Medical Policy Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma

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1 Medical Policy Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma Table of Contents Policy: Commercial Coding Information Information Pertaining to All Policies Policy: Medicare Description References Authorization Information Policy History Policy Number: 146 BCBSA Reference Number: Related Policies None Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity Medicare HMO Blue SM and Medicare PPO Blue SM Members A single course of ibritumomab tiuxetan (Zevalin ) may be 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 MEDICALLY NECESSARY in patients who are unable to tolerate standard chemotherapy, eg, 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 MEDICALLY NECESSARY. Radioimmunotherapy with ibritumomab tiuxetan for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL is 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 INVESTIGATIONAL. * Indicates an FDA-labeled indication. 1

2 Prior Authorization Information Pre-service approval is required for all inpatient services for all products. See below for situations where prior authorization may be required or may not be required for outpatient services. Yes indicates that prior authorization is required. No indicates that prior authorization is not required. Commercial Managed Care (HMO and POS) Commercial PPO and Indemnity Medicare HMO Blue SM Medicare PPO Blue SM Outpatient No No No No CPT Codes / HCPCS Codes / ICD-9 Codes The following codes are included below for informational purposes. Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member. A draft of future ICD-10 Coding related to this document, as it might look today, is included below for your reference. Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable. CPT Codes CPT codes: Code Description Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous infusion HCPCS Codes HCPCS codes: A9543 ICD-9 Diagnosis Codes ICD-9-CM Code Description Yttrium Y-90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40 millicuries diagnosis codes: Code Description Nodular lymphoma, unspecified site, extranodal and solid organ sites Nodular lymphoma of lymph nodes of head, face, and neck Nodular lymphoma of intrathoracic lymph nodes Nodular lymphoma of intra-abdominal lymph nodes Nodular lymphoma of lymph nodes of axilla and upper limb Nodular lymphoma of lymph nodes of inguinal region and lower limb Nodular lymphoma of intrapelvic lymph nodes Nodular lymphoma of spleen Nodular lymphoma of lymph nodes of multiple sites Other malignant lymphomas, unspecified site, extranodal and solid organ sites Other malignant lymphomas, lymph nodes of head, face, and neck Other malignant lymphomas, intrathoracic lymph nodes Other malignant lymphomas, intra-abdominal lymph nodes Other malignant lymphomas, lymph nodes of axilla and upper limb Other malignant lymphomas, lymph nodes of inguinal region and lower limb Other malignant lymphomas, intrapelvic lymph nodes Other malignant lymphomas, spleen 2

3 Other malignant lymphomas, lymph nodes of multiple sites ICD-10 Diagnosis Codes ICD-10-CM Diagnosis codes: Code Description C82.00 Follicular lymphoma grade I, unspecified site C82.01 Follicular lymphoma grade I, lymph nodes of head, face, and neck C82.02 Follicular lymphoma grade I, intrathoracic lymph nodes C82.03 Follicular lymphoma grade I, intra-abdominal lymph nodes C82.04 Follicular lymphoma grade I, lymph nodes of axilla and upper limb C82.05 Follicular lymphoma grade I, lymph nodes of inguinal region and lower limb C82.06 Follicular lymphoma grade I, intrapelvic lymph nodes C82.07 Follicular lymphoma grade I, spleen C82.08 Follicular lymphoma grade I, lymph nodes of multiple sites C82.09 Follicular lymphoma grade I, extranodal and solid organ sites C82.10 Follicular lymphoma grade II, unspecified site C82.11 Follicular lymphoma grade II, lymph nodes of head, face, and neck C82.12 Follicular lymphoma grade II, intrathoracic lymph nodes C82.13 Follicular lymphoma grade II, intra-abdominal lymph nodes C82.14 Follicular lymphoma grade II, lymph nodes of axilla and upper limb C82.15 Follicular lymphoma grade II, lymph nodes of inguinal region and lower limb C82.16 Follicular lymphoma grade II, intrapelvic lymph nodes C82.17 Follicular lymphoma grade II, spleen C82.18 Follicular lymphoma grade II, lymph nodes of multiple sites C82.19 Follicular lymphoma grade II, extranodal and solid organ sites C82.20 Follicular lymphoma grade III, unspecified, unspecified site C82.21 Follicular lymphoma grade III, unspecified, lymph nodes of head, face, and neck C82.22 Follicular lymphoma grade III, unspecified, intrathoracic lymph nodes C82.23 Follicular lymphoma grade III, unspecified, intra-abdominal lymph nodes C82.24 Follicular lymphoma grade III, unspecified, lymph nodes of axilla and upper limb Follicular lymphoma grade III, unspecified, lymph nodes of inguinal region and lower limb C82.25 C82.26 Follicular lymphoma grade III, unspecified, intrapelvic lymph nodes C82.27 Follicular lymphoma grade III, unspecified, spleen C82.28 Follicular lymphoma grade III, unspecified, lymph nodes of multiple sites C82.29 Follicular lymphoma grade III, unspecified, extranodal and solid organ sites C82.30 Follicular lymphoma grade IIIa, unspecified site C82.31 Follicular lymphoma grade IIIa, lymph nodes of head, face, and neck C82.32 Follicular lymphoma grade IIIa, intrathoracic lymph nodes C82.33 Follicular lymphoma grade IIIa, intra-abdominal lymph nodes C82.34 Follicular lymphoma grade IIIa, lymph nodes of axilla and upper limb C82.35 Follicular lymphoma grade IIIa, lymph nodes of inguinal region and lower limb C82.36 Follicular lymphoma grade IIIa, intrapelvic lymph nodes C82.37 Follicular lymphoma grade IIIa, spleen C82.38 Follicular lymphoma grade IIIa, lymph nodes of multiple sites C82.39 Follicular lymphoma grade IIIa, extranodal and solid organ sites C82.40 Follicular lymphoma grade IIIb, unspecified site C82.41 Follicular lymphoma grade IIIb, lymph nodes of head, face, and neck C82.42 Follicular lymphoma grade IIIb, intrathoracic lymph nodes C82.43 Follicular lymphoma grade IIIb, intra-abdominal lymph nodes 3

4 C82.44 Follicular lymphoma grade IIIb, lymph nodes of axilla and upper limb C82.45 Follicular lymphoma grade IIIb, lymph nodes of inguinal region and lower limb C82.46 Follicular lymphoma grade IIIb, intrapelvic lymph nodes C82.47 Follicular lymphoma grade IIIb, spleen C82.48 Follicular lymphoma grade IIIb, lymph nodes of multiple sites C82.49 Follicular lymphoma grade IIIb, extranodal and solid organ sites C82.50 Diffuse follicle center lymphoma, unspecified site C82.51 Diffuse follicle center lymphoma, lymph nodes of head, face, and neck C82.52 Diffuse follicle center lymphoma, intrathoracic lymph nodes C82.53 Diffuse follicle center lymphoma, intra-abdominal lymph nodes C82.54 Diffuse follicle center lymphoma, lymph nodes of axilla and upper limb C82.55 Diffuse follicle center lymphoma, lymph nodes of inguinal region and lower limb C82.56 Diffuse follicle center lymphoma, intrapelvic lymph nodes C82.57 Diffuse follicle center lymphoma, spleen C82.58 Diffuse follicle center lymphoma, lymph nodes of multiple sites C82.59 Diffuse follicle center lymphoma, extranodal and solid organ sites C82.60 Cutaneous follicle center lymphoma, unspecified site C82.61 Cutaneous follicle center lymphoma, lymph nodes of head, face, and neck C82.62 Cutaneous follicle center lymphoma, intrathoracic lymph nodes C82.63 Cutaneous follicle center lymphoma, intra-abdominal lymph nodes C82.64 Cutaneous follicle center lymphoma, lymph nodes of axilla and upper limb C82.65 Cutaneous follicle center lymphoma, lymph nodes of inguinal region and lower limb C82.66 Cutaneous follicle center lymphoma, intrapelvic lymph nodes C82.67 Cutaneous follicle center lymphoma, spleen C82.68 Cutaneous follicle center lymphoma, lymph nodes of multiple sites C82.69 Cutaneous follicle center lymphoma, extranodal and solid organ sites C82.80 Other types of follicular lymphoma, unspecified site C82.81 Other types of follicular lymphoma, lymph nodes of head, face, and neck C82.82 Other types of follicular lymphoma, intrathoracic lymph nodes C82.83 Other types of follicular lymphoma, intra-abdominal lymph nodes C82.84 Other types of follicular lymphoma, lymph nodes of axilla and upper limb C82.85 Other types of follicular lymphoma, lymph nodes of inguinal region and lower limb C82.86 Other types of follicular lymphoma, intrapelvic lymph nodes C82.87 Other types of follicular lymphoma, spleen C82.88 Other types of follicular lymphoma, lymph nodes of multiple sites C82.89 Other types of follicular lymphoma, extranodal and solid organ sites C82.90 Follicular lymphoma, unspecified, unspecified site C82.91 Follicular lymphoma, unspecified, lymph nodes of head, face, and neck C82.92 Follicular lymphoma, unspecified, intrathoracic lymph nodes C82.93 Follicular lymphoma, unspecified, intra-abdominal lymph nodes C82.94 Follicular lymphoma, unspecified, lymph nodes of axilla and upper limb C82.95 Follicular lymphoma, unspecified, lymph nodes of inguinal region and lower limb C82.96 Follicular lymphoma, unspecified, intrapelvic lymph nodes C82.97 Follicular lymphoma, unspecified, spleen C82.98 Follicular lymphoma, unspecified, lymph nodes of multiple sites C82.99 Follicular lymphoma, unspecified, extranodal and solid organ sites C85.10 Unspecified B-cell lymphoma, unspecified site C85.11 Unspecified B-cell lymphoma, lymph nodes of head, face, and neck C85.12 Unspecified B-cell lymphoma, intrathoracic lymph nodes C85.13 Unspecified B-cell lymphoma, intra-abdominal lymph nodes C85.14 Unspecified B-cell lymphoma, lymph nodes of axilla and upper limb 4

