POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY

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1 Original Issue Date (Created): 7/1/2002 Most Recent Review Date (Revised): 3/24/2015 Effective Date: 7/1/2015 POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY 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 chemotherapy 1,2 ; treatment of anemia related to therapy with AZT (zidovudine) in HIV-infected patients 1 ; reduction of allogeneic blood transfusion in surgery patients 1 ; 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

2 Epoetin or darbepoetin treatment should be discontinued following the completion of a myelosuppressive chemotherapy course. 1 FDA-approved label for epoetin alfa (Epogen, Procrit ) 2 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 ). b FDA-approved label for darbepoetin alfa (Aranesp ). c FDA-approved label for PEG-epoetin beta (Mircera ). 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

3 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, Both REMS were subsequently modified, most recently on December 31, 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

4 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 Off-Label Use of Prescription Drugs and Medical Devices II. PRODUCT VARIATIONS TOP [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] Capital Cares 4 Kids [N] Indemnity [N] PPO [N] SpecialCare [N] HMO [N] POS [Y] SeniorBlue HMO** [Y] FEP PPO* [Y] SeniorBlue PPO** * For Procrit and Epogen - Refer to FEP Medical Policy Manual MP EPOGEN / PROCRIT; for Aranesp refer to MP Aranesp. The FEP Medical Policy manual can be found at: ** Refer to Centers for Medicare and Medicaid (CMS) National Coverage Determination (NCD) 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 for coverage of ESA s for end-stage renal disease related anemia. 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 Page 4

5 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 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 Page 5

6 Products LP has rights to develop and market Procrit for any indication other than for 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 Epoetin alfa and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation 2 ; 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 ): Page 6

7 2001: Approved for use in patients with anemia due to CRF 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 ; 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 ; 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 anemia 9 ; 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 risks 11 ; 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 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

8 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 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

9 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 al 25 Outcome n/n Relative Risk a 95% CI I 2,b Vascular access thrombosis 2/ to % Stroke 4/ to % Progression to ESRD 3/ to % All-cause mortality 5/ to % 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 ( g/dl) compared with lower Hb targets ( 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 (I 2 =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 CKD 16 (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

10 bleeding events (5.2% vs 4%), serious gastrointestinal bleeding events (1.2% vs 0.2%), and thrombocytopenia less than 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 % Responders a Mean ΔHb, b g/dl Correction trials in patients not receiving ESA therapy Macdougall 2008 (ARCTOS) 30,c PEG-epoetin beta /kg SC q2wk Darbepoetin /kg SC qwk P value <0.001 d <0.001 e Klinger 2007 (AMICUS) 31 PEG-epoetin beta /kg IV q2wk Epoetin alfa/beta 46 Per product label IV 3/wk P value <0.001 d <0.001 e Maintenance trials in patients receiving ESA therapy Levin 2007 (MAXIMA) 32 PEG-epoetin beta IV q2wk PEG-epoetin beta IV q4wk Epoetin alfa/beta IV q1-3x/wk P value vs control <0.001 ef Sulowicz 2007 (PROTOS) 33 PEG-epoetin beta SC q2wk 190 PEG-epoetin beta dose PEG-epoetin beta SC q4wk 191 based on maintenance Epoetin alfa/beta SC q1-3x/wk 191 ESA dose P value vs control g <0.001 ef Canaud 2008 (STRIATA) 34 PEG-epoetin beta IV q2wk 157 Comparator ESA dose was continuation of Darbepoetin IV q1-2wk 156 maintenance dose P value 0.25 h <0.001 e Spinowitz 2008 (RUBRA) 35 PEG-epoetin beta SC/IV q2wk Epoetin alfa/beta SC/IV q1-2wk P value i <0.001 e 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 g/dl AMICUS: Hb level 11 g/dl and increased 1.0 g/dl from baseline at 24 wk; target Hb g/dl PROTOS, STRIATA: Mean Hb within ±1 g/dl of baseline values through 52 wk; target Hb 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), g/dl. f Both comparisons. Page 10

11 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 (I 2 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 hemodialysis 37 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, 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

12 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

13 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 , 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, , 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 , 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

14 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 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 AHRQ Report and 2012 Individual Patient Data: Comparison of Updated Results 2013 AHRQ Individual Patient Data 8 n/n Result (95% CI) n/n Result (95% CI) Transfusions, RR 38/10, (0.53 to 0.64) 70/16, (0.62 to 0.68) Thromboembolic events, RR a 37/12, (1.30 to 1.74) 57/15, (1.33 to 1.73) On-study mortality, HR a 37/11, (1.04 to 1.31) 70/15, (1.06 to 1.29) Tumor response, RR a 15/5577 Not pooled b 15/ (0.98 to 1.06) FACT-fatigue, mean difference 14/ c (1.69 to 3.78) 18/ c (1.43 to 2.72) Overall survival, HR for death 44/14, (0.99 to 1.10) 78/19, (1.00 to 1.11) Hypertension, RR 16/ (1.07 to 2.06) 31/ (0.94 to 1.33) Thrombocytopenia/hemorrhage, RR a 12/ (1.01 to 1.36) 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; I 2 =0%). Pegylated Epoetin Beta PEG-epoetin beta is not FDA-approved for anemia due to cancer chemotherapy, 16 and Hoffmann- LaRoche, 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

15 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

16 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, Product labels have been revised and updated subsequently, most recently in December 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

17 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 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

18 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 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

19 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 Hematology 9 and from the National Comprehensive Cancer Network, version Table 4. Summary of Current Guidelines for Treatment of Anemia in Patients with Cancer American Society of Clinical National Comprehensive Cancer Network Oncology/American Society of Hematology Guidelines, Cancer and Chemotherapy Clinical Practice Guideline Induced Anemia (v ) ESAs are indicated for: ESAs are a recommended treatment option for patients with chemotherapy-associated Based on patient preference and values, patients undergoing palliative treatment or Page 19

20 ESAs are NOT indicated for: ESA treatment symptom outcomes 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. 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 REMS Notes requirement Notes requirement Hb levels for ESA initiation Span of ESA treatment ESA dosing modifications Hb target Iron Thromboembolic risk 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 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

