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MP 8.01.50 Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/12:2012
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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Radioimmunotherapy involves the administration of an antibody linked to a radioisotope, targeted to a specific cell type. Ibritumomab (Zevalin®) and tositumomab (Bexxar®) are 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 non-Hodgkin lymphoma (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 yttrium-90, and 131I-tositumomab is an iodine-131-loaded antibody. (1)

Radioimmunotherapy offers several advantages over external-beam irradiation in the treatment of NHL, a relatively radiosensitive disease. (1) 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.

B-cell and other NHLs can be subdivided into major subcategories as indolent and aggressive. Indolent B-cell lymphomas (e.g., follicular lymphoma, a common subtype) 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. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell 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.

Review articles summarize the various approaches to using radioimmunotherapy in NHL, 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. (2, 3)

Regulatory Status

Ibritumomab tiuxetan (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 non-Hodgkin lymphoma (NHL), including patients with rituximab-refractory follicular non-Hodgkin lymphoma. In September 2009, the FDA approved ibritumomab (Zevalin®) for consolidation therapy in previously untreated follicular lymphoma in patients who achieve a partial or complete response to first-line chemotherapy.

Tositumomab (Bexxar®) was granted approval by the FDA in June 2003 for the treatment of CD20-positive, follicular NHL, with or without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy.


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 may be considered medically necessary.*

A single course of ibritumomab tiuxetan (Zevalin®) used for the treatment of patients with relapsed or refractory CD20-positive low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma, including patients with rituximab refractory follicular non-Hodgkin lymphoma, may be considered medically necessary.*

The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for the initial treatment of follicular lymphoma may be considered medically necessary 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 for CD20-positive follicular non-Hodgkin lymphoma in patients who achieve a partial or complete response may be considered medically necessary. Radioimmunotherapy with tositumomab or ibritumomab tiuxetan for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL is considered investigational.

The use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) as part of a preparatory regimen prior to autologous or allogeneic hematopoietic stem-cell transplantation in patients with non-Hodgkin lymphoma is considered investigational.

* indicates an FDA-labeled indication

Policy Guidelines

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).

Benefit Application
BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity.


Relapsed/Refractory Low-grade Non-Hodgkin Lymphoma (NHL)

Three studies led to U.S. Food and Drug Administration (FDA) approval of ibritumomab tiuxetan (Zevalin®). Study 1 was a single-arm study with 54 patients with relapsed follicular lymphoma refractory to rituximab. (4) 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 (RCT) comparing therapy with ibritumomab to rituximab in 143 patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma (B-cell NHL). (5) 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 (p=0.04). No statistical difference was seen between the ibritumomab and rituximab groups for median DR (14.2 months vs. 12.1, respectively; p=0.6) or TTP (11.2 months vs. 10.1, respectively; p=0.173).

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. (6) Objective, durable clinical responses were observed: ORR 67% (95% confidence interval [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. (7) 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 partial response [PR]) from 3 to 4.6 years after therapy.

Kaminski 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. (8) 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 131 I-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 (p<0.001). Median DR was 6.5 months with tositumomab versus 3.4 months with the last chemotherapy regimen (p<0.001). Three percent of patients had a CR after last chemotherapy versus 20% after tositumomab (p<0.001). 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 NHL with or without transformation were evaluated for efficacy. (9) 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 (as in studies 1 and 2), the 95% CIs for the median durations of response were wide.

Initial Therapy of Low-grade Non-Hodgkin Lymphoma

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. (10) 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% (95% CI: 49–71) and, for patients who achieved a CR, 5-year PFS was 77% (95% CI: 67–89). 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 for Follicular or Other Indolent CD20-positive B-cell NHL in Remission

A multicenter Phase II study with 8-year follow-up data assessed the safety and efficacy of a first-line combination of cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy and radioimmunotherapy (RIT). (11) The study included 30 patients from 3 sites in the U.S. between July 2000 and June 2001 with CD20-positive untreated stage III/IV or bulky stage II low-grade follicular lymphoma. Patients were treated with 6 cycles of CVP and then 1 cycle of RIT (tositumomab and 131I-tositumomab [Bexxar]) was initiated within 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 RIT, the ORR was 100%, and the CR rate was 93%. Median duration of response was not reached (range: 3-111+ months). PFS at 2 and 5 years was 76% and 56%, respectively, and 2- and 5-year overall survival (OS) 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 intravenous (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 that involved 414 patients from 77 centers investigated the use of ibritumomab in advanced follicular lymphoma in first remission. (12) Patients received a variety of induction chemotherapy regimens and then were randomly assigned to consolidation with RIT (n=208) or no consolidation (n=206). 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 PFS (36.5 months vs. 13.3 months in the control group; hazard ratio=0.465; p<0.0001). Median PFS was also significantly prolonged regardless of whether patients achieved partial response (PR) (29.3 vs. 6.2 months, respectively; hazard ratio [HR]: 0.304; p<0.0001) or CR (53.9 vs. 29.5 months, respectively; HR: 0.613; p=0.154). 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 2 groups. (13) 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 et al. study (12) 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. (13)