5 C85.15 Unspecified B-cell lymphoma, lymph nodes of inguinal region and lower limb C85.16 Unspecified B-cell lymphoma, intrapelvic lymph nodes C85.17 Unspecified B-cell lymphoma, spleen C85.18 Unspecified B-cell lymphoma, lymph nodes of multiple sites C85.19 Unspecified B-cell lymphoma, extranodal and solid organ sites C85.20 Mediastinal (thymic) large B-cell lymphoma, unspecified site C85.21 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of head, face, and neck C85.22 Mediastinal (thymic) large B-cell lymphoma, intrathoracic lymph nodes C85.23 Mediastinal (thymic) large B-cell lymphoma, intra-abdominal lymph nodes C85.24 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of axilla and upper limb Mediastinal (thymic) large B-cell lymphoma, lymph nodes of inguinal region and lower C85.25 limb C85.26 Mediastinal (thymic) large B-cell lymphoma, intrapelvic lymph nodes C85.27 Mediastinal (thymic) large B-cell lymphoma, spleen C85.28 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of multiple sites C85.29 Mediastinal (thymic) large B-cell lymphoma, extranodal and solid organ sites C85.80 Other specified types of non-hodgkin lymphoma, unspecified site C85.81 Other specified types of non-hodgkin lymphoma, lymph nodes of head, face, and neck C85.82 Other specified types of non-hodgkin lymphoma, intrathoracic lymph nodes C85.83 Other specified types of non-hodgkin lymphoma, intra-abdominal lymph nodes C85.84 Other specified types of non-hodgkin lymphoma, lymph nodes of axilla and upper limb Other specified types of non-hodgkin lymphoma, lymph nodes of inguinal region and C85.85 lower limb C85.86 Other specified types of non-hodgkin lymphoma, intrapelvic lymph nodes C85.87 Other specified types of non-hodgkin lymphoma, spleen C85.88 Other specified types of non-hodgkin lymphoma, lymph nodes of multiple sites C85.89 Other specified types of non-hodgkin lymphoma, extranodal and solid organ sites C85.90 Non-Hodgkin lymphoma, unspecified, unspecified site C85.91 Non-Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck C85.92 Non-Hodgkin lymphoma, unspecified, intrathoracic lymph nodes C85.93 Non-Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes C85.94 Non-Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb C85.95 Non-Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb C85.96 Non-Hodgkin lymphoma, unspecified, intrapelvic lymph nodes C85.97 Non-Hodgkin lymphoma, unspecified, spleen C85.98 Non-Hodgkin lymphoma, unspecified, lymph nodes of multiple sites C85.99 Non-Hodgkin lymphoma, unspecified, extranodal and solid organ sites Description Radioimmunotherapy (RIT) 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). 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 131 I- 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 5

6 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 (eg, 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 (eg, 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) Summary Multiple studies have shown that the use of radioimmunotherapy (RIT) in treating relapsed or refractory non-hodgkin lymphoma (NHL) can induce remissions in 50% to 80% of patients, with 15% to 50% achieving complete remission (CR). In ibritumomab studies, very few patients with transformed B-cell NHL were included. The use of RIT as initial therapy of follicular lymphoma has shown high CR rates and may be beneficial, particularly in patients who cannot tolerate chemotherapy (eg, older or frail patients). RIT for 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 2 phase 3 trials and several phase 2 studies. In contrast with follicular lymphoma, phase 3 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 or other de novo aggressive CD20-positiveNHL. Data on the use of RIT as part of the conditioning regimen before autologous or allogeneic hematopoietic stem-cell transplant are promising but still evolving, and to date consist of small case series or uncontrolled prospective studies, with heterogeneous patient populations. Preliminary data suggest there may be a role for RIT, particularly in patients who may not be able to tolerate potentially curative highdose chemotherapy and/or total body irradiation because of the risk of excessive treatment-related morbidity and mortality. A phase 3 trial (NCT ) examining the role of radioimmunotherapy in autologous hematopoietic stem-cell transplant in patients with relapsed or aggressive lymphoma may be in progress. Policy History Date Action 10/2014 BCBSA National medical policy review. Coding information clarified. Medically necessary statements and investigational statements revised, effective 10/1/ /2014 Updated Coding section with ICD10 procedure and diagnosis codes, effective 10/ /2013 BCBSA National medical policy review. New investigational indications described. Effective 6/1/ /2011- Medical policy ICD 10 remediation: Formatting, editing and coding updates. 6

7 4/2012 No changes to policy statements. 7/2011 Reviewed - Medical Policy Group Hematology and Oncology. No changes to policy statements. 4/2011 Reviewed national policy. Medically necessary statements revised. 9/2010 Reviewed - Medical Policy Group Hematology and Oncology. No changes to policy statements. 12/1/09 Medical Policy #146 issued. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines References 1. Emmanouilides C. Radioimmunotherapy for non-hodgkin lymphoma: historical perspective and current status. J Clin Exp Hematopathol 2007; 47(2): Palanca-Wessels M, Press OW. Improving the efficacy of radioimmunotherapy for non-hodgkin lymphomas. Cancer 2010; 116(4 Suppl): Stevens PL, Oluwole O, Reddy N. Advances and application of radioimmunotherapy in non-hodgkin lymphoma. Am J Blood Res 2012; 2(2): Spectrum Pharmaceuticals, Inc. Zevalin (ibritumomab tiuxetan) injection for intravenous use prescribing information - August Available online at: Last accessed April 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: BEXXAR-therapeutic-regimen.html. Last accessed April 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): 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): 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): GlaxoSmithKline. Bexxar (tositumomab and iodine I 131 tositumomab) injection for intravenous infusion prescribing information - August Available online at: History#labelinfo. Last accessed April Kaminski MS, Tuck M, Estes J et al. 131I-Tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352(5): 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): 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):

8 14. 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): Morschhauser F, Dreyling M, Rohatiner A et al. Rationale for consolidation to improve progressionfree survival in patients with non-hodgkin s lymphoma: a review of the evidence. Oncologist 2009; 14(suppl 2): Emmanouilides C. Review of Y-ibritumomab tiuxetan as first-line consolidation radio-immunotherapy 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): 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): 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): Jacobs SA, Swerdlow SH, Kant J et al. Phase II trial of short-course CHOP-R followed by 90Yibritumomab Tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res 2008; 14(21): 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): Press OW. Evidence mounts for the efficacy of radioimmunotherapy for B-cell lymphomas. J Clin Oncol 2008; 26(32): 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): 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): Provencio M, Cruz Mora MA, Gomez-Codina J et al. Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediate- and high-risk follicular lymphoma according to the follicular lymphoma international prognostic index: a multicenter, prospective phase II trial of the Spanish Lymphoma Oncology Group. Leuk Lymphoma 2014; 55(1): Tomblyn M. Radioimmunotherapy for B-cell non-hodgkin lymphomas. Cancer Control 2012; 19(3): 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): Zinzani PL, Rossi G, Franceschetti S et al. Phase II trial of short-course R-CHOP followed by 90Yibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients. Clin Cancer Res 2010; 16(15): 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): 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): 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: TFORMAT=1&andorexacttitle=and&titleabstract=439&andorexacttitleabs=and&andorexactfulltext=an 8

9 d&searchid=1&firstindex=0&sortspec=relevance&volume=118&tdate=11/30/2012&resourcetype= HWCIT. Last accessed April Kluin-Nelemans HC, Hoster E, Hermine O et al. Treatment of Older Patients with Mantle-Cell Lymphoma. N EnglJ Med 2012; 367(6): Gisselbrecht C, Vose J, Nademanee A et al. Radioimmunotherapy for stem cell transplantation in non-hodgkin s lymphoma: in pursuit of a complete response. Oncologist 2009; 14(suppl 2): Devizzi IL, Guidetti A, Tarella C et al. High-dose yttrium-90-ibritumomab tiuxetan with tandem stemcell reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation. J Clin Oncol 2008; 26(32): 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): 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): 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 Krishnan A, Palmer JM, Tsai NC et al. Matched-cohort analysis of autologous hematopoietic cell transplantation with radioimmunotherapy versus total body irradiation-based conditioning for poor-risk diffuse large cell lymphoma. Biol Blood Marrow Transplant 2012; 18(3): 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): Han EJ, Lee SE, Kim SH et al. Clinical outcomes of post-remission therapy using (90)yttrium ibritumomab tiuxetan (Zevalin(R)) for high-risk patients with diffuse large B-cell lymphoma. Ann Hematol 2011; 90(9): 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): 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 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): 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): 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): 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): Abou-Nassar KE, Stevenson KE, Antin JH et al. (90)Y-ibritumomab tiuxetan followed by reducedintensity conditioning and allo-sct in patients with advanced follicular lymphoma. Bone Marrow Transplant 2011; 46(12): 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): 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

10 50. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Non- Hodgkin s Lymphomas, v Available online at: Last accessed April