Effective on or after May 1, 2015,, refer to: Blue Cross and Blue Shield of Alabama Radiation Therapy Management RTM Policies

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1 Effective on or after May 1, 2015,, refer to: Blue Cross and Blue Shield of Alabama Radiation Therapy Management RTM Policies Name of Policy: Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma Policy #: 463 Latest Review Date: September 2014 Category: Medical Policy Grade: B Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage: 1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting. Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are: 1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient s illness, injury or disease. Page 1 of 19

2 Description of Procedure or Service: Radioimmunotherapy (RIT) involves the administration of an antibody linked to a radioisotope, targeted to a specific cell type. Ibritumomab (Zevalin ) and tositumomab (Bexxar ) are radioimmunoconjugate 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, 0 Y-ibritumomab tiuxetan uses a monoclonal anti-cd20 antibody to deliver beta-emitting yttrium-90 and 131 I- tositumomab is an iodine-131-loaded antibody. Radioimmunotherapy offers several advantages over external-beam irradiation in the treatment of NHL, a relatively radiosensitive disease. 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-antigenexpressing 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 seven to ten 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 pre-targeting strategies to minimize toxicity and the simultaneous targeting of multiple B-cell antigens. Policy: Effective for dates of service on or after May 1, 2015 refer to Blue Cross and Blue Shield of Alabama Radiation Therapy Management RTM Policies Effective for dates of service on or after October 28, 2014 and prior to May 1, 2015: A single course of ibritumomab tiuxetan (Zevalin ) meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the treatment of: Page 2 of 19

3 relapsed or refractory CD-20-positive low-grade or follicular, or transformed B-cell non-hodgkin lymphoma, including patients with rituximab refractory follicular non- Hodgkin lymphoma*; The use of ibritumomab tiuxetan (Zevalin ) for the initial treatment of follicular lymphoma meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage 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 in non- Hodgkin lymphoma patients who achieve a partial or complete response meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage. The use of radioimmunotherapy with ibritumomab tiuxetan (Zevalin ) for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. The use of tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation in patients with non-hodgkin lymphoma does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. *Indicates FDA labeled indication Effective for dates of service on or after April 29, 2014 and prior to October 28, 2014: 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 Blue Cross and Blue Shield of Alabama s medical criteria for coverage.* 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 Blue Cross and Blue Shield of Alabama s medical criteria for coverage.* The use of tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) for the initial treatment of follicular lymphoma meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage 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 Blue Cross and Blue Shield of Alabama s medical criteria for coverage. Page 3 of 19

4 The use of radioimmunotherapy with tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. The use of tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation in patients with non-hodgkin lymphoma does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. *Indicates FDA labeled indication Effective for dates of service prior to April 29, 2014: 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 Blue Cross and Blue Shield of Alabama s medical criteria for coverage.* 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 Blue Cross and Blue Shield of Alabama s medical criteria for coverage.* The use of tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) for the initial treatment of follicular lymphoma meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage 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 Blue Cross and Blue Shield of Alabama s medical criteria for coverage. The use of tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) as part of a preparatory regimen prior to hematopoietic stem-cell transplantation in patients with non-hodgkin lymphoma does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. *Indicates FDA labeled indication Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the member s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Page 4 of 19

5 Key Points: Relapsed/Refractory Low-Grade or Transformed Non-Hodgkin Lymphoma (NHL) Ibritumomab Tiuxetan Three studies led to FDA approval of ibritumomab tiuxetan (Zevalin ). Study one was a single-arm study with 54 patients with relapsed follicular lymphoma refractory to rituximab. 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 six 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 to 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 two 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 NHL. Patients either received a single dose of ibritumomab (n=73) after pretreatment with two doses of rituximab, or rituximab weekly for four 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 three 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% confidence interval [CI]: 48 to 85%) and 11.8 months median DR (range: 4 to 17 months). Tositumomab Two studies led to FDA approval of tositumomab (Bexxar ). A prospective, multicenter Phase II study evaluated 131 I-tositumomab in 40 patients with indolent, follicular large-cell or transformed B-cell lymphoma with progressive disease after rituximab. Thirty-five patients were rituximab non-responders or had a less than six-month response, and five had a rituximab response (i.e., longer than sox months). The median number of prior chemotherapy regimens per patient was four (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 three-year PFS of 73%. At the time of publication, 12 patients continued in response (11 CR, 1 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. Patients who had been treated with at least two Page 5 of 19