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. (14) Patients received 3 cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-rituximab (CHOP-R), followed by consolidation with 90-Y ibritumomab tiuxetan (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 years). 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 computed tomography [CT] and positron emission tomography [PET] imaging) was 44% and 67%, respectively. After RIT, 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%, respectively.

Press et al. reported the results of a Phase II trial conducted from 1999-2000, assessing the efficacy of consolidation therapy with tositumomab/iodine 131-I-tositumomab after 6 cycles of CHOP chemotherapy in 90 patients with previously untreated advanced-stage follicular lymphoma. (15) Median patient age was 50 years (range: 23-84 years). Eighty-four patients had sufficient documentation available to assess response, 98% of whom had objective remissions, including 74% with CR and 24% with PR. Tositumomab/iodine 131-I- 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 Southwest Oncology Group (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 131-I- tositumomab in patients with previously untreated follicular lymphoma. (16) 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 years). Thirty-eight patients were enrolled, and 35 completed both fludarabine and iodine 131-I- tositumomab therapy and were assessable for response. After 3 cycles of fludarabine, the ORR was 89%, with 9% of patients attaining a CR, 80% a PR, and 11% having stable disease. After completion of tositumomab and iodine 131-I- tositumomab, the RR 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%.

Recent review articles summarize the data on use of RIT as consolidation therapy for follicular NHL in complete or partial remission after induction chemotherapy with or without rituximab. (17-19) While available evidence shows better outcomes with RIT consolidation than with induction alone, it remains uncertain whether duration of remission and PFS are longer if post-remission therapy uses rituximab maintenance or RIT consolidation, and whether different patient subsets (e.g., rituximab-naïve patients vs. those induced with a regimen that included rituximab, or those in a complete vs. partial remission) might benefit more from one of these alternatives than the other.

Consolidation Therapy for Aggressive CD20-positive B-cell NHL in Remission

In contrast with follicular NHL, (12) RCT evidence is lacking on outcomes of RIT to consolidate complete or partial remissions following chemotherapy with or without rituximab in patients with diffuse large B-cell lymphoma (DLBCL) or other de novo aggressive CD20-positive NHL. Studies published through late 2011 have been reviewed (3, 20) and are limited to uncontrolled single-arm studies of RIT to consolidate first or subsequent remissions in patients with DLBCL or with mantle-cell lymphoma. Several studies (21-23) focused on elderly patients ineligible for stem-cell transplantation as post-remission therapy. However, small samples and lack of data for direct comparison with outcomes of alternatives in similar patients precludes firm conclusions. Only one subsequent report was identified for the 2012 update. Smith et al. (24) prospectively treated 56 patients with mantle-cell lymphoma using an abbreviated 4-cycle regimen of R-CHOP every 3 weeks followed by RIT consolidation using ibritumomab tiuxetan, and compared outcomes with historical controls reported in prior studies. Time to treatment failure (TTF) reported by Smith et al. compared favorably with PFS in earlier studies that used 6 cycles of R-CHOP without any post-remission therapy. However, data from an as-yet unpublished abstract cited by Smith et al. 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 post-remission therapy. Thus, direct comparative studies are needed.

As Part of a Preparative Regimen Prior to Hematopoietic Stem-Cell Transplantation (HSCT)

High-dose chemotherapy (HDC) with autologous stem-cell transplant in eligible patients with chemotherapy-sensitive, relapsed NHL, leads to prolonged PFS, although some patients eventually relapse. Also, while HSCT has modest success in chemotherapy-refractory disease, because of its highly toxic nature, it is unsuitable for elderly patients. (25) Therefore, there is interest in evaluating new preparative regimens to improve outcomes with HSCT in NHL with less toxicity than with current regimens.

Review articles have summarized evidence from studies on RIT in the setting of autologous or allogeneic stem-cell transplantation, either as high-dose myeloablative RIT with or without chemotherapy, as standard-dose nonmyeloablative RIT in combination with high-dose chemotherapy, or as part of a reduced-intensity conditioning regimen for allogeneic transplantation (RIC-allogeneic HSCT). (3, 25)

Autologous transplants. Several trials 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 55% at 38 months (range: 27-60 months) (26) and 87% at 30 months (range: 22-48 months), (27) 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 HSCT. (25)

A recent small RCT (28) compared BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) with (n=22) versus without (n=21) ibritumomab tiuxetan as the conditioning regimen prior to autologous hematopoietic stem-cell transplantation (HSCT) for refractory or relapsed DLBCL or transformed follicular lymphoma. Results at 2 years after HSCT suggested that PFS (59% vs. 37%; p=0.2) and OS (91% vs. 62%; p=0.05) might be greater after BEAM plus RIT than after BEAM alone. However, between-arm differences did not reach statistical significance for either efficacy outcome, possibly because of the small sample size. Investigators also reported no major between-arm differences in toxicity profiles.

Two non-randomized studies also directly compared outcomes of preparative regimens prior to autologous HSCT that did or did not include RIT. A retrospective matched cohort analysis compared results for patients conditioned with BEAM plus RIT (n=46) with results for an equivalent number of similar patients conditioned with BEAM plus total body irradiation (TBI). (29) Overall survival at 4 years (81% vs. 53%; p=0.01) was superior with BEAM plus RIT, although the 4-year cumulative incidence of relapse or progression did not differ significantly between regimens (40% and 42% for BEAM plus RIT and BEAM plus TBI, respectively; p=0 .6). Non-relapse mortality at 4 years was superior in the BEAM plus RIT group (zero vs. 16%; p<0.01), and non-lethal toxicity was also more common with BEAM plus TBI. However, these results may not be applicable to preparative regimens without TBI.

A second retrospective study compared RIT plus busulfan, cyclophosphamide, and etoposide (BuCyE) versus BuCyE alone (19 patients per group) followed by autologous HSCT for patients with relapsed or refractory B-cell NHL. (30) Investigators reported no statistically significant differences between groups with respect to overall survival, toxicity, or treatment-related mortality. The difference in median event-free survival (12.5 months for RIT plus BuCyE vs. 6.2 months for BuCyE alone) also was not statistically significant (p=0.24).

Other studies on RIT as part of conditioning for autologous HSCT reported since the 2011 update are Phase II studies that lack controls for comparison. These include: a study (n=11) of RIT followed by high-dose chemotherapy and autologous HSCT for consolidation of a first remission after R-CHOP in patients with DLBCL (31); another (n=7) of RIT to consolidate partial remissions after high-dose chemotherapy plus autologous HSCT (32); and a third (n=40) of RIT plus BEAM followed by autologous HSCT for a mixed group of patients with DLBCL either in a chemosensitive relapse, refractory to standard dose induction, or in a high-risk first remission. (33) Taken together, the available data are insufficient to determine whether inclusion of RIT in preparative regimens is superior to alternative regimens for conditioning prior to autologous HSCT.

Allogeneic transplants. Preliminary data suggest that RIT 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 RIC. (25) A small pilot trial evaluated 12 patients with chemotherapy-refractory NHL treated with a fludarabine-based regimen in combination with 90Y-ibritumomab tiuxetan. (34) Median patient age was 54 years (37-62 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% (95% CI: 7-60%). Three patients relapsed (2-year cumulative incidence of relapse was 25% [95% CI: 9-67%]).

Bethge and colleagues report the results of a multicenter Phase II trial of 40 patients who received RIT using yttrium-90-ibritumomab-tiuxetan with RIC followed by allogeneic HSCT. (35) Patients had either relapsed or refractory disease (n=28) and/or relapse after a preceding autologous HSCT (n=22). Lymphoma diagnoses were follicular lymphoma (n=17), chronic lymphocytic leukemia (CLL) (n=13), mantle cell lymphoma (n=8), marginal zone lymphoma (n=1), and lymphoplasmacytic lymphoma (n=1). Median age was 55 years (range, 34-68 years). Two-year OS for all patients was 51%, 67% for follicular lymphoma, 49% for CLL, and 37% for mantle cell lymphoma patients.

The 2012 literature search identified 4 new reports on RIT for conditioning prior to allogeneic HSCT, but no published RCTs. Gopal et al. (36) studied the addition of RIT with ibritumomab tiuxetan to a non-myeloablative regimen of fludarabine plus TBI (n=40) in heavily pre-treated (median 6, range 3-12 prior regimens) and mostly chemoresistant (85%) patients with a mix of indolent, transformed, and de novo intermediate or aggressive NHL. At 30 months, estimated OS, PFS, and non-relapse mortality were 54%, 31%, and 16%, respectively. Abou-Nassar et al. (37) reported a retrospective analysis on heavily pretreated (median 5, range 2-10 prior regimens) patients (n=12) with relapsed, refractory, or transformed follicular lymphoma treated with ibritumomab tiuxetan followed by fludarabine and low-dose busulfan as RIC for allogeneic HSCT. At 2 years, estimated OS, PFS, and non-relapse mortality were 83%, 74%, and 18%, respectively. Khouri et al. (38) reported on 26 prospectively-treated patients with follicular NHL (38% chemoresistant) treated with ibritumomab tiuxetan followed by fludarabine and cyclophosphamide (90YFC) as nonmyeloablative conditioning for allogeneic HSCT. OS and PFS at 3 years were estimated separately for chemosensitive (94% and 87%, respectively) and chemoresistant (80% for each outcome) subgroups. These outcomes were not statistically significantly different from each other or from those reported by these investigators for a group of 47 similar patients with follicular lymphoma (except that all were chemosensitive) at 3 years after treatment with fludarabine, cyclophosphamide, and rituximab (FCR) as nonmyeloablative conditioning for an allogeneic HSCT (OS: 85%; PFS: 83%). Treatment-related mortality at 100 days and one year were 4% and 8%, respectively, in the 90YFC group and 2% and 13%, respectively, in the FCR group. Finally, Bethge et al. (39) reported on 20 high-risk patients with various subtypes of relapsed or refractory B-cell NHL (including DLBCL, transformed CLL, mantle-cell lymphoma, and advanced follicular lymphoma) treated with escalated doses of ibritumomab tiuxetan RIT (10 each at 22 and 30 MBq/kg dose levels) plus RIC using fludarabine, melphalan, and alemtuzumab for conditioning prior to allogeneic HSCT. They reported no toxicities directly related to the escalated doses of RIT, 30% cumulative incidence of non-relapse mortality, and an estimated 20% for both overall and event-free survival at three years.

Key Clinical Trials

Ongoing Phase III trials sponsored by U.S. government agencies (e.g., National Cancer Institute) or conducted by U.S. cooperative clinical trials groups include:

  • The use of radioimmunotherapy as part of a conditioning regimen prior to autologous HSCT in patients with aggressive or relapsed lymphoma (NCT00463463), with patients being randomized to high-dose chemotherapy (BEAM) with or without Zevalin. This trial was approved but not yet active at the time of the 2011 update. In October 2012, the recruitment status of this trial is listed as unknown at the website because it has not been verified for more than 2 years.
  • The use of radioimmunotherapy (tositumomab) in comparison to rituximab in patients with recurrent follicular lymphoma (NCT00078598). The current recruitment status of this trial is listed as unknown on
  • An Intergroup study (SWOG S0016) comparing R-CHOP versus CHOP plus tositumomab for newly diagnosed follicular NHL (NCT00006721). This study is ongoing but no longer recruiting patients. Initial results presented at the December 2011 annual meeting of the American Society of Hematology showed no statistically significant differences between arms with respect to OS, PFS or toxicity at 2 years post-treatment. (40) However, the results have not been published yet in a peer-reviewed journal.
  • A multicenter study of ibritumomab versus observation in patients ≥60 years old with newly-diagnosed DLBCL in complete remission after R-CHOP or a similar regimen for induction (NCT01510184).

National Comprehensive Cancer Network (NCCN) Guidelines

NCCN practice guidelines (V.3.2012) (41) recommend radioimmunotherapy for:

Follicular lymphoma

  • as first-line therapy (category 3),
  • as first-line therapy for elderly or infirm if other first-line therapies are not tolerable (category 2A),
  • following chemotherapy as first-line consolidation or extended dosing (category 1, but full impact of induction regimen containing rituximab on RIT consolidation is unknown),
  • as second-line and subsequent therapy (category 1)
  • and 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 a partial response, no response, or progressive disease (category 2A).

Primary Cutaneous B-cell Lymphoma

  • as secondary therapy for generalized (skin-only) disease (stage T3) that either has relapsed or only partially responded to initial therapy (category 2A).

