report demonstrates that four cycles of BR followed by consolidation with 90YIT achieve high response rates that are durable. In addition, consolidation with 90YIT results in a high conversion rate of PR to CR/CRu. A short course of BR followed by 90YIT is a safe and effective regimen for frontline treatment of FL. (Lansigan F, Costa CA, Zaki BI, 2019).
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
79403Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous infusion
A9543Yttrium y 90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40 millicuries
A9572Indium in 111 pentetreotide, diagnostic, per study dose, up to 6 millicuries

References: Auger-Quittet S, Duny Y, Daures JP, et al.(2014) Outcomes after (90) Yttrium-ibritumomab tiuxetan-BEAM in diffuse large B-cell lymphoma: a meta-analysis. Cancer Med. Aug 2014;3(4):927-938. PMID 24740968

Bouabdallah K, Furst S, Asselineau J, et al.(2015) 90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. Ann Oncol. Jan 2015;26(1):193-198. PMID 25361987

Briones J, Novelli S, Garcia-Marco JA et al.(2014) Autologous stem cell transplantation after conditioning with yttrium-90 ibritumomab tiuxetan plus BEAM in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica 2014; 99(3):505-10.

Canadian Agency for Drugs and Technologies in Health:(2009) Radioimmunotherapies for Non-Hodgkin Lymphoma: Systematic Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines. October 2009. http://www.cadth.ca/media/pdf/M0013_Radiopharmaceuticals_NHL_L3_e.pdf. Last accessed October 2009.

Cell Therapeutics, Inc.(2008) Zevalin® (ibritumomab tiuxetan) prescribing information. Seattle, WA; 2008 April. Available online at http://www.zevalin.com/pdf/Zevalin_PI_website.pdf. Last accessed October 2009.

Devizzi IL, Guidetti A, Tarella C et al.(2008) High-dose yttrium-90-ibritumomab tiuxetan with tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation. J Clin Oncol 2008; 26(32):5175-82.

Devizzi L, Guidetti A, Seregni E et al.(2013) Long-Term Results of Autologous Hematopoietic Stem-Cell Transplantation After High-Dose 90Y-Ibritumomab Tiuxetan for Patients With Poor-Risk Non- Hodgkin Lymphoma Not Eligible for High-Dose BEAM. J Clin Oncol 2013; 31(23):2974-76.

Emmanouilides C.(2007) Radioimmunotherapy for non-Hodgkin lymphoma: historical perspective and current status. J Clin Exp Hematopathol 2007; 47(2):43-60.

Gisselbrecht C, Vose J, Nademanee A et al.(2009) Radioimmunotherapy for stem cell transplantation in non-Hodgkin’s lymphoma: in pursuit of a complete response. Oncologist 2009; 14(suppl 2):41-51.

GlaxoSmithKline.(2005) BEXXAR® (tositumomab and Iodine I 131 tositumomab) prescribing information. ResearchTriangle Park, NC; 2005 October. Available online at http://us.gsk.com/products/assets/us_bexxar.pdf. Last accessed October 2009.

GlaxoSmithKline.(2013) GSK to discontinue manufacture and sale of the Bexxar® therapeutic regimen (tositumomab and iodine I-131 tositumomab) - August 2013. . Available online at: http://us.gsk.com/html/media-news/pressreleases/2013/GSK-to-discontinuemanufacture- and-sale-of-BEXXAR-therapeutic-regimen.html. Last accessed April 2014.

Gordon LI, Witzig T, Molina A, et al.(2004) Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma. Clin Lymphoma. Sep 2004;5(2):98-101. PMID 15453924

Han EJ, Lee SE, Kim SH et al.(2011) Clinical outcomes of post-remission therapy using (90)yttrium ibritumomab tiuxetan (Zevalin®) for high-risk patients with diffuse large B-cell lymphoma. Ann Hematol 2011; 90(9):1075-82.

Hohloch K, Lankeit HK, Zinzani PL, et al.(2014) Radioimmunotherapy for first-line and relapse treatment of aggressive B-cell non-Hodgkin lymphoma: an analysis of 215 patients registered in the international RIT-Network. Eur J Nucl Med Mol Imaging. Apr 11 2014. PMID 24722703

Horning SJ, Younes A, Jain V et al.(2005) Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 2005; 23(4):712-9

Ibatici A, Pica GM, Nati S et al.(2014) Safety and efficacy of (90) yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study. Br J Haematol 2014; 164(5):710-6.

Illidge TM, Mayes S, Pettengell R et al.(2014) Fractionated (9)(0)Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria. J Clin Oncol 2014; 32(3):212-8.

Jacobs SA, Swerdlow SH, Kant J et al.(2008) Phase II trial of short-course CHOP-R followed by 90 Y-ibritumomab Tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res 2008; 14(21):7088-94

Kaminski MS, Tuck M, Estes J et al.(2005) 131 I-Tositumomab therapy as initial treatment for follicular lymphoma. Engl J Med 2005; 352(5):441-9

Kaminski MS, Zelenetz AD, Press OW et al.(2001) Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2001; 19(19):3918-28

Kluin-Nelemans HC, Hoster E, Hermine O et al.(2012) Treatment of Older Patients with Mantle-Cell Treatment of Older Patients with Mantle-Cell Lymphoma. N EnglJ Med 2012; 367(6):520-31.

