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Aetna Aetna
Clinical Policy Bulletin:
Interleukin-2 (Aldesleukin, Proleukin, IL-2)
Number: 0024


Policy

Aetna considers Interleukin-2 (Aldesleukin, Proleukin, IL-2) intravenous medically necessary for the treatment of persons with any of the following conditions:

  1. Metastatic melanoma; or
  2. Metastatic renal cell carcinoma

Aetna considers intratumoral IL-2 medically necessary for melanoma.

Aetna considers IL-2 experimental and investigational for the treatment of the following conditions (not an all inclusive list):

  • Acute myeloid leukemia 
  • Atopic dermatitis
  • Bladder cancer
  • Cutaneous T-cell lymphoma
  • Endometriomas
  • Graft-versus-host disease
  • HIV infection
  • Juvenile rheumatoid arthritis
  • Mycosis fungoides
  • MYH9 (May-Hegglin) platelet disorder
  • Neuroblastoma
  • Pancreatic cancer.

Aetna considers subcutaneous IL-2 experimental and investigational for renal cell carcinoma and all other indications other than intratumoral administration of IL-2 for melanoma.

See also CPB 0570 - Chemotherapy Inpatient.



Background

Note: Interleukin-2 requires inpatient intravenous administration, or outpatient subcutaneous administration.  If IL-2 therapy requires hospitalization, it is not medically necessary for the initial length of stay to exceed the number of days of IL-2 administration, typically 5 days or less.

Researchers have found that the immune system may recognize the difference between healthy cells and cancer cells in the body and eliminate those that become cancerous.  Cancer may develop when the immune system breaks down or is over-whelmed.  Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) uses the body's immune system, either directly or indirectly, to repair, stimulate, or enhance the immune system's natural anticancer function or to lessen side effects that may be caused by some cancer treatments.

Like interferons, interleukins are cytokines that occur naturally in the body and can be made in the laboratory.  Although many interleukins (including IL-1 through IL-15) have been identified, interleukin-2 (IL-2) has been the most widely studied in cancer treatment.  Interleukin-2, a lymphokine produced by activated T cells, has a wide variety of actions and plays a central role in immune regulation.  The primary action of IL-2 is its ability to stimulate the growth of activated T cells that bear IL-2 receptors.  Lymphocytes stimulated by IL-2, called lymphokine-activated killer (LAK) cells, have proven to be effective in destroying tumors.  Lymphocytes can be removed from a cancer patient's blood, stimulated with IL-2 in the laboratory, and returned to the patient as LAK cells, with the goal of improving the patient's anticancer immune response.

Patients with advanced renal cell carcinoma (RCC) or advanced melanoma have shown the best response to IL-2 therapy.  Response rates for patients with metastatic RCC and metastatic malignant melanoma have been reported as 21 to 38 % and 17 to 26 % respectively, which is as high as or higher than other treatment options.  According to available literature, for renal carcinoma, only those who have shown some tumor shrinkage in response to the initial course of IL-2 are considered appropriate candidates for additional treatment.  For metastatic melanoma, IL-2 is indicated as a second line treatment in persons who have failed an adequate trial of standard therapy (e.g., dacarbazine alone or in combination with other chemotherapeutic agents).

Current NCCN guidelines (2014) recommend IL-2 as first-line therapy as a high-dose single agent for selected patients with relapsed or medically unresectable state IV renal cancer with predominant clear cell histology (2A recommendation), and for subsequent therapy as a single agent for relapsed or medically unresectable stage IV renal cancer with predominant clear cell histology (2B recommendation).

In a prospective, multi-center, randomized controlled study, Atzpodien et al (2005) examined the role of adjuvant outpatient immuno-chemotherapy administered post-operatively in high-risk patients with RCC.  A total of 203 patients (status post radical tumor nephrectomy) were stratified into 3 risk groups: (i) subjects with tumor extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0), (ii) subjects with loco-regional lymph node infiltration (pN+), and (iii) subjects following complete resection of tumor relapse or solitary metastasis (R0).  Patients were randomized to undergo either: (a) 8 weeks of outpatient subcutaneous IL-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen or (b) observation. Two-, 5-, and 8-year survival rates were 81, 58, and 58 % in the treatment arm, and 91, 76, and 66 % in the observation arm (log rank  p = 0.0278), with a median follow-up of 4.3 years.  Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39 % in the treatment arm, and at 62, 49, and 49 % in the observation arm (log rank  p = 0.2398).  Stage-adapted sub-analyses revealed no survival advantages of treatment over observation, as well.  These findings established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immuno-chemotherapy compared to observation in high-risk RCC patients following radical tumor nephrectomy.

In a phase III clinical study, McDermott et al (2005) ascertained the value of outpatient IL-2 and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic RCC.  Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m2 subcutaneously every 8 hrs for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m2 subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks.  A total of 192 patients were enrolled.  Toxicities were as anticipated for these regimens.  The response rate was 23.2 % (22 of 95 patients) for HD IL-2 versus 9.9 % (9 of 91 patients) for IL-2/IFN (p = 0.018).  Ten patients receiving HD IL-2 were progression-free at 3 years versus 3 patients receiving IL-2 and IFN (p = 0.082).  The median response durations were 24 and 15 [corrected] months (p = 0.18) [corrected] and median survivals were 17.5 and 13 months (p = 0.24).  For patients with bone or liver metastases (p = 0.001) or a primary tumor in place (p = 0.040), survival was superior with HD IL-2.  These investigators concluded that this study provided additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic RCC.