21 use together with therapies that increase risk of thromboembolic events assessment; the risk of ESA-associated thrombosis is independent of Hb levels Response to treatment If a patient does not respond to ESAs after 6-8 wk, despite a dose increase, ESA therapy should be discontinued and the clinician ESA therapy should be discontinued if a patient shows no response despite iron 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

22 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

23 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

24 PEG-epoetin beta may be considered medically necessary for adult patients with CKD on dialysis: HCPCS Description Code J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis) ICD-9-CM Diagnosis Description Code* Anemia in chronic kidney disease Chronic kidney disease, stage i Chronic kidney disease, stage ii (mild) Chronic kidney disease, stage iii (moderate) Chronic kidney disease, stage iv (severe) Chronic kidney disease, stage v End stage renal disease Chronic kidney disease, unspecified *The list of covered diagnoses for SeniorBlue members may differ from the above. If applicable, please refer to the Medicare NCD or LCD for details. ICD-10- CM Diagnosis Description Code D63.1 Anemia in chronic kidney disease N18.1 Chronic kidney disease, stage 1 N18.2 Chronic kidney disease, stage 2 (mild) N18.3 Chronic kidney disease, stage 3 (moderate) N18.4 Chronic kidney disease, stage 4 (severe) N18.5 Chronic kidney disease, stage 5 N18.6 End stage renal disease N18.9 Chronic kidney disease, unspecified Covered when medically necessary: HCPCS Description Code J0881 Injection, darbepoetin alfa, 1 mcg (non-esrd use) J0882 Injection, darbepoetin alfa, 1 mcg (for esrd on dialysis) J0885 Injection, epoetin alfa, (for non-esrd use), 1000 units J0886 Injection, epoetin alfa, 1000 units (for esrd on dialysis) Page 24

25 HCPCS Code J0890 Q4081 Description Injection, peginesatide, 0.1 mg (for esrd on dialysis) Injection, epoetin alfa, 100 units (for esrd on dialysis) ICD-9-CM Diagnosis Code* Description Chronic hepatitis C with hepatic coma Chronic hepatitis c without mention of hepatic coma Malignant neoplasms Anemia in chronic kidney disease Anemia in neoplastic disease Anemia of other chronic disease Antineoplastic chemotherapy induced anemia Chronic kidney disease, stage i Chronic kidney disease, stage ii (mild) Chronic kidney disease, stage iii (moderate) Chronic kidney disease, stage iv (severe) Chronic kidney disease, stage v End stage renal disease Chronic kidney disease, unspecified 586. Unspecified renal failure V42.81 Bone marrow replaced by transplant V42.82 Peripheral stem cells replaced by transplant V58.11 Encounter for antineoplastic chemotherapy V58.12 Encounter for antineoplastic immunotherapy *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. The following ICD-10 diagnosis codes will be effective October 1, 2015: B18.2 Chronic viral hepatitis C C00.0 Malignant neoplasm of external upper lip C00.1 Malignant neoplasm of external lower lip C00.2 Malignant neoplasm of external lip, unspecified C00.3 Malignant neoplasm of upper lip, inner aspect C00.4 Malignant neoplasm of lower lip, inner aspect C00.5 Malignant neoplasm of lip, unspecified, inner aspect C00.6 Malignant neoplasm of commissure of lip, unspecified Page 25

26 C00.8 Malignant neoplasm of overlapping sites of lip C00.9 Malignant neoplasm of lip, unspecified C01 Malignant neoplasm of base of tongue C02.0 Malignant neoplasm of dorsal surface of tongue C02.1 Malignant neoplasm of border of tongue C02.2 Malignant neoplasm of ventral surface of tongue C02.3 Malignant neoplasm of anterior two-thirds of tongue, part unspecified C02.4 Malignant neoplasm of lingual tonsil C02.8 Malignant neoplasm of overlapping sites of tongue C02.9 Malignant neoplasm of tongue, unspecified C03.0 Malignant neoplasm of upper gum C03.1 Malignant neoplasm of lower gum C03.9 Malignant neoplasm of gum, unspecified C04.0 Malignant neoplasm of anterior floor of mouth C04.1 Malignant neoplasm of lateral floor of mouth C04.8 Malignant neoplasm of overlapping sites of floor of mouth C04.9 Malignant neoplasm of floor of mouth, unspecified C05.0 Malignant neoplasm of hard palate C05.1 Malignant neoplasm of soft palate C05.2 Malignant neoplasm of uvula C05.8 Malignant neoplasm of overlapping sites of palate C05.9 Malignant neoplasm of palate, unspecified C06.0 Malignant neoplasm of cheek mucosa C06.1 Malignant neoplasm of vestibule of mouth C06.2 Malignant neoplasm of retromolar area C06.80 Malignant neoplasm of overlapping sites of unspecified parts of mouth C06.89 Malignant neoplasm of overlapping sites of other parts of mouth C06.9 Malignant neoplasm of mouth, unspecified C07 Malignant neoplasm of parotid gland C08.0 Malignant neoplasm of submandibular gland C08.1 Malignant neoplasm of sublingual gland C08.9 Malignant neoplasm of major salivary gland, unspecified C09.0 Malignant neoplasm of tonsillar fossa C09.1 Malignant neoplasm of tonsillar pillar (anterior) (posterior) C09.8 Malignant neoplasm of overlapping sites of tonsil C09.9 Malignant neoplasm of tonsil, unspecified C10.0 Malignant neoplasm of vallecula C10.1 Malignant neoplasm of anterior surface of epiglottis Page 26

