Recombinant Interleukin-2 (IL-2)
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
Interleukin-2 (IL-2) is a protein that is naturally produced by lymphocytes (CD4 T-cells). It is an important regulator of the immune system, with potent effects on T cells, B cells, and natural killer (NK) cells.
Recombinant IL-2 is commercially available as Proleukin (aldesleukin) and is produced by recombinant DNA technology involving Escherichia coli containing the human gene that codes for IL-2. The resultant purified protein has the same biological activity as native human IL-2.
[INFORMATIONAL NOTE: The FDA-approved Proleukin (aldesleukin) package insert has the following BLACK BOX WARNINGS:
- Therapy should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary function testing. Extreme caution should be used in patients with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease.
- This agent should be administered in a hospital setting under the supervision of a qualified physician experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available.
- The administration of this medication has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes.
- This treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to initiation of PROLEUKIN therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated with a reduced incidence of staphylococcal infections.
- The administration of this drug should be withheld in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma.]
(Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)
1. Recombinant interleukin-2 (IL-2) is considered medically necessary for adult members with the following FDA indications when the criteria below are met:
2. Recombinant interleukin-2 (IL-2) is considered medically necessary for the following off-label uses:
- Treatment of metastatic renal cell carcinoma OR treatment of metastatic melanoma (documentation of medical records required); AND
- The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis; AND
- Prior to starting therapy, all of the following:
- Normal results from thallium stress test for cardiac function (documentation of medical records required)
- Normal pulmonary function tests (documentation of medical records required)
- Absence of organ allograft
- ECOG performance score of 0-1 (documentation of medical records required)
[INFORMATIONAL NOTE: As per the FDA-approved package insert (PI), each course of treatment consists of two 5-day treatment cycles separated by a rest period. It is recommended to administer 600,000 International Units/kg (0.037 mg/kg) dose administered by a 15-minute IV infusion every 8 hours, for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated. Each course of treatment consists of two 5-day treatment cycles separated by a rest period. Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last course and retreatment is not contraindicated.]
Proleukin is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts. Retreatment with Proleukin is contraindicated in patients who have experienced the following drug-related toxicities while receiving an earlier course of therapy: sustained ventricular tachycardia (≥5 beats), cardiac arrhythmias not controlled or unresponsive to management, chest pain with ECG changes, consistent with angina or myocardial infarction, Cardiac tamponade, intubation for >72 hours, renal failure requiring dialysis >72 hours, coma or toxic psychosis lasting >48 hours, repetitive or difficult to control seizures, bowel ischemia/perforation, GI bleeding requiring surgery.]
3. IL-2 is considered investigational including, but not limited to, the following conditions:
- High dose single-agent therapy for metastatic or unresectable disease as second line or subsequent therapy for disease progression or after maximum clinical benefit from BRAF targeted therapy
- High-dose interleukin-2 should not be used for patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases.
- Kidney cancer
- First-line therapy as a high-dose single agent for selected patients (excellent performance status and normal organ function) with relapsed or medically unresectable stage IV disease with predominant clear cell histology
- Hematopoietic Cell Transplantation
- For chronic graft-versus-host disease (GVHD) as additional therapy in conjunction with systemic corticosteroids following no response (steroid-refractory disease) to first-line therapy options
- Therapy to maintain remission after high-dose chemotherapy for a variety of malignancies (e.g., lung cancer, colorectal cancer, bladder cancer, neuroblastoma, pancreatic cancer, endometriomas, etc.) and pre-malignancies (e.g., myelodysplastic syndromes).
- Management of human immunodeficiency virus (HIV) infection, and juvenile rheumatoid arthritis
[INFORMATIONAL NOTE: The randomized open label study which served as the basis of this off-label use of IL-2 in patients with HIV suggested that intermittent therapy with IL-2 and highly active antiretroviral therapy (HAART) produced a substantially greater increase in CD4 cell counts. The study showed doses of 4.5 to 7.5 MIU twice a day for five consecutive days every 8 weeks are effective in increasing CD4 count without adversely affecting viral load.]
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ medical policy.
Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
1. 2004 Physicians' Desk Reference. 58th Edition. Medical Economics Publishing Company.
2. Davey RT, Murphy RL, Graziano FM, et al. Immunologic and Virologic Effects of Subcutaneous Interleukin 2 in Combination With Antiretroviral Therapy. JAMA. July 2000;284(2):183-189.
3. Blankson J, Siliciano RF. Interleukin 2 Treatment for HIV Infection. JAMA. July 2000;284(2):236-237.
4. Blue Cross and Blue Shield Association: TEC Clearinghouse Update on Proleukin. January 1998.
5. Scientific American Medicine. Interleukin-2 for HIV Infection. 7:XXXIIB:32.
6. Kovacs JA, Vogel S, et al. Controlled Trial of Interleukin-2 Infusions in Patients Infected with the Human Immunodeficiency Virus. The New England Journal of Medicine. October 1996;335:1350-56.
7. Kovacs JA, Baseler M, Dewar RJ, Vogel S, Davey, JR RT, Falloon J, Polis MA, Walker RE, Stevens R, Salzman NP, Metcalf JA, Masur H, Lane HC. Increases in CD4 T Lymphocytes with Intermittent Courses of Interleukin-2 in Patients with Human Immunodeficiency Virus Infection. The New England Journal of Medicine. 1995; 332(9):567-75.
8. Paredes R, Benaldo de Quiros JC, Fernandez-Cruz E, et al. The potential role of interkeukin-2 in patients with HIV infection. AIDS Rev 2002 Jan-Mar;4(1):36-40.
