Description:
Interleukin-2 (IL-2; aldesleukin [Proleukin: Chiron, Emeryville, CA]) is a cytokine with the following immune-modulating effects: enhancement of lymphocyte mitogenesis and cytotoxicity, induction of lymphocyte-activated (LAK) cells and natural killer (NK) cells and induction of interferon gamma production. Labeled indications approved by the U.S. Food and Drug Administration (FDA) include the treatment of metastatic renal cell carcinoma and metastatic malignant melanoma. In addition, other oncologic applications of IL-2 monotherapy are being actively investigated, principally as a technique to maintain remission or eliminate minimal residual disease in patients with a variety of malignancies, including, most prominently, leukemias, but also including lymphomas and other solid tumors, such as neuroblastoma and breast cancer. IL-2 has also been used post-autologous bone marrow transplantation as an immunotherapeutic technique to maintain remission and reduce the relapse rate. IL-2 has also been investigated as a component of a variety of combination therapies, for example, in combination with interferon alpha in the treatment of metastatic renal cell cancer and metastatic melanoma. Combination therapy is not addressed in this policy.

Note: Interleukin-2 may be used as a component of adoptive immunotherapy. Adoptive immunotherapy is addressed separately in Policy No. 80101.

Note: Interleukin-2 has also been investigated as a treatment for HIV-infected individuals. This application is considered separately in Policy No. 80141.

Note: Interleukin-2 may be used as a component of a melanoma vaccine. Melanoma vaccines are considered as part of Policy No. 20304, Tumor Vaccines.

Policy:
IL-2 monotherapy may be considered MEDICALLY NECESSARY in the treatment of metastatic renal cell carcinoma and metastatic melanoma.

Perilymphatic injection of IL-2 may be considered MEDICALLY NECESSARY in patients with resectable, non-metastatic squamous cell cancer of the oral cavity and oropharynx.

IL-2 in combination with chemotherapy or in combination with interferon alfa is considered INVESTIGATIONAL as a treatment of metastatic melanoma and renal cell cancer.

IL-2 is considered INVESTIGATIONAL as a therapy to maintain remission after high-dose chemotherapy for a variety of malignancies, including multiple myeloma, leukemia, lymphoma, multiple myeloma or breast cancer.

Other oncologic applications of IL-2 monotherapy are considered INVESTIGATIONAL, including, but not limited to, the following:

• Colorectal cancer
• Hepatocellular carcinoma
• Small-cell and non-small-cell lung cancers
• Acute leukemia
• Myelodysplastic syndromes
• Multiple myeloma
• Non-Hodgkin's and Hodgkin's lymphoma
• Ewing's sarcoma
• Soft tissue sarcoma
• Osteosarcoma
• Bladder
• Brain
• Breast
• Esophagus
• Ovary
• Pancreas
• Prostate
• Small bowel
• Stomach
• Testes
• Thyroid

Policy Guidelines:
IL-2 treatment protocols for metastatic melanoma and renal cancer vary in terms of dosages and duration of treatment. Higher dosages of intravenous (IV) IL-2 (at least 600,000 IU/8 hours) may require hospitalization to monitor for capillary leak syndrome. Continuous infusion or subcutaneous IL-2 may be given on an outpatient basis.

Squamous Cell Cancer of the Oral Cavity and Oropharynx
The policy statement regarding IL-2 therapy for patients with resectable malignancies of the oral cavity and oropharynx is based on the results of a randomized study that included in the following protocol:

• Patients had resectable stage T2-T4, NO-N3, MO squamous cell cancer of the oral cavity and oropharynx.
• 5,000 U IL-2 was injected into the ipsilateral cervical lymph node chain for 10 days before surgery.
• Additional five-day courses were given monthly in the residual ipsilateral lymph node chain for one year.

Rationale:
IL-2 Monotherapy for Metastatic Renal Cell Cancer
The product insert for Proleukin (Chiron, Emeryville, Calif.) summarizes clinical data used as part of the FDA approval process.¹ In clinical studies of metastatic renal cell cancer, including 255 patients treated with single agent IL-2, there was a 15 percent response rate (including both complete and partial responses) with a median response duration of 54 months. In clinical studies of metastatic melanoma, including 270 patients, there was a 16 percent response rate with a median duration of nine months. These results may be considered clinically significant, given the failure of other chemotherapeutic approaches. The labeled indication recommends a dose schedule of a 15-minute short intravenous infusion at doses of 600,000 IU every eight hours (referred to as "high dose"). This regimen requires hospitalization to monitor for toxicities, including capillary leak syndrome. Other dose schedules (i.e., continuous or subcutaneous infusion) and combinations with other agents (i.e., interferon or other chemotherapeutic agents) have also been explored, both as a method to increase effectiveness and decrease toxicity. In 2003, Yang and colleagues reported the results of a trial that randomized 306 patients with metastatic renal cell cancer to receive one of three regimens of IL-2:

1. High-dose IV (720,000 U/kg) every eight hours
2. Low-dose IV (72,000 U/kg ) IL-2 every eight hours
3. Low-dose daily subcutaneous IL-2.²

There was a higher response rate in those receiving the high-dose regimen compared to either of the two low-dose regimens, but no difference in survival rates. Toxicities were also higher with the high-dose regimen. Clark and colleagues also reported on the results of a trial of IL-2, focusing on its use in the immediate postoperative period.³ Patient selection criteria included resected locally advanced or metastatic renal cell cancer. Patients were randomized to receive either one course of high-dose IL-2 (600,000 U/kg every eight hours) or observation. The trial was closed early when interim analysis concluded that the anticipated 30 percent improvement in the two-year disease-free survival could not be achieved.

IL-2 Combination Therapy for Metastatic Renal Cell Cancer
Negrier and colleagues studied the role of a subcutaneous combination of subcutaneous IL-2 and interferon alfa with or without additional 5-FU in patients with metastatic renal cell cancer.⁴ Therefore, this study examined the incremental effect of 5-FU and did not examine whether combining IL-2 and interferon produced an incremental effect compared to either treatment alone. Overall survival in both arms was similar (53 percent). In addition, the response rate was 8.2 percent, considerably lower than the response rate seen in both preliminary phase II trials of subcutaneous IL-2 or in trials of IV IL-2, and suggesting that subcutaneous IL-2 may be inferior to IV IL-2. Two randomized studies were identified that compared the treatment outcomes of combined subcutaneous IL-2 and interferon alpha compared to treatment with tamoxifen alone.^5,6 Therefore, these studies cannot answer the question of whether combined immunotherapy has any advantage over IL-2 monotherapy. While subcutaneous IL-2 therapy is associated with decreased complications compared to IV IL-2, the relative efficacy of the two routes of administration is unknown.

IL-2 Monotherapy for Metastatic Melanoma
The product insert for Proleukin (Chiron, Emeryville, Calif.) summarizes clinical data used as part of the FDA approval process. A total of 270 patients with metastatic melanoma participated. Objective responses were seen in 16 percent of patients, with 6 percent achieving complete remission.¹

IL-2 Combination Therapy for Metastatic Melanoma
Several randomized studies were identified that reported no incremental benefit comparing interferon monotherapy to various combination therapies. For example, Rosenberg and colleagues reported on the results of a trial that randomized 102 patients with metastatic melanoma to receive chemotherapy (tamoxifen, cisplatin, dacarbazine) with or without additional IL-2 and interferon alfa (i.e., chemoimmunotherapy).⁷ The addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The authors concluded that the use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized trials. Several other randomized trials, using different regimens of subcutaneous or intravenous IL-2, have reported similar disappointing results of chemoimmunotherapy, in part due to the toxicity of IL-2 and the lack of impact on overall survival.^8,9,10,11

Oncologic Off-Label Indications
IL-2 Post-High-Dose Chemotherapy/Autologous Bone Marrow Transplant or Peripheral Stem-Cell Transplant
It is hoped that IL-2 therapy following high-dose chemotherapy and stem-cell transplant will eradicate the minimal residual disease that is presumably responsible for early relapses. It is hypothesized that IL-2 will stimulate host immune cells and increase the antigenicity of residual tumor cells. A large volume of literature has been published on these applications of IL-2, but the bulk of the literature consists of single institution case series in which there is no control group. In many instances, the outcomes focus on the effect of IL-2 on the numbers and function of natural killer (NK) cells. Many reports include patients with a variety of malignancies, including prominently leukemias, but also lymphomas and a variety of solid tumors, including neuroblastoma and breast cancer. The success of immunotherapy is not uniform across malignancies, and, thus, data regarding IL-2 therapy must be evaluated separately for each indication. In addition, the dosage and route of administration of IL-2 vary among studies; frequently, IL-2 is included as a component of an immunomodulatory regimen that may also include alpha-interferon. In the post-bone marrow transplant setting, low-dose subcutaneous IL-2 is often used. This regimen has been found to be safe and well tolerated.

In 1995, Attal and colleagues reported on a randomized trial that studied the impact of IL-2 used after autologous bone marrow transplantation as a treatment of adult acute lymphoblastic leukemia.¹² A total of 60 patients were randomized to receive or not to receive IL-2 after autologous bone marrow transplantation. The probability of complete remission was similar in the two groups, leading the authors to conclude that IL-2 does not decrease the high relapse rate observed after bone marrow transplantation for adult ALL. Other studies have also suggested that IL-2 is not effective in the post-transplant setting for ALL^13,14 or have reported improved outcomes compared with historical controls.¹⁵ Cortes and colleagues reported on a pilot study of IV IL-2 in 18 adult patients with acute myelogenous leukemia in first complete remission.¹⁶ Compared to historical controls, there was a prolongation of the duration of complete remission in those receiving IL-2. These preliminary findings require further study in controlled trials. The authors concluded that the regimen was tolerable.

Resectable Squamous Cell Cancer of the Oral Cavity and Oropharynx
De Stefani and colleagues reported on the results of a trial that randomized 220 patients with resectable squamous cell cancer of the oral cavity and oropharynx to undergo surgery alone or surgery in conjunction with preoperative and postoperative injection of IL-2 into the perilymphatic tissue.¹⁷ The group assigned to IL-2 therapy had a significantly improved length of disease-free survival and overall survival, and based on these results, this application of IL-2 may be considered medically necessary.

Ongoing Clinical Trials
A search of active clinical trials, as part of the National Cancer Institute’s Physician Data Query database¹⁸, shows a continuing research interest in IL-2. A total of 75 trials are listed, many of them involving either adoptive immunotherapy or tumor vaccines, addressed in policy Nos. 8.01.01 and 2.03.04, respectively. Other oncology indications include several phase III studies of IL-2 as part of an immunotherapy regimen after high-dose chemotherapy and bone marrow transplant for either neuroblastoma, acute myeloid leukemia, myelodysplastic syndrome, non-Hodgkin’s lymphoma or breast cancer. Phase III trials also include studies comparing the use of interferon alone to combined chemoimmunotherapy with IL-2 in patients with melanoma or renal cell carcinoma.

References:

1. Proleukin, product insert
2. Yang JC, Sherry RM, Steinberg SM et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cell cancer. J Clin Oncol 2003; 21(16):3127-32.
3. Clark JI, Atkins MB, Urba WJ et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 2003; 21(16):3133-40.
4. 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(24):4009-15.
5. Atzpodien J, Kirchner H, Illiger HJ 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 clinical trial. Br J Cancer 2001; 85(8):1130-5.
6. Henriksson 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(8):1311-7.
7. 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.
8. Ridolfi R, Chiarion-Sileni V, 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(6):1600-7.
9. 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(8):2045-52.
10. Hauschild A, Garbe C, Stolz W et al. Dacarbazine and interferon alpha with or without interleukin two in metastatic melanoma: a randomized phase III multicentre trial of Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 2001; 84(8):1036-42.
11. 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 (ACIMM). Br J Cancer 2002; 86(2):179-84.
12. 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; 86(4):1619-28.
13. 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(5-6):397-405.
14. Blaise D, Attal M, Pico JL et al. The use of a sequential high dose recombinant interleukin two 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(5-6):469-78.
15. 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(11):3951-9.
16. 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(7):1506-13.
17. De Stefani A, Forni G, Ragona R et al. Improved survival with perilymphatic interleukin two in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx. Cancer 2002; 95(1):90-7.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Index 
Aldesleukin
IL-2 (Interleukin-2)
Interleukin-2 (IL-2)
Proleukin

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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