MEDICAL POLICY – 8.01.533

Radioimmunotherapy in the Treatment of Non-Hodgkin

Lymphoma

BCBSA Ref. Policy: 8.01.50

Effective Date: Nov. 1, 2019

Last Revised: Oct. 4, 2019

Replaces: 8.01.524

and 8.01.50

RELATED MEDICAL POLICIES:

2.03.502 Monoclonal Antibodies for the Treatment of B-Cell Malignancies

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POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING

RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY

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Introduction

When the body detects something that can cause disease, like a virus or bacteria or a cancer

cell, the immune system sends out specific cells to try to destroy the invader. Antibodies connect

to harmful molecules. The antibodies act as flags for other immune system cells to attack the

harmful molecule. Monoclonal antibodies are made in a lab and are engineered to attach to very

specific targets on cancer cells. On some monoclonal antibodies, tiny particles of radiation can

be attached. When this radiation-enhanced monoclonal antibody enters the body, it seeks out

and links to its target to deliver the radiation. This treatment is known as radioimmunotherapy.

This policy describes when radioimmunotherapy may be considered medically necessary.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The

rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for

providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can

be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a

service may be covered.

Policy Coverage Criteria

https://www.premera.com/medicalpolicies/2.03.502.pdf

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Drug Medical Necessity Zevalin® (ibritumomab

tiuxetan)

The use of Zevalin® (ibritumomab tiuxetan) may be

considered medically necessary for:

• The initial treatment of follicular lymphoma in patients who are

unable to tolerate standard chemotherapy, eg, elderly or frail

patients

• Consolidation after chemotherapy for previously untreated

CD20-positive follicular non-Hodgkin lymphoma patients who

achieve a partial or complete response to first line

chemotherapy

• A single course of ibritumomab tiuxetan (Zevalin®)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

Drug Investigational Zevalin® (ibritumomab

tiuxetan)

The use of Zevalin® (ibritumomab tiuxetan) is considered

investigational for:

• Consolidation of a first remission following chemotherapy for

de novo aggressive B-cell NHL

• Use as part of a preparatory regimen before autologous or

allogeneic hematopoietic stem-cell transplantation in patients

with non-Hodgkin lymphoma

Note: 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 less than 100,000/mm3 or a neutrophil count less than 1,500/mm3).

Documentation Requirements The patient’s medical records submitted for review for all conditions should document that

medical necessity criteria are met. The record should include office visit notes that contain

the relevant history and physical supporting any of the following:

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Documentation Requirements • Initial treatment for patient with follicular lymphoma who is unable to tolerate standard

chemotherapy (for example, an elderly or frail patient)

• Patient has partially or completely responded to the initial chemotherapy for CD20-positive

follicular non-Hodgkin lymphoma and needs additional treatment

• To be used as a single course for a patient with relapsed or refractory CD20-positive low-grade

or follicular B-cell non-Hodgkin lymphoma, including patients with rituximab refractory non-

Hodgkin lymphoma

Coding

Code Description

CPT 79403 Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous

infusion

HCPCS

A9542 Indium In-111 ibritumomab tiuxetan, diagnostic, per study dose, up to 5 millicuries

A9543 Yittrium Y-90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40

millicuries (Zevalin)

Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS

codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

Related Information

N/A

Evidence Review

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Description

Radioimmunotherapy (RIT) involves the administration of an antibody linked to a radioisotope,

targeted to a specific cell type. Zevalin® (ibritumomab tiuxetan) 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, 90Y-ibritumomab tiuxetan uses a monoclonal anti-CD20 antibody to deliver beta-

emitting yttrium-90.1

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 radiation to known, as well as

unsuspected tumor cells and nearby normal cells, producing a ”bystander effect” because the

radiation emitted from the isotopes is deposited over several cell diameters with poorly

perfused or non-antigen-expressing nearby cells within a tumor mass suffering 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 or small cell lymphocytic lymphoma (SLL)

usually present with advanced stage disease (stage IV) and are not considered curable in that

stage with current treatments, including chemotherapy or radiotherapy. The disease course is

usually prolonged, with a median survival of 7 to 10 years, characterized by initial response to

chemotherapy, multiple relapses, and increasing resistance to treatment. In addition,

approximately 60% of patients may eventually 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, include

newly diagnosed disease, recurrent B-cell lymphoma, in combination with chemotherapy or

other monoclonal antibodies, as preparative regimen for hematopoietic stem-cell transplant.2,3

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Summary of Evidence

For individuals with relapsed or refractory low-grade or follicular B-cell non-Hodgkin

lymphomas (NHL) who receive ibritumomab tiuxetan, the evidence includes a randomized

controlled trial (RCT) and two single-arm studies. Relevant outcomes are overall survival (OS),

disease-specific survival, change in disease status, morbid events, quality of life, and treatment-

related mortality and morbidity. The RCT showed that ibritumomab tiuxetan resulted in a

significantly higher overall response rate of 80% compared with 56% with rituximab alone.

