CAM 80150

Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma

Category:Therapy   Last Reviewed:August 2019
Department(s):Medical Affairs   Next Review:August 2999
Original Date:December 2012    

Description
Radioimmunotherapy involves the administration of an antibody linked to a radioisotope, targeted to a specific cell type. Ibritumomab tiuxetan (Zevalin) is a radioimmunoconjugate that targets cell-surface CD20 found on normal B lymphocytes and more than 90% of B-cell non-Hodgkin lymphomas (NHL). Radioimmunotherapy has been investigated as a treatment for a number of NHLs.

For individuals with relapsed or refractory low-grade or follicular B-cell NHL who receive ibritumomab tiuxetan, the evidence includes a randomized controlled trial (RCT) and 2 single-arm studies. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. The RCT showed that ibritumomab tiuxetan resulted in a significantly higher overall response rate of 80% compared with 56% with rituximab alone. Single-arm trials have also demonstrated response rates of 74% to 89% in previously treated disease. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who receive initial treatment of follicular B-cell NHL who receive ibritumomab tiuxetan, the evidence includes 3 single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. The 3 studies have reported high overall response rates ranging from 87% to 94%. However, the median progression-free survival was less than that observed with first-line chemotherapy regimens plus rituximab in other studies. Although RCTs are needed, the current evidence has suggested that ibritumomab may be of clinical value as an initial treatment of indolent NHL, particularly in older, frail patients and that it provides long remissions and results equivalent to multicycle rituximab and chemotherapy combinations. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals with untreated follicular B-cell NHL who receive ibritumomab tiuxetan as consolidation treatment after remission, the evidence includes a pivotal RCT, a meta-analysis, and 2 single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. The pivotal RCT demonstrated that consolidation with ibritumomab tiuxetan significantly prolonged median progression-free survival by 23.2 months regardless of partial or complete response after a median follow-up of 3.5 years. The number of patients who died was too small to permit a reliable comparison of survival. Results of the single-arm studies and meta-analysis were directionally consistent with the progression-free survival benefit. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals with diffuse large B-cell or mantle cell NHL who receive ibritumomab tiuxetan as consolidation treatment after remission, the evidence includes multiple single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. Several studies, published from 2007 to 2010, have focused on elderly patients ineligible for stem cell transplantation as postremission therapy. These studies have shown 5-year OS estimates ranging from 83% to 94%. However, whether ibritumomab tiuxetan adds survival benefit over current standard rituximab-containing chemotherapy regimens cannot be determined from these studies. Further, the small samples and lack of data for direct comparison with outcomes of alternative treatments in similar patients preclude firm conclusions. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals with chemotherapy-sensitive, relapsed NHL who require hematopoietic cell transplantation and who receive ibritumomab tiuxetan as part of the conditioning regimen, the evidence includes small cohort studies or case series with heterogeneous patient populations and a meta-analysis. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. Data are promising but evolving; preliminary data have suggested there may be a role for ibritumomab tiuxetan, particularly in patients unable to tolerate potentially curative high-dose chemotherapy and/or total body irradiation because of the risk of excessive treatment-related mortality and morbidity. However, currently, the available data do not support the superiority of conditioning regimens containing ibritumomab tiuxetan over alternative conditioning regimens before hematopoietic cell transplant. RCTs comparing the efficacy and safety of conditioning regimens containing ibritumomab tiuxetan are required. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
CD20-based radioimmunotherapy (RIT) for non-Hodgkin lymphoma (NHL) is similar to the anti-CD20 monoclonal antibody rituximab, which is widely used against B-cell malignancies; however, 90 Y-ibritumomab tiuxetan uses a monoclonal anti-CD20 antibody to deliver beta-emitting yttrium-90, and 131I-tositumomab is an iodine-131-loaded antibody.1

RIT offers several advantages over external beam irradiation in the treatment of NHL, a relatively radiosensitive disease.1 RIT is given intravenously and, therefore, normal tissues overlying the tumor are spared significant radiation exposure. RIT provides systemic radiation treatment to known, as well as unsuspected, tumor cells, and a “bystander effect” may be observed, because 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 to 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 published in 2010 and 2012 summarized various uses of RIT in NHL, including for newly diagnosed disease; in patients with recurrent B-cell lymphoma; in combination with chemotherapy or other monoclonal antibodies; with hematopoietic stem cell transplant; in pretargeting strategies (e.g., infusion of unlabeled antibody followed 2 to 4 days later by radionuclide infusion) to minimize toxicity; and for simultaneous targeting of multiple B-cell antigens.2,3 

Regulatory Status
Ibritumomab tiuxetan (Zevalin®) was granted accelerated approval by 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.4 In September 2009, FDA approved ibritumomab tiuxetan (Zevalin®) for consolidation therapy in previously untreated follicular NHL in patients who achieve a PR or 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.5

Tositumomab (Bexxar®) was FDA-approved in June 2003 for rituximab-refractory follicular NHL. On Feb. 20, 2014, GlaxoSmithKline discontinued the manufacture and sale of tositumomab (Bexxar®).6

Related Policies
20305 Uses of Monoclonal Antibodies for the Treatment of Non-Hodgkin Lymphoma, Including Chronic Lymphocytic Leukemia, and Acute Myeloid Leukemia in the Non-Hematopoietic Stem-Cell Transplant Setting
80120 Hematopoietic Stem Cell Transplantation for Non-Hodgkin Lymphomas

Policy
A single course of ibritumomab tiuxetan (Zevalin®) may be considered MEDICALLY NECESSARY for the treatment of:

  • Relapsed or refractory CD20-positive, low-grade or follicular, B-cell non-Hodgkin lymphoma, including patients with rituximab refractory non-Hodgkin lymphoma.*

The use of 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 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 ibritumomab tiuxetan for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL is considered INVESTIGATIONAL.

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

* Indicates an FDA-labeled indication.

Policy Guidelines
Because of 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 <100,000/mm3 or a neutrophil count <1,500/mm3). 

Benefit Application
BlueCard®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved biologics may not be considered investigational and, thus, these drugs may be assessed only on the basis of their medical necessity.

Rationale
RELAPSED OR REFRACTORY LOW-GRADE OR FOLLICULAR B-CELL NON-HODGKIN LYMPHOMA
Three studies led to U.S. Food and Drug Administration approval of ibritumomab tiuxetan (Zevalin). Study 1, a single-arm study (2002), assessed 54 patients with relapsed follicular lymphoma refractory to rituximab.7 Seventy-four percent of patients had bulky disease, and 67% had documented resistance to last chemotherapy. Seventeen (31%) patients had a brief response to rituximab (lasting <6 months), and 37 (69%) had no response. Overall response rate (ORR), the primary efficacy end point, was 74%, with a complete response (CR) rate of 15%. Secondary end points were time-to-disease progression and duration of response. Median time-to-disease progression for responders to ibritumomab tiuxetan was 8.7 months (range, 1.7-25.9 months). In patients who had a brief response to rituximab, the response rate to ibritumomab tiuxetan was 88%, with a median duration of response of 11.5 months. 

Study 2 (2002) was a randomized controlled trial (RCT) comparing therapy with ibritumomab tiuxetan with rituximab in 143 patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL; 12% low-grade, 79% follicular, 9% transformed).8 Patients received a single dose of ibritumomab tiuxetan (n=73) after pretreatment with 2 doses of rituximab or rituximab weekly for 4 doses (n=70). ORR for the ibritumomab tiuxetan group was 80% and 56% for the rituximab group (p=0.002), and CR was 30% and 16%, respectively (p=0.04). No statistical difference was found between the ibritumomab tiuxetan and rituximab groups for the median duration of response (14.2 months vs 12.1 months, respectively; p=0.6) or time-to-disease progression (11.2 months vs 10.1 months, respectively; p=0.173). At a median follow-up of 44 months, the median time to progression (15 months vs 10 months) and duration of response (17 months vs 11 months) were longer with ibritumomab tiuxetan arm than with rituximab.9 

Study 3 was a single-arm study involving 30 patients with relapsed or refractory B-cell NHL (90% [27 patients] low-grade or follicular, 10% [3 patients] transformed) who had mild thrombocytopenia and less than 25% bone marrow involvement by lymphoma.5 Durable clinical responses were observed: the ORR was 89% (95% confidence interval [CI], 70 to 97) and the median duration of response was 11.6 months (range, 1-42.4 months). 

Section Summary: Relapsed or Refractory Low-Grade or Follicular B-Cell Non-Hodgkin Lymphoma
One RCT and 2 single-arm studies have evaluated the efficacy and safety of ibritumomab tiuxetan in relapsed or refractory, low-grade or follicular B-cell NHL. The RCT showed that ibritumomab tiuxetan resulted in a significantly higher ORR (80%) that rituximab (56%).

INITIAL TREATMENT OF FOLLICULAR B-CELL NHL
Scholz et al. (2013) reported the results of a phase 2, multicenter, open-label study of 59 patients enrolled between 2007 and 2010, ages 50 years or older (median age, 66 years; range, 51-83 years), and with untreated, stage II (extended) to IV follicular lymphoma.10 Patients received rituximab plus a single dose of yttrium 90 ibritumomab tiuxetan. At 6 months post-treatment, ORR was 87% (56% confirmed or unconfirmed CR plus 31% partial response [PR]). Thirteen patients were positive for a translocation of chromosomes 14 and 18 before treatment and obtained a CR; of these, 11 patients were tested after treatment, and one remained translocation-positive. (This patient received rituximab consolidation per the study protocol.) After a median follow-up of 31 months, median progression-free survival (PFS) was 26 months (95% CI, 18 to 34 months), 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 chemotherapy regimens and rituximab (32 months or >34 months in other studies). Grade 3 or 4 thrombocytopenia occurred in 48% of patients, one of whom required a platelet transfusion. No cases of myelodysplastic syndrome or acute myeloid leukemia were observed.  

In 2014, two 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.11 Patients had untreated, low-grade, stage II bulky or stage III or IV follicular lymphoma. Median patient age was 60 years (interquartile range, 50-67 years). Approximately 67% of patients did not meet criteria for immediate treatment. At treatment completion, 47 (94%) patients achieved an overall 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 rates were 63% and 90%, respectively. Grade 3 or 4 thrombocytopenia and neutropenia occurred in 30% and 26% of patients, respectively. 

Illidge et al. (2014) administered rituximab and 2 doses of ibritumomab tiuxetan to 74 patients in several centers across Europe.12 Patients had previously untreated, grade 1-3a, stage I (3%) to IV (43%) follicular lymphoma. Median age was 61 years (range, 28-80 years). 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 rates were 58% and 95%, respectively. Grade 3 or 4 thrombocytopenia and neutropenia occurred in 56% and 36% of patients, respectively. 

Section Summary: Initial Treatment Follicular B-Cell NHL
Three single-arm studies have evaluated the efficacy and safety of adding ibritumomab tiuxetan to rituximab in untreated patients with low-grade or follicular B-cell NHL. In all 3 trials, high ORR ranging from 87% to 94%, were observed. However, the median PFS was less than that observed with first-line chemotherapy regimens with rituximab in other studies. Based on the existing evidence, ibritumomab may result in long remissions and provide clinically meaningful benefit particularly in older, frail patients. RCTs would additionally demonstrate the benefit of adding ibritumomab tiuxetan to rituximab in untreated patients with low-grade or follicular B-cell NHL. 

CONSOLIDATION THERAPY AFTER REMISSION IN PREVIOUSLY UNTREATED PATIENTS WITH FOLLICULAR B-CELL NHL
Published reviews from 2009 and 2011 have summarized data on the use of radioimmunotherapy (RIT) as a consolidation therapy for follicular NHL after induction chemotherapy with or without rituximab.13-15 Although available evidence has shown better outcomes with RIT consolidation than with induction alone, it remains uncertain whether duration of remission and PFS are longer if postremission therapy uses rituximab maintenance or RIT consolidation and whether different patient subsets (e.g., rituximab-naive patients vs those induced with a regimen that included rituximab, or those with CR vs PR) might benefit more from one of these alternatives than the other.

A 2012 systematic review pooled results from studies of previously untreated patients with follicular lymphoma who received induction therapy, with or without rituximab, followed by RIT consolidation (total N=779 patients).16 Pooled CR and ORR were 96% and 83%, respectively. Pooled PFS rates at 2 and 5 years were 77% and 58%, respectively, and pooled OS rates at 2 and 5 years were 94% and 90%, respectively. The meta-analysis had several limitations: (1) statistical heterogeneity was significant for all outcomes except 2-year OS; (2) selected studies varied by designs, patient characteristics (e.g., sex distribution, lymphoma grade, presence of bulky disease, baseline serum lactate dehydrogenase), induction chemotherapy regimens, and RIT consolidation therapies (i.e., 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. Reviewers asserted nonetheless that these pooled results provided "a baseline estimate of the general effect of RIT consolidation after chemotherapy induction.”

Morschhauser et al. (2008) reported on the results of the pivotal RCT trial of 414 patients from 77 centers.17 In this trial, patients with follicular NHL with a PR or CR (confirmed or unconfirmed) on completion of first-line chemotherapy were randomized to consolidation therapy with ibritumomab (n=208) or to no consolidation therapy (n=206). Patient characteristics were well-balanced between treatment groups. After a median follow-up of 3.5 years, consolidation with ibritumomab tiuxetan significantly prolonged median PFS (36.5 months vs 13.3 months in the control group; hazard ratio [HR], 0.465; p<0.001). Median PFS also was significantly prolonged whether or not patients achieved PR (29.3 months vs 6.2 months, respectively; HR=0.30; p<0.001) or CR (53.9 months vs 29.5 months, respectively; HR=0.61; p=0.154). After ibritumomab tiuxetan consolidation, 77% of patients in PR after induction therapy onverted to CR, for a final CR rate of 87%. The trial had some weaknesses, including a multiplicity of induction regimens across patients, and with relatively short follow-up, no OS difference was observed between groups. Additionally, administration of rituximab with each induction cycle has become the usual treatment of follicular lymphoma, but only 15% of patients in this trial received rituximab as part of their induction therapy; in this subgroup, a statistically significant improvement in PFS in favor of ibritumomab tiuxetan consolidation was not seen.18 The longer follow-up (7.3 years) of this trial showed that the estimated 8-year PFS rate was 41% with ibritumomab compared with 22% with the control arm, with a median PFS of 4.1 years vs 1.1 years, respectively.19 