Filippetti and colleagues (2009) noted that BRIIL-2 is a clinical study for assessing the effectiveness and toxicity of third-line treatment of pulmonary metastasis from renal cancer and melanoma with flexible bronchoscopic instillation of IL-2.  Moreover, these investigators evaluated local and peripheral lymphocytic activation during this IL-2 administration.  A total of 2 patients with pulmonary metastasis from renal cancer already treated with two lines of molecular therapy, chemotherapy or systemic immunotherapy were included in this study.  With regard to immunological stimulation, lymphocytic fraction decreased from 21 % to 2 % in the first patient and from 10.5 % to 6 % in the second patient, indicating lymphocytic enrollment for activation, while TCD4/CD8 ratio is stable.  In both patients, these researchers also observed a significant increase of HLA-DR in T lymphocytes (CD3) either in local or in peripheral blood.  No significant toxicities were observed following broncho-instillation, even if the dose was progressively increased.  The authors concluded that IL-2 broncho-instillation could represent a valid administration modality to obtain an effective immunological stimulation (either local or systemic).

NCCN guidelines (2014) recommend the use of high-dose intravenous IL-2, as a single agent (preferred; 2A recommendation) or in combination with cisplatin and vinblastine with either dacarbazine or temozolomode (combination therapy 2B recommendation), with or without interferon alfa, for unresectable state III in-transit metastases, local/satellite and/or in-transit unresectable recurrence, or incompletely resected or unresectable nodal recurrrence, or recurrent or metastatic disease in patients with good performance status. NCCN guidelines state that high-dose interleukin-2 should not be used for patients with active, untreated brain metastases.

In a multi-center, phase III clinical trial, Keilholz and associates (2005) examined whether IL-2 as a component of chemo-immunotherapy influences survival of patients with metastatic melanoma.  Patients with advanced metastatic melanoma were randomly assigned to receive dacarbazine 250 mg/m2 and cisplatin 30 mg/m2 on days 1 to 3 combined with interferon-alfa-2b 10 x 106 U/m2 subcutaneously on days 1 through 5 without (arm A) or with (arm B) a high-dose intravenous decrescendo regimen of IL-2 on days 5 through 10 (18 x 106 U/m2/6 hrs, 18 x 106 U/m2/12 hrs, 18 x 106 U/m2/24 hrs, and 4.5 x 106 U/m2 for 3 x 24 hrs).  Treatment cycles were repeated in the absence of disease progression every 28 days to a maximum of four cycles.  A total of 363 patients with advanced metastatic melanoma were accrued.  The median survival was 9 months in both arms, with a 2-year survival rate of 12.9 % and 17.6 % in arms A and B, respectively (p = 0.32; hazard ratio, 0.90; 95 % confidence interval [CI[: 0.72 to 1.11).  There was also no statistically significant difference regarding progression-free survival (median, 3.0 versus 3.9 months) and response rate (22.8 % versus 20.8 %).  These investigators concluded that despite its activity in melanoma as a single agent or in combination with interferon-alfa-2b, the chosen schedule of IL-2 added to the chemo-immunotherapy combination had no clinically relevant activity.

In a Cochrane review, Sasse and colleagues (2007) compared the effects of treatment with chemotherapy and immunotherapy (chemo-immunotherapy) versus chemotherapy alone in patients with metastatic malignant melanoma.  These researchers failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic melanoma.  They stated that further use of chemo-immunotherapy should only be done in the context of clinical trials.

Guidelines from the National Comprehensive Cancer Network recommend intralesional IL-2 for melanoma with unresectable stage III metastases, particularly superficial cutaneous or dermal lesions, and for local/satellite and/or in-transit unresectable recurrence (2B recommendation).

Weide et al (2010) noted that systemic high-dose IL-2 achieved long-term survival in a subset of patients with advanced melanoma.  The authors reported previously that intra-tumorally applied IL-2 induced complete local responses of all metastases in greater than 60 % of patients.  The objectives of the current study were to confirm those results in a larger cohort and to identify patient or regimen characteristics associated with response.  Patients with melanoma who had a median of 12 injectable metastases received intra-tumoral IL-2 treatments thrice-weekly until they achieved clinical remission.  The initial dose of 3 MIU was escalated, depending on the individual patient's tolerance.  Forty-eight of 51 patients were evaluable.  Only grade 1/2 toxicity was recorded.  A complete response that lasted greater than or equal to 6 months was documented in 70 % of all injected metastases.  A complete local response of all treated metastases was achieved in 33 patients (69 %), including 11 patients who had between 20 and 100 metastases.  Response rates were higher for patients who had stage III disease compared with patients who had stage IV disease.  No objective responses of distant untreated metastases were observed.  The 2-year survival rate was 77 % for patients with stage IIIB/IIIC disease and 53 % for patients with stage IV disease.  Efficacy and survival did not differ between patients who had greater than or equal to 20 lesions and patients who had les than 20 lesions.  The authors concluded that intra-tumoral IL-2 treatment elicited complete local responses in a high percentage of patients.  They stated that further studies are needed to examine the mode of action of this treatment and its impact on survival.

Researchers are investigating the benefits of IL-2, used alone or with other treatments, in other cancers such as colorectal cancer, ovarian cancer, and small cell lung cancer in ongoing clinical trials.  Combinations of IL-2 with other treatment methods such as chemotherapy, surgery, or other biological response modifiers are also under study.