Single-arm trials have also demonstrated response rates of 74% to 89% in previously treated

disease. The evidence is sufficient to determine that the technology results in a meaningful

improvement in the net health outcome.

For individuals who receive initial treatment of follicular B-cell NHL who receive ibritumomab

tiuxetan, the evidence includes 3 single-arm studies. Relevant outcomes are OS, disease-specific

survival, change in disease status, morbid events, quality of life, and treatment-related mortality

and morbidity. The 3 studies have reported high overall response rates ranging from 87% to

94%. However, the median progression-free survival was less than that observed with first-line

chemotherapy regimens plus rituximab in other studies. Although RCTs are needed, the current

evidence has suggested that ibritumomab may be of clinical value as an initial treatment of

indolent NHL, particularly in older, frail patients and that it provides long remissions and results

equivalent to multicycle rituximab and chemotherapy combinations. The evidence is sufficient to

determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with untreated follicular B-cell NHL who receive ibritumomab tiuxetan as

consolidation treatment after remission, the evidence includes a pivotal RCT, a meta-analysis,

and 2 single-arm studies. Relevant outcomes are OS, disease-specific survival, change in disease

status, morbid events, quality of life, and treatment-related mortality and morbidity. The pivotal

RCT demonstrated that consolidation with ibritumomab tiuxetan significantly prolonged median

progression-free survival by 23.2 months regardless of partial or complete response after a

median follow-up of 3.5 years. The number of patients who died was too small to permit a

reliable comparison of survival. Results of the single-arm studies and meta-analysis were

directionally consistent with the progression-free survival benefit. The evidence is sufficient to

determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with diffuse large B-cell or mantle cell NHL who receive ibritumomab tiuxetan as

consolidation treatment after remission, the evidence includes multiple single-arm studies.

Relevant outcomes are OS, disease-specific survival, change in disease status, morbid events,

quality of life, and treatment-related mortality and morbidity. Several studies, published from

2007 to 2010, have focused on elderly patients ineligible for stem cell transplantation as

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postremission therapy. These studies have shown 5-year OS estimates ranging from 83% to

94%. However, whether ibritumomab tiuxetan adds survival benefit over current standard

rituximab-containing chemotherapy regimens cannot be determined from these studies.

Further, the small samples and lack of data for direct comparison with outcomes of alternative

treatments in similar patients preclude firm conclusions. The evidence is insufficient to

determine the effects of the technology on health outcomes, therefore this is considered

investigational.

For individuals with chemotherapy-sensitive, relapsed NHL who require hematopoietic cell

transplantation and who receive ibritumomab tiuxetan as part of the conditioning regimen, the

evidence includes small cohort studies or case series with heterogeneous patient populations

and a meta-analysis. Relevant outcomes are OS, disease-specific survival, change in disease

status, morbid events, quality of life, and treatment-related mortality and morbidity. Data are

promising but evolving; preliminary data have suggested there may be a role for ibritumomab

tiuxetan, particularly in patients unable to tolerate potentially curative high-dose chemotherapy

and/or total body irradiation because of the risk of excessive treatment-related mortality and

morbidity. However, currently, the available data do not support the superiority of conditioning

regimens containing ibritumomab tiuxetan over alternative conditioning regimens before

hematopoietic cell transplant. RCTs comparing the efficacy and safety of conditioning regimens

containing ibritumomab tiuxetan are required. The evidence is insufficient to determine the

effects of the technology on health outcomes, therefore this is considered investigational.

Clinical Input Received from Physician Specialty Societies and Academic

Medical Centers

While the various physician specialty societies and academic medical centers may collaborate

with and make recommendations during this process, through the provision of appropriate

reviewers, input received does not represent an endorsement or position statement by the

physician specialty societies or academic medical centers, unless otherwise noted.

2014 Input

In response to requests, input was received from two physician specialty societies, one academic

medical center, and three Blue Distinction Centers for Transplant when this policy was under

review in 2014. Reviewers unanimously agreed that tositumomab and ibritumomab tiuxetan

Page | 7 of 12 ∞

were investigational as part of a preparatory regimen before autologous or allogeneic

hematopoietic cell transplantation in patients with non-Hodgkin lymphoma (NHL).