6 chemotherapy regimens without response or who had progressed within six months after their last regimen were given a single course of I-131 tositumomab. Patients had received a median of four prior chemotherapy regimens. A CR or PR was observed in 65% of patients with tositumomab versus 28% after their last chemotherapy regimen (p less than 0.001). Median DR was 6.5 months with tositumomab versus 3.4 months with the last chemotherapy regimen (p less than 0.001). Three percent of patients had a CR after last chemotherapy versus 20% after tositumomab (p less than 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 three single-arm studies, with a total of 130 patients. In these studies, patients with rituximabnaive follicular NHL 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 (as in studies one and two), the 95% CIs for the median durations of response were wide. Initial Therapy of Low-Grade Non-Hodgkin Lymphoma Tositumomab 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 Patients received as initial therapy a single course of treatment with 131 I-tositumomab. Median patient age was 49 years (range: 23 to 69), and the median time from the diagnosis of lymphoma to treatment was eight 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 to 71) and, for patients who achieved a CR, five-year PFS was 77% (95% CI: 67 to 89). Seventy percent of the patients who had a CR remained in CR for 4.3 to 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. Ibritumomab Scholz et al 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. Patients received rituximab plus a single dose of 90 Y-ibritumomab tiuxetan. At six months after treatment, ORR was 87% (56% confirmed or unconfirmed CR plus 31% PR). Thirteen patients were positive for the t-translocation before treatment and obtained a CR; of these, eleven 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 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 >34 months in other studies). Grade 3 or higher thrombocytopenia Page 6 of 19

7 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. 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 three-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 two doses of ibritumomab tiuxetan to 74 patients in several centers across Europe. 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 three 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 three-year PFS and OS were 58% and 95%, respectively. Grade 3-4 thrombocytopenia and neutropenia occurred in 56% and 36% of patients, respectively. Consolidation Therapy for Follicular or Other Indolent CD20-positive B-cell NHL in Remission Published reviews from 2009 and 2011 summarized data on the use of radioimmunotherapy (RIT) as consolidation therapy for follicular NHL in CR or PR after induction chemotherapy with or without rituximab. Although available evidence showed 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-naïve patients vs those induced with a regimen that included rituximab, or those in a CR vs PR) might benefit more from one of these alternatives than the other. In 2005, Leonard et al reported on the safety and efficacy of a regimen of three cycles of fludarabine followed by consolidation with 131 I-tositumomab in patients with previously untreated follicular lymphoma. The study was an open-label, prospective, Phase 2 study conducted between August 1998 and June Median patient age was 49 years (range, 25-82). Thirty-eight patients were enrolled, and 35 (92%) completed both fludarabine and 131 I- tositumomab therapy and were assessable for response. After three 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 131 I-tositumomab, the response rate was 100% with 86% CR. After a median follow-up of 58 months, median PFS had not been reached (95% CI, 27 months to not reached). Five-year estimated PFS was 60%. Page 7 of 19

8 Press et al reported the results of a Phase 2 trial conducted from 1999 to 2000, assessing the efficacy of consolidation therapy with 131 I-tositumomab after six cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) chemotherapy in 90 patients with previously untreated advanced-stage follicular lymphoma.(19) Median patient age was 50 years (range, 23-84). Eighty-four patients had sufficient documentation available to assess response, 98% of whom had objective remissions, including 74% with CR and 24% with PR. 131 I-tositumomab improved the CR rate from 39% after six cycles of CHOP to 69%. After a median follow-up of 5.1 years, estimated five-year OS was 87% and PFS was 67%. Five-year OS and PFS each were 23% better (absolute difference) than the corresponding figures for patients previously treated on Southwest Oncology Group (SWOG) protocols with CHOP only. Jacobs et al reported the results of a Phase 2, 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 Patients received three cycles of CHOP-rituximab (CHOP-R), followed by consolidation with ibritumomab tiuxetan (RIT) and then extended rituximab consisting of four 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, ). For 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, two-year PFS and OS were 78.4% and 100%, respectively. A 2008 Phase 3, randomized, international trial of 414 patients from 77 centers investigated the use of ibritumomab tiuxetan in advanced follicular lymphoma in first remission. 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 wellbalanced between the two 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 regardless of whether patients achieved PR (29.3 vs 6.2 months, respectively; HR=0.30; p<0.001) or CR (53.9 vs 29.5 months, respectively; HR=0.61; p=0.154). After ibritumomab tiuxetan consolidation, 77% of patients in PR after induction therapy converted to CR, for a final CR rate of 87%. The trial had some weaknesses, including the multiplicity of induction regimens across patients, and with relatively short follow-up, no OS difference was observed between the two groups. In addition, administration of rituximab with each induction cycle has become the usual treatment of follicular lymphoma, but only 15% of patients in the 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. A 2010 multicenter Phase II study with eight-year follow-up data assessed the safety and efficacy of a first-line combination of cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy and radioimmunotherapy. The study included 30 patients from three 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 six cycles of CVP and then Page 8 of 19

9 one cycle of radioimmunotherapy (tositumomab and 131 I-tositumomab [Bexxar]) was initiated with 56 days after day one 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 six cycles of CVP, the complete remission (CR) rate was 53%. After completion of radioimmunotherapy, the ORR was 100%, and the CR rate was 93%. Median duration of response was not reached (range: months). Progression-free survival at two and five years was 76% and 56%, respectively, and two- and five-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 eight 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 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). Pooled CR and ORRs were 96% and 83%, respectively. Pooled PFS at two and five years was 77% and 58%, respectively, and pooled OS at two and five years was 94% and 90%, respectively. The meta-analysis had several limitations: 1) Statistical heterogeneity was significant for all outcomes except two-year OS; 2) included studies varied in design, patient characteristics (e.g., sex distribution, lymphoma grade, presence of bulky disease, baseline serum lactate dehydrogenase), induction chemotherapy regimen, and radioimmunotherapy consolidation therapy (i.e., both ibritumomab tiuxetan and tositumomab were used); 3) median patient age (range, 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 (four cycles) and CHOP (two cycles). 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 3-4 thrombocytopenia and neutropenia occurred in 46% and 56% of patients, respectively. Consolidation Therapy for Aggressive CD20-positive B-cell NHL in Remission In contrast with follicular NHL, 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 and are limited to uncontrolled singlearm studies of RIT to consolidate first or subsequent remissions in patients with DLBCL or with mantle-cell lymphoma. Several studies 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 prospectively treated 56 patients with mantle-cell lymphoma using an abbreviated four-cycle regimen of R-CHOP every Page 9 of 19

10 three 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 six cycles of R-CHOP without any post-remission therapy. However, data from an as-yet unpublished abstract cited by Smith et al (subsequently published in 2012) raises 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. As Part of a Preparatory 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. 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). Autologous transplants 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 chemotherapyrefractory disease have demonstrated OS rates of 87% at 30 months (range: 22 to 48 months), 55% at 38 months (range: 27 to 60 months) and 73% at 60 months, as compared to historical controls with chemotherapy-refractory disease with an estimated three-year survival rate of less than 20% with standard high-dose chemotherapy and autologous HSCT. A recent small 2012 RCT compared BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) with (n=22) versus without (n=21) ibritumomab tiuxetan as the conditioning regimen prior to autologous HSCT for refractory or relapsed DLBCL or transformed follicular lymphoma. Results at two 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 2012 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 Page 10 of 19

11 (TBI). Overall survival at four years (81% vs. 53%; p=0.01) was superior with BEAM plus RIT, although the four-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 four 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. Investigators reported no statistically significant differences between groups with respect to overall survival, toxicity, or treatmentrelated 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; another (n=7) of RIT to consolidate partial remissions after high-dose chemotherapy plus autologous HSCT; 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. 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 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. A small pilot trial evaluated 12 patients with chemotherapy-refractory NHL treated with a fludarabinebased regimen in combination with 90 Y-ibritumomab tiuxetan. Median patient age was 54 years (37 to 62 years). Eighty-three percent of patients achieved a partial or complete remission, and at a median follow-up of 21 months, the actuarial two-year PFS and OS were 33% (95% CI: 7-60%). Three patients relapsed (two-year cumulative incidence of relapse was 25% [95% CI: 9-67%]). Bethge et al report the results of a multicenter Phase II trial of 40 patients who received radioimmunotherapy using yttrium-90-ibritumomab-tiuxetan with RIC followed by allogeneic HSCT. 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 to 68 years). Two-year OS for all patients was 51%, 67% for follicular lymphoma, 49% for CLL and 37% for mantle cell lymphoma patients. Page 11 of 19

12 The 2012 literature search identified four new reports on RIT for conditioning prior to allogeneic HSCT, but no published RCTs. Gopal et al 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 to 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 reported a retrospective analysis on heavily pretreated (median 5, range 2 to 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 two years, estimated OS, PFS, and non-relapse mortality were 83%, 74%, and 18%, respectively. Khouri et al reported on 26 prospectively-treated patients with follicular NHL (38% chemoresistant) treated with ibritumomab tiuxetan followed by fludarabine and cyclophosphamide ( 90 YFC) as nonmyeloablative conditioning for allogeneic HSCT. OS and PFS at three 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 three 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 90 YFC group and 2% and 13%, respectively, in the FCR group. Finally, Bethge et al 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 (ten 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. National Comprehensive Cancer Network (NCCN) Guidelines NCCN practice guidelines (V ) recommend radioimmunotherapy for: 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) 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). Page 12 of 19

13 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). 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). Summary 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 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 treatmentrelated morbidity and mortality. A Phase III trial is underway examining the role of radioimmunotherapy in autologous HSCT in patients with relapsed or aggressive lymphoma. Key Words: Radiolabeled monoclonal antibody therapy, non-hodgkin lymphoma, Bexxar, tositumomab, ibritumomab tiuxetan, Zevalin Approved by Governing Bodies: 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 March 2008, the indication for transformed B-cell NHL was removed. In September 2009, the FDA approved ibritumomab (Zevalin ) for consolidation therapy in previously untreated follicular lymphoma in patients Page 13 of 19

14 who achieve a partial or complete response 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. Tositumomab (Bexxar ) was granted approval by the FDA in June 2003 for rituximabrefractory follicular NHL. On February 20, 2014, GlaxoSmithKline discontinued the manufacture and sale of tositumomab (Bexxar ). Benefit Application: Coverage is subject to member s specific benefits. Group specific policy will supersede this policy when applicable. ITS: Home Policy provisions apply FEP: Special benefit consideration may apply. Refer to member s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Current Coding: CPT Codes: HCPCS Codes: Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous administration A9543 Yttrium Y-90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40 millicuries A9545 Iodine I-131 tositumomab, therapeutic, per treatment dose References: 1. Abou-Nassar KE, Stevenson KE, Antin JH et al. (90)Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo-sct in patients with advanced follicular lymphoma. Bone Marrow Transplant 2011; 46(12): Bethge WA, von Harsdorf S, Bornhauser M et al. Dose-escalated radioimmunotherapy as part of reduced intensity conditioning for allogeneic transplantation in patients with advanced high-grade non-hodgkin lymphoma. Bone Marrow Transplant 2012; 47(11): Bethge W, Lange T, Meisner C et al. Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-hodgkin lymphoma: results of a phase 2 study. Blood 2010;116(10): Briones J, Novelli S, Garcia-Marco JA et al. 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): Cell Therapeutics, Inc. Zevalin (ibritumomab tiuxetan) prescribing information Available online at: Last accessed October Page 14 of 19

15 6. Devizzi L, Guidetti A, Seregni E et al. 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): Devizzi IL, Guidetti A, Tarella C et al. 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): Emmanouilides C. Radioimmunotherapy for non-hodgkin lymphoma: historical perspective and current status. J Clin Exp Hematopathol 2007; 47(2): Emmanouilides C. Review of Y-ibritumomab tiuxetan as first-line consolidation radioimmunotherapy for B-cell follicular non-hodgkin s lymphoma. Cancer Manag Res 2009; 1: Forstpointner R, Dreyling M. Rituximab maintenance versus radioimmunotherapy consolidation in follicular lymphoma: which, when, and for whom? Curr Hematol Malig Rep 2011; 6(4): Gisselbrecht C, Vose J, Nademanee A et al. ituximab notherapy for stem cell transplantation in non-hodgkin s lymphoma: in pursuit of a complete response. Oncologist 2009; 14(suppl 2): GlaxoSmithKline. Press release archive. GSK to discontinue manufacture and sale of the Bexxar therapeutic regimen (tositumomab and iodine I-131 tositumomab) August Available online at: us.gsk.com/html/media-news/pressreleases/2013/gsk-to-discontinuemanufacture-and-sale-of-bexxar-therapeutic-regimen.html. Last accessed April GlaxoSmithKline. Bexxar (tositumomab and iodine I 131 tositumomab) injection for intravenous infusion prescribing information August Available online at: ovalhistory#labelinfo. Last accessed April GlaxoSmithKline. BEXXAR (tositumomab and Iodine I 131 tositumomab) prescribing information Available online at: us.gsk.com/products/assets/us_bexxar.pdf. Last accessed October, Gopal AK, Guthrie KA, Rajendran J et al. (9)(0)Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma. Blood 2011; 118(4): Han EJ, Lee SE, Kim SH et al. Clinical outcomes of post-remission therapy using (90)yttrium ibritumomab tiuxetan (ZevalinI) for high-risk patients with diffuse large B-cell lymphoma. Ann Hematol 2011; 90(9): Horning SJ, Younes A, Jain V et al. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 2005; 23(4): Ibatici A, Pica GM, Nati S et al. Safety and efficacy of (90) yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study. Br J Haematol 2014; 164(5): Illidge TM, Mayes S, Pettengell R et al. 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): Page 15 of 19

16 20. Jacobs SA, Swerdlow SH, Kant J et al. 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): Jo JC, Yoon DH, Kim S et al. Yttrium-90 ibritumomab tiuxetan plus busulfan, cyclophosphamide, and etoposide (BuCyE) versus BuCyE alone as a conditioning regimen for non-hodgkin lymphoma. Korean J Hematol 2012; 47(2): Kaminski MS, Zelenetz AD, Press OW et al. 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): Kaminski MS, Tuck M, Estes J et al. 131 I-Tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352(5): Khouri IF, Saliba RM, Erwin WD et al. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood 2012; 119(26): Kluin-Nelemans HC, Hoster E, Hermine O et al. Treatment of Older Patients with Mantle- Cell Lymphoma. N EnglJ Med 2012; 367(6): Kluin-Nelemans JC, Hoster E, Walewski J, et al. 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: abstracts.hematologylibrary.org/cgi/content/abstract/118/21/439?maxtoshow=&hits=10&r ESULTFORMAT=1&andorexacttitle=and&titleabstract=439&andorexacttitleabs=and&and orexactfulltext=and& ituxima=1&firstindex=0&sortspec=relevance&volume=118&t date=11/30/2012&resourcetype=hwcit. Last accessed April Krishnan A, Palmer JM, Tsai NC et al. Matched-cohort analysis of autologous hematopoietic cell transplantation with radioimmunotherapy versus total body irradiationbased conditioning for poor-risk diffuse large cell lymphoma. Biol Blood Marrow Transplant 2012; 18(3): 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): 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): Morschhauser F, Illidge T, Huglo D et al. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood 2007; 110(1): Morschhauser F, Radford J, Van Hoof A et al. 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): Morschhauser F, Dreyling M, Rohatiner A et al. 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): Page 16 of 19