Grande et al (2006) stated that IL-2 has been used to stimulate the immune system for the treatment of multiples tumors.  The authors reviewed the reports published from 1990 to 2004 on the IL-2 treatment of tumors other than melanoma and renal carcinoma.  They concluded that adjuvant IL-2 may be of value in early stages combined with standard treatment for colon and pancreas cancers.  In other neoplasms, the indication for adjuvant IL-2 has been sporadic and does not allow conclusions to be drawn.  Assessment of the efficacy of IL-2 combined with chemotherapy as treatment for advanced stages is complex, due to the lack of a control, and the variety of dosages and schemes.  The activity of IL-2 in monotherapy or in association with immunotherapy is clinically relevant in hepatocarcinoma, mesothelioma and in malignant overflows as palliative treatment.  The authors noted that randomized studies are needed to draw conclusions about its indication in other tumors.

Zlotta and Schulman (2000) stated that for over 2 decades, superficial bladder tumors have been demonstrated to be sensitive to several biological response modifiers and especially to immunomodulators.  The best-known and studied immunomodulator is the bacillus Calmette-Guérin (BCG).  However, despite its well-recognized effectiveness, BCG is not a panacea and is associated with potentially significant adverse events.  New perspectives in BCG therapy aiming to increase BCG efficacy or to decrease side effects include the use of genetically engineered BCG strains producing cytokines as well as the use of purified BCG subcomponents.  Because a cascade of immunological reactions including the secretion of several cytokines has been demonstrated in the BCG mode of action, many other biological response modifiers and especially immunomodulators have been studied for superficial transitional cell carcinoma therapy.  Some were investigated in human trials, others are still in laboratory studies; some are administered intravesically whereas others are given orally.  Intravesical instillations of Interferon-alpha (IFN-alpha) have been evaluated in several controlled studies.  Although toxicity of intravesical IFN is minimal, its optimal dose, schedule and effectiveness remain to be defined.  Recent prospective studies comparing IFN to BCG intravesical therapy have been somewhat disappointing although this cytokine may be effective in some patients with mucosally confined [T(a)]-papillary or sessile tumors extending into the lamina propria [T(1)] disease who have failed BCG therapy.  Other immunomodulators administered intravesically investigated in clinical studies include IL-2, levamisole, Rubratin, and keyhole limpet hemocyanin.  Several biological response modifiers administered orally such as vitamin A (and its derivatives), Lactobacillus casei or bropirimine have been tested in clinical trials as well.  In contrast, Allium sativum (garlic) or OK-432 (a streptococcal preparation) or BCG sub-fractions have been tested in laboratory studies only.  The authors concluded that published reports on several of these biological response modifiers suggest that these compounds may be an alternative in patients with superficial bladder cancer who have failed or have not tolerated BCG, but further evaluation to improve effectiveness, durability and understand their mechanism of action is warranted.

In addition, the National Comprehensive Cancer Network's guidelines as well as the National Cancer Institute's Drug Information on aldesleukin (2008) do not include bladder cancer as an established indication.

The drug compendium Clinical Pharmacology (Elsevier/Gold Standard) has recommended off-label use of aldesleukin for mycosis fungoides and cutaneous T-cell lymphoma.

Kolitz (2006) stated that biological therapies, including monoclonal antibodies, peptide vaccines and IL-2, are undergoing evaluation for the treatment of acute myeloid leukemia.  Dummer (2006) noted that therapies under investigation for the treatment of cutaneous T-cell lymphoma include topical retinoids, fusion molecules like denileukin diftitox (ONTAK), pegylated interferon, IL-2, and IL-12.

Interleukin-2 has been studied in HIV since the early days of the epidemic.  Researchers have found that IL-2 administered in low doses appears to activate natural killer cells, and at high intermittent doses, it appears to be a potent T-cell growth factor, resulting in large and sustained increases in CD4+ cell counts, which may take upwards of 6 months to occur.  However, IL-2 has not been shown to improve survival of HIV-infected patients.

Guidelines from the Centers for Disease Control and Prevention (CDC, 2008) state that interleukin-2 has demonstrated robust and sustained CD4 T-cell count increases in some studies.  The guidelines note, however, that controversy persists as to how much enhancement of immune function occurs.  The guidelines state that, "[w]ith this controversy, drug-associated side effects, and the need for parenteral administration, this strategy cannot be recommended unless with enrollment into a clinical trial".

Two randomized clinical studies have provided definitive evidence of the lack of effectiveness of IL-2 in HIV infection.  The INSIGHT-ESPRIT Study Group and the SILCAAT Scientific Committee (Abrams et al, 2009) noted that when used in combination with anti-retroviral therapy (ART), subcutaneous recombinant IL-2 raises CD4+ cell counts more than does ART alone.  However, the clinical implication of these increases is not known.  These investigators conducted 2 trials: (i) the subcutaneous recombinant, human IL-2 in HIV-infected patients with low CD4+ counts under active ART (SILCAAT) study, and (ii) the evaluation of subcutaneous proleukin in a randomized international trial (ESPRIT).  In each trial, patients infected with the HIV who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive IL-2 plus ART or ART alone.  The IL-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals.  The SILCAAT study involved 6 cycles and a dose of 4.5 million international units [MIU] of IL-2 twice-daily; ESPRIT involved 3 cycles and a dose of 7.5 MIU twice-daily.  Additional cycles were recommended to maintain the CD4+ cell count above pre-defined target levels.  The primary end point of both studies was opportunistic disease or death from any cause.  In the SILCAAT study, 1,695 patients (849 receiving IL-2 plus ART and 846 receiving ART alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4,111 patients (2,071 receiving IL-2 plus ART and 2,040 receiving ART alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled.  Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the IL-2 group than in the group receiving ART alone -- by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively.  Hazard ratios for opportunistic disease or death from any cause with IL-2 plus ART (versus ART alone) were 0.91 (95 % CI: 0.70 to 1.18; p = 0.47) in the SILCAAT study and 0.94 (95 % CI: 0.75 to 1.16; p = 0.55) in ESPRIT.  The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (p = 0.73) and 1.10 (p = 0.35), respectively, in the SILCAAT study and 0.90 (p = 0.42) and 1.23 (p = 0.003), respectively, in ESPRIT.  The authors concluded that despite a substantial and sustained increase in the CD4+ cell count, as compared with ART alone, IL-2 plus ART yielded no clinical benefit in either study.  An editorialist (Gandhi, 2009) commented that "[t]hese large studies demonstrate that although IL-2 raises CD4-cell counts, it does not improve clinical outcomes".