2010 Input

In response to requests, input was received from one specialty medical society and one

academic medical center and while this policy was under review in 2010. Both reviewers agreed

that tositumomab was medically necessary for relapsed or rituximab-refractory follicular

lymphoma and that use of ibritumomab tiuxetan would be medically necessary for relapsed or

refractory NHL, although one reviewer questioned the use of ibritumomab tiuxetan in

lymphoma transformed to diffuse large B-cell lymphoma. Both reviewers indicated that there is

a role for radioimmunotherapy in the initial treatment of indolent NHL, particularly in older, frail

patients and that it provides long remissions and results equivalent to multicycle rituximab and

chemotherapy combinations. Both reviewers indicated that radioimmunotherapy is medically

necessary as consolidation therapy, and both agreed that there conditioning regimens are

beneficial role before hematopoietic cell transplantation.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

NCCN practice guidelines (V 5.2019)51 make the following recommendations for

radioimmunotherapy (RIT) in non-Hodgkin lymphoma (NHL):

• Follicular lymphoma (These guidelines apply to patients with histological grade 1 or 2

follicular lymphoma; grade 3 follicular lymphoma is commonly treated like diffuse large B-

cell lymphoma.)

o As first-line therapy for elderly or infirm if other first-line therapies are not tolerable

(category 2B)

o As first-line consolidation after induction with chemotherapy or chemoimmunotherapy

(category 2B)

• For histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma, either

after multiple prior therapies, or after minimal or no prior chemotherapy if initial treatment

for transformed disease yields only partial response, no response, or progressive disease RIT

(category 2B)

Page | 8 of 12 ∞

• Primary Cutaneous Diffuse Large B-Cell Lymphoma, leg type

o As secondary therapy for generalized (skin-only) disease (stage T3) that either has

relapsed or only partially responded to initial therapy (category 2B).

National Comprehensive Cancer Network guidelines do not list RIT among its recommended

primary or secondary treatments for any other type of B-cell NHL (eg, de novo diffuse large B-

cell or mantle cell lymphomas).51

Medicare National Coverage

There is no national coverage determination.

Regulatory Status

In 2002, ibritumomab tiuxetan (Zevalin®) was granted accelerated approval by the U.S. Food

and Drug Administration (FDA) for the treatment of patients with relapsed or refractory low-

grade, follicular or transformed B-cell NHL, including patients with rituximab-refractory follicular

NHL. In March 2008, the indication for transformed B-cell NHL was removed.4 In 2009, FDA

approved ibritumomab tiuxetan (Zevalin®) for consolidation therapy in previously untreated

follicular NHL in patients 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 partial or complete

response to first-line chemotherapy.5

In 2003, tositumomab (Bexxar®) was approved by FDA for rituximab-refractory follicular NHL. In

February 2014, GlaxoSmithKline discontinued the manufacture and sale of tositumomab

(Bexxar®).6

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Jan 2015;26(1):193-198. PMID 25361987

51. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas. Version

5.2019 Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf Accessed October 2019.

History

https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf

Page | 12 of 12 ∞

Date Comments 10/14/13 New policy. Policy approved with medically necessary indications for non-Hodgkin

lymphoma when utilized as outlines. Policy replaces 8.01.524 which is now deleted.

07/14/14 Annual Review. Policy updated with literature review on April 16, 2014. Clinical input

reviewed. Rationale reorganized and references renumbered. References 4, 10, and 50

updated; references 5, 12-14, 24-25, 31-32, 35-36, 43 added. Policy statements

reorganized and updated to reflect discontinuation of tositumomab and current FDA

labeling of ibritumomab tiuxetan. Policy renumbered to 8.01.533.

07/14/15 Annual Review. Policy updated with literature search; no change to policy statement.

References updated.

10/13/15 Annual Review. Policy updated with literature review; no change in policy statements.

12/01/16 Annual Review, approved November 8, 2016. No changes to policy statement.

10/01/17 Annual Review, approved September 5, 2017. Policy updated with literature review

through June 2, 2017; references 9 and 19 added; no change in policy statements.

10/01/18 Annual Review, approved September 20, 2018. No changes to policy statement.

11/01/19 Annual Review, approved October 4, 2019. Policy updated to reflect current NCCN

guidelines, no changes to policy statements.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The

Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and

local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review

and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit

booklet or contact a member service representative to determine coverage for a specific medical service or supply.

CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). ©2019 Premera

All Rights Reserved.

Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when

determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to

the limits and conditions of the member benefit plan. Members and their providers should consult the member

benefit booklet or contact a customer service representative to determine whether there are any benefit limitations

applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

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( ةالعربي :(. امةھ ماتولعم اإلشعار ھذا يحوي

خالل من ھاعلي صولحلا تريد لتيا التغطيةلل أو ةصحيلاكطيتتغ لىع اظلحفل نةعيم يخراوت في إجراء خاذتال تحتاج وقد .اإلشعار ھذا في

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اعدةمس تصلايفكالتال دفع فيبـ

.