27 C10.2 Malignant neoplasm of lateral wall of oropharynx C10.3 Malignant neoplasm of posterior wall of oropharynx C10.4 Malignant neoplasm of branchial cleft C10.8 Malignant neoplasm of overlapping sites of oropharynx C10.9 Malignant neoplasm of oropharynx, unspecified C11.0 Malignant neoplasm of superior wall of nasopharynx C11.1 Malignant neoplasm of posterior wall of nasopharynx C11.2 Malignant neoplasm of lateral wall of nasopharynx C11.3 Malignant neoplasm of anterior wall of nasopharynx C11.8 Malignant neoplasm of overlapping sites of nasopharynx C11.9 Malignant neoplasm of nasopharynx, unspecified C12 Malignant neoplasm of pyriform sinus C13.0 Malignant neoplasm of postcricoid region C13.1 Malignant neoplasm of aryepiglottic fold, hypopharyngeal aspect C13.2 Malignant neoplasm of posterior wall of hypopharynx C13.8 Malignant neoplasm of overlapping sites of hypopharynx C13.9 Malignant neoplasm of hypopharynx, unspecified C14.0 Malignant neoplasm of pharynx, unspecified C14.2 Malignant neoplasm of Waldeyer's ring C14.8 Malignant neoplasm of overlapping sites of lip, oral cavity and pharynx C15.3 Malignant neoplasm of upper third of esophagus C15.4 Malignant neoplasm of middle third of esophagus C15.5 Malignant neoplasm of lower third of esophagus C15.8 Malignant neoplasm of overlapping sites of esophagus C15.9 Malignant neoplasm of esophagus, unspecified C16.0 Malignant neoplasm of cardia C16.1 Malignant neoplasm of fundus of stomach C16.2 Malignant neoplasm of body of stomach C16.3 Malignant neoplasm of pyloric antrum C16.4 Malignant neoplasm of pylorus C16.5 Malignant neoplasm of lesser curvature of stomach, unspecified C16.6 Malignant neoplasm of greater curvature of stomach, unspecified C16.8 Malignant neoplasm of overlapping sites of stomach C16.9 Malignant neoplasm of stomach, unspecified C17.0 Malignant neoplasm of duodenum C17.1 Malignant neoplasm of jejunum C17.2 Malignant neoplasm of ileum C17.3 Meckel's diverticulum, malignant Page 27

28 C17.8 Malignant neoplasm of overlapping sites of small intestine C17.9 Malignant neoplasm of small intestine, unspecified C18.0 Malignant neoplasm of cecum C18.1 Malignant neoplasm of appendix C18.2 Malignant neoplasm of ascending colon C18.3 Malignant neoplasm of hepatic flexure C18.4 Malignant neoplasm of transverse colon C18.5 Malignant neoplasm of splenic flexure C18.6 Malignant neoplasm of descending colon C18.7 Malignant neoplasm of sigmoid colon C18.8 Malignant neoplasm of overlapping sites of colon C18.9 Malignant neoplasm of colon, unspecified C19 Malignant neoplasm of rectosigmoid junction C20 Malignant neoplasm of rectum C21.0 Malignant neoplasm of anus, unspecified C21.1 Malignant neoplasm of anal canal C21.2 Malignant neoplasm of cloacogenic zone C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal C22.0 Liver cell carcinoma C22.1 Intrahepatic bile duct carcinoma C22.2 Hepatoblastoma C22.3 Angiosarcoma of liver C22.4 Other sarcomas of liver C22.7 Other specified carcinomas of liver C22.8 Malignant neoplasm of liver, primary, unspecified as to type C22.9 Malignant neoplasm of liver, not specified as primary or secondary C23 Malignant neoplasm of gallbladder C24.0 Malignant neoplasm of extrahepatic bile duct C24.1 Malignant neoplasm of ampulla of Vater C24.8 Malignant neoplasm of overlapping sites of biliary tract C24.9 Malignant neoplasm of biliary tract, unspecified C25.0 Malignant neoplasm of head of pancreas C25.1 Malignant neoplasm of body of pancreas C25.2 Malignant neoplasm of tail of pancreas C25.3 Malignant neoplasm of pancreatic duct C25.4 Malignant neoplasm of endocrine pancreas C25.7 Malignant neoplasm of other parts of pancreas C25.8 Malignant neoplasm of overlapping sites of pancreas Page 28

29 C25.9 Malignant neoplasm of pancreas, unspecified C26.0 Malignant neoplasm of intestinal tract, part unspecified C26.1 Malignant neoplasm of spleen C26.9 Malignant neoplasm of ill-defined sites within the digestive system C30.0 Malignant neoplasm of nasal cavity C30.1 Malignant neoplasm of middle ear C31.0 Malignant neoplasm of maxillary sinus C31.1 Malignant neoplasm of ethmoidal sinus C31.2 Malignant neoplasm of frontal sinus C31.3 Malignant neoplasm of sphenoid sinus C31.8 Malignant neoplasm of overlapping sites of accessory sinuses C31.9 Malignant neoplasm of accessory sinus, unspecified C32.0 Malignant neoplasm of glottis C32.1 Malignant neoplasm of supraglottis C32.2 Malignant neoplasm of subglottis C32.3 Malignant neoplasm of laryngeal cartilage C32.8 Malignant neoplasm of overlapping sites of larynx C32.9 Malignant neoplasm of larynx, unspecified C33 Malignant neoplasm of trachea C34.00 Malignant neoplasm of unspecified main bronchus C34.01 Malignant neoplasm of right main bronchus C34.02 Malignant neoplasm of left main bronchus C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung C34.11 Malignant neoplasm of upper lobe, right bronchus or lung C34.12 Malignant neoplasm of upper lobe, left bronchus or lung C34.2 Malignant neoplasm of middle lobe, bronchus or lung C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung C34.31 Malignant neoplasm of lower lobe, right bronchus or lung C34.32 Malignant neoplasm of lower lobe, left bronchus or lung C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung C34.82 Malignant neoplasm of overlapping sites of left bronchus and lung C34.90 Malignant neoplasm of unspecified part of unspecified bronchus or lung C34.91 Malignant neoplasm of unspecified part of right bronchus or lung C34.92 Malignant neoplasm of unspecified part of left bronchus or lung C37 Malignant neoplasm of thymus C38.0 Malignant neoplasm of heart C38.1 Malignant neoplasm of anterior mediastinum Page 29