In a randomized, open-label, multi-center controlled trial, Viard and colleagues (2009) evaluated the efficacy of adding IL-2 to an optimized background treatment in HIV-1 patients with advanced failure.  Patients with CD4 T-cell count of less than 200 cells/microl, plasma HIV-1 RNA of more than 10 000 copies/ml and a genotypic sensitivity score showing 2 or less active drugs were randomized to either 8 IL-2 cycles with optimized background treatment or optimized background treatment alone.  Optimization was made according to genotypic sensitivity score.  Enfuvirtide was added in enfuvirtide-naive patients.  Evaluation was performed at week 52 on the proportions of patients with CD4 cell count of at least 200 cells/microl (primary outcome), of patients with a CD4 cell count increase of at least 50 cells/microl from week 0, on plasma HIV-1 RNA and HIV-related events.  A total of 56 patients were analyzed.  Median age was 43 years, 61 % were at Center for Disease Control and Prevention stage C, 43 % had a genotypic sensitivity score of 0, median baseline CD4 cell count and plasma HIV-1 RNA values were 64 cells/microl and 4.9 log10 copies/ml, respectively.  Treatment could be optimized in 23 patients.  At week 52, in the IL-2 and control groups, the proportion of patients with CD4 cell count of at least 200 cells/microl (14 % and 18 %) or a CD4 cell count increase of at least 50 cells/microl (25 % and 32 %) and median plasma HIV-1 RNA were not significantly different. In multi-variate analysis, optimization with enfuvirtide and baseline CD4 cell count were statistically associated with CD4 cell count of at least 200 cells/microl at week 52 (p = 0.003 and p = 0.01).  Optimization with enfuvirtide was the only factor associated with a CD4 cell count gain of at least 50 cells/microl (p < 0.001).  There was no difference in the rate of AIDS events between groups.  The authors concluded that IL-2 failed to increase CD4 cell count in immunocompromised patients with multiple therapeutic failures; while use of enfuvirtide was highly associated with success.

Acien and colleagues (2010) analyzed the therapeutic results of rIL-2 left in the cysts after trans-vaginal ultrasound (US)-guided drainage of endometriomas as an alternative to surgery.  A total of 25 consecutive patients were included.  Two trans-vaginal US-guided punctures were performed, and 3 MIU of rIL-2 were left in the aspirated cysts once (group I) or both (group II) times according to randomization.  Main outcome measures included clinical results, prevented surgeries, and recurrences.  Results were moderate or good in only 16 % of subjects at 3 months and in 33 % of subjects at 6 months after treatment in group I; these numbers were 66 % and 33%, respectively, in group II.  Differences were not statistically significant.  However, the evolution of symptoms, endometriomas, and CA-125 revealed the low efficacy of rIL-2 left intra-cyst as well as a poor control of the clinical manifestations.  After 1 year, 20 % (group I) and 73 % (group II) of patients had to be operated; after 2 years, these numbers were 55 % and 82 %, respectively.  The authors concluded that treatment of endometriomas with trans-vaginal US-guided drainage and rIL-2 left in the cysts, without using endometrial suppressive therapy with gonadotropin-releasing hormone analogs as done in previous studies, has low efficacy.  Furthermore, recurrences are even more frequent after the use of 2 rIL-2 doses.

Buyse et al (2011) stated that IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy.  The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) from 5 RCTs (n = 905) and summary data from a 6th RCT (n = 550).  Hazard ratios (HRs) were estimated using Cox regression models stratified by trial, with HR less than 1 indicating treatment benefit.  Combined IPD showed no benefit of IL-2 over no treatment in terms of leukemia-free survival (HR = 0.97; p = 0.74) or overall survival (HR = 1.08; p = 0.39).  Analyses including the 6th RCT yielded qualitatively identical results (leukemia-free survival HR = 0.96, p = 0.52; overall survival HR = 1.06; p = 0.46).  No significant heterogeneity was found between the trials.  Pre-specified subset analyses showed no interaction between the lack of IL-2 effect and any factor, including age, sex, baseline performance status, karyotype, AML subtype, and time from achievement of CR1 to initiation of maintenance therapy.  The authors concluded that IL-2 alone is not an effective remission maintenance therapy for AML patients in CR1.

Koerth and colleagues (2011) hypothesized that low-dose IL-2 could preferentially enhance regulatory T (Treg) cells in vivo and suppress clinical manifestations of chronic graft-versus-host disease (GVHD).  In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous IL-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks.  The end points were safety and clinical and immunologic response.  After a 4-week hiatus, patients with a response could receive IL-2 for an extended period.  A total of 29 patients were enrolled.  None had progression of chronic GVHD or relapse of a hematologic cancer.  The maximum tolerated dose of IL-2 was 1×10(6) IU per square meter.  The highest dose level induced unacceptable constitutional symptoms.  Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites.  The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than 8 times the baseline value (p < 0.001), without affecting CD4+ conventional T (Tcon) cells.  The Treg:Tcon ratio increased to a median of more than 5 times the baseline value (p < 0.001).  The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (p < 0.001 for both comparisons with baseline values), then declined when the patients were not receiving IL-2.  The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells.  Immunologic and clinical responses were sustained in patients who received IL-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60 % (range of 25 to 100 %).  The authors concluded that daily low-dose IL-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy.  Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients.

In an editorial that accompanied the afore-mentioned study, Bluestone (2011) stated that "[f]uture trials involving larger numbers of patients and appropriate control groups are needed to determine the efficacy of not only interleukin-2 therapy but also other approaches to improving Treg numbers and function in autoimmune diseases and GVHD and inhibiting them in cancer.  The design of these trials will need to take into account the challenge of interpretation of data in patients who are receiving complex therapies".

Pistoia et al (2011) stated that cytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment.  These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis.  IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-γ can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis.  On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies.  These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy.

An UpToDate review on “Treatment and prognosis of neuroblastoma” (Russell et al, 2012) states that “One approach under active investigation uses immunotherapy to treat minimal residual disease following aggressive systemic therapy.  The disialoganglioside GD2 is universally expressed by neuroblastomas.  A monoclonal antibody, ch14.18, targets this tumor-associated antigen.  This approach was assessed in a phase III trial conducted by the Children’s Oncology Group in 226 patients who had undergone intensive multimodality therapy that included stem-cell transplantation after induction chemotherapy.  Patients were randomly assigned a regimen including isotretinoin, ch14.18, GM-CSF, and interleukin-2 or to standard maintenance therapy (isotretinoin alone).  The immunotherapy approach resulted in a statistically significant improvement in the two-year event-free and overall survival rates (66 versus 46 percent, and 86 versus 75 percent, respectively).  This approach remains under investigation to clarify the toxicities associated with the immunotherapy arm”.

The prescribing information for Proleukin notes the lack of efficacy of low dose aldesleukin regimens, which are administered subcutaneously. The prescribing information describes the results of a single-center, open label, non-randomized trial involving 65 patients with metastatic renal cell cancer that sequentially evaluated the safety and anti-tumor activity of two low dose aldesleukin regimens. The regimens administered 18 million International Units aldesleukin as a single subcutaneous injection, daily for 5 days during week 1; aldesleukin was then administered at 9 x106 International Units days 1-2 and 18 x106 International Units days 3-5, weekly for an additional 3 weeks (n=40) followed by a 2 week rest or 5 weeks (n=25) followed by a 3 week rest, for a maximum of 3 or 2 treatment cycles, respectively. The prescribing information states that these low dose regimens yielded substantially lower and less durable responses than those observed with the approved regimen. The prescribing information states that, based on the level of activity, these low dose regimens are not effective.

Appendix

According to the Food and Drug Administration-approved product labeling and available literature, IL-2 is contraindicated in persons with any of the following:

  • Abnormal pulmonary function tests (e.g., FEV1 less than 75 % of predicted); or
  • Active infections; or
  • An abnormal thallium stress test; or
  • Autoimmune disorders; or
  • HIV with hepatitis B positive; or
  • Organ allografts; or
  • Renal or hepatic impairment; or
  • Seizure disorders.

Re-treatment with IL-2 is contraindicated in persons who have experienced any of the following drug-related toxicity while receiving an earlier course of therapy:

  • Bowel ischemia/perforation; or
  • Cardiac arrhythmia not controlled or unresponsive to management; or
  • Cardiac tamponade; or
  • Chest pain with ECG changes, consistent with angina or myocardial infarction; or
  • Coma or toxic psychosis lasting more than 48 hours; or
  • Gastrointestinal bleeding requiring surgery; or
  • Intubation required for more than 72 hours; or
  • Renal failure requiring dialysis for longer than 72 hours; or
  • Repetitive or difficult to control seizures; or
  • Sustained ventricular tachycardia (5 beats).
 
CPT Codes / HCPCS Codes / ICD-9 Codes
Inpatient intravenous administration:
Other CPT codes related to the CPB:
96365 - 96368
96374 - 96376
96379
96405 - 96406
96409
+96411
96413 - 96417
HCPCS codes covered if selection criteria are met:
J9015 Injection, aldesleukin, per single use vial
ICD-9 codes covered if selection criteria are met:
172.0 - 172.9 Malignant melanoma of skin
189.0 - 189.1 Malignant neoplasm of kidney and renal pelvis
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
042 Human immunodeficiency virus [HIV] disease
157.1 - 157.9 Malignant neoplasm of pancreas
188.0 - 188.9 Malignant neoplasm of bladder
194.0 Malignant neoplasm of adrenal gland [Neuroblastoma]
202.10 - 202.28 Mycosis fungoides and Sezary's disease [cutaneous T-cell lymphoma]
205.00 - 205.02 Acute myeloid leukemia
219.1 Other benign neoplasm of corpus uteri [endometrioma]
279.50 - 279.53 Graft-versus-host disease
288.2 Genetic anomalies of leukocytes [May-Hegglin platelet disorder]
617.0 - 617.9 Endometriosis
691.8 Other atopic dermatitis and related conditions
714.30 - 714.33 Juvenile chronic polyarthritis
Other ICD-9 codes related to the CPB:
V58.11 - V58.12 Encounter for antineoplastic chemotherapy and immunotherapy
ICD-9 codes contraindicated for this CPB:
001.0 - 139.8 Infectious and parasitic diseases [active infections]
279.00 - 279.9 Disorders involving the immune mechanism
293.0 - 293.9 Transient mental disorders due to conditions classified elsewhere [toxic psychosis > 48 hours - adverse effect of earlier IL-2 treatment]
345.00 - 345.91 Epilepsy and recurrent seizures [repetitive, difficult to control - adverse effect of earlier IL-2 treatment]
410.00 - 410.92 Acute myocardial infarction [if adverse effect of earlier IL-2 treatment]
413.0 - 413.9 Angina pectoris [if adverse effect of earlier IL-2 treatment]
423.3 Cardiac tamponade [if adverse effect of earlier IL-2 treatment]
423.8 - 423.9 Other and unspecified disease of pericardium [cardiac tamponade - adverse effect of earlier IL-2 treatment]
427.0 - 427.9 Cardiac dysrhythmias [sustained VT (5 beats) or arrhythmias not controlled/managed - adverse effect of earlier IL-2 treatment]
518.81 - 518.89 Respiratory failure, insufficiency, and other diseases of lung not elsewhere classified [requiring intubation > 72 hours - adverse effect of earlier IL-2 treatment]
557.0 - 557.9 Vascular insufficiency of intestine [bowel ischemia - adverse effect of earlier IL-2 treatment]
569.83 Perforation of intestine [adverse effect of earlier IL-2 treatment]
570 - 573.9 Diseases of liver [renal or hepatic impairment- adverse effect of earlier IL-2 treatment]
578.0 - 578.9 Gastrointestinal hemorrhage [requiring surgery - adverse effect of earlier IL-2 treatment]
584.5 - 586 Renal failure [requiring dialysis > 72 hours - adverse effect of earlier IL-2 treatment]
780.01 Coma [lasting > 48 hours - adverse effect of earlier IL-2 treatment]
780.39 Other convulsions [repetitive, difficult to control - adverse effect of earlier IL-2 treatment]
786.50 - 786.59 Chest pain [with EKG changes consistent with MI or angina - adverse effect of earlier IL-2 treatment]
794.2 Nonspecific abnormal results of function studies of the pulmonary system
794.31 Nonspecific abnormal electrocardiogram [ECG] [EKG] [with changes consistent with MI or angina - adverse effect of earlier IL-2 treatment]
794.39 Nonspecific abnormal results of cardiovascular function studies [abnormal thallium test - adverse effect of earlier IL-2 treatment]
V42.0 - V43.8 Organ or tissue grafts [allografts]
Subcutaneous administration:
CPT codes not covered for indications listed in the CPB:
96369 - 96371
96401 - 96402
ICD-9 not covered for indications listed in the CPB (not all inclusive):
189.0 - 189.1 Malignant neoplasm of kidney and renal pelvis
Intra-tumoral administration:
CPT codes covered for indications listed in the CPB:
96405
96406
HCPCS codes covered if selection criteria are met:
J9015 Injection, aldesleukin, per single use vial
ICD-9 covered if selection criteria are met:
172.0 - 172.9 Malignant melanoma of skin


The above policy is based on the following references:
  1. United States Pharmacopeial Convention, Inc. USP DI Oncology Drug Information 1997-1998. 1st ed. Rockville, MD: Association of Community Cancer Centers; 1997.
  2. Mosby-Year Book, Inc. Mosby's GenRx: The Complete Reference for Generic and Brand Drugs.  8th ed. St. Louis, MO: Mosby; 1998.
  3. American Society of Health-System Pharmacists, Inc. American Hospital Formulary Service Drug Information 98. Bethesda, MD: American Society of Health-System Pharmacists; 1998.
  4. Medical Economics, Inc. Physicians' Desk Reference. 52nd ed. Montvale, NJ: Medical Economics; 1998.
  5. Atzpodien J, Buer J, Sel S, et al. Chemoimmunotherapy in the systemic treatment of advanced renal carcinoma. Urologe A. 1999;38(5):474-478.
  6. Rocca Rossetti S, Terrone C. The therapy of metastatic renal carcinoma. Recenti Prog Med. 1999;90(4):206-212.
  7. Hidalgo Pardo F, Gutierrez Sanz-Gadea C, et al. [Immunotherapeutic treatment for metastatic renal carcinoma] Actas Urol Esp. 1998;22(1):29-33.
  8. Hidalgo OF, Aramendia JM, Alonso G, et al. Results of two sequential phase II studies of interleukin-2 (IL2) in metastatic renal cell carcinoma and melanoma: High-dose continuous intravenous IL2 infusion and subcutaneous IL2 administration in combination with alpha interferon. Rev Med Univ Navarra. 1996;40(3):6-12.
  9. Lissoni P, Barni S, Ardizzoia A, et al. Immunotherapy for metastatic renal carcinoma with interleukin-2 in a subcutaneous administration schedule of short duration. Subcutaneous IL-2 in renal carcinoma. Arch Ital Urol Androl. 1997;69(3):159-162.
  10. Lissoni P, Barni S, Tancini G, et al. [Clinical response and survival in metastatic renal carcinoma during subcutaneous administration of interleukin-2 alone. Subcutaneous IL-2 in renal carcinoma] Arch Ital Urol Androl. 1997;69(1):41-47.
  11. Atzpodien J, Kirchner H. The out-patient use of recombinant human interleukin-2 and interferon alfa-2b in advanced malignancies. Eur J Cancer. 1991;27(Suppl 4):S88-S91; discussion S92.
  12. Richards JM, Gale D, Mehta N, et al. Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol. 1999;17(2):651-657.
  13. Negrier S. Cytokines and cancer: Update in 1998. Bull Cancer. 1999;86(1):37-39.
  14. Proebstle TM, Fuchs T, Scheibenbogen C, et al. Long-term outcome of treatment with dacarbazine, cisplatin, interferon-alpha and intravenous high dose interleukin-2 in poor risk melanoma patients. Melanoma Res. 1998;8(6):557-563.
  15. Rosenberg SA, Yang JC, White DE, et al. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: Identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
  16. Keilholz U, Conradt C, Legha SS, et al. Results of interleukin-2-based treatment in advanced melanoma: A case record-based analysis of 631 patients. J Clin Oncol. 1998;16(9):2921-2929.
  17. Andres P, Cupissol D, Guillot B, et al. Subcutaneous interleukin-2 and interferon-alpha therapy associated with cisplatin monochemotherapy in the treatment of metastatic melanoma. Eur J Dermatol. 1998;8(4):235-239.
  18. Mitchell MS. Immunotherapy of melanoma. J Investig Dermatol Symp Proc. 1996;1(2):215-218.
  19. Cohen GL, Falkson CI. Current treatment options for malignant melanoma. Drugs. 1998;55(6):791-799.
  20. Nathan FE, Mastrangelo MJ. Systemic therapy in melanoma. Semin Surg Oncol. 1998;14(4):319-327.
  21. Vulcano M, Galassi N, Felippo M, et al. Interleukin-2 restores natural killer activity inhibited by sera from HIV+ hemophilic patients. Medicina (B Aires). 1999;59(2):162-166.
  22. Davey RT Jr, Chaitt DG, Albert JM, et al. A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. J Infect Dis. 1999;179(4):849-858.
  23. Hengge UR, Goos M, Esser S, et al. Randomized, controlled phase II trial of subcutaneous interleukin-2 in combination with highly active antiretroviral therapy (HAART) in HIV patients. AIDS. 1998;12(17):F225-F234.
  24. Bartlett JA, Berend C, Petroni GR, et al. Coadministration of zidovudine and interleukin-2 increases absolute CD4 cells in subjects with Walter Reed stage 2 human immunodeficiency virus infection: Results of ACTG protocol 042. J Infect Dis. 1998;178(4):1170-1173.
  25. Witzke O, Winterhagen T, Reinhardt W, et al. Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease. J Intern Med. 1998;244(3):235-240.
  26. De Paoli P, Zanussi S, Simonelli C, et al. Effects of subcutaneous interleukin-2 therapy on CD4 subsets and in vitro cytokine production in HIV+ subjects. J Clin Invest. 1997;100(11):2737-2743.
  27. Berg WJ, Divgi CR, Nanus DM, et al. Novel investigative approaches for advanced renal cell carcinoma. Semin Oncol. 2000;27(2):234-239.
  28. Bukowski RM. Cytokine combinations: Therapeutic use in patients with advanced renal cell carcinoma. Semin Oncol. 2000;27(2):204-212.
  29. Vallanti G, Bovolenta C, Brambilla A, et al. Immunologic reconstitution by interleukin-2: Facts and open questions. J Biol Regul Homeost Agents. 2000;14(1):41-44.
  30. Keilholz U, Eggermont AM. The emerging role of cytokines in the treatment of advanced melanoma. For the EORTC Melanoma Cooperative Group. Oncology. 2000;58(2):89-95.
  31. Scadden DT. Cytokine use in the management of HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16(Suppl 1):S23-S29.
  32. Philip PA, Flaherty L. Treatment of malignant melanoma with interleukin-2. Semin Oncol. 1997;24(1 Suppl 4):S32-S38.
  33. Bukowski RM, Novick AC. Clinical practice guidelines: Renal cell carcinoma. Cleve Clin J Med. 1997;64(Suppl 1):S1-S47.
  34. Atkins MB. Interleukin-2: Clinical applications. Semin Oncol. 2002;29(3 Suppl 7):12-17.
  35. Glaspy JA. Therapeutic options in the management of renal cell carcinoma. Semin Oncol. 2002;29(3 Suppl 7):41-46.
  36. Paredes R, Lopez Benaldo de Quiros JC, Fernandez-Cruz E, et al. The potential role of interleukin-2 in patients with HIV infection. AIDS Rev. 2002;4(1):36-40.
  37. Pau AK, Tavel JA. Therapeutic use of interleukin-2 in HIV-infected patients. Curr Opin Pharmacol. 2002;2(4):433-439.
  38. Agarwala S. Improving survival in patients with high-risk and metastatic melanoma: Immunotherapy leads the way. Am J Clin Dermatol. 2003;4(5):333-346.
  39. Baaten G, Voogd A C, Wagstaff J. A systematic review of the relation between interleukin-2 schedule and outcome in patients with metastatic renal cell cancer. Eur J Cancer. 2004;40(8):1127-1144.
  40. Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2004;(3):CD001425.
  41. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23(1):133-141.
  42. Atzpodien J, Schmitt E, Gertenbach U, et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: Results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer. 2005;92(5):843-846.
  43. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: A randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol. 2005;23(27):6747-6755.
  44. Grande C, Firvida JL, Navas V, Casal J. Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma. Anticancer Drugs. 2006;17(1):1-12.
  45. Kolitz JE. Current therapeutic strategies for acute myeloid leukaemia. Br J Haematol. 2006;134(6):555-572.
  46. Dummer R. Future perspectives in the treatment of cutaneous T-cell lymphoma (CTCL). Semin Oncol. 2006;33(1 Suppl 3):S33-S36.
  47. Petrella T, Quirt I, Verma S, et al.; Melanoma Disease Site Group. Single-agent interleukin-2 in the treatment of metastatic melanoma: A clinical practice guideline. Evidence-Based Series No. 8-5. Toronto, ON: Cancer Care Ontario (CCO); March 20, 2006.
  48. Hotte S, Waldron T, Canil C, Winquist E; Genitourinary Cancer Disease Site Group. Interleukin-2 in the treatment of patients with unresectable or metastatic renal cell cancer: A clinical practice guideline. Evidence-Based Series No. 3-8-2. Toronto, ON: Cancer Care Ontario (CCO); June 8, 2006.
  49. Centers for Disease Control and Prevention (CDC), Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD: Department of Health and Human Services (DHHS); October 10, 2006.
  50. Chien CH, Hsieh KH. Interleukin-2 immunotherapy in children. Pediatrics. 1990;86(6):937-943.
  51. Sasse AD, Sasse EC, Clark LG, et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database Syst Rev. 2007;(1):CD005413.
  52. Zlotta AR, Schulman CC. Biological response modifiers for the treatment of superficial bladder tumors. Eur Urol. 2000;37 Suppl 3:10-15.
  53. National Comprehensive Cancer Network (NCCN). Aldesleukin; Interleukin-2, recombinant. NCCN Drugs and Biologics Compendium. Fort Washington, PA: NCCN; 2009. Available at: http://www.nccn.org/. Accessed January 5, 2009.
  54. National Cancer Institute (NCI). Aldesleukin. Drug Information. Cancer Topics. Bethesda, MD: NCI; October 30, 2008. Available at: http://www.nci.nih.gov/cancertopics/druginfo/aldesleukin. Accessed January 5, 2009.
  55. Centers for Disease Control and Prevention (CDC), Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD: Department of Health and Human Services (DHHS); 2008.
  56. INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee, Abrams D, Lévy Y, Losso MH, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361(16):1548-1559.
  57. Gandhi RT. IL-2 and HIV: Two definitive studies published. Comment. JWatch Infect Diseases. 2009:3-3.
  58. No authors lsited. IL-2 immunotherapy does not benefit patients taking antiretrovirals. AIDS Patient Care STDS. 2009;23(3):221-222.
  59. Viard JP, Fagard C, Chaix ML, et al. Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients. AIDS. 2009;23(11):1383-1388.
  60. Filippetti M, Torsello A, Cordiali Fei P, et al. IL-2 bronchoscopic instillation and immune cell activation: Preliminary results of the BRIIL-2 study for treatment of pulmonary metastasis from renal cancer and melanoma. Clin Ter. 2009;160(2):139-143.
  61. Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: Results of the ALFA-9801 study. J Clin Oncol. 2010;28(5):808-814.
  62. Pett SL, Kelleher AD, Emery S. Role of interleukin-2 in patients with HIV infection. Drugs. 2010;70(9):1115-1130.
  63. Weide B, Derhovanessian E, Pflugfelder A, et al. High response rate after intratumoral treatment with interleukin-2: Results from a phase 2 study in 51 patients with metastasized melanoma. Cancer. 2010;116(17):4139-4146.
  64. Acién P, Velasco I, Acién M, Quereda F. Treatment of endometriosis with transvaginal ultrasound-guided drainage and recombinant interleukin-2 left in the cysts: A third clinical trial. Gynecol Obstet Invest. 2010;69(3):203-211.
  65. Duvic M, Sherman ML, Wood GS, et al. A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides. J Am Acad Dermatol. 2006;55(5):807-813.
  66. Gerami P, Guitart J, Rosen S, Kuzel TM. Interleukins in the treatment of mycosis fungoides. G Ital Dermatol Venereol. 2008;143(1):55-58.
  67. Buyse M, Squifflet P, Lange BJ, et al. Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia. Blood. 2011;117(26):7007-7013.
  68. 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.
  69. Bluestone JA. The yin and yang of interleukin-2-mediated immunotherapy. N Engl J Med. 2011;365(22):2129-2131.
  70. Pistoia V, Bianchi G, Borgonovo G, Raffaghello L. Cytokines in neuroblastoma: From pathogenesis to treatment. Immunotherapy. 2011;3(7):895-907.
  71. Russell HV, Shohet JM, Nuchtern JG. Treatment and prognosis of neuroblastoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed September 2012. 
  72. National Comprehensive Cancer Network (NCCN). Melanoma. NCCN Clinical Practice Guidelines in Oncology v.2.2014. Fort Washington, PA: NCCN; 2014.
  73. National Comprehensive Cancer Network (NCCN). Kidney cancer. NCCN Clincal Practice Guidelines in Oncology v.2.2014. Fort Washington, PA: NCCN, 2014.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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