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Italian

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037338 (07-2016)

https://www.hhs.gov/ocr/office/file/index.htmlhttps://ocrportal.hhs.gov/ocr/portal/lobby.jsfmailto:AppealsDepartmentInquiries@Premera.com

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ູຂໍ້

່

ສໍ ັ

ຈ

ໝ

ສິ

ັ

່

ວ

ຄ

ມ

ມູຮັ

ູມີ ມຂໍ້

ភាសាែខមរ ( ): ឹ

រងរបស់

Premera Blue Cross ។ របែហលជាមាន កាលបរ ិ ឆ ំខានេនៅកងេសចក

េសចកតជី ូ

ជាមានព័ ៌ ៉ ងសំ ់អពី ់ ៉ ប់

នដំ ងេនះមានព័ ី

តមានយា ខាន ំ ទរមងែបបបទ ឬការរា

ណ ត៌មានយ៉ា ំ ់ តងសខាន។ េសចក

េចទស ់ ន ុ ត

ណងេនះ។ អ វការបេញញសមតភាព ដលកណតៃថ ចបាស

កតាមរយៈ

ដំ ឹ នករបែហលជារតូ ច ថ ់ ំ ់ ងជាក់ ់

នដ

ន

ី ន

ូ

អ

ូ

ជ

ជ

ំណឹងេនះរបែហល

នានា េដើ ីនងរកសាទុ ៉ បរងស់ ុ ់ ក ឬរបាក់ ំ

អ

មប ឹ កការធានារា ខភាពរបស ជ

ធនកមានសិ ទទលព័ មានេនះ និ ំ យេនៅកុងភាសារបសទិ ួ ត៌ ងជ ននួ

ន

់ កេដាយម

អ

នអ

យេចញៃថល។ ួ

នអស

ន

ិ

លុ ើ ូ ូយេឡយ។ សមទ ទ រស័ព 800-722-1471 (TTY: 800-842-5357)។

Khmer

ਕਵਰਜ ਅਤ ਅਰਜੀ ਬਾਰ ਮਹ ਤਵਪਰਨ ਜਾਣਕਾਰੀ ਹ ਸਕਦੀ ਹ . ਇਸ ਨ ਿਜਸ ਜਵਚ ਖਾਸ

ਤਾਰੀਖਾ ਹ ਸਕਦੀਆ ਹਨ. ਜੇਕਰ ਤਸੀ ਜਸਹਤ ਕਵਰਜ ਿਰਖਣੀ ਹਵ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵਚ ਮਦਦ ਦ ੇਇਛ ੁਕ ਹ ਤਾਂ ਤਹਾਨ ਅ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁ ਝ ਖਾਸ ਕਦਮ ਚ ਕਣ ਦੀ ਲੜ ਹ ਸਕਦੀ ਹ ,ਤਹੁਾਨ ਮਫ਼ਤ ਿਵਚ ਤ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵ ਚ ਜਾਣਕਾਰੀ ਅਤ ਮਦਦ ਪਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹ ,ਕਾਲ 800-722-1471 (TTY: 800-842-5357).

ਪ ਜਾਬੀ (Punjabi): ਇਸ ਨ ਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹ. ਇਸ ਨ ਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ਤੁਹਾਡੀ

ੰ

ੰ

ੇ ੇ ੇ ੱ ੂ ੋ ੈ ੋੋ ਂ ੁ ੇ ੱ ੋ ੇ ੱੱ ੁ ੱ ੂੁ ੱ ੇ ੱ ੇ ੍ਰ ੈ

ੋ ੰ ੂ ੱ ੁ ੋ ੋ ੈ ੰ

ੋ ੈ ੋ

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Premera Blue Cross طريق از ماش مهبيوشش يا و تقاضا ای پ. يدماين جهتو يهمالعا اين

حق شما. يدشاب داشته اجتياح صیاخ کارھای امانج برای صیمشخ ایھ خيتار به تان، انیمدر ھای کسب برای .نماييد دريافت گانيرا ورط به ودخ زبان به را کمک و اطالعات اين که داريد را اين

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้

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Spanish

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้ี ี ้ ู ํ ั ้ี ี ้ ู ่ี ํ ั ่ี ั ั ื ัุ ุ ่ ี ํ ี ุ ้ํ ิ ํ ่ี ่ ่ื ั ั ุ ุ ื ่ ื ่ีี ่ ้ ่ ุ ี ิ ิ ่ี ้ ั ้ ู ่ ื ้ี ุ ี ่ ้ ่

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