30 C38.2 Malignant neoplasm of posterior mediastinum C38.3 Malignant neoplasm of mediastinum, part unspecified C38.4 Malignant neoplasm of pleura C38.8 Malignant neoplasm of overlapping sites of heart, mediastinum and pleura C39.0 Malignant neoplasm of upper respiratory tract, part unspecified C39.9 Malignant neoplasm of lower respiratory tract, part unspecified C40.00 Malignant neoplasm of scapula and long bones of unspecified upper limb C40.01 Malignant neoplasm of scapula and long bones of right upper limb C40.02 Malignant neoplasm of scapula and long bones of left upper limb C40.10 Malignant neoplasm of short bones of unspecified upper limb C40.11 Malignant neoplasm of short bones of right upper limb C40.12 Malignant neoplasm of short bones of left upper limb C40.20 Malignant neoplasm of long bones of unspecified lower limb C40.21 Malignant neoplasm of long bones of right lower limb C40.22 Malignant neoplasm of long bones of left lower limb C40.30 Malignant neoplasm of short bones of unspecified lower limb C40.31 Malignant neoplasm of short bones of right lower limb C40.32 Malignant neoplasm of short bones of left lower limb C40.80 Malignant neoplasm of overlapping sites of bone and articular cartilage of unspecified limb C40.81 Malignant neoplasm of overlapping sites of bone and articular cartilage of right limb C40.82 Malignant neoplasm of overlapping sites of bone and articular cartilage of left limb C40.90 Malignant neoplasm of unspecified bones and articular cartilage of unspecified limb C40.91 Malignant neoplasm of unspecified bones and articular cartilage of right limb C40.92 Malignant neoplasm of unspecified bones and articular cartilage of left limb C41.0 Malignant neoplasm of bones of skull and face C41.1 Malignant neoplasm of mandible C41.2 Malignant neoplasm of vertebral column C41.3 Malignant neoplasm of ribs, sternum and clavicle C41.4 Malignant neoplasm of pelvic bones, sacrum and coccyx C41.9 Malignant neoplasm of bone and articular cartilage, unspecified C43.0 Malignant melanoma of lip C43.10 Malignant melanoma of unspecified eyelid, including canthus C43.11 Malignant melanoma of right eyelid, including canthus C43.12 Malignant melanoma of left eyelid, including canthus C43.20 Malignant melanoma of unspecified ear and external auricular canal C43.21 Malignant melanoma of right ear and external auricular canal C43.22 Malignant melanoma of left ear and external auricular canal C43.30 Malignant melanoma of unspecified part of face Page 30

31 C43.31 Malignant melanoma of nose C43.39 Malignant melanoma of other parts of face C43.4 Malignant melanoma of scalp and neck C43.51 Malignant melanoma of anal skin C43.52 Malignant melanoma of skin of breast C43.59 Malignant melanoma of other part of trunk C43.60 Malignant melanoma of unspecified upper limb, including shoulder C43.61 Malignant melanoma of right upper limb, including shoulder C43.62 Malignant melanoma of left upper limb, including shoulder C43.70 Malignant melanoma of unspecified lower limb, including hip C43.71 Malignant melanoma of right lower limb, including hip C43.72 Malignant melanoma of left lower limb, including hip C43.8 Malignant melanoma of overlapping sites of skin C43.9 Malignant melanoma of skin, unspecified C44.00 Unspecified malignant neoplasm of skin of lip C44.01 Basal cell carcinoma of skin of lip C44.02 Squamous cell carcinoma of skin of lip C44.09 Other specified malignant neoplasm of skin of lip C Unspecified malignant neoplasm of skin of unspecified eyelid, including canthus C Unspecified malignant neoplasm of skin of right eyelid, including canthus C Unspecified malignant neoplasm of skin of left eyelid, including canthus C Basal cell carcinoma of skin of unspecified eyelid, including canthus C Basal cell carcinoma of skin of right eyelid, including canthus C Basal cell carcinoma of skin of left eyelid, including canthus C Squamous cell carcinoma of skin of unspecified eyelid, including canthus C Squamous cell carcinoma of skin of right eyelid, including canthus C Squamous cell carcinoma of skin of left eyelid, including canthus C Other specified malignant neoplasm of skin of unspecified eyelid, including canthus C Other specified malignant neoplasm of skin of right eyelid, including canthus C Other specified malignant neoplasm of skin of left eyelid, including canthus C Unspecified malignant neoplasm of skin of unspecified ear and external auricular canal C Unspecified malignant neoplasm of skin of right ear and external auricular canal C Unspecified malignant neoplasm of skin of left ear and external auricular canal C Basal cell carcinoma of skin of unspecified ear and external auricular canal C Basal cell carcinoma of skin of right ear and external auricular canal C Basal cell carcinoma of skin of left ear and external auricular canal C Squamous cell carcinoma of skin of unspecified ear and external auricular canal C Squamous cell carcinoma of skin of right ear and external auricular canal Page 31

32 C Squamous cell carcinoma of skin of left ear and external auricular canal C Other specified malignant neoplasm of skin of unspecified ear and external auricular canal C Other specified malignant neoplasm of skin of right ear and external auricular canal C Other specified malignant neoplasm of skin of left ear and external auricular canal C Unspecified malignant neoplasm of skin of unspecified part of face C Unspecified malignant neoplasm of skin of nose C Unspecified malignant neoplasm of skin of other parts of face C Basal cell carcinoma of skin of unspecified parts of face C Basal cell carcinoma of skin of nose C Basal cell carcinoma of skin of other parts of face C Squamous cell carcinoma of skin of unspecified parts of face C Squamous cell carcinoma of skin of nose C Squamous cell carcinoma of skin of other parts of face C Other specified malignant neoplasm of skin of unspecified parts of face C Other specified malignant neoplasm of skin of nose C Other specified malignant neoplasm of skin of other parts of face C44.40 Unspecified malignant neoplasm of skin of scalp and neck C44.41 Basal cell carcinoma of skin of scalp and neck C44.42 Squamous cell carcinoma of skin of scalp and neck C44.49 Other specified malignant neoplasm of skin of scalp and neck C Unspecified malignant neoplasm of anal skin C Unspecified malignant neoplasm of skin of breast C Unspecified malignant neoplasm of skin of other part of trunk C Basal cell carcinoma of anal skin C Basal cell carcinoma of skin of breast C Basal cell carcinoma of skin of other part of trunk C Squamous cell carcinoma of anal skin C Squamous cell carcinoma of skin of breast C Squamous cell carcinoma of skin of other part of trunk C Other specified malignant neoplasm of anal skin C Other specified malignant neoplasm of skin of breast C Other specified malignant neoplasm of skin of other part of trunk C Unspecified malignant neoplasm of skin of unspecified upper limb, including shoulder C Unspecified malignant neoplasm of skin of right upper limb, including shoulder C Unspecified malignant neoplasm of skin of left upper limb, including shoulder C Basal cell carcinoma of skin of unspecified upper limb, including shoulder C Basal cell carcinoma of skin of right upper limb, including shoulder C Basal cell carcinoma of skin of left upper limb, including shoulder Page 32

33 C Squamous cell carcinoma of skin of unspecified upper limb, including shoulder C Squamous cell carcinoma of skin of right upper limb, including shoulder C Squamous cell carcinoma of skin of left upper limb, including shoulder C Other specified malignant neoplasm of skin of unspecified upper limb, including shoulder C Other specified malignant neoplasm of skin of right upper limb, including shoulder C Other specified malignant neoplasm of skin of left upper limb, including shoulder C Unspecified malignant neoplasm of skin of unspecified lower limb, including hip C Unspecified malignant neoplasm of skin of right lower limb, including hip C Unspecified malignant neoplasm of skin of left lower limb, including hip C Basal cell carcinoma of skin of unspecified lower limb, including hip C Basal cell carcinoma of skin of right lower limb, including hip C Basal cell carcinoma of skin of left lower limb, including hip C Squamous cell carcinoma of skin of unspecified lower limb, including hip C Squamous cell carcinoma of skin of right lower limb, including hip C Squamous cell carcinoma of skin of left lower limb, including hip C Other specified malignant neoplasm of skin of unspecified lower limb, including hip C Other specified malignant neoplasm of skin of right lower limb, including hip C Other specified malignant neoplasm of skin of left lower limb, including hip C44.80 Unspecified malignant neoplasm of overlapping sites of skin C44.81 Basal cell carcinoma of overlapping sites of skin C44.82 Squamous cell carcinoma of overlapping sites of skin C44.89 Other specified malignant neoplasm of overlapping sites of skin C44.90 Unspecified malignant neoplasm of skin, unspecified C44.91 Basal cell carcinoma of skin, unspecified C44.92 Squamous cell carcinoma of skin, unspecified C44.99 Other specified malignant neoplasm of skin, unspecified C45.0 Mesothelioma of pleura C45.1 Mesothelioma of peritoneum C45.2 Mesothelioma of pericardium C45.7 Mesothelioma of other sites C45.9 Mesothelioma, unspecified C46.0 Kaposi's sarcoma of skin C46.1 Kaposi's sarcoma of soft tissue C46.2 Kaposi's sarcoma of palate C46.3 Kaposi's sarcoma of lymph nodes C46.4 Kaposi's sarcoma of gastrointestinal sites C46.50 Kaposi's sarcoma of unspecified lung C46.51 Kaposi's sarcoma of right lung Page 33

34 C46.52 Kaposi's sarcoma of left lung C46.7 Kaposi's sarcoma of other sites C46.9 Kaposi's sarcoma, unspecified C47.0 Malignant neoplasm of peripheral nerves of head, face and neck C47.10 Malignant neoplasm of peripheral nerves of unspecified upper limb, including shoulder C47.11 Malignant neoplasm of peripheral nerves of right upper limb, including shoulder C47.12 Malignant neoplasm of peripheral nerves of left upper limb, including shoulder C47.20 Malignant neoplasm of peripheral nerves of unspecified lower limb, including hip C47.21 Malignant neoplasm of peripheral nerves of right lower limb, including hip C47.22 Malignant neoplasm of peripheral nerves of left lower limb, including hip C47.3 Malignant neoplasm of peripheral nerves of thorax C47.4 Malignant neoplasm of peripheral nerves of abdomen C47.5 Malignant neoplasm of peripheral nerves of pelvis C47.6 Malignant neoplasm of peripheral nerves of trunk, unspecified C47.8 Malignant neoplasm of overlapping sites of peripheral nerves and autonomic nervous system C47.9 Malignant neoplasm of peripheral nerves and autonomic nervous system, unspecified C48.0 Malignant neoplasm of retroperitoneum C48.1 Malignant neoplasm of specified parts of peritoneum C48.2 Malignant neoplasm of peritoneum, unspecified C48.8 Malignant neoplasm of overlapping sites of retroperitoneum and peritoneum C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck C49.10 Malignant neoplasm of connective and soft tissue of unspecified upper limb, including shoulder C49.11 Malignant neoplasm of connective and soft tissue of right upper limb, including shoulder C49.12 Malignant neoplasm of connective and soft tissue of left upper limb, including shoulder C49.20 Malignant neoplasm of connective and soft tissue of unspecified lower limb, including hip C49.21 Malignant neoplasm of connective and soft tissue of right lower limb, including hip C49.22 Malignant neoplasm of connective and soft tissue of left lower limb, including hip C49.3 Malignant neoplasm of connective and soft tissue of thorax C49.4 Malignant neoplasm of connective and soft tissue of abdomen C49.5 Malignant neoplasm of connective and soft tissue of pelvis C49.6 Malignant neoplasm of connective and soft tissue of trunk, unspecified C49.8 Malignant neoplasm of overlapping sites of connective and soft tissue C49.9 Malignant neoplasm of connective and soft tissue, unspecified C4A.0 Merkel cell carcinoma of lip C4A.10 Merkel cell carcinoma of unspecified eyelid, including canthus C4A.11 Merkel cell carcinoma of right eyelid, including canthus C4A.12 Merkel cell carcinoma of left eyelid, including canthus C4A.20 Merkel cell carcinoma of unspecified ear and external auricular canal Page 34

35 C4A.21 Merkel cell carcinoma of right ear and external auricular canal C4A.22 Merkel cell carcinoma of left ear and external auricular canal C4A.30 Merkel cell carcinoma of unspecified part of face C4A.31 Merkel cell carcinoma of nose C4A.39 Merkel cell carcinoma of other parts of face C4A.4 Merkel cell carcinoma of scalp and neck C4A.51 Merkel cell carcinoma of anal skin C4A.52 Merkel cell carcinoma of skin of breast C4A.59 Merkel cell carcinoma of other part of trunk C4A.60 Merkel cell carcinoma of unspecified upper limb, including shoulder C4A.61 Merkel cell carcinoma of right upper limb, including shoulder C4A.62 Merkel cell carcinoma of left upper limb, including shoulder C4A.70 Merkel cell carcinoma of unspecified lower limb, including hip C4A.71 Merkel cell carcinoma of right lower limb, including hip C4A.72 Merkel cell carcinoma of left lower limb, including hip C4A.8 Merkel cell carcinoma of overlapping sites C4A.9 Merkel cell carcinoma, unspecified C Malignant neoplasm of nipple and areola, right female breast C Malignant neoplasm of nipple and areola, left female breast C Malignant neoplasm of nipple and areola, unspecified female breast C Malignant neoplasm of nipple and areola, right male breast C Malignant neoplasm of nipple and areola, left male breast C Malignant neoplasm of nipple and areola, unspecified male breast C Malignant neoplasm of central portion of right female breast C Malignant neoplasm of central portion of left female breast C Malignant neoplasm of central portion of unspecified female breast C Malignant neoplasm of central portion of right male breast C Malignant neoplasm of central portion of left male breast C Malignant neoplasm of central portion of unspecified male breast C Malignant neoplasm of upper-inner quadrant of right female breast C Malignant neoplasm of upper-inner quadrant of left female breast C Malignant neoplasm of upper-inner quadrant of unspecified female breast C Malignant neoplasm of upper-inner quadrant of right male breast C Malignant neoplasm of upper-inner quadrant of left male breast C Malignant neoplasm of upper-inner quadrant of unspecified male breast C Malignant neoplasm of lower-inner quadrant of right female breast C Malignant neoplasm of lower-inner quadrant of left female breast C Malignant neoplasm of lower-inner quadrant of unspecified female breast Page 35

36 C Malignant neoplasm of lower-inner quadrant of right male breast C Malignant neoplasm of lower-inner quadrant of left male breast C Malignant neoplasm of lower-inner quadrant of unspecified male breast C Malignant neoplasm of upper-outer quadrant of right female breast C Malignant neoplasm of upper-outer quadrant of left female breast C Malignant neoplasm of upper-outer quadrant of unspecified female breast C Malignant neoplasm of upper-outer quadrant of right male breast C Malignant neoplasm of upper-outer quadrant of left male breast C Malignant neoplasm of upper-outer quadrant of unspecified male breast C Malignant neoplasm of lower-outer quadrant of right female breast C Malignant neoplasm of lower-outer quadrant of left female breast C Malignant neoplasm of lower-outer quadrant of unspecified female breast C Malignant neoplasm of lower-outer quadrant of right male breast C Malignant neoplasm of lower-outer quadrant of left male breast C Malignant neoplasm of lower-outer quadrant of unspecified male breast C Malignant neoplasm of axillary tail of right female breast C Malignant neoplasm of axillary tail of left female breast C Malignant neoplasm of axillary tail of unspecified female breast C Malignant neoplasm of axillary tail of right male breast C Malignant neoplasm of axillary tail of left male breast C Malignant neoplasm of axillary tail of unspecified male breast C Malignant neoplasm of overlapping sites of right female breast C Malignant neoplasm of overlapping sites of left female breast C Malignant neoplasm of overlapping sites of unspecified female breast C Malignant neoplasm of overlapping sites of right male breast C Malignant neoplasm of overlapping sites of left male breast C Malignant neoplasm of overlapping sites of unspecified male breast C Malignant neoplasm of unspecified site of right female breast C Malignant neoplasm of unspecified site of left female breast C Malignant neoplasm of unspecified site of unspecified female breast C Malignant neoplasm of unspecified site of right male breast C Malignant neoplasm of unspecified site of left male breast C Malignant neoplasm of unspecified site of unspecified male breast C51.0 Malignant neoplasm of labium majus C51.1 Malignant neoplasm of labium minus C51.2 Malignant neoplasm of clitoris C51.8 Malignant neoplasm of overlapping sites of vulva C51.9 Malignant neoplasm of vulva, unspecified Page 36

37 C52 Malignant neoplasm of vagina C53.0 Malignant neoplasm of endocervix C53.1 Malignant neoplasm of exocervix C53.8 Malignant neoplasm of overlapping sites of cervix uteri C53.9 Malignant neoplasm of cervix uteri, unspecified C54.0 Malignant neoplasm of isthmus uteri C54.1 Malignant neoplasm of endometrium C54.2 Malignant neoplasm of myometrium C54.3 Malignant neoplasm of fundus uteri C54.8 Malignant neoplasm of overlapping sites of corpus uteri C54.9 Malignant neoplasm of corpus uteri, unspecified C55 Malignant neoplasm of uterus, part unspecified C56.1 Malignant neoplasm of right ovary C56.2 Malignant neoplasm of left ovary C56.9 Malignant neoplasm of unspecified ovary C57.00 Malignant neoplasm of unspecified fallopian tube C57.01 Malignant neoplasm of right fallopian tube C57.02 Malignant neoplasm of left fallopian tube C57.10 Malignant neoplasm of unspecified broad ligament C57.11 Malignant neoplasm of right broad ligament C57.12 Malignant neoplasm of left broad ligament C57.20 Malignant neoplasm of unspecified round ligament C57.21 Malignant neoplasm of right round ligament C57.22 Malignant neoplasm of left round ligament C57.3 Malignant neoplasm of parametrium C57.4 Malignant neoplasm of uterine adnexa, unspecified C57.7 Malignant neoplasm of other specified female genital organs C57.8 Malignant neoplasm of overlapping sites of female genital organs C57.9 Malignant neoplasm of female genital organ, unspecified C58 Malignant neoplasm of placenta C60.0 Malignant neoplasm of prepuce C60.1 Malignant neoplasm of glans penis C60.2 Malignant neoplasm of body of penis C60.8 Malignant neoplasm of overlapping sites of penis C60.9 Malignant neoplasm of penis, unspecified C61 Malignant neoplasm of prostate C62.00 Malignant neoplasm of unspecified undescended testis C62.01 Malignant neoplasm of undescended right testis Page 37

38 C62.02 Malignant neoplasm of undescended left testis C62.10 Malignant neoplasm of unspecified descended testis C62.11 Malignant neoplasm of descended right testis C62.12 Malignant neoplasm of descended left testis C62.90 Malignant neoplasm of unspecified testis, unspecified whether descended or undescended C62.91 Malignant neoplasm of right testis, unspecified whether descended or undescended C62.92 Malignant neoplasm of left testis, unspecified whether descended or undescended C63.00 Malignant neoplasm of unspecified epididymis C63.01 Malignant neoplasm of right epididymis C63.02 Malignant neoplasm of left epididymis C63.10 Malignant neoplasm of unspecified spermatic cord C63.11 Malignant neoplasm of right spermatic cord C63.12 Malignant neoplasm of left spermatic cord C63.2 Malignant neoplasm of scrotum C63.7 Malignant neoplasm of other specified male genital organs C63.8 Malignant neoplasm of overlapping sites of male genital organs C63.9 Malignant neoplasm of male genital organ, unspecified C64.1 Malignant neoplasm of right kidney, except renal pelvis C64.2 Malignant neoplasm of left kidney, except renal pelvis C64.9 Malignant neoplasm of unspecified kidney, except renal pelvis C65.1 Malignant neoplasm of right renal pelvis C65.2 Malignant neoplasm of left renal pelvis C65.9 Malignant neoplasm of unspecified renal pelvis C66.1 Malignant neoplasm of right ureter C66.2 Malignant neoplasm of left ureter C66.9 Malignant neoplasm of unspecified ureter C67.0 Malignant neoplasm of trigone of bladder C67.1 Malignant neoplasm of dome of bladder C67.2 Malignant neoplasm of lateral wall of bladder C67.3 Malignant neoplasm of anterior wall of bladder C67.4 Malignant neoplasm of posterior wall of bladder C67.5 Malignant neoplasm of bladder neck C67.6 Malignant neoplasm of ureteric orifice C67.7 Malignant neoplasm of urachus C67.8 Malignant neoplasm of overlapping sites of bladder C67.9 Malignant neoplasm of bladder, unspecified C68.0 Malignant neoplasm of urethra C68.1 Malignant neoplasm of paraurethral glands Page 38

39 C68.8 Malignant neoplasm of overlapping sites of urinary organs C68.9 Malignant neoplasm of urinary organ, unspecified C69.00 Malignant neoplasm of unspecified conjunctiva C69.01 Malignant neoplasm of right conjunctiva C69.02 Malignant neoplasm of left conjunctiva C69.10 Malignant neoplasm of unspecified cornea C69.11 Malignant neoplasm of right cornea C69.12 Malignant neoplasm of left cornea C69.20 Malignant neoplasm of unspecified retina C69.21 Malignant neoplasm of right retina C69.22 Malignant neoplasm of left retina C69.30 Malignant neoplasm of unspecified choroid C69.31 Malignant neoplasm of right choroid C69.32 Malignant neoplasm of left choroid C69.40 Malignant neoplasm of unspecified ciliary body C69.41 Malignant neoplasm of right ciliary body C69.42 Malignant neoplasm of left ciliary body C69.50 Malignant neoplasm of unspecified lacrimal gland and duct C69.51 Malignant neoplasm of right lacrimal gland and duct C69.52 Malignant neoplasm of left lacrimal gland and duct C69.60 Malignant neoplasm of unspecified orbit C69.61 Malignant neoplasm of right orbit C69.62 Malignant neoplasm of left orbit C69.80 Malignant neoplasm of overlapping sites of unspecified eye and adnexa C69.81 Malignant neoplasm of overlapping sites of right eye and adnexa C69.82 Malignant neoplasm of overlapping sites of left eye and adnexa C69.90 Malignant neoplasm of unspecified site of unspecified eye C69.91 Malignant neoplasm of unspecified site of right eye C69.92 Malignant neoplasm of unspecified site of left eye C70.0 Malignant neoplasm of cerebral meninges C70.1 Malignant neoplasm of spinal meninges C70.9 Malignant neoplasm of meninges, unspecified C71.0 Malignant neoplasm of cerebrum, except lobes and ventricles C71.1 Malignant neoplasm of frontal lobe C71.2 Malignant neoplasm of temporal lobe C71.3 Malignant neoplasm of parietal lobe C71.4 Malignant neoplasm of occipital lobe C71.5 Malignant neoplasm of cerebral ventricle Page 39

40 C71.6 Malignant neoplasm of cerebellum C71.7 Malignant neoplasm of brain stem C71.8 Malignant neoplasm of overlapping sites of brain C71.9 Malignant neoplasm of brain, unspecified C72.0 Malignant neoplasm of spinal cord C72.1 Malignant neoplasm of cauda equina C72.20 Malignant neoplasm of unspecified olfactory nerve C72.21 Malignant neoplasm of right olfactory nerve C72.22 Malignant neoplasm of left olfactory nerve C72.30 Malignant neoplasm of unspecified optic nerve C72.31 Malignant neoplasm of right optic nerve C72.32 Malignant neoplasm of left optic nerve C72.40 Malignant neoplasm of unspecified acoustic nerve C72.41 Malignant neoplasm of right acoustic nerve C72.42 Malignant neoplasm of left acoustic nerve C72.50 Malignant neoplasm of unspecified cranial nerve C72.59 Malignant neoplasm of other cranial nerves C72.9 Malignant neoplasm of central nervous system, unspecified C73 Malignant neoplasm of thyroid gland C74.00 Malignant neoplasm of cortex of unspecified adrenal gland C74.01 Malignant neoplasm of cortex of right adrenal gland C74.02 Malignant neoplasm of cortex of left adrenal gland C74.10 Malignant neoplasm of medulla of unspecified adrenal gland C74.11 Malignant neoplasm of medulla of right adrenal gland C74.12 Malignant neoplasm of medulla of left adrenal gland C74.90 Malignant neoplasm of unspecified part of unspecified adrenal gland C74.91 Malignant neoplasm of unspecified part of right adrenal gland C74.92 Malignant neoplasm of unspecified part of left adrenal gland C75.0 Malignant neoplasm of parathyroid gland C75.1 Malignant neoplasm of pituitary gland C75.2 Malignant neoplasm of craniopharyngeal duct C75.3 Malignant neoplasm of pineal gland C75.4 Malignant neoplasm of carotid body C75.5 Malignant neoplasm of aortic body and other paraganglia C75.8 Malignant neoplasm with pluriglandular involvement, unspecified C75.9 Malignant neoplasm of endocrine gland, unspecified C76.0 Malignant neoplasm of head, face and neck C76.1 Malignant neoplasm of thorax Page 40