Two single-arm studies have reported on the role of ibritumomab as consolidation therapy for follicular or NHL after remission. Jacobs et al. (2008) reported on the results of a phase 2 study that enrolled 60 patients with stage II to IV symptomatic or bulky follicular lymphoma from a single institution between 2004 and 2007.20 Patients received 3 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), followed by consolidation therapy with ibritumomab and then extended rituximab consisting of 4 additional weekly treatments. Fifty-five patients completed the protocol therapy. The CR rates after R-CHOP (by computed tomography and positron emission tomography imaging) were 44% and 67%, respectively. After ibritumomab consolidation, the CR rates were 89% and 96% by computed tomography and positron emission tomography, respectively. For patients who completed the therapy, 2-year PFS and OS rates were 78.4% and 100%, respectively. Provencio et al. (2014) reported on the results of a study of 30 patients with follicular lymphoma who received ibritumomab tiuxetan consolidation therapy after induction with R-CHOP (4 cycles) and CHOP (2 cycles).21 ORR after consolidation was 93%. Of 18 patients with PR after induction, 11 (61%) achieved CR after consolidation.  At 26-month follow-up, mean PFS and OS had not been reached. Grade 3 or 4 thrombocytopenia and neutropenia occurred in 46% and 56% of patients, respectively. 

Section Summary: Consolidation Therapy After Remission in Previously Untreated Patients with Follicular B-Cell NHL
A large pivotal RCT, a meta-analysis, and 2 single-arm studies have evaluated the efficacy and safety of consolidation therapy with ibritumomab tiuxetan in patients with follicular NHL who obtained CR or PR after induction chemotherapy with or without rituximab. The pivotal RCT trial demonstrated that consolidation therapy with ibritumomab tiuxetan significantly prolonged median PFS regardless of PR or CR after a median follow-up of 3.5 years. The number of patients who died was too small to permit a reliable comparison of survival. Two single-arm studies reported CR rates in the range of 89% to 96% with the use of ibritumomab tiuxetan as a consolidation treatment for follicular NHL. The meta-analysis pooled results from studies of previously untreated patients with follicular lymphoma who had received induction therapy, with or without rituximab, followed by ibritumomab consolidation and reported CR and ORR of 96% and 83%, respectively. Pooled PFS rates at 2 and 5 years were 77% and 58%, respectively, and pooled OS rates at 2 and 5 years were 94% and 90%, respectively. Although available evidence has shown better outcomes with ibritumomab tiuxetan consolidation than with induction alone, it remains uncertain whether the duration of remission and PFS are longer if postremission therapy uses rituximab maintenance or ibritumomab consolidation and whether different patient subsets (e.g., rituximab-naive patients vs those induced with a regimen that included rituximab, or those with CR vs PR) might benefit more from one of these alternatives than the other.

CONSOLIDATION THERAPY AFTER REMISSION FOR DIFFUSE LARGE B-CELL OR MANTLE CELL NHL
In contrast with follicular NHL,17 RCT evidence is lacking on outcomes for ibritumomab tiuxetan to consolidate CR or PR 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 reviewed3,22 and are limited to uncontrolled single-arm studies of ibritumomab to consolidate first or subsequent remissions in patients with DLBCL or with mantle cell lymphoma. Several studies from 2007 to 2010 focused on elderly patients ineligible for stem cell transplantation as postremission therapy.23-25 However, small samples and lack of data for direct comparison with outcomes of alternatives in similar patients preclude firm conclusions. 

Hohloch et al. (2014) reported on 215 patients enrolled in an international RIT registry who had DLBCL and received RIT, primarily ibritumomab tiuxetan.26 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. Most patients received ibritumomab as consolidation therapy after rituximab-containing first-line therapy (26%). At a median follow-up of 11.5 months, 1- and 2-year PFS rates were 60% and 49%, respectively, and 1- and 2-year OS rates were 69% and 56%, respectively, for the entire cohort. In patients receiving ibritumomab in first-line therapy, 2-year PFS and OS rates were 55% and 74%, respectively. 

Persky et al. (2015) in the SWOG S0313 used ibritumomab tiuxetan consolidation therapy in 46 patients with early-stage, high-risk, aggressive B-cell NHL (96% DLBCL) who received 3 cycles of CHOP plus involved field radiotherapy.27 Investigators used CHOP instead of R-CHOP due to data from previous studies that indicated rituximab might interfere with ibritumomab consolidation. At a median follow-up of 7.3 years, estimated 2-, 5-, and 7-year PFS rates were 89%, 82%, and 75%, respectively. Estimated 2-, 5-, and 7-year OS rates were 91%, 87%, and 82%, respectively. Results were slightly better than a previous SWOG study in similar patients who received R-CHOP plus involved field radiotherapy without ibritumomab tiuxetan consolidation (5-year PFS, 78%; 5-year OS, 83%). No unexpected toxicities were observed; 2 (4%) patients discontinued treatment due to adverse events. An ongoing trial is testing RCHOP plus involved field radiotherapy followed by ibritumomab consolidation in early-stage DLBCL (NCT01359592). 

Witzig et al. (2015) in the Eastern Cooperative Oncology Group administered ibritumomab tiuxetan to 53 patients with early-stage (stage I with high-risk features or stage II) DLBCL who achieved positron emission tomography-negative CR (confirmed or unconfirmed) or PR after receiving first-line R-CHOP chemotherapy with or without external-beam radiotherapy.28 High-risk features were age greater than 60 years, bulky disease, elevated lactate dehydrogenase, or an Eastern Cooperative Oncology Group Performance Status of 2. Ibritumomab tiuxetan was delivered 3 to 12 weeks after the last dose of R-CHOP. Ninety-seven percent of patients received 4 to 6 cycles of R-CHOP based on restaging computed tomography; 79% of patients achieved CR, and 19% achieved PR. Forty-eight (91%) patients proceeded to consolidation with ibritumomab; of 5 patients who withdrew, two had achieved CR, two had achieved PR, and 1 was not evaluable. After consolidation, 34 (97%) of 35 patients in CR maintained CR; 4 (80%) of 5 patients with unconfirmed CR converted to CR; 4 (50%) of 8 patients in PR converted to CR or unconfirmed CR. Of the remaining 4 patients in PR after R-CHOP, three maintained PR and one progressed on ibritumomab. ORR for all patients, including those who did not receive ibritumomab, was 89%. At a median follow-up of 5.9 years, the estimated 5-year PFS rate was 78% (95% CI, 66 to 92), and the 5-year OS rate was 94% (95% CI, 88 to 100). The median PFS and OS were not reached. Reversible myelosuppression was the only toxicity observed during the post-ibritumomab period. Whether ibritumomab adds survival benefit over R-CHOP alone cannot be determined from this study. An RCT is required to evaluate further ibritumomab consolidation after R-CHOP induction in patients with early-stage DLBCL. 

Smith et al. (2012) prospectively treated 56 patients with mantle cell lymphoma using an abbreviated 4-cycle regimen of R-CHOP every 3 weeks followed by ibritumomab consolidation using ibritumomab tiuxetan and compared outcomes with historical controls reported in previous studies.29 Time-to-treatment failure reported by Smith et al. compared favorably with PFS reported in earlier studies that used 6 cycles of R-CHOP without any postremission therapy. However, data from a 2011 abstract30 cited by Smith et al. (subsequently published in 201231) raised the possibility that median PFS duration for patients with mantle cell lymphoma may be substantially longer with rituximab maintenance (56 months) than time-to-treatment failure (34 months) after ibritumomab consolidation as postremission therapy. Thus, direct comparative studies are needed. 

Section Summary: Consolidation Therapy After Remission for Diffuse Large B-Cell or Mantle Cell NHL
RCT evidence is lacking on outcomes for ibritumomab tiuxetan to consolidate CR or PR following chemotherapy in patients with DLBCL or mantle cell lymphoma. The evidence is limited to uncontrolled single-arm studies of ibritumomab tiuxetan to consolidate first or subsequent remissions. Several studies from 2007 to 2010 focused on elderly patients ineligible for stem cell transplantation as postremission therapy. These studies have shown 5-year OS estimates ranging from 83% to 94%. However, whether ibritumomab tiuxetan adds survival benefit over current standard rituximab-containing chemotherapy regimens cannot be determined from these studies. Further, the small samples and lack of data for direct comparison with outcomes of alternatives in similar patients preclude firm conclusions.

AS A CONDITIONING REGIMEN BEFORE HEMATOPOIETIC CELL TRANSPLANTATION
High-dose chemotherapy (HDC) with autologous hematopoietic cell transplantation (HCT) in eligible patients with chemotherapy-sensitive, relapsed NHL, leads to prolonged PFS, although some patients eventually relapse. Also, while HCT has modest success in chemotherapy-refractory disease, because of its highly toxic nature, it is unsuitable for elderly patients.32 Therefore, there is interest in evaluating new preparative regimens with less toxicity than current regimens to improve outcomes with HCT in NHL.  

Review articles have summarized evidence from studies on RIT in the setting of autologous or allogeneic (allo-) HCT (1) as high-dose myeloablative RIT with or without chemotherapy, (2) as standard-dose nonmyeloablative RIT in combination with HDC, or (3) as part of a reduced intensity conditioning (RIC) regimen for allo-HCT.3,32

Autologous HCT
Several studies have suggested that incorporating RIT into a 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 months),33 55% at 38 months (range, 27-60 months),34 and 73% at 60 months,35 compared with historical controls who had chemotherapy-refractory disease and estimated 3-year survival rates of less than 20% with standard HDC and autologous HCT.32 

A small 2012 RCT compared carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with (n=22) and without (n=21) ibritumomab tiuxetan as the conditioning regimen before autologous HCT for refractory or relapsed DLBCL or transformed follicular lymphoma.36 Results at 2 years after HCT suggested that PFS (59% vs 37%; p=0.2) and OS (91% vs 62%; p=0.05) might be greater after BEAM plus  ibritumomab than after BEAM alone. However, between-arm differences were not statistically significant for either efficacy outcome, possibly because of the small sample size. Investigators also reported no major between-arm differences in toxicity profiles.  

Two 2012 nonrandomized studies also directly compared outcomes of preparative regimens that did or did not include ibritumomab tiuxetan before autologous HCT. A retrospective matched cohort analysis compared results for patients conditioned with BEAM plus ibritumomab tiuxetan (n=46) with results for an equivalent number of similar patients conditioned with BEAM plus total body irradiation (TBI).37 OS at 4 years (81% vs 53%; p=0.01) was superior with BEAM plus ibritumomab, although the 4-year cumulative incidence of relapse or progression did not differ significantly between regimens (40% for BEAM plus ibritumomab vs 42% for BEAM plus TBI; p=0.6). Nonrelapse mortality at 4 years was superior in the BEAM plus ibritumomab group (0% vs 16%; p<0.01), and nonlethal toxicity was also more common with BEAM plus TBI. However, these results may not apply to preparative regimens without TBI. 

A second retrospective study compared ibritumomab plus busulfan, cyclophosphamide, and etoposide (BuCyE) with BuCyE alone (19 patients per group) followed by autologous HCT for patients with relapsed or refractory B-cell NHL.38 Investigators reported no statistically significant differences between groups on OS, toxicity, or treatment-related mortality. The difference in median event-free survival (12.5 months for ibritumomab 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 HCT reported since the 2011 update are phase 2 studies that lack controls for comparison. They include: 

  • A 2011 study (N=11) of ibritumomab followed by HDC and autologous HCT for consolidation of a first remission after R-CHOP in patients with DLBCL39;
  • A 2011 study (N=7) of ibritumomab to consolidate PR after HDC plus autologous HCT40
  • A 2014 study (N=30) of ibritumomab tiuxetan plus high-dose BEAM followed by autologous HCT in patients with refractory de novo (n=22) or transformed (n=8) DLBCL.41 

In 2014, Kolstad et al. in reported on 160 Scandinavian patients with untreated, stage II, III, or IV mantle cell lymphoma who received high-dose BEAM conditioning before autologous HCT.42 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 when assessing similar patients who did not receive ibritumomab tiuxetan. 

A 2014 meta-analysis43 of ibritumomab tiuxetan-BEAM conditioning regimens included 2 of the studies previously described36,37 along with 8 other single-arm studies presented primarily in abstract form (total N=328 patients). Pooled 2-year OS and PFS rates were 85% (n=328; I2=57%) and 67% (n=285; I2 =24%), respectively. 

Subsection Summary: Autologous HCT
The evidence for incorporating ibritumomab tiuxetan as part of the conditioning regimen before autologous HCT includes an RCT, multiple retrospective observational studies, and a meta-analysis. The RCT failed to show a statistically significant difference in PFS or OS between patients who received ibritumomab tiuxetan as part of conditioning regimen and those who did not in in an accounting of patients with refractory or relapsed DLBCL or transformed follicular lymphoma. One of the 2 retrospective studies showed a superior OS at 4 years, although the 4-year cumulative incidence of relapse or progression did not differ. The second retrospective study failed to show any difference between groups for OS or treatment-related mortality. Taken together, the available data are insufficient to determine whether inclusion of ibritumomab tiuxetan in preparative regimens is superior to alternative regimens for conditioning before autologous HCT. 

Allo-HCT
Preliminary data suggest that RIT in combination with RIC allo-HCT may improve clinical outcomes with better disease eradication and decreased disease recurrence, while maintaining the low toxicity of RIC.32 A small 2008 pilot study evaluated 12 patients with chemotherapy-refractory NHL treated with a fludarabine-based regimen in combination with ibritumomab tiuxetan.44 Median patient age was 54 years (range, 37-62 years). Eighty-three percent of patients achieved a PR or CR, and at a median follow-up of 21 months, actuarial 2-year PFS and OS rates were both 33% (95% CI, 7% to 60%). Three patients relapsed (2-year cumulative incidence of relapse, 25%; 95% CI, 9% to 67%). 

Bethge et al. (2010) reported the results of a multicenter phase 2 study of 40 patients who received ibritumomab tiuxetan with RIC followed by allo-HCT.45 Patients had either relapsed or refractory disease (n=28) and/or relapse after a preceding autologous HCT (n=22). Lymphoma diagnoses were follicular lymphoma (n=17), chronic lymphocytic leukemia (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 rates were 51% for all patients, 67% for follicular lymphoma, 49% for chronic lymphocytic leukemia, and 37% for mantle cell lymphoma. 

Our 2012 literature search identified 4 reports on RIT for conditioning before allo-HCT, but no published RCTs. Gopal et al. (2011) studied the addition of ibritumomab tiuxetan to a nonmyeloablative regimen of fludarabine plus TBI (n=40) in heavily pretreated (median, 6 previous regimens; range, 3-12) and mostly chemoresistant (85%) patients with a mix of indolent, transformed, and de novo intermediate or aggressive NHL.46 At 30 months, estimated OS, PFS, and nonrelapse mortality rates were 54%, 31%, and 16%, respectively. Abou-Nassar et al. (2011) retrospectively analyzed heavily pretreated (median, 5; range, 2-10 previous 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 allo-HCT.47 At 2 years, estimated OS, PFS, and nonrelapse mortality rates were 83%, 74%, and 18%, respectively. Khouri et al. (2012) 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 allo-HCT.48 OS and PFS rates at 3 years were estimated separately for the chemosensitive (94% and 87%, respectively) and chemoresistant (80% for each outcome) subgroups. These outcomes did not differ statistically significantly 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 as nonmyeloablative conditioning for an allo-HCT (OS, 85%; PFS, 83%). Treatment-related mortality rates at 100 days and 1 year were 4% and 8%, respectively, in the90 YFC group and 2% and 13%, respectively, in the fludarabine, cyclophosphamide, and rituximab group. Finally, Bethge et al. (2012) reported on 20 high-risk patients with various subtypes of relapsed or refractory B-cell NHL (including DLBCL, transformed chronic lymphocytic leukemia, mantle cell lymphoma, advanced follicular lymphoma) treated with escalated doses of ibritumomab tiuxetan (10 each at 22 and 30 MBq/kg dose levels) plus RIC using fludarabine, melphalan, and alemtuzumab for conditioning before allo-HCT.49 They reported no toxicities directly related to the escalated doses of RIT, 30% cumulative incidence of nonrelapse mortality, and an estimated 20% for both OS and event-free survival at 3 years. 

In France in 2015, Bouabdallah et al. 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 chemotherapy regimens with or without autologous HCT [33%]).50 The median number of previous treatments was 3 (range, 2-4), all patients had received rituximab previously, and almost all patients (97%) had received autologous HCT. Patients received fludarabine-based RIC with ibritumomab tiuxetan followed by allo-HCT (67% matched related; 27% matched unrelated). By day 30, all patients experienced a sustained engraftment. At a median follow-up of 32 months (range, 29-60 months), 2-year event-free and OS were both 80%. Sixteen patients experienced grade I, II, III, or 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 (73%) patients had grade 4 thrombocytopenia (median days to recovery, 11 [range, 6-16]).

Subsection Summary: Allo-HCT
The evidence for incorporating ibritumomab tiuxetan as part of the conditioning regimen before allo-HCT includes multiple retrospective observational studies. Data from these preliminary studies have suggested a role for conditioning regimens with ibritumomab tiuxetan, particularly in patients who were unable to tolerate potentially curative HDC and/or TBI because of the risk of excessive treatment-related mortality and morbidity. However, RCTs comparing the efficacy and safety of ibritumomab tiuxetan conditioning regimens are required. 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 ibritumomab tiuxetan.

SUMMARY OF EVIDENCE
For individuals with relapsed or refractory low-grade or follicular B-cell non-Hodgkin lymphomas (NHL) who receive ibritumomab tiuxetan, the evidence includes a randomized controlled trial (RCT) and 2 single-arm studies. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. The RCT showed that ibritumomab tiuxetan resulted in a significantly higher overall response rate of 80% compared with 56% with rituximab alone. Single-arm trials have also demonstrated response rates of 74% to 89% in previously treated disease. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who receive initial treatment of follicular B-cell NHL who receive ibritumomab tiuxetan, the evidence includes 3 single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. The 3 studies have reported high overall response rates ranging from 87% to 94%. However, the median progression-free survival was less than that observed with first-line chemotherapy regimens plus rituximab in other studies. Although RCTs are needed, the current evidence has suggested that ibritumomab may be of clinical value as an initial treatment of indolent NHL, particularly in older, frail patients and that it provides long remissions and results equivalent to multicycle rituximab and chemotherapy combinations. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with untreated follicular B-cell NHL who receive ibritumomab tiuxetan as consolidation treatment after remission, the evidence includes a pivotal RCT, a meta-analysis, and 2 single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. The pivotal RCT demonstrated that consolidation with ibritumomab tiuxetan significantly prolonged median progression-free survival by 23.2 months regardless of partial or complete response after a median follow-up of 3.5 years. The number of  patients who died was too small to permit a reliable comparison of survival. Results of the single-arm studies and meta-analysis were directionally consistent with the progression-free survival benefit. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with diffuse large B-cell or mantle cell NHL who receive ibritumomab tiuxetan as consolidation treatment after remission, the evidence includes multiple single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. Several studies, published from 2007 to 2010, have focused on elderly patients ineligible for stem cell transplantation as postremission therapy. These studies have shown 5-year OS estimates ranging from 83% to 94%. However, whether ibritumomab tiuxetan adds survival benefit over current standard rituximab-containing chemotherapy regimens cannot be determined from these studies. Further, the small samples and lack of data for direct comparison with outcomes of alternative treatments in similar patients preclude firm conclusions. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals with chemotherapy-sensitive, relapsed NHL who require hematopoietic cell transplantation and who receive ibritumomab tiuxetan as part of the conditioning regimen, the evidence includes small cohort studies or case series with heterogeneous patient populations and a meta-analysis. Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events, quality of life, and treatment-related mortality and morbidity. Data are promising but evolving; preliminary data have suggested there may be a role for ibritumomab tiuxetan, particularly in patients unable to tolerate potentially curative high-dose chemotherapy and/or total body irradiation because of the risk of excessive treatment-related mortality and morbidity. However, currently, the available data do not support the superiority of conditioning regimens containing ibritumomab tiuxetan over alternative conditioning regimens before hematopoietic cell transplant. RCTs comparing the efficacy and safety of conditioning regimens containing ibritumomab tiuxetan are required. The evidence is insufficient to determine the effects of the technology on health outcomes.

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
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.

2014 Input
In response to requests, input was received from 2 physician specialty societies, 1 academic medical center, and 3 Blue Distinction Centers for Transplant when this policy was under review in 2014. Reviewers unanimously agreed that tositumomab and ibritumomab tiuxetan were investigational as part of a preparatory regimen before autologous or allogeneic hematopoietic cell transplantation in patients with non-Hodgkin lymphoma (NHL).

2010 Input
In response to requests, input was received from 1 specialty medical society and 1 academic medical center and while this policy was under review in 2010. Both reviewers agreed that tositumomab was medically necessary for relapsed or rituximab-refractory follicular lymphoma and that use of ibritumomab tiuxetan would be medically necessary for relapsed or refractory NHL, although 1 reviewer questioned the use of ibritumomab tiuxetan in lymphoma transformed to diffuse large B-cell lymphoma. Both reviewers indicated that there is a role for radioimmunotherapy in the initial treatment of indolent NHL, particularly in older, frail patients, and that it provides long remissions and results equivalent to multicycle rituximab and chemotherapy combinations. Both reviewers indicated that radioimmunotherapy is medically necessary as consolidation therapy, and both agreed that conditioning regimens play a beneficial role before hematopoietic cell transplantation.

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network practice guidelines (v.3.2017)51 make the following recommendations for radioimmunotherapy (RIT) in non-Hodgkin lymphoma (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)
    • As first-line consolidation after induction with chemotherapy or chemoimmunotherapy (category 2B)
  • 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
    • RIT (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).

National Comprehensive Cancer Network guidelines do not list RIT among its recommended primary or secondary treatments for any other type of B-cell NHL(e.g., de novo diffuse large B-cell or mantle cell lymphomas).51

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials
NCT No. Trial Name Planned Enrollment Completion Date
Ongoing

NCT01827605

A Phase III Multicenter, Randomized Study Comparing Consolidation With 90yttrium-Labeled Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy Versus Autologous Stem Cell Transplantation (ASCT) in Patients With Relapsed Follicular Lymphoma (FL)

265

Jan 2018

NCT02063685

A Multicenter, Phase III, Randomized Study to Evaluate the Efficacy of Response-adapted Strategy to Define Maintenance After Standard Chemoimmunotherapy in Patients With Advanced-stage Follicular Lymphoma

602

Jul 2019

NCT02320292 

The Asymptomatic Follicular Lymphoma (AFL) Trial: A Phase III Study of Single-Agent Rituximab Immunotherapy Versus Zevalin Radioimmunotherapy for Patients With New, Untreated Follicular Lymphoma Who Are Candidates for Observation 

128  Jan 2026 

NCT:  national clinical trial. 

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Coding Section 

Codes Number Description
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 Procedure 92.28

Injection or instillation 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 10/01/15) C82.00-C82.99

Follicular lymphoma, code range

  C85.10-C85.99

Other and unspecified types of non-Hodgkin lymphoma

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

Type of Service    
Place of Service    

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

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

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

History From 2013 Forward     

08/07/2019 

Annual review, no change to policy intent. 

08/07/2018 

Annual review, no change to policy intent. 

08/10/2017 

Annual review, no change to policy intent. Updating description, rationale and references.

08/08/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

07/11/2016 

Updated Review date to reflect August review date 

08/06/2015 

Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references. Added coding and related policies.

 07/07/2014

 Updated description, background, FDA status, rationale and references. Policy being updated to remove the use of Bexxar/tositumomab. Changed review due date.

12/02/2013

Annual review, updated rationale and references. Policy verbiage change to include: radioimmunotherapy with tositumomab or ibritumomab for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL is considered investigational. Add Benefit applications.  


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