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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 for a number of NHLs.
CD20-based radioimmunotherapy (RIT) for NHL is similar to the anti-CD20 monoclonal antibody rituximab, which is widely used against B-cell malignancies, however, 90Y-ibritumomab tiuxetan uses a monoclonal anti-CD20 antibody to deliver beta-emitting yttium-90 and 131I-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-antigen-expressing cells within a tumor mass suffering the cytotoxic radiation effect.
B-cell and other NHLs can be subdivided into major subcategories as indolent and aggressive. Indolent B-cell lymphomas (e.g., follicular lymphoma, a common subtype) usually present with advanced stage disease and are not considered curable with current treatments, including chemotherapy. The disease course is usually prolonged, with a median survival of 7–10 years, and is characterized by initial response to chemotherapy, multiple relapses and increasing resistance to treatment. In addition, approximately 60% of patients may transform to a more aggressive type of lymphoma. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell lymphoma. Although rituximab is widely used in the treatment of B-cell NHL, not all patients respond, and a certain number of patients eventually develop resistance to the drug, necessitating additional treatments after rituximab.
Review articles published in 2010 and 2012 summarized various uses of radioimmunotherapy 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.
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, including patients with rituximab-refractory follicular non-Hodgkin lymphoma. In March 2008, the indication for transformed B-cell NHL was removed. In September 2009, FDA approved ibritumomab tiuxetan (Zevalin®) for consolidation therapy in previously untreated follicular NHL in patients who achieve a partial (PR) or complete response (CR) to first-line chemotherapy. Current FDA-approved indications are relapsed or refractory, low-grade or follicular B-cell NHL and 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 rituximab-refractory follicular NHL. On February 20, 2014, GlaxoSmithKline discontinued the manufacture and sale of tositumomab (Bexxar®).
POLICYA 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.*
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.
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.
Radioimmunotherapy with ibritumomab tiuxetan (Zevalin®) 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 prior to autologous or allogeneic hematopoietic stem-cell transplantation in patients with non-Hodgkin lymphoma is considered investigational.
* Indicates an FDA-labeled indication.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
Because of the hematologic effects associated with the use of these agents (ie, 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 (ie, a platelet count <100,000/mm³ or a neutrophil count <1500/mm³).
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY6/2/2009: Policy added
7/16/2009: Approved by Medical Policy Advisory Committee (MPAC)
12/30/2010: Policy statement regarding the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for the initial treatment of follicular lymphoma changed to may be considered medically necessary under specific conditions. Policy statement regarding the use of tositumomab (Bexxar®) or ibritumomab tiuxetan (Zevalin®) for consolidation after chemotherapy in patients who achieve a partial or complete response also changed to may be considered medically necessary.
09/28/2011: Policy reviewed; no changes.
04/10/2013: Policy description updated. Added the following policy statement: Radioimmunotherapy with tositumomab or ibritumomab tiuxetan for consolidation of a first remission following chemotherapy for de novo aggressive B-cell NHL is considered investigational.
10/30/2014: Policy reviewed. Policy description and statements updated to reflect discontinuation of tositumomab. Second medically necessary statement revised to state that 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. Added "(Zevalin®)" to the fourth policy statement for consistency. Investigational statement revised to state that the use of ibritumomab tiuxetan (Zevalin®) as part of a preparatory regimen prior to autologous or allogeneic hematopoietic stem-cell transplantation in patients with non-Hodgkin lymphoma is considered investigational. Policy guidelines updated.
09/01/2015: Code Reference section updated for ICD-10.
10/16/2015: Policy reviewed; description updated. First medically necessary policy statement re-worded; intent unchanged. It previously stated: A single course of ibritumomab tiuxetan (Zevalin®) used for the treatment of patients with relapsed or refractory CD-20 positive low-grade, follicular, or B-cell non-Hodgkin lymphoma, including patients with rituximab refractory non-Hodgkin lymphoma*, may be considered medically necessary. Policy guidelines section updated to add medically necessary and investigative definitions.
05/26/2016: Policy number added.
SOURCESBlue Cross & Blue Shield Association policy # 8.01.50
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.