The NCCN guideline does not list radioimmunotherapy among the recommended primary or secondary treatments for any other types of B-cell NHL (e.g., de novo diffuse large B-cell or mantle cell lymphomas). (41)

Physician Specialty Society and Academic Medical Center Input (July 2010)

In response to requests, input was received from 1 academic medical center and 1 specialty medical society while this policy was under review. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

The two reviewers agreed that tositumomab was medically necessary for relapsed or rituximab-refractory follicular lymphoma and on the use of ibritumomab with relapsed or refractory NHL, although one reviewer questioned the use of ibritumomab in lymphoma transformed to diffuse large B-cell lymphoma (DLBCL). Both reviewers felt there is a role for radioimmunotherapy in the initial treatment of indolent non-Hodgkin lymphoma (NHL), particularly in older, frail patients and that it provides long remissions and results equivalent to multicycle rituximab/chemotherapy combinations. Both reviewers felt that radioimmunotherapy is medically necessary as consolidation therapy, and both agreed that there is a beneficial role as part of a preparative regimen prior to hematopoietic stem-cell transplantation.


  • Multiple studies have shown that the use of radioimmunotherapy in treating relapsed or refractory non-Hodgkin lymphoma can induce remissions in 50–80% of patients, with 15–50% achieving complete remission (CR).
  • The use of radioimmunotherapy as initial therapy of follicular lymphoma has shown high CR rates and may be beneficial, particularly in patients who cannot tolerate chemotherapy (e.g., older or frail patients).
  • Radioimmunotherapy as consolidation following induction therapy in previously untreated patients with advanced follicular lymphoma has demonstrated high overall response rates, complete remission rates, and prolonged progression-free survival in one phase III and several phase II trials.

In contrast with follicular lymphoma, phase III evidence is lacking on outcomes of radioimmunotherapy to consolidate complete or partial remissions following chemotherapy with or without rituximab in patients with DLBCL or other de novo aggressive CD20-positive non-Hodgkin lymphoma.

  • Data on the use of radioimmunotherapy as part of the conditioning regimen prior to autologous or allogeneic hematopoietic stem-cell transplant are promising but still evolving, and to date consist of small case series or uncontrolled prospective studies, with heterogeneous patient populations. Preliminary data suggest there may be a role for radioimmunotherapy, particularly in patients who may not be able to tolerate potentially curative high-dose chemotherapy and/or total body irradiation because of the risk of excessive treatment-related morbidity and mortality. A phase III trial is underway examining the role of radioimmunotherapy in autologous hematopoietic stem-cell transplant in patients with relapsed or aggressive lymphoma.


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  11. Link BK, Martin P, Kaminski MS et al. 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.
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  14. Jacobs SA, Swerdlow SH, Kant J et al. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab Tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res 2008; 14(21):7088-94.
  15. Press OW, Unger JM, Braziel RM et al. 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.
  16. Leonard JP, Coleman M, Kostakoglu L et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol 2005; 23(24):5696-704.
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CPT  79403 Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous administration
ICD-9 Diagnosis  202.00-202.08 Nodular lymphoma (including follicular), coding range
  202.80-202.88 Other lymphomas (including non-Hodgkin lymphoma not otherwise specified), coding range
ICD-9-CM Procedure 92.28 Injection or instillatio of radioisotopes
HCPCS  A9543 Yttrium Y-90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40 millicuries
  A9545 Iodine I-131 tositumomab, therapeutic, per treatment dose
ICD-10-CM (effective 10/1/14) C82.00-C82.99 Follicular lymphoma, code range 
  C85.10-C85.99 Other and unspecified types of non-Hodgkin lymphoma 
ICD-10-PCS (effective 10/1/14 CW7NGZZ, CW7NYZZ Systematic nuclear medicine therapy, whole body code list (Iodine 131 and other radionuclide specific codes) 
  DWY5GDZ, DWY5GYZ Radiation oncology, other radiation, whole body, isotope administration code list (Iodine 131 and other isotope specific codes) 


Radiolabeled monoclonal antibody therapy, non-Hodgkin lymphoma

Policy History

Date Action Reason
04/24/09 Add to Therapy section New policy
08/12/10 Replace policy Policy updated with literature search. Clinical input reviewed. References 2, 10, 16-20 added; references 5 and 21 updated. Policy statement regarding the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for the initial treatment of follicular lymphoma changed to may be considered medically necessary under specific conditions. Policy statement regarding the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for consolidation after chemotherapy in patients who achieve a partial or complete response also changed to may be considered medically necessary.
8/11/11 Replace policy

Policy updated with literature search. Reference 21 added. No change in policy statements

12/13/12 Replace Policy Policy updated with literature search. References 3, 20-24, 28-33, 36-39 added; references renumbered. Policy statement added that radioimmunotherapy with tositumomab or ibritumomab tiuxetan for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL is considered investigational.



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