9. Emery S, Abrams DI, Cooper DA, et al. The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials 2002 Apr;23(2):198-220.
10. Abrams DI, Bebchuk JD, Denning ET, et al. Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3: CPCRA 059. J Acquir Immune Defic Syndr 2002 Mar;29(3):221-231.
11. Lalezari JP, Beal JA, Ruane PJ et al. Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial. HIV Clin Trials 2000;1(3):1-15.
12. Tambussi G, Ghezzi S, Nozza S et al. Efficacy of low-dose intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced human immunodeficiency virus-infected persons with detectable virus load: a controlled study of 3 IL-2 regimens with antiviral drug therapy. J Infect Dis 2001;183(10):1476-84.
13. David D, Nait-Ighil L, Dupont B et al. Rapid effect of interleukin-2 therapy in human immunodeficiency virus-infected patients whose CD4 cell counts increase only slightly in response to combined antiretroviral treatment. J Infect Dis 2001;183(5):730-5.
14. Attal M, Blaise D, Marit G et al. Consolidation treatment of adult acute lymphoblastic leukemia: A prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. Blood 1995;4:1619-28.
15. Klingeman HG, Phillips GL. Is there a place for immunotherapy with interleukin-2 to prevent relapse after autologous stem cell transplantation for acute leukemia? Leuk Lymphoma 1995;16:397-405.
16. Blaise D, Attal M, Pico JL et al. The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission. Leuk Lymphoma 1997;25:469-78.
17. Nagler A, Ackerstein A, Or R, et al. Immunotherapy with recombinant interleukin-2 and recombinant interferon-alpha in lymphoma patients postautologous bone marrow or stem cell transplantation. Blood 1997;89:3951-9.
18. Rosenberg SA, Yang JC, Schwartzentruber DJ et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999;17(3):968-75.
19. Ridolfi R, Chiarion-Silena, Guida M et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2 and interferon alfa-2b in advanced melanoma outpatients: Results from an Italian Multicenter Phase III randomized clinical trial. J Clin Oncol 2002;20:1600-7.
20. Eton O, Legha SS, Bedikian AY et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 2002;20:2045-52.
21. Hauschild A, Garber C, Stolz W et al. Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 2001;84:1036-42.
22. Atzpodien J, Neuber K, Kamanabrou D et al. Combination chemotherapy with or without s.c. IL-2 and IFN-alpha. Results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group. Br J Cancer 2002;86:179-84.
23. Negrier S, Caty A, Lesimple T et al. Treatment of patients with metastatic renal carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil. J Clin Oncol 2000;18:4009-15.
24. Atzpodien J, Kirchner H, Illinger JH et al. IL-2 in combination with IFN-alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: Long-term results of a controlled randomized trial. Br J Cancer 2001;85:1130-5.
25. Henrikkson R, Nilsson S, Colleen S et al. Survival in renal cell carcinoma - a randomized evaluation of tamoxifen vs. interleukin 2, alpha interferon and tamoxifen. Br J Cancer 1998;77:1311-37.
26. Cortes JE, Kantarjian HM, O’Brien S et al. A pilot study of interleukin-2 for adult patients with acute myelogenous leukemia in first complete remission. Cancer 1999;85:1506-13.
27. De Stefani A, Forni G, Ragona R et al. Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx. Cancer 2002;95:90-7.
28. Sundin D, Wolin M, et al. Aldesleukin therapy in HIV-infected patients. AJHP July 1998;1520-1523.
29. Lu A, Jones E, et al. Increases in CD4+ T lymphocytes occur without increases in thymic size in HIV infected subjects receiving interleukin-2 therapy. JAIDS 2003;34(3):299-303.
30. Simpson W, Heys S, et al. Acute phase proteins and recombinant IL-2 therapy: prediction of response and survival of patients with colorectal cancer. Clin Exp Immunol 1995;99:143-147.
31. Maxwel-Armstrong C, Durrant L, et al. Increased activation of lymphocytes infiltrating primary colorectal following immunization with anti-idiotypic monoclonal antibody 105AD7. GUT 1999;45(4):593-598.
32. Mitsuyasu R, Gelman R, Cherng DW, et al. The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection. Arch Intern Med 2007;167:597-605.
33. Proleukin« product information. Prometheus Laboratories Inc. San Diego, CA. August 2018.
34. De Stefani A, Forni G, Ragona R etc. Improved survival with perilymphatic interleukin 2 in patients with respectable squamous cell carcinoma of the oral cavity and oropharynx. Cancer 2002;95(1):90-7.
35. NCCN Drugs and Biologics Compendium™. Aldesleukin, interleukin-2, recombinant 2013. [Available at: https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=27 ][ cited December 29 2017]
36. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Kidney Cancer. Version 2.2020 [Available at http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf ] [cited 18 Dec 2019]
37. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Cutaneous Melanoma. Version 3.2019 [Available at http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf ] [cited 18 Dec 2019]
38. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and Regulatory T Cells in Graft-versus-Host Disease. N Engl J Med 2011; 365:2055-66.
39. Querfeld C, Rosen S, Guitart J, et al. Phase II trial of subcutaneous injections of human recombinant interleukin-2 for the treatment of mycosis fungoides and SÚzary syndrome. JAAD. 2007; 2007: 580-83.
40. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055-2066.
41. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000;6 Suppl 1: S11-14. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10685652
42. Proleukin Clinical Pharmacology. Elsevier. Amsterdam, Netherlands. Available at: www.clinicalkey.com/. Accessed December 2019.
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy