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MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Original Issue Date (Created): 7/1/2002 Most Recent Review Date (Revised): 3/29/2016 Effective Date: 1/1/2017 POLICY RATIONALE DISCLAIMER POLICY HISTORY PRODUCT VARIATIONS DEFINITIONS CODING INFORMATION DESCRIPTION/BACKGROUND BENEFIT VARIATIONS REFERENCES I. POLICY Note: Throughout this policy, unless otherwise stated, the term “ESA” (erythropoiesis-stimulating agents) refers to epoetin alfa (Epogen®, Procrit®), and darbepoetin alfa (Aranesp®). The use of epoetin alfa, darbepoetin, or pegylated (PEG)-epoetin beta may be considered medically necessary for: treatment of anemia associated with chronic kidney disease.a,b,c The use of PEG-epoetin beta is investigational for all other indications. There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with these procedures The use of epoetin alfa or darbepoetin may be considered medically necessary for: treatment of anemia in cancer patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy1,2; treatment of anemia related to therapy with AZT (zidovudine) in HIV-infected patients1; reduction of allogeneic blood transfusion in surgery patients1; treatment of patients following allogeneic bone marrow transplantation; and treatment of patients with myelodysplastic syndromes to reduce transfusion dependency. treatment of patients with hepatitis C and anemia related to ribavirin treatment. In the medically necessary conditions noted above, the following criteria also apply: The lowest dose of ESAs should be used in order to avoid red blood cell transfusions, ESAs should not be used to raise the Hb level above 12 g/dL, and ESA therapy should not be administered without adequate iron stores. For the medically necessary use in cancer patients, these additional FDA criteria also apply: Epoetin or darbepoetin therapy should not be initiated at Hb levels ≥10 g/dL and Page 1 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Epoetin or darbepoetin treatment should be discontinued following the completion of a myelosuppressive chemotherapy course. 1 2 FDA-approved label for epoetin alfa (Epogen®, Procrit®) FDA-approved label for darbepoetin alfa (Aranesp®) The use of epoetin alfa or darbepoetin is considered investigational for: Treatment of patients following high-dose chemotherapy with autologous stem-cell support. Treatment of non-iatrogenic chronic anemia of cancer; Other cancer-associated anemia excepted as noted in the policy section Treatment of orthostatic hypotension There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with these procedures. a FDA-approved label for epoetin alfa (Epogen®, Procrit®). label for darbepoetin alfa (Aranesp®). c FDA-approved label for PEG-epoetin beta (Mircera®). b FDA-approved Policy Guidelines Non-myeloid malignancies include solid tumors and the non-myeloid hematologic malignancies myeloma, lymphoma, and chronic lymphocytic leukemia. Administration ESAs and pegylated (PEG)-epoietin beta are to be administered according to current FDAapproved labeling for each product, using recommended Hb levels for starting, stopping, and dose adjustment. This includes decreasing the dose of ESA as the Hb approaches the target level. Prior to commencing ESA or PEG-epoietin beta therapy, the patient’s iron stores, blood ferritin, and transferrin saturation should be evaluated, adjusted, and maintained within normal physiological limits. ESA therapy should not be administered without adequate iron stores. Blood Pressure Monitoring Blood pressure should be adequately controlled prior to initiation of ESA therapy and closely monitored and controlled during treatment ESAs and PEG-epoetin beta are contraindicated in patients with uncontrolled hypertension. Page 2 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Discontinuation Erythropoiesis-Stimulating Agents Patients with myelodysplastic syndromes should be initially limited to a 3-month trial period with ESA. If no response to ESA is observed, ongoing therapy would be futile. ESAs and PEG-Epoetin Beta Patients with chronic kidney disease who do not respond adequately over a 12-week dose escalation period should not have their ESA or PEG-epoetin beta dose increased further. Increasing ESA or PEG-epoetin beta dose further is unlikely to improve response and may increase risks; the lowest ESA or PEG-epoetin beta dose that maintains adequate Hb to avoid recurrent red blood cell transfusions should be used. Other causes of anemia should be evaluated. If responsiveness does not. Risk Evaluation and Mitigation Strategy Epoetin alfa and darbepoetin must be prescribed and dispensed in accordance with a risk evaluation and mitigation strategy (REMS) drafted by the manufacturer and approved by FDA.1 REMS for epoetin alfa and darbepoetin alfa each comprises elements to assure safe use and an implementation system. ESA manufacturers must ensure that all hospitals and healthcare professionals who prescribe and/or dispense ESAs to patients with cancer have enrolled and completed training in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program. The ESA APPRISE program began on March 24, 2010 after FDA’s initial approval of separate but similar REMS for epoetin alfa and darbepoetin alfa on February 16, 2010. Both REMS were subsequently modified, most recently on December 31, 2013. Healthcare providers and hospitals that prescribe and/or dispense an ESA for chronic kidney disease (CKD) must provide each patient with a copy of the REMS Medication Guide included in the product label and ensure that patients are adequately informed of the risks associated with ESA treatment. However, prescribers are not required to enroll in and complete the ESA APPRISE program. PEG-epoetin beta does not have a REMS. On March 27, 2012, FDA approved a REMS for peginesatide with a communication plan as its only component. The plan’s goal was to inform all healthcare professionals who might prescribe the drug Page 3 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 that peginesatide is indicated only for adult patients with CKD on dialysis, and of potentially fatal risks associated with its use in CKD patients not on dialysis. Peginesatide is currently discontinued. Cross-reference: MP-2.103 Off-Label Use of Medications II. PRODUCT VARIATIONS TOP This policy is applicable to all programs and products administered by Capital BlueCross unless otherwise indicated below. BlueJourney HMO* BlueJourney PPO* FEP PPO** * Refer to Centers for Medicare and Medicaid (CMS) National Coverage Determination (NCD) 110.21 Erythropoiesis-Stimulating Agents (ESA’s) in Cancer and Related Neoplastic Conditions. Also refer to the Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Chapter 15, section 50.5.2 for coverage of ESA’s for end-stage renal disease related anemia. ** For Procrit and Epogen - Refer to FEP Medical Policy Manual MP-5.10.16 EPOGEN / PROCRIT; for Aranesp refer to MP-5.10.01Aranesp. The FEP Medical Policy manual can be found at: www.fepblue.org III. DESCRIPTION/BACKGROUND TOP EPO is a glycoprotein hematopoietic growth factor synthesized by cells near the renal tubules in response to changes in the blood oxygen concentration. When a patient is anemic, the ability of the blood to carry oxygen is decreased. An oxygen-sensing protein in the kidney detects the decrease in blood oxygen concentration and induces the production of EPO, which then acts on the erythroid cell line in the bone marrow to stimulate hematopoiesis, thereby effectively increasing blood Hb concentrations. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin results in anemia in several disease processes, including chronic kidney disease (CKD), many types of cancer treatment, other chronic diseases, and use of certain drugs. The severity of anemia is defined by blood Hb concentration. Normal ranges are 12 to 16 g/dL in women and 14 to 18 g/dL in men. Mild anemia is defined as Hb from 10 g/dL to the lower limit of normal ranges, moderate anemia is 8 to 10 g/dL, and severe anemia is 8 g/dL or less. ESAs are produced using recombinant DNA technologies. They were initially developed as replacement therapy to treat anemia due to endogenous erythropoietin deficiency that commonly occurs in patients with CRF secondary to CKD. Patients with CRF will become severely anemic and experience severe fatigue and reduced exercise tolerance unless treated with blood transfusions or an Page 4 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ESA. Partial correction of anemia by ESA treatment of patients with CRF reduces the need for red blood cell (RBC) transfusions and enhances physical functioning. In cancer, anemia occurs with varying degrees of frequency and severity. It occurs most commonly in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment. Oncologic anemia occurs by a variety of mechanisms: (1) Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B12) essential for RBC production. (2) Antibodies and/or immunoregulatory abnormalities associated with certain tumor types (most commonly, B cell malignancies) may cause increased erythrocyte destruction (hemolysis). (3) Tumors may cause blood loss via tissue invasion, for example gastrointestinal bleeding from colon cancer. (4) Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment. (5) In more advanced cases, there may be marrow replacement with tumor or amyloid. (6) However, marrow dysfunction can occur even in the absence of frank invasion. (7) Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization, as well as a direct suppression of RBC production. Cancer treatments also may cause anemia: (1) radical cancer surgery can result in acute blood loss; and (2) radiotherapy and many cytotoxic chemotherapeutic agents suppress marrow to varying degrees. Damage is due to a variety of mechanisms. For example, alkylating agents cause cumulative DNA damage; antimetabolites damage DNA indirectly; and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells. RBC transfusion is the traditional approach to quickly ameliorate anemia symptoms. However, this approach carries risk for several potential adverse events. The highest adverse event risk (1 per 432 whole blood units transfused) is for transfusion-related acute lung injury (TRALI). Adverse events due to errors in transfusion (e.g., type mismatch) are estimated to occur at a rate of 1 per 5000 to 10,000 units of blood transfused. Current transfusion medicine and blood bank practices have significantly reduced the risk of transmissible infections, primarily due to better donor selection and screening for infectious diseases. Estimated risks per unit of blood transfused for transmission of hepatitis B virus (<1 in 400,000), hepatitis C virus (<1 in 1,000,000), HIV (<1 in 1,000,000), and bacterial contaminants (1 per 10,000 to 100,000) have fallen dramatically since the early 1990s. Therefore, although the initial impetus to commercialize erythropoietin replacement products was based on reduction in the risks associated with blood transfusion, current practices have mitigated many of those risks. Nonetheless, blood shortages, transfusion errors, and risks of alloimmunization and TRALI provide sufficient rationale for the use of ESA therapy in appropriately indicated patients. Four ESA products have been licensed in the United States: Epoetin alfa is manufactured, distributed, and marketed by Amgen, Inc. under the proprietary name, Epogen®. The same epoetin alfa product manufactured by Amgen Inc. is also marketed and distributed by Janssen Products, LP, a subsidiary of Johnson and Johnson, under the proprietary name, Procrit®. Under a contractual agreement with Amgen, Janssen Products LP has rights to develop and market Procrit® for any indication other than for Page 5 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 treatment of anemia associated with CRF in patients on dialysis or use in diagnostic test kits. Epogen® and Procrit® have identical labeling information for all FDA-approved indications. A second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp®. The third ESA product, peginesatide, was codeveloped and commercialized by Affymax Inc. and Takeda Pharmaceuticals, who market it under the proprietary name, Omontys®. In February 2013, Affymax, Takeda, and FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. FDA currently lists peginesatide (Omontys®) as discontinued. Epoetin beta was unavailable in the U.S. However, a methoxy pegylated (PEG) form of epoetin beta, called “continuous erythropoietin receptor activator” or CERA, has a prolonged half-life that permits once monthly dosing. PEG-epoetin beta was FDA-approved in 2007 and was marketed outside the U.S. by Hoffmann-LaRoche under the proprietary name Mircera®. Due to a copyright infringement lawsuit brought by Amgen in 2009, U.S. sales were prohibited until mid-2014. Epoetin alfa and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation2; clinical effects are considered interchangeable.2,3 Darbepoetin alfa is similar to endogenous erythropoietin but has 2 additional oligosaccharide chains. In contrast, peginesatide lacks any amino acid sequence homology to erythropoietin. It is a synthetic dimer of identical 21-amino acid peptides bound to a linker and to polyethylene glycol, with a total molecular weight of approximately 45,000 Da. (The molecular weight of endogenous erythropoietin is approximately 34,000 Da.) However, the epoetins, darbepoetin, and peginesatide all have pharmacologic actions similar to those of the endogenous hormone. Each binds to and activates the human erythropoietin receptor and thus increases the number of RBCs and the blood concentration of hemoglobin, when given to individuals with functioning erythropoiesis. Both epoetin alfas, PEGepoetin beta, and darbepoetin are FDA-approved to treat anemia in patients with CKD who are on dialysis or not on dialysis. Peginesatide is approved only for adult patients with anemia from CKD who are on dialysis. Epoetin alfa and darbepoetin also are approved for other indications (see Policy section). REGULATORY STATUS The major regulatory timelines for approval actions pertaining to new indications are summarized next: Epoetin alfa (Epogen®/Procrit®): 1989: Approved for use in patients with anemia due to CRF 1991: Approved for use in zidovudine-treated, HIV-infected patients 1993: Approved for chemotherapy-induced anemia in patients with nonmyeloid malignancies 1996: Approved for presurgical use in certain patients undergoing surgery Darbepoetin alfa (Aranesp®): 2001: Approved for use in patients with anemia due to CRF Page 6 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 2002: Approved for chemotherapy-induced anemia in patients with nonmyeloid malignancies Peginesatide (Omontys®): 2012: Approved for use in adults with anemia due to CKD who are on dialysis 2013: Voluntary recall of all lots due to postmarketing reports of serious hypersensitivity Methoxy polyethylene glycol (PEG) epoetin-beta (Mircera®) 2007: Approved for use in patients with anemia due to CRF who are on dialysis or not on dialysis 2009: Injunction prohibiting U.S. sales until mid-2014 due to copyright infringement 2014: Resumption of U.S. sales anticipated IV. RATIONALE TOP Two 1995 TEC Assessments (Myelodysplastic Syndrome and Chronic Anemia of Cancer - Tab 10; Allogeneic Bone Marrow Transplantation or High-Dose Chemotherapy with Autologous Stem-Cell Support - Tab 11) provided the basis for the original policy statements regarding these two settings. Primary data sources for oncology included a 2006 comparative meta-analysis on the outcomes of epoetin or darbepoetin for managing anemia in patients undergoing cancer treatment prepared for the Agency for Healthcare Research and Quality (AHRQ) and the 2005 AHRQ report, updated in 201335 ; a meta-analysis using individual patient data for outcomes of erythropoiesis-stimulating agent (ESA) therapy in patients with cancer,6,7 with additional outcomes reported in 20128; American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) 2010 clinical practice guidelines on the use of epoetin and darbepoetin to treat chemotherapy-associated anemia9; 2007 briefing documents available from the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC)2; and a 2007 Decision Memorandum from the Centers for Medicare and Medicaid Services on the use of ESAs for nonrenal disease indications.10 Information on the use of ESAs in chronic renal failure (CRF) was obtained from several sources including 2007 briefing documents from a joint meeting of FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) and Drug Safety and Risk Management Advisory Committee (DSRMAC) to reassess ESA risks11; and, a meta-analysis of blood hemoglobin (Hb) targets for patients with CRF-associated anemia.12 FDA-approved labels for ESAs available (or soon to be available) in the United States comprised additional data sources for this Policy, in particular, recommended dosing information for the different clinical settings covered.13-16 The 2010 ASCO/ASH clinical practice guideline for the use of ESAs considers epoetin and darbepoetin, used at dosages recommended in current FDA-approved package inserts, to be equivalent with respect to effectiveness and safety. Epoetin and darbepoetin are identical with respect to: (1) indications for use in chemotherapy-induced anemia, (2) Hb limits for adjusting doses, initiating or discontinuing treatment, (3) warnings and cautions to consider, and (4) increased rates Page 7 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 of thromboembolic events in the experimental arms of separate trials on each product versus controls/placebo.9 Chronic Kidney Disease (Chronic Renal Failure) Epoetin Alfa, Epoetin Beta, and Darbepoetin At initial approval of epoetin in 1989, the primary objective of treatment was to raise Hb concentration sufficiently to avoid transfusion, with a target range of 9 to 10 g/dL in anemic patients with chronic kidney disease (CKD). The first National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines in 1997 recommended an Hb concentration of 11 g/dL, a level that was increased by subsequent NKF-KDOQI anemia guidelines, to 11 to 13 g/dL in 2007.17 With increased experience in the use of ESAs, it became unclear whether higher Hb target concentrations, including normalization, would yield additional benefits, in particular in physical function and improved cardiovascular outcomes. Clinical doubts increased with publication of the first large randomized controlled trial (RCT) of Hb normalization using epoetin alfa in hemodialysis patients (Normal Hematocrit Cardiac Trial [NHCT]).18 NHCT showed a trend toward increased mortality risk and significantly increased risk for vascular access thrombosis with ESA treatment to a hematocrit (Hct) target of 42%. Subsequently, 4 published RCTs in hemodialysis patients with end-stage renal disease (ESRD) and 8 in nondialysis patients with CKD found improved physical function at higher Hb targets, but none demonstrated significant improvements in cardiovascular end points or mortality.19 The Epogen®/Procrit® label was modified in 1996 to include results of the NHCT study that showed a higher mortality rate for anemic dialysis patients randomized to an Hct of 42%, compared with an Hct of 30%. Ten years later, the CHOIR study reported worse cardiovascular outcomes for anemic CRF patients who were not undergoing dialysis and who were randomized to a target Hb of 13.5 g/dL, compared with an Hb of 11.3 g/dL.20 Subsequent analyses of outcomes in CHOIR showed shorter times to progression of kidney disease and higher rates of renal replacement therapy and death among patients randomized to the higher Hb target.21 The CREATE study, also reported in 2006, was similar to CHOIR but enrolled fewer patients.22 CREATE did not demonstrate statistically significant differences in adverse cardiovascular outcomes for the higher Hb group, but the general trend of major cardiovascular outcomes was similar to the CHOIR findings. The 2009 TREAT study randomized 4038 patients with type 2 diabetes mellitus, Hb of 11 g/dL or less, and CKD not on dialysis.23 Patients in 1 arm were treated with darbepoetin to a target Hb of 13 g/dL, and those in the other arm received darbepoetin only if Hb fell below 9 g/dL. Risks for 2 end points were not significantly different between arms: death or a cardiovascular event (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.94 to 1.17; p=0.41) and death or ESRD (HR=1.06; 95% CI, 0.95 to 1.19; p=0.29). However, fatal or nonfatal stroke was significantly increased among patients randomized to the higher Hb target (HR=1.92; 95% CI, 1.38 to 2.68; p<0.001). Multivariate analysis found no statistically significant relationship of increased stroke risk to any baseline characteristic; to effects on blood pressure, Hb, or platelet count; or to darbepoetin dose.24 A 2012 meta-analysis by Vinhas et al included only large RCTs (N >500) with a minimum duration of 1 year.25 Outcomes of interest were vascular access thrombosis, stroke, progression to ESRD, and Page 8 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 all-cause mortality. Five trials (7902 patients), including the CHOIR, CREATE, NHCT, and TREAT trials, were identified. Mean or median follow-up duration ranged from 14 to 36 months. As shown in Table 1, higher Hb targets were associated with increased risks of vascular access thrombosis and stroke but not with progression to ESRD or all-cause mortality. Table 1. Results of Meta-Analysis by Vinhas et al25 Outcome n/N Relative Riska 95% CI I2,b Vascular access thrombosis 2/1829 1.34 1.16 to 1.55 0% Stroke 4/7305 1.74 1.32 to 2.28 0% Progression to ESRD 3/6073 1.09 0.99 to 1.20 0% All-cause mortality 5/7902 1.15 0.98 to 1.35 0% CI: confidence interval; ESRD: end-stage renal disease; n/N: number of trials/number of patients. a Relative risk for outcome at higher Hb targets (13.0-15.0 g/dL) compared with lower Hb targets (9.5-11.5 g/dL). b Describes the proportion of total variation across studies that is due to heterogeneity rather than chance. In 2012, the American Society of Nephrology released its evidence-based recommendations for the “Choosing Wisely” campaign to improve patient care and resource use.26 Citing the evidence reviewed here, the society included the following among its top 5 recommendations: “Do not administer erythropoiesis-stimulating agents to CKD patients with hemoglobin levels ≥10 g/dL without symptoms of anemia.” A 2014 Cochrane review included 8 trials (total N=2051) that compared darbepoetin with epoetin (alfa or beta) in adults with anemia due to CKD.27 No statistically significant differences were observed in random effects meta-analyses of final Hb or mean change in Hb level, overall mortality, cardiovascular events or cardiovascular mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis. Risk of bias was rated as moderate to high, and statistical heterogeneity was minimal (I2=0%) for all outcomes. Pegylated Epoetin Beta FDA’s 2007 approval of PEG-epoetin beta (Mircera®) was based on 6 phase 3, international, openlabel, RCTs in patients with anemia due to CKD16 (see Table 2). In 2 trials (total N=505), patients were not receiving ESA therapy (correction trials), and in 6 trials (total N=1894), Hb was stable on maintenance ESA therapy (maintenance trials). All but1 trial (ARCTOS) enrolled dialysis-dependent patients. The primary efficacy outcome in all trials was maintenance of Hb levels over 24 to 52 weeks, adjusted for baseline Hb and center, in the intent-to-treat and per protocol patient samples. For this outcome, the trials demonstrated noninferiority of PEG-epoetin beta once or twice monthly to epoetin (alfa or beta) 1 to 3 times weekly (AMICUS, MAXIMA, PROTOS, RUBRA) and to darbepoetin weekly or twice monthly (ARCTOS and STRIATA). In the correction trials (ARCTOS and AMICUS), median time to response was longer in the PEG-epoetin beta groups (43 days and 57 days, respectively) compared with the darbepoetin (29 days) and epoetin (31 days) groups. Although target Hb ranges in these trials included levels that have since been associated with increased mortality in CKD (i.e., >11 g/dL),28 FDA’s summary review of safety (based on 1789 PEG-epoetin beta-treated patients [64% for >1 year] and 948 ESA-treated patients) reported that mortality was similar between the 2 groups (10% vs 11%, respectively).29 Incidence of serious adverse events also was similar between groups (37% vs 40%, respectively), although serious Page 9 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 bleeding events (5.2% vs 4%), serious gastrointestinal bleeding events (1.2% vs 0.2%), and thrombocytopenia less than 100109 platelets/L (7.5% vs 4.4%) occurred more commonly in PEGepoetin beta-treated patients. FDA reviewers attributed these imbalances to the greater proportion of patients on hemodialysis in the PEG-epoetin beta group (84% vs 80%), and considered the risks of hemorrhage and thrombocytopenia similar to or slightly increased above that for other ESAs. Trials excluded patients with poorly controlled hypertension; 27% of enrolled patients required increases in antihypertensive therapy.16 Table 2. Pivotal Trials of PEG-Epoetin Beta N Initial Dose Results % Respondersa Mean ΔHb,b g/dL Correction trials in patients not receiving ESA therapy Macdougall 2008 (ARCTOS)30,c PEG-epoetin beta 162 98 2.15 0.6 /kg SC q2wk Darbepoetin 162 96 2.00 0.45 /kg SC qwk P value <0.001d <0.001e Klinger 2007 (AMICUS)31 PEG-epoetin beta 135 93 2.70 0.4 /kg IV q2wk Epoetin alfa/beta 46 91 2.56 Per product label IV 3/wk P value <0.001d <0.001e Maintenance trials in patients receiving ESA therapy Levin 2007 (MAXIMA)32 PEG-epoetin beta IV q2wk 223 ‒ -0.71 PEG-epoetin beta IV q4wk 224 ‒ -0.25 Epoetin alfa/beta IV q1-3x/wk 226 ‒ -0.75 P value vs control ‒ <0.001ef Sulowicz 2007 (PROTOS)33 PEG-epoetin beta SC q2wk 190 76 -0.03 PEG-epoetin beta dose PEG-epoetin beta SC q4wk 191 66 -0.13 based on maintenance Epoetin alfa/beta SC q1-3x/wk 191 72 -0.11 ESA dose P value vs control ‒g <0.001ef Canaud 2008 (STRIATA)34 Comparator ESA dose PEG-epoetin beta IV q2wk 157 66 0.06 was continuation of Darbepoetin IV q1-2wk 156 72 -0.12 maintenance dose P value 0.25h <0.001e Spinowitz 2008 (RUBRA)35 PEG-epoetin beta SC/IV q2wk 168 69 0.09 Epoetin alfa/beta SC/IV q1-2wk 168 68 -0.03 P value ‒i <0.001e ESA: erythropoiesis-stimulating agents; Hb: hemoglobin; IV: intravenous; PEG: pegylated; q2wk: every 2 weeks; q4wk: every 4 weeks; SC: subcutaneous. a Defined as: ARCTOS: Hb level ≥11 g/dL and increased ≥1.0 g/dL from baseline at 28 wk; target Hb 11-13 g/dL AMICUS: Hb level ≥11 g/dL and increased ≥1.0 g/dL from baseline at 24 wk; target Hb 11-13 g/dL PROTOS, STRIATA: Mean Hb within ±1 g/dL of baseline values through 52 wk; target Hb 10-13.5 g/dL b Change from baseline Hb at 24 wk (AMICUS), 28 wk (ARCTOS), 36 wk (MAXIMA, STRIATA, RUBRA), or 52 wk (PROTOS). c Patients with stage 3 or 4 CKD (creatinine clearance <59 mL/min) who were not on dialysis. d For noninferiority to a predefined minimum of 60%. e For noninferiority to comparator; noninferiority margin for difference in mean Hb level (PEG-epoetin beta minus comparator), -0.75 g/dl. f Both comparisons. Page 10 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 g Trial investigators did not report statistical testing. Neither PEG-epoetin beta group was statistically different from comparator by 2 test (author calculation; p=0.52 for q2wk PEG-epoetin beta, p=0.36 for q4wk PEG-epoetin beta). h Chi-square test. i Trial investigators did not report statistical testing. There was no statistical difference between groups by 2 test (author calculation; p=0.88). A 2014 Cochrane review included random effects meta-analyses of the 5 trials in dialysis patients listed in Table 2 and reported no statistical between-group differences in final Hb level (compared with epoetin), overall mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis.36 In the STRIATA trial, final Hb level was statistically higher in the PEG-epoetin group compared with the darbepoetin group (mean difference, 0.30 g/dL [95% CI, 0.05 to 0.55]). Risk of bias was rated as low to moderate, and statistical heterogeneity was low to moderate (I2 range, 0%-34%). Since FDA approval, subsequent short-term trials (24-40 weeks; total N=841) have replicated the findings of the pivotal correction trials in patients on hemodialysis37 and not on hemodialysis,38,39 and of the pivotal maintenance trials in patients on hemodialysis.40,41 Of 324 nondialysis patients in the ARCTOS correction trial, 296 (96%) entered a 24-week extension study.42 Patients who responded to PEG-epoetin beta biweekly (n=145) were rerandomized 1:1 to biweekly or monthly dosing to maintain Hb between 11 to 13 g/dL. Mean (SD) Hb levels were 11.9 (0.9) g/dL, 11.7 (0.9) g/dL, and 11.9 (1.0) g/dL in the PEG-epoetin biweekly, PEG-epoetin monthly, and darbepoetin (weekly or biweekly) groups (n=151), respectively. Within-patient variation in Hb levels was similar across groups. Peginesatide FDA approved Omontys® (peginesatide) to treat anemia in CKD patients on dialysis in March 2012 based on 2 randomized active-controlled noninferiority trials, which were summarized in a TEC Specialty Pharmacy Report.43 The first trial, EMERALD-1, enrolled 803 patients in the United States, and controls received epoetin alfa (Epogen®, Procrit®). The second trial, EMERALD-2, enrolled 823 patients in the United States and Europe, and controls received epoetin alfa or epoetin beta (not available in the United States). Adults on dialysis for at least 3 months with stable Hb concentrations (between 10.0 g/dL and 12.0 g/dL) on ESA therapy for at least 8 weeks were eligible for randomization to peginesatide once monthly or continued epoetin 1 to 3 times weekly for 36 weeks. Results for the primary efficacy outcome (between-arm difference of the change from baseline Hb to the mean value during weeks 29 to 36 [the evaluation period], with a noninferiority margin of -1.0 g/dL) demonstrated the noninferiority of peginesatide in each trial (-0.15 g/dL in EMERALD-1, +0.10 in EMERALD-2). The relative risk (RR) for red blood cell (RBC) transfusion also did not differ significantly between arms (RR=1.21; 95% CI, 0.76 to 1.92 in EMERALD 1; RR=0.79; 95% CI, 0.50 to 1.24 in EMERALD-2). Two other trials (PEARL-1 and PEARL-2; total N=656 randomized to peginesatide, N=327 to darbepoetin) were conducted for patients with CKD who were not on dialysis. The trials prospectively evaluated cardiovascular risk of ESAs. The 4 trials together were powered for a primary safety outcome, which was to rule out an increase of 30% or more in the risk of the composite safety end point, based on a 2-sided 90% CI. The composite safety end point comprised Page 11 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 death, stroke, myocardial infarction, and hospitalization for congestive heart failure, unstable angina or arrhythmia. Incidence of the composite safety outcome did not differ significantly between groups randomized to peginesatide or active comparator (HR=1.06; 95% CI, 0.89 to 1.26). In an analysis limited to the 2 trials of patients on dialysis (EMERALD-1 and -2), the 2 groups again did not differ with respect to incidence of the composite safety end point (HR=0.95; 90% CI, 0.79 to 1.13). However, peginesatide significantly increased the incidence of this composite safety end point in a pooled analysis of the 2 trials for patients not on dialysis (PEARL-1 and -2; HR=-1.32; 90% CI, 1.02 to 1.72). Cardiovascular harms in the nondialysis population were considered unacceptably high and the indication was abandoned. The risk evaluation and mitigation strategy (REMS) communication plan developed by the manufacturer and approved by FDA (see Policy Guidelines section) was designed to inform health care providers who might prescribe peginesatide of these findings. Note also that thus far, no data are available on safety or efficacy of peginesatide for any other ESA indications (e.g., patients with a nonmyeloid malignancy who are anemic while receiving palliative chemotherapy, HIV patients who are anemic while receiving zidovudine, or perisurgical patients unable to donate autologous blood). On February 23, 2013, Affymax, Takeda, and FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis.44 Serious reactions occurred within 30 minutes of the first dose of peginesatide; serious reactions after subsequent doses have not been reported. Among approximately 25,000 patients who received peginesatide postapproval, the estimated overall incidence of hypersensitivity reactions was 2 per 1000, and the estimated incidence of fatal reactions was 2 per 10,000. FDA currently lists peginesatide (Omontys®) as “Discontinued” on its website (Drugs@FDA). Section Summary Three ESAs are FDA-approved for use in patients with CRF: epoetin alfa, pegylated epoetin beta (PEG-epoetin beta), and darbepoetin alfa; PEG-epoetin beta is expected to be available in the U.S. soon. Placebo-controlled clinical trials have established that epoetin alfa and darbepoetin alfa effectively increase Hb concentrations and decrease the need for blood transfusions. Evidence does not support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or quality of life (QOL). Some trials and a meta-analysis published in 2012 have reported increased cardiovascular events and/or increased mortality in patients treated with ESAs. These trials generally have treated to a Hb of 12 g/dL or higher. The optimal target Hb is unclear, and it is uncertain whether treating to lower Hb levels avoids the increase in adverse events. Both peginesatide and PEG-epoetin beta have been compared with other ESAs in randomized trials. Peginesatide has shown noninferiority to epoetin for adult patients with CRF on dialysis. There are no trials reporting benefit for peginesatide for other indications or in pediatric patients with kidney disease. Currently, peginesatide is unavailable and should not be used. PEG-epoetin beta has shown noninferiority to epoetin and darbepoetin for correcting or maintaining Hb levels in RCTs of patients on dialysis or not on dialysis. In meta-analyses of trials in dialysis patients, no statistical differences were reported in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. PEG-epoetin beta currently is unavailable in the U.S. Page 12 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Oncology Epoetin Alfa, Epoetin Beta, and Darbepoetin In 1993, FDA approved Procrit®/Epogen® (epoetin alfa) to treat anemia in patients receiving cancer chemotherapy based on data from 2 multicenter randomized placebo-controlled, double-blind clinical trials; 1 enrolled 344 adult patients and the second enrolled 222 pediatric patients, and an additional pooled analysis of 6 smaller double-blind RCTs enrolled a total of 131 patients. Patients in all 3 studies received at least 12 weeks of concurrent chemotherapy and were randomized (1:1) to receive Procrit®/Epogen® or placebo subcutaneously for 12 weeks. Overall, the data showed a reduction in the proportion of patients requiring blood transfusion during the second and third months of epoetin treatment. The approval of Aranesp® (darbepoetin alfa) in 2002 for the treatment of anemia associated with cancer chemotherapy was based on demonstration of a significant reduction in the proportion of patients transfused during chemotherapy from week 5 through the end of treatment. Study 980297, a phase 3, double-blind, placebo-controlled randomized (1:1) multicenter, multinational trial of darbepoetin alfa enrolled 314 anemic patients with previously untreated non-small cell or small cell lung cancer receiving at least 12 weeks of platinum-containing chemotherapy. After the first approval of an ESA) for treatment of chemotherapy-associated anemia in 1993, additional data became available regarding increased risks of mortality and possible tumor promotion from the use of ESAs. Increased mortality has been observed in patients with cancer (BEST, ENHANCE, 20000161, EPO-CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain Hb levels above 12 g/dL.9 In addition, ESA treatment strategies intended to achieve and maintain Hb levels above 12 g/dL have demonstrated poorer tumor outcomes (BEST, ENHANCE, DAHANCA studies). More recently, a 2009 meta-analysis using individual patient data on 13,933 subjects from 53 RCTs reported significantly greater on-study mortality (HR=1.17; 95% CI, 1.06 to 1.30) and poorer survival to end of follow-up (HR=1.06; 95% CI, 1.00 to 1.12), with little heterogeneity between trials.6,7 Results were qualitatively similar when the analysis was limited to 10,441 patients receiving concurrent chemotherapy in 38 trials, and there was little evidence for a difference between trials of patients receiving different chemotherapy regimens. Data from multiple trials, consistent with data presented to ODAC in May 2004, led to revised product labeling with broader and more detailed warnings against ESA treatment strategies targeting Hb levels above 12 g/dL. More recent data, including the individual patient data meta-analysis summarized earlier,6,7 suggested that factors such as the planned Hb ceiling for stopping ESA therapy had little influence on increased mortality resulting from ESA treatment. Although risks of Hb targets greater than needed to avoid transfusions are now well-established, data from adequate, well-controlled studies employing recommended ESA doses and Hb targets are as yet insufficient to assess effects on survival or tumor promotion. The only data provided to FDA which used the recommended dose and Hb target was from Amgen Study 20010103, which demonstrated significantly shorter survival in cancer patients receiving ESAs compared with those supported by transfusion alone. However, this study was not adequately designed to assess effects on tumor promotion or on thrombotic risks. Page 13 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Despite these caveats, data from available studies were sufficient for FDA to reassess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting. Results of the updated AHRQ comparative effectiveness review (2013) were consistent with those reported in 2006.3 Among patients receiving chemotherapy and/or radiotherapy for malignancy, use of ESAs to treat anemia reduced the risk of transfusion and increased the risk of thromboembolic events and on-study mortality. Both thromboembolic events and on-study mortality were reduced (but not eliminated) when ESA treatment was initiated at Hb less than 10 g/dL. Although the reviewed evidence incorporated higher baseline and target Hb levels than those currently recommended, sensitivity analyses suggested that these findings were robust. QOL, as assessed by the Functional Assessment of Cancer Therapy (FACT) fatigue scale, was improved in patients receiving ESAs, but the magnitude of improvement was less than the minimal clinically important difference of 3 points. Fifteen included trials did not support an association between ESA use and tumor response or progression; meta-analysis was not possible due to varying outcome definitions. The AHRQ update incorporated the individual patient data meta-analysis previously described.6,7 Despite differing inclusion criteria and methodologies, additional analyses of these data by Tonia et al (2012)8 supported results of the updated AHRQ review, as shown in Table 3. Table 3. 2013 AHRQ Report and 2012 Individual Patient Data: Comparison of Updated Results 2013 AHRQ3 2012 Individual Patient Data8 n/N Result (95% CI) n/N Result (95% CI) Transfusions, RR 38/10,809 0.58 (0.53 to 0.64) 70/16,093 0.65 (0.62 to 0.68) Thromboembolic events, RRa 37/12,570 1.51 (1.30 to 1.74) 57/15,278 1.52 (1.33 to 1.73) On-study mortality, HRa 37/11,266 1.17 (1.04 to 1.31) 70/15,935 1.17 (1.06 to 1.29) Tumor response, RRa 15/5577 Not pooledb 15/5012 1.02 (0.98 to 1.06) FACT-fatigue, mean difference 14/3643 2.74c (1.69 to 3.78) 18/4965 2.08c (1.43 to 2.72) Overall survival, HR for death 44/14,278 1.04 (0.99 to 1.10) 78/19,003 1.05 (1.00 to 1.11) Hypertension, RR 16/4318 1.48 (1.07 to 2.06) 31/7228 1.12 (0.94 to 1.33) Thrombocytopenia/hemorrhage, RRa 12/3714 1.17 (1.01 to 1.36) 21/4507 1.21 (1.04 to 1.42) CI: confidence interval; FACT: Functional Assessment of Cancer Therapy; HR: hazard ratio; n/N: number of trials/number of patients; RR: relative risk. a Results are similar between the 2 analyses. b No evidence of an association with erythropoiesis-stimulating agents. c Point estimate is less than the minimal clinically important difference (3 points). A 2014 meta-analysis examined the incidence of thromboembolic events in patients with solid and hematologic cancers who received ESAs, and found a similar result.45 Gao et al pooled 51 RCTs (12,115 patients) and reported a 75% increased odds of thromboembolic events among patients receiving ESAs (pooled odds ratio, 1.75; 95% CI, 1.50 to 2.05; I2=0%). Pegylated Epoetin Beta PEG-epoetin beta is not FDA-approved for anemia due to cancer chemotherapy,16 and HoffmannLaRoche, manufacturer of PEG-epoetin beta, has not sought this indication.29 A 2010 phase 2, openlabel RCT by Gascon et al compared 3 doses of subcutaneous PEG-epoetin beta with subcutaneous darbepoetin in 153 patients who were receiving first-line chemotherapy for stage 3B or 4 non-smallcell lung cancer.46 Baseline Hb at screening was 11 g/dL or less. PEG-epoetin beta was administered every 3 weeks, and darbepoetin was administered weekly or every 3 weeks. The primary efficacy Page 14 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 outcome, mean change from baseline Hb during weeks 5 to 13, did not differ between groups and indicated inadequate treatment responses in all groups (0.17 g/dL and 0.26 g/dL in the PEG-epoetin beta and darbepoetin groups, respectively). At week 12, the trial was terminated due to more deaths in the 3 PEG-epoetin beta groups compared with the darbepoetin group (29 [25%] of 114 patients vs 4 [10%] of 39 patients, respectively). Post hoc analyses did not convincingly demonstrate that baseline imbalances accounted for the mortality difference. Section Summary Epoetin alfa and darbepoetin alfa are approved for patients with anemia associated with concurrent cancer chemotherapy. These ESAs effectively increase Hb concentrations and decrease the need for blood transfusions in patients with anemia caused by cancer chemotherapy. The evidence does not support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or QOL. Some trials have reported higher thromboembolic events and/or mortality in cancer patients treated with ESAs, and 2 meta-analyses published in 2012 and 2013 also reported increases in mortality and thromboembolic events. Trials that reported increased adverse events have generally treated to a Hb of 12 g/dL or higher, and adverse events appear to be correlated with higher treatment targets. However, it is unclear whether treating to a lower Hb reduces or eliminates these adverse events. These concerns over potential harm from ESAs have led FDA to reassess the risk/benefit ratio and to modify the labeled indications. Current FDA labeling recommends against starting ESA therapy in a cancer patient whose Hb exceeds 10 g/dL. PEG-epoetin beta is not FDA-approved for patients with anemia due to cancer chemotherapy. A phase 2 RCT demonstrated increased mortality among patients with advanced non-small cell lung cancer who received PEG-epoetin beta compared with those who received darbepoetin. ESAs for Treatment of Hepatitis C-Related Anemia Standard treatment for hepatitis C infection includes ribavirin. Anemia related to ribavirin use often is the limiting step in treatment. Options for treatment of ribavirin-related anemia are reduction in the dose of ribavirin and use of ESAs and/or blood transfusions as needed. However, a reduction in ribavirin dose has been associated with less favorable response rates, and some experts therefore prefer using ESAs to maintain full-dose ribavirin. Evidence on the benefit of using ESAs for this purpose comprises several RCTs, some of which are reviewed next. At least 2 RCTs randomized patients with hepatitis C and ribavirin-related anemia to epoetin alfa or usual care. The larger of these was conducted by Afdhal et al (2004).47 This trial included 185 patients with a Hb level of 12 g/dL or less who received 8 weeks of epoetin alfa at a dose of 40,000 units weekly. Outcomes included the proportion of patients who were able to maintain full-dose treatment with ribavirin, mean Hb level, and QOL as measured by 36-Tiem Short-Form Health Survey. More patients in the epo group (88%) than in the usual care group (60%, p<0.001) were able to maintain full-dose ribavirin. Increase in mean Hb level also was higher in the epo group (2.2 g/dL) than in the usual care group (0.1 g/dL, p<0.001). Improvement in QOL was significantly greater for the epo group on 7 of 8 domains, with incremental improvement ranging from 1.3 to 10.0 for patients on epoetin. Page 15 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 A second RCT by Dieterich et al (2003) was similar to the Afdhal trial.48 Dieterich et al enrolled 64 patients with hepatitis C and ribavirin-related anemia, as defined by Hb less than 12 g/dL. Patients were followed for 16 weeks and treated with epoetin alfa 40,000 units weekly. Primary end points were ribavirin dose and Hb level. Mean ribavirin dose decreased less in the epoetin group (-34 mg/d) than in the usual care group (-146 mg/d), but this difference was not statistically significant (p=0.06). More patients in the epo group (83%) than in the usual care group (54%, p=0.02) were able to maintain full-dose ribavirin. Mean Hb level was higher in the epo group (13.8 g/dL) than in the usual care group (11.4 g/dL, p<0.001). A third RCT by Shiffman et al (2007) evaluated ESAs for anemia in patients with hepatitis C who were treated with ribavirin.49 This trial randomized 150 patients to 3 groups at the onset of treatment: (1) ribavirin at standard dose; (2) ribavirin at standard dose plus epoetin alfa; and (3) ribavirin at higher dose plus epoetin alfa. Primary end points were reduction in ribavirin dose and the proportion of patients with a sustained virologic response (SVR). Fewer patients treated with epoetin required dose reduction (10%) compared with patients not treated with epo (40%, p<0.05), but the proportion of patients with SVR did not differ between groups. Section Summary RCTs of ESAs versus placebo for patients with hepatitis C and ribavirin-related anemia have demonstrated that use of ESAs can improve Hb levels and allow more patients to maintain treatment at full ribavirin doses. One RCT also reported improvement in QOL for patients treated with ESAs. Improvements in these parameters may lead to health outcome benefits, although no study has reported an improvement in clinical outcomes such as SVR or survival. Postapproval FDA Regulatory Actions In November 2006, FDA issued a Public Health Advisory regarding the serious cardiovascular risks from ESA therapy in patients with CKD evidenced in the CHOIR study and the NHCT study.50 Subsequently, FDA received reports of increased risks associated with ESAs used to treat anemia in cancer patients who were receiving or not receiving chemotherapy, as well as a report of thrombotic risks in patients receiving ESAs in the perisurgical setting. These data prompted reassessment of the safety information contained in the Aranesp®, Epogen®, and Procrit® labels and culminated in the approval of revised labels on March 9, 2007. Product labels have been revised and updated subsequently, most recently in December 2013.50 Regarding dosage information, periodic reassessment of ESA safety has determined that clinical data do not support a therapeutic Hb target free of risk for mortality. Consequently, revised “Dosage and Administration” sections of the product label deleted any specific therapeutic Hb or Hct "target" range for ESAs. Instead, revised labels recommended that prescribers use the lowest ESA dose that will gradually increase Hb concentration to the lowest level sufficient to avoid the need for RBC transfusion. For anemic CRF patients, this recommendation was primarily based on the NHCT and CHOIR study findings, as well as the lack of data for any specific Hb or Hct threshold or range. Clinical data did not identify specific Hb or Hct levels that directly correlated with a "reduction in the need for red blood cell transfusion," the main treatment benefit supporting ESA efficacy. The Page 16 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 March 2007 label revision allowed prescribers to use their clinical judgment in determining the "lowest level sufficient to avoid the need for red blood cell transfusion." On November 8, 2007, FDA revised the product labeling for epoetin alfa and darbepoetin alfa.11 These revisions clarified the evidence for safety and effectiveness of these products and provided more explicit directions and recommendations for their use. These recommendations were consistent with those made during the May 10, 2007 ODAC and the September 11, 2007 CRDAC and DSRMAC meetings. Revisions included strengthened boxed warnings and “Warnings and Precautions” sections, and changes to the “Indications and Usage,” “Clinical Trials Experience”, and “Dosage and Administration” sections of the product labels. Product labels for Epogen®/Procrit® and Aranesp® have been revised many times since then. The revised black box warnings and limitations of use shown next reflect current labeling for these ESAs.13-15 Although the Mircera® product label has not been updated since 2007, “Warnings” for use in CRF are similar to those listed next.16 Cancer ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small-cell lung, head, and neck, lymphoid, and cervical cancers. Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense an ESA to patients with cancer. To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Discontinue after the completion of a chemotherapy course. Chronic Renal Failure In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a Hb level of greater than 11 g/dL. No trial has identified a Hb target level, ESA dose, or dosing strategy that does not increase these risks. Use the lowest Epogen®/Procrit® or Aranesp® dose sufficient to reduce the need for RBC transfusions. Perisurgery (Epogen®/Procrit® only) Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended. Page 17 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Limitations of Use Epogen®/Procrit® and Aranesp® have not been shown to improve QOL, fatigue, or patient wellbeing (for any indication). Epogen®/Procrit® and Aranesp® are not indicated for use: In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. As a substitute for RBC transfusions in patients who require immediate correction of anemia Epogen®/Procrit® also is not indicated for use: In patients scheduled for surgery who are willing to donate autologous blood. In patients undergoing cardiac or vascular surgery. On February 23, 2013, FDA announced a voluntary recall of all lots of peginesatide (Omontys®) due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. Peginesatide is currently discontinued. Clinical Input Received Through 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. Responses were received from 4 academic medical centers and 2 specialty societies in 2012. Reviewers agreed with the current medically necessary indications. There was support among reviewers for treatment of patients with hepatitis C and ribavirin-related anemia. For investigational indications, reviewers agreed with the current policy statements. Summary of Evidence This policy is based on available clinical trial evidence, as well as on recommendations for use from the Food and Drug Administration (FDA) and from specialty societies. Erythropoiesis-stimulating agents (ESAs) have been used extensively in patients with anemia due to cancer chemotherapy or renal failure. Initial trials of epoetin alfa and darbepoetin alfa established that these agents effectively increase hemoglobin (Hb) concentrations and decrease the need for blood transfusions. However, these agents also have been associated with increases in thromboembolic events and/or mortality, especially when the target Hb for treatment is higher. These concerns over potential harm from ESAs led FDA to reassess the risk/benefit ratio and to modify labeled indications. Modifications include treating to a lower target Hb and limiting ESA use in cancer to patients receiving myelosuppressive treatment with palliative intent whose Hb concentration is less than 10 Page 18 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 g/dL. These additional recommendations have led to more limitations on ESA use and enhanced surveillance systems that are intended to closely monitor and mitigate the risk of adverse events. Based on these factors, epoetin alfa and darbepoetin alfa may be considered medically necessary for patients with chronic renal failure (CRF) when used under the guidelines in the policy statement. Epoetin alfa and darbepoetin alfa may be considered medically necessary in patients on dialysis and not on dialysis and in pediatric patients with renal disease. For patients with cancer chemotherapyassociated anemia, epoetin alfa and darbepoetin may be considered medically necessary when used under the guidelines in the policy statement. For patients with hepatitis C and anemia related to ribavirin treatment, epoetin and darbepoetin may be considered medically necessary as a method for avoiding dose reduction of ribavirin. Pegylated (PEG)-epoetin beta is a long-acting epoetin that is FDA-approved for patients with anemia due to CRF. Evidence for this indication comprises RCTs in patients on dialysis or not on dialysis that showed noninferiority to standard ESAs for correction or maintenance of Hb levels. Metaanalyses in dialysis patients reported no difference in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. Based on this evidence, PEGepoetin beta may be considered medically necessary for treatment of anemia due to CRF. For treatment of anemia due to cancer chemotherapy, 1 phase 2 trial showed increased mortality with PEG-epoetin beta compared with darbepoetin. PEG-epoetin beta is expected to become available in the United States soon. SUPPLEMENTAL INFORMATION Practice Guidelines and Position Statements ESAs in Chronic Kidney Disease In 2007, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative updated its evidence-based, consensus guidelines for the treatment of anemia in chronic kidney disease.17 The guidelines reviewed evidence for epoetin alfa, epoetin beta, and darbepoetin. Updated recommendations included Hb target of 11 to 12 g/dL (consensus recommendation); target Hb should not exceed 13 g/dL (guideline supported by moderately strong evidence). Guideline authors provided no specific Hb level at which to initiate ESA therapy and emphasized that treatment decisions should be individualized (consensus recommendation). ESAs in Oncology Table 4 summarizes current clinical practice guidelines published jointly by the American Society of Clinical Oncology and the American Society of Hematology9 and from the National Comprehensive Cancer Network, version 2.2015.51 Table 4. Summary of Current Guidelines for Treatment of Anemia in Patients with Cancer ESAs are indicated for: American Society of Clinical Oncology/American Society of Hematology 2010 Clinical Practice Guideline ESAs are a recommended treatment option for patients with chemotherapy-associated National Comprehensive Cancer Network Guidelines, Cancer and ChemotherapyInduced Anemia (v. 2.2015) Based on patient preference and values, patients undergoing palliative treatment or Page 19 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ESAs are NOT indicated for: ESA treatment symptom outcomes REMS Hb levels for ESA initiation Span of ESA treatment ESA dosing modifications Hb target Iron Thromboembolic risk anemia; RBC transfusion may also be an option ESAs are also a treatment option for patients with lower risk MDS who are not undergoing concurrent chemotherapy “Although FDA label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent . . . determining the treatment intent requires clinical judgment of an individual patient’s circumstances.” Clinicians should consider other correctable causes of anemia before considering ESA therapy Recommends against using ESAs to treat anemia associated with malignancy in patients (excepting those with lower risk MDS) who are not receiving concurrent myelosuppressive chemotherapy Evidence does not conclusively show that ESA use leads to improved quality of life as can be perceived and valued by patients; recommends that the goal of ESA use should be to avoid transfusions. Notes requirement Recommended when Hb level has decreased to <10 g/dL. Whether to initiate treatment when Hb is between 10 and 12 g/dL should be determined by clinical judgment, consideration of ESA risks and benefits (transfusion avoidance), and patient preferences Transfusion is also an option Recommends discontinuing ESA treatment when chemotherapy concludes, per FDA guidelines Recommends ESA starting doses and dose adjustments follow FDA guidelines, noting that alternative doses and schedules have not improved medical outcomes Refers to product label directing clinicians to use the lowest possible ESA dose (i.e., minimize ESA exposure) to reach the lowest Hb level sufficient to avoid RBC transfusions Hb can be raised to the lowest Hb level needed to avoid RBC transfusions. An optimal target Hb cannot be determined from the available evidence Iron studies at baseline and periodically during treatment may be valuable to minimize the need for ESA treatment, maximize improvement of symptoms, or determine the reason for failure to respond Caution is urged in the use of these agents with patients judged to be at high risk for thromboembolic events, and regarding ESA myelosuppressive chemotherapy without curative intent may be treated with ESAs using FDA-approved indications/dosing/dosing adjustments, under REMS guidelines, with informed consent of patient OR may be treated with RBC transfusions per provided guidelines Patients with anemia due to myelosuppressive chemotherapy should be assessed for risk of adverse events due to anemia and need for initial transfusion ESA treatment is not recommended when patients are treated with myelosuppressive chemotherapy with curative intent Not discussed Notes requirement If Hb is <11 g/dL or >2 g/dL below baseline, an evaluation for possible causes of anemia is suggested. If a cause is not identified, then anemia due to myelosuppressive chemotherapy is considered. Physicians are advised not to administer ESAs outside the treatment period of cancer-related chemotherapy Dosing and titration directions for epoetin-alfa and darbepoetin-alfa are reproduced from FDAapproved labels; alternative dosing regimens are provided, e.g., every 2 or 3 wk instead of weekly injections No Hb target is mentioned; notes that the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to a target Hb <12 g/dL Iron studies and supplementation of functional iron deficiency are recommended for patients treated with ESAs Patients with previous risk factors for thrombosis may be at higher risk when administered ESAs and should undergo risk Page 20 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 use together with therapies that increase risk assessment; the risk of ESA-associated of thromboembolic events thrombosis is independent of Hb levels Response to If a patient does not respond to ESAs after 6-8 ESA therapy should be discontinued if a patient treatment wk, despite a dose increase, ESA therapy shows no response despite iron should be discontinued and the clinician supplementation after 8-9 wk of treatment should investigate possible underlying tumor progression, iron deficiency, or other causes of the anemia ESA: erythrocyte stimulating agent; FDA: U.S. Food and Drug Administration; Hb: hemoglobin; MDS: myelodysplastic syndrome; RBC: red blood cell; REMS: risk evaluation and mitigation strategy. U.S. Preventive Services Task Force Recommendations Erythropoiesis stimulating agents for the treatment of anemia due to chronic kidney disease, cancer chemotherapy, or ribavirin treatment of hepatitis C infection is not a preventive service. Medicare National Coverage In July 2007, Centers for Medicare and Medicaid Services (CMS) released a Decision Memorandum on the use of ESAs for nonrenal disease indications (CAG-00383N).10 Safety concerns such as thrombosis, cardiovascular events, tumor progression, and reduced survival, derived from clinical trials in several cancer and noncancer populations, prompted CMS to review its coverage of ESAs. CMS reviewed a large volume of scientific literature, including basic science research, to see if safety findings observed in RCTs could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. Based on this review, CMS proposed conditions of coverage based on expression of erythropoietin receptors. However, the scientific understanding of this mechanism is controversial and requires additional study. CMS also reviewed comments on ESAs for treatment of myelodysplastic syndrome (MDS), a precursor of acute myeloid leukemia (AML) in many patients. CMS retains interest in these specific issues but does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease and has decided at this time to make no national coverage determination (NCD) on ESAs in MDS. CMS has determined that evidence is sufficient to conclude that ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on the underlying disease or because the underlying disease increases the risk of adverse effects related to ESA use. These conditions include: Any anemia in cancer or cancer treatment patients due to folate deficiency, vitamin B12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis Anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers Anemia of cancer not related to cancer treatment Any anemia associated only with radiotherapy Prophylactic use to prevent chemotherapy-induced anemia Prophylactic use to reduce tumor hypoxia Patients with erythropoietin-type resistance due to neutralizing antibodies Page 21 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 Anemia due to cancer treatment if patients have uncontrolled hypertension CMS also determined that ESA treatment for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is reasonable and necessary under the following specified conditions only: The hemoglobin (Hb) level immediately before initiation or maintenance of ESA treatment is less than 10 g/dL (or the hematocrit [Hct] is <30%). The starting dose for ESA treatment is the recommended FDA-labelled starting dose (no more than 150 U/kg 3 times weekly for epoetin alfa and 2.25 mcg/kg weekly for darbepoetin alpha). Equivalent doses may be given over other approved time periods. Maintenance of ESA therapy is the starting dose if the Hb level remains below 10 g/dL (or Hct is <30%) 4 weeks after initiation of therapy and the increase in Hb is greater than 1 g/dL (Hct >3%). For patients whose Hb increases less than 1 g/dL (Hct <3%) compared with pretreatment baseline over 4 weeks of treatment and whose Hb level remains less than 10 g/dL after 4 weeks of treatment (or Hct is <30%), the recommended FDA-labelled starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if Hb increases less than 1 g/dL (Hct <3%) compared with pretreatment baseline after 8 weeks of treatment. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in Hb greater than 1 g/dL (Hct >3%) over 2 weeks of treatment unless Hb remains below or subsequently falls to less than 10 g/dL (Hct <30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose. ESA treatment duration for each course of chemotherapy includes the 8 weeks after the last dose of myelosuppressive chemotherapy in a chemotherapy regimen. PEG-epoetin beta is not addressed in the Decision Memorandum or NCD.52 This decision by CMS allows local Medicare contractors to continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD. V. DEFINITIONS TOP ALLOGENEIC refers to having a different genetic constitution but belonging to the same species, i.e., involves a donor and a recipient. FERRITIN is an iron storage protein found in the liver, spleen and bone marrow. HEMATOPOIESIS refers to the production and development of blood cells. Page 22 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 IATROGENIC refers to any adverse mental or physical condition induced in a patient through the effects of treatment. MYELODYSPLASTIC SYNDROMES ARE a group of diseases in which the bone marrow does not make enough healthy blood cells. NONMYELOID REFERS to conditions not involving or affecting bone marrow. TRANSFERRIN SATURATION IS the proportion of transferrin proteins that are carrying iron. Normal range is 16%-45% in a fasting TS. VI. BENEFIT VARIATIONS TOP The existence of this medical policy does not mean that this service is a covered benefit under the member’s contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member’s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member’s benefit information or contact Capital for benefit information. VII. DISCLAIMER TOP Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member’s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. VIII. CODING INFORMATION TOP Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. Page 23 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 May be considered medically necessary for adult patients with CKD on dialysis: HCPCS Code J0882 J0887 J0890 Q4081 Description Injection, darbepoetin alfa, 1 mcg (for esrd on dialysis) Injection, epoetin beta, 1 microgram, (for ESRD on dialysis) Injection, peginesatide, 0.1 mg (for esrd on dialysis) Injection, epoetin alfa, 100 units (for esrd on dialysis) ICD-10CM Diagnosis Code D63.1 N18.3 N18.4 N18.5 N18.6 Description Anemia in chronic kidney disease Chronic kidney disease, stage 3 (moderate) Chronic kidney disease, stage 4 (severe) Chronic kidney disease, stage 5 End stage renal disease *The list of covered diagnoses for Senior Blue members may differ from the above. If applicable, please refer to the Medicare NCD or LCD for details. Covered when medically necessary: HCPCS Code J0881 J0885 ICD-10CM Diagnosis Code* B18.2 B19.20 Description Injection, darbepoetin alfa, 1 mcg (non-esrd use) Injection, epoetin alfa, (for non-esrd use), 1000 units Description Chronic viral hepatitis C Unspecified viral hepatitis C without hepatic coma B19.21 B20 Unspecified viral hepatitis C with hepatic coma Human immunodeficiency virus [HIV] disease C00.0 C00.1 C00.2 C00.3 C00.4 Malignant neoplasm of external upper lip Malignant neoplasm of external lower lip Malignant neoplasm of external lip, unspecified Malignant neoplasm of upper lip, inner aspect Malignant neoplasm of lower lip, inner aspect Page 24 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C00.5 C00.6 C00.8 C00.9 C01 C02.0 C02.1 C02.2 C02.3 C02.4 C02.8 C02.9 C03.0 C03.1 C03.9 C04.0 C04.1 C04.8 C04.9 C05.0 C05.1 C05.2 C05.8 C05.9 C06.0 C06.1 C06.2 C06.80 C06.89 C06.9 C07 C08.0 C08.1 C08.9 C09.0 Description Malignant neoplasm of lip, unspecified, inner aspect Malignant neoplasm of commissure of lip, unspecified Malignant neoplasm of overlapping sites of lip Malignant neoplasm of lip, unspecified Malignant neoplasm of base of tongue Malignant neoplasm of dorsal surface of tongue Malignant neoplasm of border of tongue Malignant neoplasm of ventral surface of tongue Malignant neoplasm of anterior two-thirds of tongue, part unspecified Malignant neoplasm of lingual tonsil Malignant neoplasm of overlapping sites of tongue Malignant neoplasm of tongue, unspecified Malignant neoplasm of upper gum Malignant neoplasm of lower gum Malignant neoplasm of gum, unspecified Malignant neoplasm of anterior floor of mouth Malignant neoplasm of lateral floor of mouth Malignant neoplasm of overlapping sites of floor of mouth Malignant neoplasm of floor of mouth, unspecified Malignant neoplasm of hard palate Malignant neoplasm of soft palate Malignant neoplasm of uvula Malignant neoplasm of overlapping sites of palate Malignant neoplasm of palate, unspecified Malignant neoplasm of cheek mucosa Malignant neoplasm of vestibule of mouth Malignant neoplasm of retromolar area Malignant neoplasm of overlapping sites of unspecified parts of mouth Malignant neoplasm of overlapping sites of other parts of mouth Malignant neoplasm of mouth, unspecified Malignant neoplasm of parotid gland Malignant neoplasm of submandibular gland Malignant neoplasm of sublingual gland Malignant neoplasm of major salivary gland, unspecified Malignant neoplasm of tonsillar fossa Page 25 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C09.1 C09.8 C09.9 C10.0 C10.1 C10.2 C10.3 C10.4 C10.8 C10.9 C11.0 C11.1 C11.2 C11.3 C11.8 C11.9 C12 C13.0 C13.1 C13.2 C13.8 C13.9 C14.0 C14.2 C14.8 C15.3 C15.4 C15.5 C15.8 C15.9 C16.0 C16.1 C16.2 C16.3 C16.4 Description Malignant neoplasm of tonsillar pillar (anterior) (posterior) Malignant neoplasm of overlapping sites of tonsil Malignant neoplasm of tonsil, unspecified Malignant neoplasm of vallecula Malignant neoplasm of anterior surface of epiglottis Malignant neoplasm of lateral wall of oropharynx Malignant neoplasm of posterior wall of oropharynx Malignant neoplasm of branchial cleft Malignant neoplasm of overlapping sites of oropharynx Malignant neoplasm of oropharynx, unspecified Malignant neoplasm of superior wall of nasopharynx Malignant neoplasm of posterior wall of nasopharynx Malignant neoplasm of lateral wall of nasopharynx Malignant neoplasm of anterior wall of nasopharynx Malignant neoplasm of overlapping sites of nasopharynx Malignant neoplasm of nasopharynx, unspecified Malignant neoplasm of pyriform sinus Malignant neoplasm of postcricoid region Malignant neoplasm of aryepiglottic fold, hypopharyngeal aspect Malignant neoplasm of posterior wall of hypopharynx Malignant neoplasm of overlapping sites of hypopharynx Malignant neoplasm of hypopharynx, unspecified Malignant neoplasm of pharynx, unspecified Malignant neoplasm of Waldeyer's ring Malignant neoplasm of overlapping sites of lip, oral cavity and pharynx Malignant neoplasm of upper third of esophagus Malignant neoplasm of middle third of esophagus Malignant neoplasm of lower third of esophagus Malignant neoplasm of overlapping sites of esophagus Malignant neoplasm of esophagus, unspecified Malignant neoplasm of cardia Malignant neoplasm of fundus of stomach Malignant neoplasm of body of stomach Malignant neoplasm of pyloric antrum Malignant neoplasm of pylorus Page 26 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C16.5 C16.6 C16.8 C16.9 C17.0 C17.1 C17.2 C17.3 C17.8 C17.9 C18.0 C18.1 C18.2 C18.3 C18.4 C18.5 C18.6 C18.7 C18.8 C18.9 C19 C20 C21.0 C21.1 C21.2 C21.8 C22.0 C22.1 C22.2 C22.3 C22.4 C22.7 C22.8 C22.9 C23 Description Malignant neoplasm of lesser curvature of stomach, unspecified Malignant neoplasm of greater curvature of stomach, unspecified Malignant neoplasm of overlapping sites of stomach Malignant neoplasm of stomach, unspecified Malignant neoplasm of duodenum Malignant neoplasm of jejunum Malignant neoplasm of ileum Meckel's diverticulum, malignant Malignant neoplasm of overlapping sites of small intestine Malignant neoplasm of small intestine, unspecified Malignant neoplasm of cecum Malignant neoplasm of appendix Malignant neoplasm of ascending colon Malignant neoplasm of hepatic flexure Malignant neoplasm of transverse colon Malignant neoplasm of splenic flexure Malignant neoplasm of descending colon Malignant neoplasm of sigmoid colon Malignant neoplasm of overlapping sites of colon Malignant neoplasm of colon, unspecified Malignant neoplasm of rectosigmoid junction Malignant neoplasm of rectum Malignant neoplasm of anus, unspecified Malignant neoplasm of anal canal Malignant neoplasm of cloacogenic zone Malignant neoplasm of overlapping sites of rectum, anus and anal canal Liver cell carcinoma Intrahepatic bile duct carcinoma Hepatoblastoma Angiosarcoma of liver Other sarcomas of liver Other specified carcinomas of liver Malignant neoplasm of liver, primary, unspecified as to type Malignant neoplasm of liver, not specified as primary or secondary Malignant neoplasm of gallbladder Page 27 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C24.0 C24.1 C24.8 C24.9 C25.0 C25.1 C25.2 C25.3 C25.4 C25.7 C25.8 C25.9 C26.0 C26.1 C26.9 C30.0 C30.1 C31.0 C31.1 C31.2 C31.3 C31.8 C31.9 C32.0 C32.1 C32.2 C32.3 C32.8 C32.9 C33 C34.00 C34.01 C34.02 C34.10 C34.11 Description Malignant neoplasm of extrahepatic bile duct Malignant neoplasm of ampulla of Vater Malignant neoplasm of overlapping sites of biliary tract Malignant neoplasm of biliary tract, unspecified Malignant neoplasm of head of pancreas Malignant neoplasm of body of pancreas Malignant neoplasm of tail of pancreas Malignant neoplasm of pancreatic duct Malignant neoplasm of endocrine pancreas Malignant neoplasm of other parts of pancreas Malignant neoplasm of overlapping sites of pancreas Malignant neoplasm of pancreas, unspecified Malignant neoplasm of intestinal tract, part unspecified Malignant neoplasm of spleen Malignant neoplasm of ill-defined sites within the digestive system Malignant neoplasm of nasal cavity Malignant neoplasm of middle ear Malignant neoplasm of maxillary sinus Malignant neoplasm of ethmoidal sinus Malignant neoplasm of frontal sinus Malignant neoplasm of sphenoid sinus Malignant neoplasm of overlapping sites of accessory sinuses Malignant neoplasm of accessory sinus, unspecified Malignant neoplasm of glottis Malignant neoplasm of supraglottis Malignant neoplasm of subglottis Malignant neoplasm of laryngeal cartilage Malignant neoplasm of overlapping sites of larynx Malignant neoplasm of larynx, unspecified Malignant neoplasm of trachea Malignant neoplasm of unspecified main bronchus Malignant neoplasm of right main bronchus Malignant neoplasm of left main bronchus Malignant neoplasm of upper lobe, unspecified bronchus or lung Malignant neoplasm of upper lobe, right bronchus or lung Page 28 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C34.12 C34.2 C34.30 C34.31 C34.32 C34.80 C34.81 C34.82 C34.90 C34.91 C34.92 C37 C38.0 C38.1 C38.2 C38.3 C38.4 C38.8 C39.0 C39.9 C40.00 C40.01 C40.02 C40.10 C40.11 C40.12 C40.20 C40.21 C40.22 C40.30 C40.31 C40.32 C40.80 C40.81 C40.82 Description Malignant neoplasm of upper lobe, left bronchus or lung Malignant neoplasm of middle lobe, bronchus or lung Malignant neoplasm of lower lobe, unspecified bronchus or lung Malignant neoplasm of lower lobe, right bronchus or lung Malignant neoplasm of lower lobe, left bronchus or lung Malignant neoplasm of overlapping sites of unspecified bronchus and lung Malignant neoplasm of overlapping sites of right bronchus and lung Malignant neoplasm of overlapping sites of left bronchus and lung Malignant neoplasm of unspecified part of unspecified bronchus or lung Malignant neoplasm of unspecified part of right bronchus or lung Malignant neoplasm of unspecified part of left bronchus or lung Malignant neoplasm of thymus Malignant neoplasm of heart Malignant neoplasm of anterior mediastinum Malignant neoplasm of posterior mediastinum Malignant neoplasm of mediastinum, part unspecified Malignant neoplasm of pleura Malignant neoplasm of overlapping sites of heart, mediastinum and pleura Malignant neoplasm of upper respiratory tract, part unspecified Malignant neoplasm of lower respiratory tract, part unspecified Malignant neoplasm of scapula and long bones of unspecified upper limb Malignant neoplasm of scapula and long bones of right upper limb Malignant neoplasm of scapula and long bones of left upper limb Malignant neoplasm of short bones of unspecified upper limb Malignant neoplasm of short bones of right upper limb Malignant neoplasm of short bones of left upper limb Malignant neoplasm of long bones of unspecified lower limb Malignant neoplasm of long bones of right lower limb Malignant neoplasm of long bones of left lower limb Malignant neoplasm of short bones of unspecified lower limb Malignant neoplasm of short bones of right lower limb Malignant neoplasm of short bones of left lower limb Malignant neoplasm of overlapping sites of bone and articular cartilage of unspecified limb Malignant neoplasm of overlapping sites of bone and articular cartilage of right limb Malignant neoplasm of overlapping sites of bone and articular cartilage of left limb Page 29 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C40.90 C40.91 C40.92 C41.0 C41.1 C41.2 C41.3 C41.4 C41.9 C43.0 C43.10 C43.11 C43.12 C43.20 C43.21 C43.22 C43.30 C43.31 C43.39 C43.4 C43.51 C43.52 C43.59 C43.60 C43.61 C43.62 C43.70 C43.71 C43.72 C43.8 C43.9 C44.00 C44.01 C44.02 C44.09 Description Malignant neoplasm of unspecified bones and articular cartilage of unspecified limb Malignant neoplasm of unspecified bones and articular cartilage of right limb Malignant neoplasm of unspecified bones and articular cartilage of left limb Malignant neoplasm of bones of skull and face Malignant neoplasm of mandible Malignant neoplasm of vertebral column Malignant neoplasm of ribs, sternum and clavicle Malignant neoplasm of pelvic bones, sacrum and coccyx Malignant neoplasm of bone and articular cartilage, unspecified Malignant melanoma of lip Malignant melanoma of unspecified eyelid, including canthus Malignant melanoma of right eyelid, including canthus Malignant melanoma of left eyelid, including canthus Malignant melanoma of unspecified ear and external auricular canal Malignant melanoma of right ear and external auricular canal Malignant melanoma of left ear and external auricular canal Malignant melanoma of unspecified part of face Malignant melanoma of nose Malignant melanoma of other parts of face Malignant melanoma of scalp and neck Malignant melanoma of anal skin Malignant melanoma of skin of breast Malignant melanoma of other part of trunk Malignant melanoma of unspecified upper limb, including shoulder Malignant melanoma of right upper limb, including shoulder Malignant melanoma of left upper limb, including shoulder Malignant melanoma of unspecified lower limb, including hip Malignant melanoma of right lower limb, including hip Malignant melanoma of left lower limb, including hip Malignant melanoma of overlapping sites of skin Malignant melanoma of skin, unspecified Unspecified malignant neoplasm of skin of lip Basal cell carcinoma of skin of lip Squamous cell carcinoma of skin of lip Other specified malignant neoplasm of skin of lip Page 30 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C44.101 C44.102 C44.109 C44.111 C44.112 C44.119 C44.121 C44.122 C44.129 C44.191 C44.192 C44.199 C44.201 C44.202 C44.209 C44.211 C44.212 C44.219 C44.221 C44.222 C44.229 C44.291 C44.292 C44.299 C44.300 C44.301 C44.309 C44.310 C44.311 C44.319 C44.320 C44.321 C44.329 C44.390 C44.391 Description Unspecified malignant neoplasm of skin of unspecified eyelid, including canthus Unspecified malignant neoplasm of skin of right eyelid, including canthus Unspecified malignant neoplasm of skin of left eyelid, including canthus Basal cell carcinoma of skin of unspecified eyelid, including canthus Basal cell carcinoma of skin of right eyelid, including canthus Basal cell carcinoma of skin of left eyelid, including canthus Squamous cell carcinoma of skin of unspecified eyelid, including canthus Squamous cell carcinoma of skin of right eyelid, including canthus Squamous cell carcinoma of skin of left eyelid, including canthus Other specified malignant neoplasm of skin of unspecified eyelid, including canthus Other specified malignant neoplasm of skin of right eyelid, including canthus Other specified malignant neoplasm of skin of left eyelid, including canthus Unspecified malignant neoplasm of skin of unspecified ear and external auricular canal Unspecified malignant neoplasm of skin of right ear and external auricular canal Unspecified malignant neoplasm of skin of left ear and external auricular canal Basal cell carcinoma of skin of unspecified ear and external auricular canal Basal cell carcinoma of skin of right ear and external auricular canal Basal cell carcinoma of skin of left ear and external auricular canal Squamous cell carcinoma of skin of unspecified ear and external auricular canal Squamous cell carcinoma of skin of right ear and external auricular canal Squamous cell carcinoma of skin of left ear and external auricular canal Other specified malignant neoplasm of skin of unspecified ear and external auricular canal Other specified malignant neoplasm of skin of right ear and external auricular canal Other specified malignant neoplasm of skin of left ear and external auricular canal Unspecified malignant neoplasm of skin of unspecified part of face Unspecified malignant neoplasm of skin of nose Unspecified malignant neoplasm of skin of other parts of face Basal cell carcinoma of skin of unspecified parts of face Basal cell carcinoma of skin of nose Basal cell carcinoma of skin of other parts of face Squamous cell carcinoma of skin of unspecified parts of face Squamous cell carcinoma of skin of nose Squamous cell carcinoma of skin of other parts of face Other specified malignant neoplasm of skin of unspecified parts of face Other specified malignant neoplasm of skin of nose Page 31 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C44.399 C44.40 C44.41 C44.42 C44.49 C44.500 C44.501 C44.509 C44.510 C44.511 C44.519 C44.520 C44.521 C44.529 C44.590 C44.591 C44.599 C44.601 C44.602 C44.609 C44.611 C44.612 C44.619 C44.621 C44.622 C44.629 C44.691 C44.692 C44.699 C44.701 C44.702 C44.709 C44.711 C44.712 C44.719 Description Other specified malignant neoplasm of skin of other parts of face Unspecified malignant neoplasm of skin of scalp and neck Basal cell carcinoma of skin of scalp and neck Squamous cell carcinoma of skin of scalp and neck Other specified malignant neoplasm of skin of scalp and neck Unspecified malignant neoplasm of anal skin Unspecified malignant neoplasm of skin of breast Unspecified malignant neoplasm of skin of other part of trunk Basal cell carcinoma of anal skin Basal cell carcinoma of skin of breast Basal cell carcinoma of skin of other part of trunk Squamous cell carcinoma of anal skin Squamous cell carcinoma of skin of breast Squamous cell carcinoma of skin of other part of trunk Other specified malignant neoplasm of anal skin Other specified malignant neoplasm of skin of breast Other specified malignant neoplasm of skin of other part of trunk Unspecified malignant neoplasm of skin of unspecified upper limb, including shoulder Unspecified malignant neoplasm of skin of right upper limb, including shoulder Unspecified malignant neoplasm of skin of left upper limb, including shoulder Basal cell carcinoma of skin of unspecified upper limb, including shoulder Basal cell carcinoma of skin of right upper limb, including shoulder Basal cell carcinoma of skin of left upper limb, including shoulder Squamous cell carcinoma of skin of unspecified upper limb, including shoulder Squamous cell carcinoma of skin of right upper limb, including shoulder Squamous cell carcinoma of skin of left upper limb, including shoulder Other specified malignant neoplasm of skin of unspecified upper limb, including shoulder Other specified malignant neoplasm of skin of right upper limb, including shoulder Other specified malignant neoplasm of skin of left upper limb, including shoulder Unspecified malignant neoplasm of skin of unspecified lower limb, including hip Unspecified malignant neoplasm of skin of right lower limb, including hip Unspecified malignant neoplasm of skin of left lower limb, including hip Basal cell carcinoma of skin of unspecified lower limb, including hip Basal cell carcinoma of skin of right lower limb, including hip Basal cell carcinoma of skin of left lower limb, including hip Page 32 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C44.721 C44.722 C44.729 C44.791 C44.792 C44.799 C44.80 C44.81 C44.82 C44.89 C44.90 C44.91 C44.92 C44.99 C45.0 C45.1 C45.2 C45.7 C45.9 C46.0 C46.1 C46.2 C46.3 C46.4 C46.50 C46.51 C46.52 C46.7 C46.9 C47.0 C47.10 C47.11 C47.12 C47.20 C47.21 Description Squamous cell carcinoma of skin of unspecified lower limb, including hip Squamous cell carcinoma of skin of right lower limb, including hip Squamous cell carcinoma of skin of left lower limb, including hip Other specified malignant neoplasm of skin of unspecified lower limb, including hip Other specified malignant neoplasm of skin of right lower limb, including hip Other specified malignant neoplasm of skin of left lower limb, including hip Unspecified malignant neoplasm of overlapping sites of skin Basal cell carcinoma of overlapping sites of skin Squamous cell carcinoma of overlapping sites of skin Other specified malignant neoplasm of overlapping sites of skin Unspecified malignant neoplasm of skin, unspecified Basal cell carcinoma of skin, unspecified Squamous cell carcinoma of skin, unspecified Other specified malignant neoplasm of skin, unspecified Mesothelioma of pleura Mesothelioma of peritoneum Mesothelioma of pericardium Mesothelioma of other sites Mesothelioma, unspecified Kaposi's sarcoma of skin Kaposi's sarcoma of soft tissue Kaposi's sarcoma of palate Kaposi's sarcoma of lymph nodes Kaposi's sarcoma of gastrointestinal sites Kaposi's sarcoma of unspecified lung Kaposi's sarcoma of right lung Kaposi's sarcoma of left lung Kaposi's sarcoma of other sites Kaposi's sarcoma, unspecified Malignant neoplasm of peripheral nerves of head, face and neck Malignant neoplasm of peripheral nerves of unspecified upper limb, including shoulder Malignant neoplasm of peripheral nerves of right upper limb, including shoulder Malignant neoplasm of peripheral nerves of left upper limb, including shoulder Malignant neoplasm of peripheral nerves of unspecified lower limb, including hip Malignant neoplasm of peripheral nerves of right lower limb, including hip Page 33 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C47.22 C47.3 C47.4 C47.5 C47.6 C47.8 C47.9 C48.0 C48.1 C48.2 C48.8 C49.0 C49.10 C49.11 C49.12 C49.20 C49.21 C49.22 C49.3 C49.4 C49.5 C49.6 C49.8 C49.9 C4A.0 C4A.10 C4A.11 C4A.12 C4A.20 C4A.21 C4A.22 C4A.30 C4A.31 Description Malignant neoplasm of peripheral nerves of left lower limb, including hip Malignant neoplasm of peripheral nerves of thorax Malignant neoplasm of peripheral nerves of abdomen Malignant neoplasm of peripheral nerves of pelvis Malignant neoplasm of peripheral nerves of trunk, unspecified Malignant neoplasm of overlapping sites of peripheral nerves and autonomic nervous system Malignant neoplasm of peripheral nerves and autonomic nervous system, unspecified Malignant neoplasm of retroperitoneum Malignant neoplasm of specified parts of peritoneum Malignant neoplasm of peritoneum, unspecified Malignant neoplasm of overlapping sites of retroperitoneum and peritoneum Malignant neoplasm of connective and soft tissue of head, face and neck Malignant neoplasm of connective and soft tissue of unspecified upper limb, including shoulder Malignant neoplasm of connective and soft tissue of right upper limb, including shoulder Malignant neoplasm of connective and soft tissue of left upper limb, including shoulder Malignant neoplasm of connective and soft tissue of unspecified lower limb, including hip Malignant neoplasm of connective and soft tissue of right lower limb, including hip Malignant neoplasm of connective and soft tissue of left lower limb, including hip Malignant neoplasm of connective and soft tissue of thorax Malignant neoplasm of connective and soft tissue of abdomen Malignant neoplasm of connective and soft tissue of pelvis Malignant neoplasm of connective and soft tissue of trunk, unspecified Malignant neoplasm of overlapping sites of connective and soft tissue Malignant neoplasm of connective and soft tissue, unspecified Merkel cell carcinoma of lip Merkel cell carcinoma of unspecified eyelid, including canthus Merkel cell carcinoma of right eyelid, including canthus Merkel cell carcinoma of left eyelid, including canthus Merkel cell carcinoma of unspecified ear and external auricular canal Merkel cell carcinoma of right ear and external auricular canal Merkel cell carcinoma of left ear and external auricular canal Merkel cell carcinoma of unspecified part of face Merkel cell carcinoma of nose Page 34 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C4A.39 C4A.4 C4A.51 C4A.52 C4A.59 C4A.60 C4A.61 C4A.62 C4A.70 C4A.71 C4A.72 C4A.8 C4A.9 C50.011 C50.012 C50.019 C50.021 C50.022 C50.029 C50.111 C50.112 C50.119 C50.121 C50.122 C50.129 C50.211 C50.212 C50.219 C50.221 C50.222 C50.229 C50.311 C50.312 C50.319 C50.321 Description Merkel cell carcinoma of other parts of face Merkel cell carcinoma of scalp and neck Merkel cell carcinoma of anal skin Merkel cell carcinoma of skin of breast Merkel cell carcinoma of other part of trunk Merkel cell carcinoma of unspecified upper limb, including shoulder Merkel cell carcinoma of right upper limb, including shoulder Merkel cell carcinoma of left upper limb, including shoulder Merkel cell carcinoma of unspecified lower limb, including hip Merkel cell carcinoma of right lower limb, including hip Merkel cell carcinoma of left lower limb, including hip Merkel cell carcinoma of overlapping sites Merkel cell carcinoma, unspecified Malignant neoplasm of nipple and areola, right female breast Malignant neoplasm of nipple and areola, left female breast Malignant neoplasm of nipple and areola, unspecified female breast Malignant neoplasm of nipple and areola, right male breast Malignant neoplasm of nipple and areola, left male breast Malignant neoplasm of nipple and areola, unspecified male breast Malignant neoplasm of central portion of right female breast Malignant neoplasm of central portion of left female breast Malignant neoplasm of central portion of unspecified female breast Malignant neoplasm of central portion of right male breast Malignant neoplasm of central portion of left male breast Malignant neoplasm of central portion of unspecified male breast Malignant neoplasm of upper-inner quadrant of right female breast Malignant neoplasm of upper-inner quadrant of left female breast Malignant neoplasm of upper-inner quadrant of unspecified female breast Malignant neoplasm of upper-inner quadrant of right male breast Malignant neoplasm of upper-inner quadrant of left male breast Malignant neoplasm of upper-inner quadrant of unspecified male breast Malignant neoplasm of lower-inner quadrant of right female breast Malignant neoplasm of lower-inner quadrant of left female breast Malignant neoplasm of lower-inner quadrant of unspecified female breast Malignant neoplasm of lower-inner quadrant of right male breast Page 35 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C50.322 C50.329 C50.411 C50.412 C50.419 C50.421 C50.422 C50.429 C50.511 C50.512 C50.519 C50.521 C50.522 C50.529 C50.611 C50.612 C50.619 C50.621 C50.622 C50.629 C50.811 C50.812 C50.819 C50.821 C50.822 C50.829 C50.911 C50.912 C50.919 C50.921 C50.922 C50.929 C51.0 C51.1 C51.2 Description Malignant neoplasm of lower-inner quadrant of left male breast Malignant neoplasm of lower-inner quadrant of unspecified male breast Malignant neoplasm of upper-outer quadrant of right female breast Malignant neoplasm of upper-outer quadrant of left female breast Malignant neoplasm of upper-outer quadrant of unspecified female breast Malignant neoplasm of upper-outer quadrant of right male breast Malignant neoplasm of upper-outer quadrant of left male breast Malignant neoplasm of upper-outer quadrant of unspecified male breast Malignant neoplasm of lower-outer quadrant of right female breast Malignant neoplasm of lower-outer quadrant of left female breast Malignant neoplasm of lower-outer quadrant of unspecified female breast Malignant neoplasm of lower-outer quadrant of right male breast Malignant neoplasm of lower-outer quadrant of left male breast Malignant neoplasm of lower-outer quadrant of unspecified male breast Malignant neoplasm of axillary tail of right female breast Malignant neoplasm of axillary tail of left female breast Malignant neoplasm of axillary tail of unspecified female breast Malignant neoplasm of axillary tail of right male breast Malignant neoplasm of axillary tail of left male breast Malignant neoplasm of axillary tail of unspecified male breast Malignant neoplasm of overlapping sites of right female breast Malignant neoplasm of overlapping sites of left female breast Malignant neoplasm of overlapping sites of unspecified female breast Malignant neoplasm of overlapping sites of right male breast Malignant neoplasm of overlapping sites of left male breast Malignant neoplasm of overlapping sites of unspecified male breast Malignant neoplasm of unspecified site of right female breast Malignant neoplasm of unspecified site of left female breast Malignant neoplasm of unspecified site of unspecified female breast Malignant neoplasm of unspecified site of right male breast Malignant neoplasm of unspecified site of left male breast Malignant neoplasm of unspecified site of unspecified male breast Malignant neoplasm of labium majus Malignant neoplasm of labium minus Malignant neoplasm of clitoris Page 36 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C51.8 C51.9 C52 C53.0 C53.1 C53.8 C53.9 C54.0 C54.1 C54.2 C54.3 C54.8 C54.9 C55 C56.1 C56.2 C56.9 C57.00 C57.01 C57.02 C57.10 C57.11 C57.12 C57.20 C57.21 C57.22 C57.3 C57.4 C57.7 C57.8 C57.9 C58 C60.0 C60.1 C60.2 Description Malignant neoplasm of overlapping sites of vulva Malignant neoplasm of vulva, unspecified Malignant neoplasm of vagina Malignant neoplasm of endocervix Malignant neoplasm of exocervix Malignant neoplasm of overlapping sites of cervix uteri Malignant neoplasm of cervix uteri, unspecified Malignant neoplasm of isthmus uteri Malignant neoplasm of endometrium Malignant neoplasm of myometrium Malignant neoplasm of fundus uteri Malignant neoplasm of overlapping sites of corpus uteri Malignant neoplasm of corpus uteri, unspecified Malignant neoplasm of uterus, part unspecified Malignant neoplasm of right ovary Malignant neoplasm of left ovary Malignant neoplasm of unspecified ovary Malignant neoplasm of unspecified fallopian tube Malignant neoplasm of right fallopian tube Malignant neoplasm of left fallopian tube Malignant neoplasm of unspecified broad ligament Malignant neoplasm of right broad ligament Malignant neoplasm of left broad ligament Malignant neoplasm of unspecified round ligament Malignant neoplasm of right round ligament Malignant neoplasm of left round ligament Malignant neoplasm of parametrium Malignant neoplasm of uterine adnexa, unspecified Malignant neoplasm of other specified female genital organs Malignant neoplasm of overlapping sites of female genital organs Malignant neoplasm of female genital organ, unspecified Malignant neoplasm of placenta Malignant neoplasm of prepuce Malignant neoplasm of glans penis Malignant neoplasm of body of penis Page 37 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C60.8 C60.9 C61 C62.00 C62.01 C62.02 C62.10 C62.11 C62.12 C62.90 C62.91 C62.92 C63.00 C63.01 C63.02 C63.10 C63.11 C63.12 C63.2 C63.7 C63.8 C63.9 C64.1 C64.2 C64.9 C65.1 C65.2 C65.9 C66.1 C66.2 C66.9 C67.0 C67.1 C67.2 C67.3 Description Malignant neoplasm of overlapping sites of penis Malignant neoplasm of penis, unspecified Malignant neoplasm of prostate Malignant neoplasm of unspecified undescended testis Malignant neoplasm of undescended right testis Malignant neoplasm of undescended left testis Malignant neoplasm of unspecified descended testis Malignant neoplasm of descended right testis Malignant neoplasm of descended left testis Malignant neoplasm of unspecified testis, unspecified whether descended or undescended Malignant neoplasm of right testis, unspecified whether descended or undescended Malignant neoplasm of left testis, unspecified whether descended or undescended Malignant neoplasm of unspecified epididymis Malignant neoplasm of right epididymis Malignant neoplasm of left epididymis Malignant neoplasm of unspecified spermatic cord Malignant neoplasm of right spermatic cord Malignant neoplasm of left spermatic cord Malignant neoplasm of scrotum Malignant neoplasm of other specified male genital organs Malignant neoplasm of overlapping sites of male genital organs Malignant neoplasm of male genital organ, unspecified Malignant neoplasm of right kidney, except renal pelvis Malignant neoplasm of left kidney, except renal pelvis Malignant neoplasm of unspecified kidney, except renal pelvis Malignant neoplasm of right renal pelvis Malignant neoplasm of left renal pelvis Malignant neoplasm of unspecified renal pelvis Malignant neoplasm of right ureter Malignant neoplasm of left ureter Malignant neoplasm of unspecified ureter Malignant neoplasm of trigone of bladder Malignant neoplasm of dome of bladder Malignant neoplasm of lateral wall of bladder Malignant neoplasm of anterior wall of bladder Page 38 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C67.4 C67.5 C67.6 C67.7 C67.8 C67.9 C68.0 C68.1 C68.8 C68.9 C69.00 C69.01 C69.02 C69.10 C69.11 C69.12 C69.20 C69.21 C69.22 C69.30 C69.31 C69.32 C69.40 C69.41 C69.42 C69.50 C69.51 C69.52 C69.60 C69.61 C69.62 C69.80 C69.81 C69.82 C69.90 Description Malignant neoplasm of posterior wall of bladder Malignant neoplasm of bladder neck Malignant neoplasm of ureteric orifice Malignant neoplasm of urachus Malignant neoplasm of overlapping sites of bladder Malignant neoplasm of bladder, unspecified Malignant neoplasm of urethra Malignant neoplasm of paraurethral glands Malignant neoplasm of overlapping sites of urinary organs Malignant neoplasm of urinary organ, unspecified Malignant neoplasm of unspecified conjunctiva Malignant neoplasm of right conjunctiva Malignant neoplasm of left conjunctiva Malignant neoplasm of unspecified cornea Malignant neoplasm of right cornea Malignant neoplasm of left cornea Malignant neoplasm of unspecified retina Malignant neoplasm of right retina Malignant neoplasm of left retina Malignant neoplasm of unspecified choroid Malignant neoplasm of right choroid Malignant neoplasm of left choroid Malignant neoplasm of unspecified ciliary body Malignant neoplasm of right ciliary body Malignant neoplasm of left ciliary body Malignant neoplasm of unspecified lacrimal gland and duct Malignant neoplasm of right lacrimal gland and duct Malignant neoplasm of left lacrimal gland and duct Malignant neoplasm of unspecified orbit Malignant neoplasm of right orbit Malignant neoplasm of left orbit Malignant neoplasm of overlapping sites of unspecified eye and adnexa Malignant neoplasm of overlapping sites of right eye and adnexa Malignant neoplasm of overlapping sites of left eye and adnexa Malignant neoplasm of unspecified site of unspecified eye Page 39 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C69.91 C69.92 C70.0 C70.1 C70.9 C71.0 C71.1 C71.2 C71.3 C71.4 C71.5 C71.6 C71.7 C71.8 C71.9 C72.0 C72.1 C72.20 C72.21 C72.22 C72.30 C72.31 C72.32 C72.40 C72.41 C72.42 C72.50 C72.59 C72.9 C73 C74.00 C74.01 C74.02 C74.10 C74.11 Description Malignant neoplasm of unspecified site of right eye Malignant neoplasm of unspecified site of left eye Malignant neoplasm of cerebral meninges Malignant neoplasm of spinal meninges Malignant neoplasm of meninges, unspecified Malignant neoplasm of cerebrum, except lobes and ventricles Malignant neoplasm of frontal lobe Malignant neoplasm of temporal lobe Malignant neoplasm of parietal lobe Malignant neoplasm of occipital lobe Malignant neoplasm of cerebral ventricle Malignant neoplasm of cerebellum Malignant neoplasm of brain stem Malignant neoplasm of overlapping sites of brain Malignant neoplasm of brain, unspecified Malignant neoplasm of spinal cord Malignant neoplasm of cauda equina Malignant neoplasm of unspecified olfactory nerve Malignant neoplasm of right olfactory nerve Malignant neoplasm of left olfactory nerve Malignant neoplasm of unspecified optic nerve Malignant neoplasm of right optic nerve Malignant neoplasm of left optic nerve Malignant neoplasm of unspecified acoustic nerve Malignant neoplasm of right acoustic nerve Malignant neoplasm of left acoustic nerve Malignant neoplasm of unspecified cranial nerve Malignant neoplasm of other cranial nerves Malignant neoplasm of central nervous system, unspecified Malignant neoplasm of thyroid gland Malignant neoplasm of cortex of unspecified adrenal gland Malignant neoplasm of cortex of right adrenal gland Malignant neoplasm of cortex of left adrenal gland Malignant neoplasm of medulla of unspecified adrenal gland Malignant neoplasm of medulla of right adrenal gland Page 40 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C74.12 C74.90 C74.91 C74.92 C75.0 C75.1 C75.2 C75.3 C75.4 C75.5 C75.8 C75.9 C76.0 C76.1 C76.2 C76.3 C76.40 C76.41 C76.42 C76.50 C76.51 C76.52 C76.8 C77.0 C77.1 C77.2 C77.3 C77.4 C77.5 C77.8 C77.9 C78.00 C78.01 C78.02 C78.1 Description Malignant neoplasm of medulla of left adrenal gland Malignant neoplasm of unspecified part of unspecified adrenal gland Malignant neoplasm of unspecified part of right adrenal gland Malignant neoplasm of unspecified part of left adrenal gland Malignant neoplasm of parathyroid gland Malignant neoplasm of pituitary gland Malignant neoplasm of craniopharyngeal duct Malignant neoplasm of pineal gland Malignant neoplasm of carotid body Malignant neoplasm of aortic body and other paraganglia Malignant neoplasm with pluriglandular involvement, unspecified Malignant neoplasm of endocrine gland, unspecified Malignant neoplasm of head, face and neck Malignant neoplasm of thorax Malignant neoplasm of abdomen Malignant neoplasm of pelvis Malignant neoplasm of unspecified upper limb Malignant neoplasm of right upper limb Malignant neoplasm of left upper limb Malignant neoplasm of unspecified lower limb Malignant neoplasm of right lower limb Malignant neoplasm of left lower limb Malignant neoplasm of other specified ill-defined sites Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck Secondary and unspecified malignant neoplasm of intrathoracic lymph nodes Secondary and unspecified malignant neoplasm of intra-abdominal lymph nodes Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes Secondary and unspecified malignant neoplasm of inguinal and lower limb lymph nodes Secondary and unspecified malignant neoplasm of intrapelvic lymph nodes Secondary and unspecified malignant neoplasm of lymph nodes of multiple regions Secondary and unspecified malignant neoplasm of lymph node, unspecified Secondary malignant neoplasm of unspecified lung Secondary malignant neoplasm of right lung Secondary malignant neoplasm of left lung Secondary malignant neoplasm of mediastinum Page 41 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C78.2 C78.30 C78.39 C78.4 C78.5 C78.6 C78.7 C78.80 C78.89 C79.00 C79.01 C79.02 C79.10 C79.11 C79.19 C79.2 C79.31 C79.32 C79.40 C79.49 C79.51 C79.52 C79.60 C79.61 C79.62 C79.70 C79.71 C79.72 C79.81 C79.82 C79.89 C79.9 C7A.00 C7A.010 C7A.011 Description Secondary malignant neoplasm of pleura Secondary malignant neoplasm of unspecified respiratory organ Secondary malignant neoplasm of other respiratory organs Secondary malignant neoplasm of small intestine Secondary malignant neoplasm of large intestine and rectum Secondary malignant neoplasm of retroperitoneum and peritoneum Secondary malignant neoplasm of liver and intrahepatic bile duct Secondary malignant neoplasm of unspecified digestive organ Secondary malignant neoplasm of other digestive organs Secondary malignant neoplasm of unspecified kidney and renal pelvis Secondary malignant neoplasm of right kidney and renal pelvis Secondary malignant neoplasm of left kidney and renal pelvis Secondary malignant neoplasm of unspecified urinary organs Secondary malignant neoplasm of bladder Secondary malignant neoplasm of other urinary organs Secondary malignant neoplasm of skin Secondary malignant neoplasm of brain Secondary malignant neoplasm of cerebral meninges Secondary malignant neoplasm of unspecified part of nervous system Secondary malignant neoplasm of other parts of nervous system Secondary malignant neoplasm of bone Secondary malignant neoplasm of bone marrow Secondary malignant neoplasm of unspecified ovary Secondary malignant neoplasm of right ovary Secondary malignant neoplasm of left ovary Secondary malignant neoplasm of unspecified adrenal gland Secondary malignant neoplasm of right adrenal gland Secondary malignant neoplasm of left adrenal gland Secondary malignant neoplasm of breast Secondary malignant neoplasm of genital organs Secondary malignant neoplasm of other specified sites Secondary malignant neoplasm of unspecified site Malignant carcinoid tumor of unspecified site Malignant carcinoid tumor of the duodenum Malignant carcinoid tumor of the jejunum Page 42 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C7A.012 C7A.019 C7A.020 C7A.021 C7A.022 C7A.023 C7A.024 C7A.025 C7A.026 C7A.029 C7A.090 C7A.091 C7A.092 C7A.093 C7A.094 C7A.095 C7A.096 C7A.098 C7A.1 C7A.8 C80.0 C80.1 C80.2 C81.00 C81.01 C81.02 C81.03 C81.04 C81.05 C81.06 C81.07 C81.08 C81.09 Description Malignant carcinoid tumor of the ileum Malignant carcinoid tumor of the small intestine, unspecified portion Malignant carcinoid tumor of the appendix Malignant carcinoid tumor of the cecum Malignant carcinoid tumor of the ascending colon Malignant carcinoid tumor of the transverse colon Malignant carcinoid tumor of the descending colon Malignant carcinoid tumor of the sigmoid colon Malignant carcinoid tumor of the rectum Malignant carcinoid tumor of the large intestine, unspecified portion Malignant carcinoid tumor of the bronchus and lung Malignant carcinoid tumor of the thymus Malignant carcinoid tumor of the stomach Malignant carcinoid tumor of the kidney Malignant carcinoid tumor of the foregut, unspecified Malignant carcinoid tumor of the midgut, unspecified Malignant carcinoid tumor of the hindgut, unspecified Malignant carcinoid tumors of other sites Malignant poorly differentiated neuroendocrine tumors Other malignant neuroendocrine tumors Disseminated malignant neoplasm, unspecified Malignant (primary) neoplasm, unspecified Malignant neoplasm associated with transplanted organ Nodular lymphocyte predominant Hodgkin lymphoma, unspecified site Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of head, face, and neck Nodular lymphocyte predominant Hodgkin lymphoma, intrathoracic lymph nodes Nodular lymphocyte predominant Hodgkin lymphoma, intra-abdominal lymph nodes Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of axilla and upper limb Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Nodular lymphocyte predominant Hodgkin lymphoma, intrapelvic lymph nodes Nodular lymphocyte predominant Hodgkin lymphoma, spleen Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of multiple sites Nodular lymphocyte predominant Hodgkin lymphoma, extranodal and solid organ sites Page 43 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C81.10 C81.11 C81.12 C81.13 C81.14 C81.15 C81.16 C81.17 C81.18 C81.19 C81.20 C81.21 C81.22 C81.23 C81.24 C81.25 C81.26 C81.27 C81.28 C81.29 C81.30 C81.31 C81.32 C81.33 C81.34 C81.35 C81.36 C81.37 C81.38 C81.39 C81.40 C81.41 C81.42 C81.43 C81.44 Description Nodular sclerosis Hodgkin lymphoma, unspecified site Nodular sclerosis Hodgkin lymphoma, lymph nodes of head, face, and neck Nodular sclerosis Hodgkin lymphoma, intrathoracic lymph nodes Nodular sclerosis Hodgkin lymphoma, intra-abdominal lymph nodes Nodular sclerosis Hodgkin lymphoma, lymph nodes of axilla and upper limb Nodular sclerosis Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Nodular sclerosis Hodgkin lymphoma, intrapelvic lymph nodes Nodular sclerosis Hodgkin lymphoma, spleen Nodular sclerosis Hodgkin lymphoma, lymph nodes of multiple sites Nodular sclerosis Hodgkin lymphoma, extranodal and solid organ sites Mixed cellularity Hodgkin lymphoma, unspecified site Mixed cellularity Hodgkin lymphoma, lymph nodes of head, face, and neck Mixed cellularity Hodgkin lymphoma, intrathoracic lymph nodes Mixed cellularity Hodgkin lymphoma, intra-abdominal lymph nodes Mixed cellularity Hodgkin lymphoma, lymph nodes of axilla and upper limb Mixed cellularity Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Mixed cellularity Hodgkin lymphoma, intrapelvic lymph nodes Mixed cellularity Hodgkin lymphoma, spleen Mixed cellularity Hodgkin lymphoma, lymph nodes of multiple sites Mixed cellularity Hodgkin lymphoma, extranodal and solid organ sites Lymphocyte depleted Hodgkin lymphoma, unspecified site Lymphocyte depleted Hodgkin lymphoma, lymph nodes of head, face, and neck Lymphocyte depleted Hodgkin lymphoma, intrathoracic lymph nodes Lymphocyte depleted Hodgkin lymphoma, intra-abdominal lymph nodes Lymphocyte depleted Hodgkin lymphoma, lymph nodes of axilla and upper limb Lymphocyte depleted Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Lymphocyte depleted Hodgkin lymphoma, intrapelvic lymph nodes Lymphocyte depleted Hodgkin lymphoma, spleen Lymphocyte depleted Hodgkin lymphoma, lymph nodes of multiple sites Lymphocyte depleted Hodgkin lymphoma, extranodal and solid organ sites Lymphocyte-rich Hodgkin lymphoma, unspecified site Lymphocyte-rich Hodgkin lymphoma, lymph nodes of head, face, and neck Lymphocyte-rich Hodgkin lymphoma, intrathoracic lymph nodes Lymphocyte-rich Hodgkin lymphoma, intra-abdominal lymph nodes Lymphocyte-rich Hodgkin lymphoma, lymph nodes of axilla and upper limb Page 44 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C81.45 C81.46 C81.47 C81.48 C81.49 C81.70 C81.71 C81.72 C81.73 C81.74 C81.75 C81.76 C81.77 C81.78 C81.79 C81.90 C81.91 C81.92 C81.93 C81.94 C81.95 C81.96 C81.97 C81.98 C81.99 C82.00 C82.01 C82.02 C82.03 C82.04 C82.05 C82.06 C82.07 C82.08 C82.09 Description Lymphocyte-rich Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Lymphocyte-rich Hodgkin lymphoma, intrapelvic lymph nodes Lymphocyte-rich Hodgkin lymphoma, spleen Lymphocyte-rich Hodgkin lymphoma, lymph nodes of multiple sites Lymphocyte-rich Hodgkin lymphoma, extranodal and solid organ sites Other Hodgkin lymphoma, unspecified site Other Hodgkin lymphoma, lymph nodes of head, face, and neck Other Hodgkin lymphoma, intrathoracic lymph nodes Other Hodgkin lymphoma, intra-abdominal lymph nodes Other Hodgkin lymphoma, lymph nodes of axilla and upper limb Other Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Other Hodgkin lymphoma, intrapelvic lymph nodes Other Hodgkin lymphoma, spleen Other Hodgkin lymphoma, lymph nodes of multiple sites Other Hodgkin lymphoma, extranodal and solid organ sites Hodgkin lymphoma, unspecified, unspecified site Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck Hodgkin lymphoma, unspecified, intrathoracic lymph nodes Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb Hodgkin lymphoma, unspecified, intrapelvic lymph nodes Hodgkin lymphoma, unspecified, spleen Hodgkin lymphoma, unspecified, lymph nodes of multiple sites Hodgkin lymphoma, unspecified, extranodal and solid organ sites Follicular lymphoma grade I, unspecified site Follicular lymphoma grade I, lymph nodes of head, face, and neck Follicular lymphoma grade I, intrathoracic lymph nodes Follicular lymphoma grade I, intra-abdominal lymph nodes Follicular lymphoma grade I, lymph nodes of axilla and upper limb Follicular lymphoma grade I, lymph nodes of inguinal region and lower limb Follicular lymphoma grade I, intrapelvic lymph nodes Follicular lymphoma grade I, spleen Follicular lymphoma grade I, lymph nodes of multiple sites Follicular lymphoma grade I, extranodal and solid organ sites Page 45 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C82.10 C82.11 C82.12 C82.13 C82.14 C82.15 C82.16 C82.17 C82.18 C82.19 C82.20 C82.21 C82.22 C82.23 C82.24 C82.25 C82.26 C82.27 C82.28 C82.29 C82.30 C82.31 C82.32 C82.33 C82.34 C82.35 C82.36 C82.37 C82.38 C82.39 C82.40 C82.41 C82.42 C82.43 C82.44 Description Follicular lymphoma grade II, unspecified site Follicular lymphoma grade II, lymph nodes of head, face, and neck Follicular lymphoma grade II, intrathoracic lymph nodes Follicular lymphoma grade II, intra-abdominal lymph nodes Follicular lymphoma grade II, lymph nodes of axilla and upper limb Follicular lymphoma grade II, lymph nodes of inguinal region and lower limb Follicular lymphoma grade II, intrapelvic lymph nodes Follicular lymphoma grade II, spleen Follicular lymphoma grade II, lymph nodes of multiple sites Follicular lymphoma grade II, extranodal and solid organ sites Follicular lymphoma grade III, unspecified, unspecified site Follicular lymphoma grade III, unspecified, lymph nodes of head, face, and neck Follicular lymphoma grade III, unspecified, intrathoracic lymph nodes Follicular lymphoma grade III, unspecified, intra-abdominal lymph nodes Follicular lymphoma grade III, unspecified, lymph nodes of axilla and upper limb Follicular lymphoma grade III, unspecified, lymph nodes of inguinal region and lower limb Follicular lymphoma grade III, unspecified, intrapelvic lymph nodes Follicular lymphoma grade III, unspecified, spleen Follicular lymphoma grade III, unspecified, lymph nodes of multiple sites Follicular lymphoma grade III, unspecified, extranodal and solid organ sites Follicular lymphoma grade IIIa, unspecified site Follicular lymphoma grade IIIa, lymph nodes of head, face, and neck Follicular lymphoma grade IIIa, intrathoracic lymph nodes Follicular lymphoma grade IIIa, intra-abdominal lymph nodes Follicular lymphoma grade IIIa, lymph nodes of axilla and upper limb Follicular lymphoma grade IIIa, lymph nodes of inguinal region and lower limb Follicular lymphoma grade IIIa, intrapelvic lymph nodes Follicular lymphoma grade IIIa, spleen Follicular lymphoma grade IIIa, lymph nodes of multiple sites Follicular lymphoma grade IIIa, extranodal and solid organ sites Follicular lymphoma grade IIIb, unspecified site Follicular lymphoma grade IIIb, lymph nodes of head, face, and neck Follicular lymphoma grade IIIb, intrathoracic lymph nodes Follicular lymphoma grade IIIb, intra-abdominal lymph nodes Follicular lymphoma grade IIIb, lymph nodes of axilla and upper limb Page 46 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C82.45 C82.46 C82.47 C82.48 C82.49 C82.50 C82.51 C82.52 C82.53 C82.54 C82.55 C82.56 C82.57 C82.58 C82.59 C82.60 C82.61 C82.62 C82.63 C82.64 C82.65 C82.66 C82.67 C82.68 C82.69 C82.80 C82.81 C82.82 C82.83 C82.84 C82.85 C82.86 C82.87 C82.88 C82.89 Description Follicular lymphoma grade IIIb, lymph nodes of inguinal region and lower limb Follicular lymphoma grade IIIb, intrapelvic lymph nodes Follicular lymphoma grade IIIb, spleen Follicular lymphoma grade IIIb, lymph nodes of multiple sites Follicular lymphoma grade IIIb, extranodal and solid organ sites Diffuse follicle center lymphoma, unspecified site Diffuse follicle center lymphoma, lymph nodes of head, face, and neck Diffuse follicle center lymphoma, intrathoracic lymph nodes Diffuse follicle center lymphoma, intra-abdominal lymph nodes Diffuse follicle center lymphoma, lymph nodes of axilla and upper limb Diffuse follicle center lymphoma, lymph nodes of inguinal region and lower limb Diffuse follicle center lymphoma, intrapelvic lymph nodes Diffuse follicle center lymphoma, spleen Diffuse follicle center lymphoma, lymph nodes of multiple sites Diffuse follicle center lymphoma, extranodal and solid organ sites Cutaneous follicle center lymphoma, unspecified site Cutaneous follicle center lymphoma, lymph nodes of head, face, and neck Cutaneous follicle center lymphoma, intrathoracic lymph nodes Cutaneous follicle center lymphoma, intra-abdominal lymph nodes Cutaneous follicle center lymphoma, lymph nodes of axilla and upper limb Cutaneous follicle center lymphoma, lymph nodes of inguinal region and lower limb Cutaneous follicle center lymphoma, intrapelvic lymph nodes Cutaneous follicle center lymphoma, spleen Cutaneous follicle center lymphoma, lymph nodes of multiple sites Cutaneous follicle center lymphoma, extranodal and solid organ sites Other types of follicular lymphoma, unspecified site Other types of follicular lymphoma, lymph nodes of head, face, and neck Other types of follicular lymphoma, intrathoracic lymph nodes Other types of follicular lymphoma, intra-abdominal lymph nodes Other types of follicular lymphoma, lymph nodes of axilla and upper limb Other types of follicular lymphoma, lymph nodes of inguinal region and lower limb Other types of follicular lymphoma, intrapelvic lymph nodes Other types of follicular lymphoma, spleen Other types of follicular lymphoma, lymph nodes of multiple sites Other types of follicular lymphoma, extranodal and solid organ sites Page 47 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C82.90 C82.91 C82.92 C82.93 C82.94 C82.95 C82.96 C82.97 C82.98 C82.99 C83.00 C83.01 C83.02 C83.03 C83.04 C83.05 C83.06 C83.07 C83.08 C83.09 C83.10 C83.11 C83.12 C83.13 C83.14 C83.15 C83.16 C83.17 C83.18 C83.19 C83.30 C83.31 C83.32 C83.33 C83.34 Description Follicular lymphoma, unspecified, unspecified site Follicular lymphoma, unspecified, lymph nodes of head, face, and neck Follicular lymphoma, unspecified, intrathoracic lymph nodes Follicular lymphoma, unspecified, intra-abdominal lymph nodes Follicular lymphoma, unspecified, lymph nodes of axilla and upper limb Follicular lymphoma, unspecified, lymph nodes of inguinal region and lower limb Follicular lymphoma, unspecified, intrapelvic lymph nodes Follicular lymphoma, unspecified, spleen Follicular lymphoma, unspecified, lymph nodes of multiple sites Follicular lymphoma, unspecified, extranodal and solid organ sites Small cell B-cell lymphoma, unspecified site Small cell B-cell lymphoma, lymph nodes of head, face, and neck Small cell B-cell lymphoma, intrathoracic lymph nodes Small cell B-cell lymphoma, intra-abdominal lymph nodes Small cell B-cell lymphoma, lymph nodes of axilla and upper limb Small cell B-cell lymphoma, lymph nodes of inguinal region and lower limb Small cell B-cell lymphoma, intrapelvic lymph nodes Small cell B-cell lymphoma, spleen Small cell B-cell lymphoma, lymph nodes of multiple sites Small cell B-cell lymphoma, extranodal and solid organ sites Mantle cell lymphoma, unspecified site Mantle cell lymphoma, lymph nodes of head, face, and neck Mantle cell lymphoma, intrathoracic lymph nodes Mantle cell lymphoma, intra-abdominal lymph nodes Mantle cell lymphoma, lymph nodes of axilla and upper limb Mantle cell lymphoma, lymph nodes of inguinal region and lower limb Mantle cell lymphoma, intrapelvic lymph nodes Mantle cell lymphoma, spleen Mantle cell lymphoma, lymph nodes of multiple sites Mantle cell lymphoma, extranodal and solid organ sites Diffuse large B-cell lymphoma, unspecified site Diffuse large B-cell lymphoma, lymph nodes of head, face, and neck Diffuse large B-cell lymphoma, intrathoracic lymph nodes Diffuse large B-cell lymphoma, intra-abdominal lymph nodes Diffuse large B-cell lymphoma, lymph nodes of axilla and upper limb Page 48 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C83.35 C83.36 C83.37 C83.38 C83.39 C83.50 C83.51 C83.52 C83.53 C83.54 C83.55 C83.56 C83.57 C83.58 C83.59 C83.70 C83.71 C83.72 C83.73 C83.74 C83.75 C83.76 C83.77 C83.78 C83.79 C83.80 C83.81 C83.82 C83.83 C83.84 C83.85 C83.86 C83.87 C83.88 C83.89 Description Diffuse large B-cell lymphoma, lymph nodes of inguinal region and lower limb Diffuse large B-cell lymphoma, intrapelvic lymph nodes Diffuse large B-cell lymphoma, spleen Diffuse large B-cell lymphoma, lymph nodes of multiple sites Diffuse large B-cell lymphoma, extranodal and solid organ sites Lymphoblastic (diffuse) lymphoma, unspecified site Lymphoblastic (diffuse) lymphoma, lymph nodes of head, face, and neck Lymphoblastic (diffuse) lymphoma, intrathoracic lymph nodes Lymphoblastic (diffuse) lymphoma, intra-abdominal lymph nodes Lymphoblastic (diffuse) lymphoma, lymph nodes of axilla and upper limb Lymphoblastic (diffuse) lymphoma, lymph nodes of inguinal region and lower limb Lymphoblastic (diffuse) lymphoma, intrapelvic lymph nodes Lymphoblastic (diffuse) lymphoma, spleen Lymphoblastic (diffuse) lymphoma, lymph nodes of multiple sites Lymphoblastic (diffuse) lymphoma, extranodal and solid organ sites Burkitt lymphoma, unspecified site Burkitt lymphoma, lymph nodes of head, face, and neck Burkitt lymphoma, intrathoracic lymph nodes Burkitt lymphoma, intra-abdominal lymph nodes Burkitt lymphoma, lymph nodes of axilla and upper limb Burkitt lymphoma, lymph nodes of inguinal region and lower limb Burkitt lymphoma, intrapelvic lymph nodes Burkitt lymphoma, spleen Burkitt lymphoma, lymph nodes of multiple sites Burkitt lymphoma, extranodal and solid organ sites Other non-follicular lymphoma, unspecified site Other non-follicular lymphoma, lymph nodes of head, face, and neck Other non-follicular lymphoma, intrathoracic lymph nodes Other non-follicular lymphoma, intra-abdominal lymph nodes Other non-follicular lymphoma, lymph nodes of axilla and upper limb Other non-follicular lymphoma, lymph nodes of inguinal region and lower limb Other non-follicular lymphoma, intrapelvic lymph nodes Other non-follicular lymphoma, spleen Other non-follicular lymphoma, lymph nodes of multiple sites Other non-follicular lymphoma, extranodal and solid organ sites Page 49 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C83.90 C83.91 C83.92 C83.93 C83.94 C83.95 C83.96 C83.97 C83.98 C83.99 C84.00 C84.01 C84.02 C84.03 C84.04 C84.05 C84.06 C84.07 C84.08 C84.09 C84.10 C84.11 C84.12 C84.13 C84.14 C84.15 C84.16 C84.17 C84.18 C84.19 C84.40 C84.41 C84.42 C84.43 Description Non-follicular (diffuse) lymphoma, unspecified, unspecified site Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of head, face, and neck Non-follicular (diffuse) lymphoma, unspecified, intrathoracic lymph nodes Non-follicular (diffuse) lymphoma, unspecified, intra-abdominal lymph nodes Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of axilla and upper limb Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of inguinal region and lower limb Non-follicular (diffuse) lymphoma, unspecified, intrapelvic lymph nodes Non-follicular (diffuse) lymphoma, unspecified, spleen Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of multiple sites Non-follicular (diffuse) lymphoma, unspecified, extranodal and solid organ sites Mycosis fungoides, unspecified site Mycosis fungoides, lymph nodes of head, face, and neck Mycosis fungoides, intrathoracic lymph nodes Mycosis fungoides, intra-abdominal lymph nodes Mycosis fungoides, lymph nodes of axilla and upper limb Mycosis fungoides, lymph nodes of inguinal region and lower limb Mycosis fungoides, intrapelvic lymph nodes Mycosis fungoides, spleen Mycosis fungoides, lymph nodes of multiple sites Mycosis fungoides, extranodal and solid organ sites Sézary disease, unspecified site Sézary disease, lymph nodes of head, face, and neck Sézary disease, intrathoracic lymph nodes Sézary disease, intra-abdominal lymph nodes Sézary disease, lymph nodes of axilla and upper limb Sézary disease, lymph nodes of inguinal region and lower limb Sézary disease, intrapelvic lymph nodes Sézary disease, spleen Sézary disease, lymph nodes of multiple sites Sézary disease, extranodal and solid organ sites Peripheral T-cell lymphoma, not classified, unspecified site Peripheral T-cell lymphoma, not classified, lymph nodes of head, face, and neck Peripheral T-cell lymphoma, not classified, intrathoracic lymph nodes Peripheral T-cell lymphoma, not classified, intra-abdominal lymph nodes Page 50 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C84.44 C84.45 C84.46 C84.47 C84.48 C84.49 C84.60 C84.61 C84.62 C84.63 C84.64 C84.65 C84.66 C84.67 C84.68 C84.69 C84.70 C84.71 C84.72 C84.73 C84.74 C84.75 C84.76 C84.77 C84.78 C84.79 C84.90 C84.91 C84.92 C84.93 C84.94 C84.95 C84.96 Description Peripheral T-cell lymphoma, not classified, lymph nodes of axilla and upper limb Peripheral T-cell lymphoma, not classified, lymph nodes of inguinal region and lower limb Peripheral T-cell lymphoma, not classified, intrapelvic lymph nodes Peripheral T-cell lymphoma, not classified, spleen Peripheral T-cell lymphoma, not classified, lymph nodes of multiple sites Peripheral T-cell lymphoma, not classified, extranodal and solid organ sites Anaplastic large cell lymphoma, ALK-positive, unspecified site Anaplastic large cell lymphoma, ALK-positive, lymph nodes of head, face, and neck Anaplastic large cell lymphoma, ALK-positive, intrathoracic lymph nodes Anaplastic large cell lymphoma, ALK-positive, intra-abdominal lymph nodes Anaplastic large cell lymphoma, ALK-positive, lymph nodes of axilla and upper limb Anaplastic large cell lymphoma, ALK-positive, lymph nodes of inguinal region and lower limb Anaplastic large cell lymphoma, ALK-positive, intrapelvic lymph nodes Anaplastic large cell lymphoma, ALK-positive, spleen Anaplastic large cell lymphoma, ALK-positive, lymph nodes of multiple sites Anaplastic large cell lymphoma, ALK-positive, extranodal and solid organ sites Anaplastic large cell lymphoma, ALK-negative, unspecified site Anaplastic large cell lymphoma, ALK-negative, lymph nodes of head, face, and neck Anaplastic large cell lymphoma, ALK-negative, intrathoracic lymph nodes Anaplastic large cell lymphoma, ALK-negative, intra-abdominal lymph nodes Anaplastic large cell lymphoma, ALK-negative, lymph nodes of axilla and upper limb Anaplastic large cell lymphoma, ALK-negative, lymph nodes of inguinal region and lower limb Anaplastic large cell lymphoma, ALK-negative, intrapelvic lymph nodes Anaplastic large cell lymphoma, ALK-negative, spleen Anaplastic large cell lymphoma, ALK-negative, lymph nodes of multiple sites Anaplastic large cell lymphoma, ALK-negative, extranodal and solid organ sites Mature T/NK-cell lymphomas, unspecified, unspecified site Mature T/NK-cell lymphomas, unspecified, lymph nodes of head, face, and neck Mature T/NK-cell lymphomas, unspecified, intrathoracic lymph nodes Mature T/NK-cell lymphomas, unspecified, intra-abdominal lymph nodes Mature T/NK-cell lymphomas, unspecified, lymph nodes of axilla and upper limb Mature T/NK-cell lymphomas, unspecified, lymph nodes of inguinal region and lower limb Mature T/NK-cell lymphomas, unspecified, intrapelvic lymph nodes Page 51 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C84.97 C84.98 C84.99 C84.A0 C84.A1 C84.A2 C84.A3 C84.A4 C84.A5 C84.A6 C84.A7 C84.A8 C84.A9 C84.Z0 C84.Z1 C84.Z2 C84.Z3 C84.Z4 C84.Z5 C84.Z6 C84.Z7 C84.Z8 C84.Z9 C85.10 C85.11 C85.12 C85.13 C85.14 C85.15 C85.16 C85.17 C85.18 C85.19 C85.20 C85.21 Description Mature T/NK-cell lymphomas, unspecified, spleen Mature T/NK-cell lymphomas, unspecified, lymph nodes of multiple sites Mature T/NK-cell lymphomas, unspecified, extranodal and solid organ sites Cutaneous T-cell lymphoma, unspecified, unspecified site Cutaneous T-cell lymphoma, unspecified lymph nodes of head, face, and neck Cutaneous T-cell lymphoma, unspecified, intrathoracic lymph nodes Cutaneous T-cell lymphoma, unspecified, intra-abdominal lymph nodes Cutaneous T-cell lymphoma, unspecified, lymph nodes of axilla and upper limb Cutaneous T-cell lymphoma, unspecified, lymph nodes of inguinal region and lower limb Cutaneous T-cell lymphoma, unspecified, intrapelvic lymph nodes Cutaneous T-cell lymphoma, unspecified, spleen Cutaneous T-cell lymphoma, unspecified, lymph nodes of multiple sites Cutaneous T-cell lymphoma, unspecified, extranodal and solid organ sites Other mature T/NK-cell lymphomas, unspecified site Other mature T/NK-cell lymphomas, lymph nodes of head, face, and neck Other mature T/NK-cell lymphomas, intrathoracic lymph nodes Other mature T/NK-cell lymphomas, intra-abdominal lymph nodes Other mature T/NK-cell lymphomas, lymph nodes of axilla and upper limb Other mature T/NK-cell lymphomas, lymph nodes of inguinal region and lower limb Other mature T/NK-cell lymphomas, intrapelvic lymph nodes Other mature T/NK-cell lymphomas, spleen Other mature T/NK-cell lymphomas, lymph nodes of multiple sites Other mature T/NK-cell lymphomas, extranodal and solid organ sites Unspecified B-cell lymphoma, unspecified site Unspecified B-cell lymphoma, lymph nodes of head, face, and neck Unspecified B-cell lymphoma, intrathoracic lymph nodes Unspecified B-cell lymphoma, intra-abdominal lymph nodes Unspecified B-cell lymphoma, lymph nodes of axilla and upper limb Unspecified B-cell lymphoma, lymph nodes of inguinal region and lower limb Unspecified B-cell lymphoma, intrapelvic lymph nodes Unspecified B-cell lymphoma, spleen Unspecified B-cell lymphoma, lymph nodes of multiple sites Unspecified B-cell lymphoma, extranodal and solid organ sites Mediastinal (thymic) large B-cell lymphoma, unspecified site Mediastinal (thymic) large B-cell lymphoma, lymph nodes of head, face, and neck Page 52 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C85.22 C85.23 C85.24 C85.25 C85.26 C85.27 C85.28 C85.29 C85.80 C85.81 C85.82 C85.83 C85.84 C85.85 C85.86 C85.87 C85.88 C85.89 C85.90 C85.91 C85.92 C85.93 C85.94 C85.95 C85.96 C85.97 C85.98 C85.99 C86.0 C86.1 C86.2 C86.3 C86.4 Description Mediastinal (thymic) large B-cell lymphoma, intrathoracic lymph nodes Mediastinal (thymic) large B-cell lymphoma, intra-abdominal lymph nodes Mediastinal (thymic) large B-cell lymphoma, lymph nodes of axilla and upper limb Mediastinal (thymic) large B-cell lymphoma, lymph nodes of inguinal region and lower limb Mediastinal (thymic) large B-cell lymphoma, intrapelvic lymph nodes Mediastinal (thymic) large B-cell lymphoma, spleen Mediastinal (thymic) large B-cell lymphoma, lymph nodes of multiple sites Mediastinal (thymic) large B-cell lymphoma, extranodal and solid organ sites Other specified types of non-Hodgkin lymphoma, unspecified site Other specified types of non-Hodgkin lymphoma, lymph nodes of head, face, and neck Other specified types of non-Hodgkin lymphoma, intrathoracic lymph nodes Other specified types of non-Hodgkin lymphoma, intra-abdominal lymph nodes Other specified types of non-Hodgkin lymphoma, lymph nodes of axilla and upper limb Other specified types of non-Hodgkin lymphoma, lymph nodes of inguinal region and lower limb Other specified types of non-Hodgkin lymphoma, intrapelvic lymph nodes Other specified types of non-Hodgkin lymphoma, spleen Other specified types of non-Hodgkin lymphoma, lymph nodes of multiple sites Other specified types of non-Hodgkin lymphoma, extranodal and solid organ sites Non-Hodgkin lymphoma, unspecified, unspecified site Non-Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck Non-Hodgkin lymphoma, unspecified, intrathoracic lymph nodes Non-Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes Non-Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb Non-Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb Non-Hodgkin lymphoma, unspecified, intrapelvic lymph nodes Non-Hodgkin lymphoma, unspecified, spleen Non-Hodgkin lymphoma, unspecified, lymph nodes of multiple sites Non-Hodgkin lymphoma, unspecified, extranodal and solid organ sites Extranodal NK/T-cell lymphoma, nasal type Hepatosplenic T-cell lymphoma Enteropathy-type (intestinal) T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Blastic NK-cell lymphoma Page 53 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C86.5 C86.6 C88.2 C88.3 C88.4 C88.8 C88.9 C90.00 C90.01 C90.02 C90.10 C90.11 C90.12 C90.20 C90.21 C90.22 C90.30 C90.31 C90.32 C91.00 C91.01 C91.02 C91.10 C91.11 C91.12 C91.30 C91.31 C91.32 C91.40 C91.41 C91.42 C91.50 C91.51 C91.52 Description Angioimmunoblastic T-cell lymphoma Primary cutaneous CD30-positive T-cell proliferations Heavy chain disease Immunoproliferative small intestinal disease Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALTlymphoma] Other malignant immunoproliferative diseases Malignant immunoproliferative disease, unspecified Multiple myeloma not having achieved remission Multiple myeloma in remission Multiple myeloma in relapse Plasma cell leukemia not having achieved remission Plasma cell leukemia in remission Plasma cell leukemia in relapse Extramedullary plasmacytoma not having achieved remission Extramedullary plasmacytoma in remission Extramedullary plasmacytoma in relapse Solitary plasmacytoma not having achieved remission Solitary plasmacytoma in remission Solitary plasmacytoma in relapse Acute lymphoblastic leukemia not having achieved remission Acute lymphoblastic leukemia, in remission Acute lymphoblastic leukemia, in relapse Chronic lymphocytic leukemia of B-cell type not having achieved remission Chronic lymphocytic leukemia of B-cell type in remission Chronic lymphocytic leukemia of B-cell type in relapse Prolymphocytic leukemia of B-cell type not having achieved remission Prolymphocytic leukemia of B-cell type, in remission Prolymphocytic leukemia of B-cell type, in relapse Hairy cell leukemia not having achieved remission Hairy cell leukemia, in remission Hairy cell leukemia, in relapse Adult T-cell lymphoma/leukemia (HTLV-1-associated) not having achieved remission Adult T-cell lymphoma/leukemia (HTLV-1-associated), in remission Adult T-cell lymphoma/leukemia (HTLV-1-associated), in relapse Page 54 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C91.60 C91.61 C91.62 C91.90 C91.91 C91.92 C91.A0 C91.A1 C91.A2 C91.Z0 C91.Z1 C91.Z2 C92.00 C92.01 C92.02 C92.10 C92.11 C92.12 C92.20 C92.21 C92.22 C92.30 C92.31 C92.32 C92.40 C92.41 C92.42 C92.50 C92.51 C92.52 C92.60 C92.61 C92.62 C92.90 C92.91 Description Prolymphocytic leukemia of T-cell type not having achieved remission Prolymphocytic leukemia of T-cell type, in remission Prolymphocytic leukemia of T-cell type, in relapse Lymphoid leukemia, unspecified not having achieved remission Lymphoid leukemia, unspecified, in remission Lymphoid leukemia, unspecified, in relapse Mature B-cell leukemia Burkitt-type not having achieved remission Mature B-cell leukemia Burkitt-type, in remission Mature B-cell leukemia Burkitt-type, in relapse Other lymphoid leukemia not having achieved remission Other lymphoid leukemia, in remission Other lymphoid leukemia, in relapse Acute myeloblastic leukemia, not having achieved remission Acute myeloblastic leukemia, in remission Acute myeloblastic leukemia, in relapse Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission Chronic myeloid leukemia, BCR/ABL-positive, in remission Chronic myeloid leukemia, BCR/ABL-positive, in relapse Atypical chronic myeloid leukemia, BCR/ABL-negative, not having achieved remission Atypical chronic myeloid leukemia, BCR/ABL-negative, in remission Atypical chronic myeloid leukemia, BCR/ABL-negative, in relapse Myeloid sarcoma, not having achieved remission Myeloid sarcoma, in remission Myeloid sarcoma, in relapse Acute promyelocytic leukemia, not having achieved remission Acute promyelocytic leukemia, in remission Acute promyelocytic leukemia, in relapse Acute myelomonocytic leukemia, not having achieved remission Acute myelomonocytic leukemia, in remission Acute myelomonocytic leukemia, in relapse Acute myeloid leukemia with 11q23-abnormality not having achieved remission Acute myeloid leukemia with 11q23-abnormality in remission Acute myeloid leukemia with 11q23-abnormality in relapse Myeloid leukemia, unspecified, not having achieved remission Myeloid leukemia, unspecified in remission Page 55 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C92.92 C92.A0 C92.A1 C92.A2 C92.Z0 C92.Z1 C92.Z2 C93.00 C93.01 C93.02 C93.10 C93.11 C93.12 C93.30 C93.31 C93.32 C93.90 C93.91 C93.92 C93.Z0 C93.Z1 C93.Z2 C94.00 C94.01 C94.02 C94.20 C94.21 C94.22 C94.30 C94.31 C94.32 C94.80 C94.81 C94.82 C95.00 Description Myeloid leukemia, unspecified in relapse Acute myeloid leukemia with multilineage dysplasia, not having achieved remission Acute myeloid leukemia with multilineage dysplasia, in remission Acute myeloid leukemia with multilineage dysplasia, in relapse Other myeloid leukemia not having achieved remission Other myeloid leukemia, in remission Other myeloid leukemia, in relapse Acute monoblastic/monocytic leukemia, not having achieved remission Acute monoblastic/monocytic leukemia, in remission Acute monoblastic/monocytic leukemia, in relapse Chronic myelomonocytic leukemia not having achieved remission Chronic myelomonocytic leukemia, in remission Chronic myelomonocytic leukemia, in relapse Juvenile myelomonocytic leukemia, not having achieved remission Juvenile myelomonocytic leukemia, in remission Juvenile myelomonocytic leukemia, in relapse Monocytic leukemia, unspecified, not having achieved remission Monocytic leukemia, unspecified in remission Monocytic leukemia, unspecified in relapse Other monocytic leukemia, not having achieved remission Other monocytic leukemia, in remission Other monocytic leukemia, in relapse Acute erythroid leukemia, not having achieved remission Acute erythroid leukemia, in remission Acute erythroid leukemia, in relapse Acute megakaryoblastic leukemia not having achieved remission Acute megakaryoblastic leukemia, in remission Acute megakaryoblastic leukemia, in relapse Mast cell leukemia not having achieved remission Mast cell leukemia, in remission Mast cell leukemia, in relapse Other specified leukemias not having achieved remission Other specified leukemias, in remission Other specified leukemias, in relapse Acute leukemia of unspecified cell type not having achieved remission Page 56 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* C95.01 C95.02 C95.10 C95.11 C95.12 C95.90 C95.91 C95.92 C96.0 C96.2 C96.4 C96.9 C96.A C96.Z D03.0 D03.10 D03.11 D03.12 D03.20 D03.21 D03.22 D03.30 D03.39 D03.4 D03.51 D03.52 D03.59 D03.60 D03.61 D03.62 D03.70 D03.71 D03.72 D03.8 D03.9 Description Acute leukemia of unspecified cell type, in remission Acute leukemia of unspecified cell type, in relapse Chronic leukemia of unspecified cell type not having achieved remission Chronic leukemia of unspecified cell type, in remission Chronic leukemia of unspecified cell type, in relapse Leukemia, unspecified not having achieved remission Leukemia, unspecified, in remission Leukemia, unspecified, in relapse Multifocal and multisystemic (disseminated) Langerhans-cell histiocytosis Malignant mast cell tumor Sarcoma of dendritic cells (accessory cells) Malignant neoplasm of lymphoid, hematopoietic and related tissue, unspecified Histiocytic sarcoma Other specified malignant neoplasms of lymphoid, hematopoietic and related tissue Melanoma in situ of lip Melanoma in situ of unspecified eyelid, including canthus Melanoma in situ of right eyelid, including canthus Melanoma in situ of left eyelid, including canthus Melanoma in situ of unspecified ear and external auricular canal Melanoma in situ of right ear and external auricular canal Melanoma in situ of left ear and external auricular canal Melanoma in situ of unspecified part of face Melanoma in situ of other parts of face Melanoma in situ of scalp and neck Melanoma in situ of anal skin Melanoma in situ of breast (skin) (soft tissue) Melanoma in situ of other part of trunk Melanoma in situ of unspecified upper limb, including shoulder Melanoma in situ of right upper limb, including shoulder Melanoma in situ of left upper limb, including shoulder Melanoma in situ of unspecified lower limb, including hip Melanoma in situ of right lower limb, including hip Melanoma in situ of left lower limb, including hip Melanoma in situ of other sites Melanoma in situ, unspecified Page 57 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 ICD-10CM Diagnosis Code* D45 D46.21 D46.20 D46.1 D46.0 D46.4 D46.a D46.b D46.22 D46.c D46.9 D46.z D47.1 D47.Z1 D63.0 D63.1 D63.8 D64.81 N18.1 N18.2 N18.3 N18.4 N18.5 N18.6 N18.9 N19 Z48.290 Z51.11 Z51.12 Z94.81 Z94.84 Description Polycythemia vera Refractory anemia with excess of blasts 1 Refractory anemia with excess of blasts, unspecified Refractory anemia with ring sideroblasts Refractory anemia without ring sideroblasts, so stated Refractory anemia, unspecified Refractory cytopenia with multilineage dysplasia Refractory cytopenia with multilineage dysplasia and ring sideroblasts Refractory anemia with excess of blasts 2 Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality Myelodysplastic syndrome, unspecified Other myelodysplastic Chronic myeloproliferative disease Post-transplant lymphoproliferative disorder (PTLD Anemia in neoplastic disease Anemia in chronic kidney disease Anemia in other chronic diseases classified elsewhere Anemia due to antineoplastic chemotherapy Chronic kidney disease, stage 1 Chronic kidney disease, stage 2 (mild) Chronic kidney disease, stage 3 (moderate) Chronic kidney disease, stage 4 (severe) Chronic kidney disease, stage 5 End stage renal disease Chronic kidney disease, unspecified Unspecified kidney failure Encounter for aftercare following bone marrow transplant Encounter for antineoplastic chemotherapy Encounter for antineoplastic immunotherapy Bone marrow transplant status Stem cells transplant status *The list of covered diagnoses for Senior Blue members may differ from the above. If applicable, please refer to the Medicare NCD or LCD for details. Page 58 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 IX. REFERENCES TOP 1. U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS), page last updated: 08/01/2014 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider s/ucm111350.htm. Accessed . January 11, 2016. 2. U.S. Food and Drug Administration. FDA Briefing Document, May 10, 2007 Oncologic Drugs Advisory Committee. Continuing reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with cancer chemotherapy. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Accessed January 11, 2016. 3. Grant MD, Piper M, Bohlius J, et al. Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update. Comparative Effectiveness Review No. 113. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-2007-10058-I.) AHRQ Publication No. 13-EHC077-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2013. http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-andreports/?pageaction=displayproduct&productID=1480. Accessed January 11, 2016. 4. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. May 17 2006;98(10):708-714. PMID 16705125 5. Seidenfeld J, Piper M, Bohlius J, et al. Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment. Comparative Effectiveness Review No. 3. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026.) Rockville, MD: Agency for Healthcare Research and Quality; May 2006. http://www.ncbi.nlm.nih.gov/books/NBK42982/. Accessed January 11, 2016. 6. Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or Darbepoetin for patients with cancer-meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009(3):CD007303. PMID 19588423 7. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. May 2 2009;373(9674):1532-1542. PMID 19410717 8. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;12:CD003407. PMID 23235597 9. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. Nov 20 2010;28(33):4996-5010. PMID 20975064 10. Centers for Medicare and Medicaid Services (CMS). Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N), July 30, 2007. http://www.cms.gov/medicare-coverage-database/details/nca-decision- Page 59 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 memo.aspx?NCAId=203&ver=12&NcaName=Erythropoiesis+Stimulating+Agents+&bc=BEA AAAAAIAAA&. Accessed January 11, 2016. 11. U.S. Food and Drug Administration. FDA Briefing Document, September 11, 2007 Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Committee. Reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with chronic renal failure. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4315b1-01-FDA.pdf. Accessed January 11, 2016. 12. Strippoli GF, Craig JC, Manno C, et al. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol. Dec 2004;15(12):3154-3165. PMID 15579519 13. Amgen Inc. Epogen® (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, April 2014. http://www.epogen.com/. Accessed January11, 2016.. 14. Amgen Inc. Procrit® (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, December 2013. http://www.procrit.com/. Accessed January 11, 2016. 15. Amgen Inc. Aranesp® (darbepoetin alfa) injection for intravenous or subcutaneous use prescribing information, July 2015.http://www.aranesp.com. Accessed January 11, 2016. 16. Hoffmann-La Roche, Inc. Mircera® (methoxy polyethylene glycol-epoetin beta) solution for injection: intravenous (IV) or subcutaneous (SC) use prescribing information, November 2007. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/125164lbl.pdf. Accessed January 11, 2016. 17. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. Sep 2007;50(3):471-530. PMID 17720528 18. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. Aug 27 1998;339(9):584-590. PMID 9718377 19. Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol. Nov 2007;2(6):1274-1282. PMID 17942772 20. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. Nov 16 2006;355(20):2085-2098. PMID 17108343 21. Inrig JK, Barnhart HX, Reddan D, et al. Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. Am J Kidney Dis. Sep 2012;60(3):390-401. PMID 22537421 22. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. Nov 16 2006;355(20):2071-2084. PMID 17108342 23. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. Nov 19 2009;361(21):2019-2032. PMID 19880844 24. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. Dec 20 2011;124(25):2903-2908. PMID 22104547 Page 60 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 25. Vinhas J, Barreto C, Assuncao J, et al. Treatment of anaemia with erythropoiesis-stimulating agents in patients with chronic kidney disease does not lower mortality and may increase cardiovascular risk: a meta-analysis. Nephron Clin Pract. 2012;121(3-4):c95-101. PMID 23182871 26. Williams AW, Dwyer AC, Eddy AA, et al. Critical and honest conversations: the evidence behind the "Choosing Wisely" campaign recommendations by the American Society of Nephrology. Clin J Am Soc Nephrol. Oct 2012;7(10):1664-1672. PMID 22977214 27. Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2014;3:CD009297. PMID 24683046 28. Walker RG, Strippoli GF. A pegylated epoetin in anaemia of renal disease: non-inferiority for an unvalidated surrogate. Lancet. Oct 20 2007;370(9596):1395-1396. PMID 17950848 29. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Office Director Memo: application number BLA 125164. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/125164TOC.cfm. Accessed AJanuary 11, 2106. 30. Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. Mar 2008;3(2):337-347. PMID 18287255 31. Klinger M, Arias M, Vargemezis V, et al. Efficacy of intravenous methoxy polyethylene glycolepoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. Am J Kidney Dis. Dec 2007;50(6):989-1000. PMID 18037099 32. Levin NW, Fishbane S, Canedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet. Oct 20 2007;370(9596):1415-1421. PMID 17950856 33. Sulowicz W, Locatelli F, Ryckelynck JP, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol. Jul 2007;2(4):637-646. PMID 17699476 34. Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant. Nov 2008;23(11):3654-3661. PMID 18586762 35. Spinowitz B, Coyne DW, Lok CE, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. Am J Nephrol. 2008;28(2):280-289. PMID 18004064 36. Hahn D, Cody JD, Hodson EM. Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients. Cochrane Database Syst Rev. 2014;5:CD003895. PMID 24872328 37. Oh J, Joo KW, Chin HJ, et al. Correction of anemia with continuous erythropoietin receptor activator in Korean patients on long-term hemodialysis. J Korean Med Sci. Jan 2014;29(1):7683. PMID 24431909 Page 61 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 38. Vankar SG, Dutta P, Kohli HS, et al. Efficacy & safety of continuous erythropoietin receptor activator (CERA) in treating renal anaemia in diabetic patients with chronic kidney disease not on dialysis. Indian J Med Res. Jan 2014;139(1):112-116. PMID 24604046 39. Roger SD, Locatelli F, Woitas RP, et al. C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis. Nephrol Dial Transplant. Dec 2011;26(12):3980-3986. PMID 21505096 40. Al-Ali FS, El-Sayed Abdelfattah M, Fawzy AA, et al. Erythropoietin-stimulating agents in the management of anemia of end-stage renal disease patients on regular hemodialysis: A prospective randomized comparative study from Qatar. Hemodial Int. Jun 3 2014. PMID 24894344 41. Hirai T, Nishizawa Y, Nakazono H, et al. Hemoglobin maintenance and dosing strategies using intravenous continuous erythropoietin receptor activator in Japanese hemodialysis patients. Ther Apher Dial. Oct 2013;17(5):498-503. PMID 24107278 42. Kessler M, Martinez-Castelao A, Siamopoulos KC, et al. C.E.R.A. once every 4 weeks in patients with chronic kidney disease not on dialysis: The ARCTOS extension study. Hemodial Int. Apr 2010;14(2):233-239. PMID 19888948 43. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Specialty Pharmacy Reports 2012. Peginesatide: #6-2012. 44. U.S. Food and Drug Administration. MedWatch Safety Information and Adverse Event Reporting. Omontys (peginesatide) Injection by Affymax and Takeda: Recall of All Lots - Serious Hypersensitivity Reactions. February 23, 2013. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm340895.htm?source=govdelivery. Accessed January 11, 2016. 45. Gao S, Ma JJ, Lu C. Venous thromboembolism risk and erythropoiesis-stimulating agents for the treatment of cancer-associated anemia: a meta-analysis. Tumour Biol. Jan 2014;35(1):603-613. PMID 23959477 46. Gascon P, Pirker R, Del Mastro L, et al. Effects of CERA (continuous erythropoietin receptor activator) in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy: results of a phase II study. Ann Oncol. Oct 2010;21(10):2029-2039. PMID 20335369 47. Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCVinfected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. May 2004;126(5):1302-1311. PMID 15131791 48. Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. Nov 2003;98(11):2491-2499. PMID 14638354 49. Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. Aug 2007;46(2):371-379. PMID 17559152 50. U.S. Food and Drug Administration. Postmarket Drug Safety Information for Patients and Providers: Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp). Page 62 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/u cm109375.htm. Accessed January11, 2016.. 51. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: cancer- and chemotherapy-induced anemia, version 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/anemia.pdf. Accessed January 11, 2016. 52. Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (110.21), July 30, 2007. http://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?NCDId=322&ncdver=1&bc=AAAAgAAAAAAAAA%3d%3d&. Accessed January 11, 2016. Other: FDA Recall-Firm Press Release. Affymax and Takeda Announce a Nationwide Voluntary Recall of All Lots of OMONTYS® (peginesatide) Injection February 23, 2013. [Website]: http://www.fda.gov/Safety/Recalls/ucm340893.htm Accessed January11, 2016. Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) 110.21. Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions. Effective 7/30/07. CMS [Website]: https://www.cms.gov Accessed January 11, 2016. Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual. Publication 100-02. Chapter 15 Covered Medical and Other Services. Effective 01/14/14. [Website]: http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c15.pdf Accessed January 11, 2016. Taber's Cyclopedic Medical Dictionary, 20th edition X. POLICY HISTORY MP 2.111 TOP CAC 5/25/04 CAC 11/30/04 CAC 10/25/05 CAC 9/26/06 CAC 4/24/07 CAC 7/29/08 CAC 7/28/09 Consensus Review CAC 11/24/09 Policy revised with additional medical necessity criteria for treatment of anemia associated with Hepatitis C medications. CAC 9/28/10 Added “not medically necessary” indication for orthostatic hypotension. Page 63 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 CAC 11/22/11 Adopted BCBSA. Retained CBC investigational indication for orthostatic hypotension. Policy criteria for use of ESAs for autologous stem-cell support, noniatrogenic chronic anemia of cancer and orthostatic hypotension revised from not medically necessary to investigational. FDA qualifying statement added to criteria for ESA use in cancer conditions. Description and Background revised per BCBSA updates. FEP variation added. Added Medicare variation for treatment of anemia related to specified chronic diseases. CAC 6/26/12 Minor Revision. Added recently approved (3/12) new long –acting ESA Peginesatide (Omontys) to the policy considered medically necessary for treatment of anemia due to chronic kidney disease in adult patients on dialysis. Also added an off label indication for treatment of ribavirin induced anemia in patients being treated for Hepatitis C. FEP variation revised. FEP requires prior-approval for these agents. Boxed warnings revised to reflect current FDA-prescribing information. 2013 Codes added-12/20/2013 Admin posting 2/28/13. Information in policy related to Omontys removed from policy due to product recall. Admin posting 3-8-13 Prior auth requirement removed from FEP variation. Code J0890 added CAC 7/30/13 Minor review. Added the following: Information on Omontys (peginesatice) recall to Background/Description Policy guidelines Reference to NCD 110.11 Erythropoiesis Stimulating Agnets (ESAs) in Cancer and Related Neoplastic Conditions in the Medicare variation. Rationale section. CAC 3/25/14 Consensus review. References updated. No change to policy statements. Background information updated. LCD variation removed as policy was retired. Variation now refers to the Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Chapter 15 for coverage of ESA’s for end-stage renal disease related anemia. CAC 3/24/15 Minor. Information about pegylated (PEG) epoetin beta (Mircera®) added and medically necessary policy statement updated to include PEG-epoetin beta for treatment of anemia associated with chronic kidney disease; PEG-epoetin beta is investigational for all other uses. Rationale and references updated. Coding reviewed. 10/22/15 Coding updated. Added additional diagnosis codes applicable to the policy. CAC 3/29/16 Consensus review. No changes to the policy statements. Reference and rationale updated. Coding reviewed. 1/1/17 Administrative-Variations reformatted. Revised code definitions updated effective 10/1/2016 Page 64 MEDICAL POLICY POLICY TITLE ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) POLICY NUMBER MP-2.111 TOP Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company®, Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies. Page 65