17 33. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Non-Hodgkin s Lymphomas, V Available online at: Last accessed April Palanca-Wessels M, Press OW. Improving the efficacy of radioimmunotherapy for non- Hodgkin lymphomas. Cancer 2010; 116(4 Suppl): Press OW. Evidence mounts for the efficacy of radioimmunotherapy for B-cell lymphomas. J Clin Oncol 2008; 26(32): 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): Press OW, Unger JM, Rimsza LM et al. A phase III randomized intergroup trial (SWOG S0016) of CHOP chemotherapy plus ituximab vs. CHOP chemotherapy plus Iodine-131 tositumomab for the treatment of newly diagnosed follicular non-hodgkin s lymphoma. ASH Annual Meeting Abstracts 2011; 118(21): Provencio M, Cruz Mora MA, Gomez-Codina J et al. Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediateand 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): Ria R, Musto P, Reale A et al. 90Y-ibritumomab tiuxetan as consolidation therapy after autologous stem cell transplantation in aggressive non-hodgkin lymphoma. J Nucl Med 2011; 52(6): Rose AC, Shenoy PJ, Garrett G et al. A Systematic Literature Review and Meta-Analysis of Radioimmunotherapy Consolidation for Patients With Untreated Follicular Lymphoma. Clin Lymphoma Myeloma Leuk 2012; 12(6): Scholz CW, Pinto A, Linkesch W et al. 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): Shimoni A, Avivi I, Rowe JM et al. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer 2012; 118(19): Shimoni A, Zwas S, Oksman Y et al. 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): Smith MR, Li H, Gordon L et al. Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90- Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol 2012; 30(25): Spectrum Pharmaceuticals, Inc. Zevalin (ibritumomab tiuxetan) injection for intravenous use prescribing information August Available online at: Last accessed April Stevens PL, Oluwole O, Reddy N. Advances and application of radioimmunotherapy in non-hodgkin lymphoma. Am J Blood Res 2012; 2(2): Page 17 of 19

18 47. Tomblyn M. Radioimmunotherapy for B-cell non-hodgkin lymphomas. Cancer Control 2012; 19(3): Vose J, Bierman P, Enke C et al. 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): Vose JM, Bierman PJ, Loberiza FR et al. 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 Witzig TE, Flinn IW, Gordon LI et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-hodgkin s lymphoma. J Clin Oncol 2002; 20(15): Witzig TE, Gordon LI, Cabanillas F et al. 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): Zinzani PL, Rossi G, Franceschetti S et al. Phase II trial of short-course R-CHOP followed by 90Y-ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients. Clin Cancer Res 2010; 16(15): Zinzani PL, Tani M, Fanti S et al. A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B- cell lymphoma patients. Ann Oncol 2008; 19(4): Policy History: Medical Policy Panel, June 2010 Medical Policy Group, January 2011 (2) Medical Policy Administration Committee, February 2011 Available for comment February 9 March 25, 2011 Medical Policy Panel, August 2011 Medical Policy Group, September 2011 (2): Key Points, Reference updated Medical Policy Panel, December 2012 Medical Policy Group, March 2014 (3): 2012 Updates to Description, Key Points & References; policy statement updated to reflect The use of radioimmunotherapy with tositumomab (Bexxar ) or ibritumomab tiuxetan (Zevalin ) for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. Available for comment March 14 through April 28, 2014 Medical Policy Group, June 2014 (3): Updated policy with link to CareCore National medical policies effective August 1, 2014 Medical Policy Administration Committee, June 2014 Available for comment June 16 through July 31, 2014 Medical Policy Group, July 2014: Removed CareCore link. Transfer to CareCore is on hold until further notice. The policy has been returned to FINAL. Medical Policy Panel, May 2014 Medical Policy Group, September 2014 (3): 2014 Updates to Description, Key Points, Governing Bodies & References; policy statements updated to remove Bexxar and update FDA indications for Zevalin ; Bexxar is no longer being manufactured. Page 18 of 19

19 Medical Policy Administration Committee, September 2014 Medical Policy Group, September 12 through October 27, 2014 Medical Policy Group, February 2015: Added Care Core Draft link Available for comment February 12 through April 30, 2015 Medical Policy Group, May 2015: Changed RTM link from Draft to Current, removed Draft from header. Medical Policy Group, October 2015: Added/removed evicore Draft link and comment period This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a caseby-case basis according to the terms of the member s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield s administration of plan contracts. Page 19 of 19