Kluin-Nelemans JC, Hoster E, Walewski J, et al.(2012) R-CHOP versus R-FC followed by maintenance with rituximab versus interferon-alfa: Outcome of the first randomized trial for elderly patients with mantle cell lymphoma. Blood 118, 2011 (abstr 439). Available online at: http://abstracts.hematologylibrary.org/cgi/content/abstract/118/21/439?maxtoshow=&hits=10&RE SULTFORMAT=1&andorexacttitle=and&titleabstract=439&andorexacttitleabs=and&andorexactful ltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=118&tdate=11/30/2012&re sourcetype=HWCIT. Last accessed April 2014.

Kolstad A, Laurell A, Jerkeman M, et al.(2014) Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood. May 8 2014;123(19):2953-2959. PMID 24652994

Lansigan F, Costa CA, Zaki BI,(2019) Multicenter, Open-Label, Phase II Study of Bendamustine and Rituximab Followed by 90-Yttrium (Y) Ibritumomab Tiuxetan for Untreated Follicular Lymphoma (Fol-BRITe). Clin Cancer Res. 2019 Oct 15;25(20):6073-6079. doi: 10.1158/1078-0432.CCR-18-3755. Epub 2019 Jun 26. PMID: 31243122.

Leonard JP, Coleman M, Kostakoglu L et al.(2005) Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol 2005; 23(24):5696-704

Link BK, Martin P, Kaminski MS et al.(2010) Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: eight –year follow-up of a multicenter phase II study. J Clin Oncol 2010; 28(18):3035-41.

Morschhauser F, Dreyling M, Rohatiner A et al.(2009) Rationale for consolidation to improve progression-free survival in patients with non-Hodgkin’s lymphoma: a review of the evidence. Oncologist 2009; 14(suppl 2):17-29.

Morschhauser F, Radford J, Van Hoof A et al.(2008) Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 2008; 26(32):5156-64.

Morschhauser F, Radford J, Van Hoof A, et al.(2013) 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol. Jun 01 2013;31(16):1977-1983. PMID 23547079

National Comprehensive Cancer Network (NCCN)(2014) Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphomas, v. 2.2014. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Last accessed April 2014.

National Comprehensive Cancer Network (NCCN). (2008).(2008) Clinical Practice Guidelines in Oncology™: Non-Hodgkin’s Lymphomas v.1.2009. Available online at www.nccn.org . Last accessed October 2009.

National Comprehensive Cancer Network (NCCN).(2015) Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas, version 2.2015. . http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed April 28, 2015.

National Comprehensive Cancer Network (NCCN).(2021) Clinical practice guidelines in oncology. B-Cell Lymphomas, version 4.2021. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf

Palanca-Wessels M, Press OW.(2010) Improving the efficacy of radioimmunotherapy for non-Hodgkin lymphomas. Cancer 2010; 116(4 Suppl):1126-33.

Persky DO, Miller TP, Unger JM, et al.(2015) Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. Jan 8 2015;125(2):236-241. PMID 25395425

Press OW, Unger JM, Braziel RM et al.(2006) Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006; 24(25):4143-9.

Press OW.(2008) Evidence mounts for the efficacy of radioimmunotherapy for B-cell lymphomas. J Clin Oncol 2008; 26(32):5147-50

Provencio M, Cruz Mora MA, Gomez-Codina J et al.(2014) Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediate- and high-risk follicular lymphoma according to the follicular lymphoma international prognostic index: a multicenter, prospective phase II trial of the Spanish Lymphoma Oncology Group. Leuk Lymphoma 2014; 55(1):51-5.

Ria R, Musto P, Reale A et al.(2011) 90Y-ibritumomab tiuxetan as consolidation therapy after autologous stem cell transplantation in aggressive non-Hodgkin lymphoma. J Nucl Med 2011; 52(6):891-5.

Rose AC, Shenoy PJ, Garrett G et al.(2012) A Systematic Literature Review and Meta-Analysis of Radioimmunotherapy Consolidation for Patients With Untreated Follicular Lymphoma. Clin Lymphoma Myeloma Leuk 2012; 12(6):393-99.

Scholz CW, Pinto A, Linkesch W et al.(2013) 90Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial. J Clin Oncol 2013; 31(3):308-13.

Shimoni A, Zwas S, Oksman Y et al.(2008) Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin’s lymphoma. Bone Marrow Transplant 2008; 41(4):355-61.

U.S. Food and Drug Administration (FDA).(2019) ZEVALIN - ibritumomab tiuxetan. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label

Vose J, Bierman P, Enke C et al.(2005) Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23(3):461-7.

Vose J, Bierman P, Enke C et al.(2005) Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23(3):461-7.

Vose JM, Bierman PJ, Loberiza FR et al.(2012) Phase II Trial of 131-Iodine Tositumomab with High-Dose Chemotherapy and Autologous Stem Cell Transplantation For Relapsed Diffuse Large B-Cell Lymphoma. Biol Blood Marrow Transplant 2012.

Witzig TE, Flinn IW, Gordon LI et al.(2002) Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 2002; 20(15):3262-9.

Witzig TE, Gordon LI, Cabanillas F et al.(2002) Randomized controlled trial of Yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2002; 20(10):2453-63.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2023 American Medical Association.