41 C76.2 Malignant neoplasm of abdomen C76.3 Malignant neoplasm of pelvis C76.40 Malignant neoplasm of unspecified upper limb C76.41 Malignant neoplasm of right upper limb C76.42 Malignant neoplasm of left upper limb C76.50 Malignant neoplasm of unspecified lower limb C76.51 Malignant neoplasm of right lower limb C76.52 Malignant neoplasm of left lower limb C76.8 Malignant neoplasm of other specified ill-defined sites C77.0 Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck C77.1 Secondary and unspecified malignant neoplasm of intrathoracic lymph nodes C77.2 Secondary and unspecified malignant neoplasm of intra-abdominal lymph nodes C77.3 Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes C77.4 Secondary and unspecified malignant neoplasm of inguinal and lower limb lymph nodes C77.5 Secondary and unspecified malignant neoplasm of intrapelvic lymph nodes C77.8 Secondary and unspecified malignant neoplasm of lymph nodes of multiple regions C77.9 Secondary and unspecified malignant neoplasm of lymph node, unspecified C78.00 Secondary malignant neoplasm of unspecified lung C78.01 Secondary malignant neoplasm of right lung C78.02 Secondary malignant neoplasm of left lung C78.1 Secondary malignant neoplasm of mediastinum C78.2 Secondary malignant neoplasm of pleura C78.30 Secondary malignant neoplasm of unspecified respiratory organ C78.39 Secondary malignant neoplasm of other respiratory organs C78.4 Secondary malignant neoplasm of small intestine C78.5 Secondary malignant neoplasm of large intestine and rectum C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct C78.80 Secondary malignant neoplasm of unspecified digestive organ C78.89 Secondary malignant neoplasm of other digestive organs C79.00 Secondary malignant neoplasm of unspecified kidney and renal pelvis C79.01 Secondary malignant neoplasm of right kidney and renal pelvis C79.02 Secondary malignant neoplasm of left kidney and renal pelvis C79.10 Secondary malignant neoplasm of unspecified urinary organs C79.11 Secondary malignant neoplasm of bladder C79.19 Secondary malignant neoplasm of other urinary organs C79.2 Secondary malignant neoplasm of skin C79.31 Secondary malignant neoplasm of brain Page 41

42 C79.32 Secondary malignant neoplasm of cerebral meninges C79.40 Secondary malignant neoplasm of unspecified part of nervous system C79.49 Secondary malignant neoplasm of other parts of nervous system C79.51 Secondary malignant neoplasm of bone C79.52 Secondary malignant neoplasm of bone marrow C79.60 Secondary malignant neoplasm of unspecified ovary C79.61 Secondary malignant neoplasm of right ovary C79.62 Secondary malignant neoplasm of left ovary C79.70 Secondary malignant neoplasm of unspecified adrenal gland C79.71 Secondary malignant neoplasm of right adrenal gland C79.72 Secondary malignant neoplasm of left adrenal gland C79.81 Secondary malignant neoplasm of breast C79.82 Secondary malignant neoplasm of genital organs C79.89 Secondary malignant neoplasm of other specified sites C79.9 Secondary malignant neoplasm of unspecified site C7A.00 Malignant carcinoid tumor of unspecified site C7A.010 Malignant carcinoid tumor of the duodenum C7A.011 Malignant carcinoid tumor of the jejunum C7A.012 Malignant carcinoid tumor of the ileum C7A.019 Malignant carcinoid tumor of the small intestine, unspecified portion C7A.020 Malignant carcinoid tumor of the appendix C7A.021 Malignant carcinoid tumor of the cecum C7A.022 Malignant carcinoid tumor of the ascending colon C7A.023 Malignant carcinoid tumor of the transverse colon C7A.024 Malignant carcinoid tumor of the descending colon C7A.025 Malignant carcinoid tumor of the sigmoid colon C7A.026 Malignant carcinoid tumor of the rectum C7A.029 Malignant carcinoid tumor of the large intestine, unspecified portion C7A.090 Malignant carcinoid tumor of the bronchus and lung C7A.091 Malignant carcinoid tumor of the thymus C7A.092 Malignant carcinoid tumor of the stomach C7A.093 Malignant carcinoid tumor of the kidney C7A.094 Malignant carcinoid tumor of the foregut NOS C7A.095 Malignant carcinoid tumor of the midgut NOS C7A.096 Malignant carcinoid tumor of the hindgut NOS C7A.098 Malignant carcinoid tumors of other sites C7A.1 Malignant poorly differentiated neuroendocrine tumors C7A.8 Other malignant neuroendocrine tumors Page 42

43 C80.0 Disseminated malignant neoplasm, unspecified C80.1 Malignant (primary) neoplasm, unspecified C80.2 Malignant neoplasm associated with transplanted organ C81.00 Nodular lymphocyte predominant Hodgkin lymphoma, unspecified site C81.01 Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of head, face, and neck C81.02 Nodular lymphocyte predominant Hodgkin lymphoma, intrathoracic lymph nodes C81.03 Nodular lymphocyte predominant Hodgkin lymphoma, intra-abdominal lymph nodes C81.04 Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of axilla and upper limb C81.05 Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of inguinal region and lower limb C81.06 Nodular lymphocyte predominant Hodgkin lymphoma, intrapelvic lymph nodes C81.07 Nodular lymphocyte predominant Hodgkin lymphoma, spleen C81.08 Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of multiple sites C81.09 Nodular lymphocyte predominant Hodgkin lymphoma, extranodal and solid organ sites C81.10 Nodular sclerosis classical Hodgkin lymphoma, unspecified site C81.11 Nodular sclerosis classical Hodgkin lymphoma, lymph nodes of head, face, and neck C81.12 Nodular sclerosis classical Hodgkin lymphoma, intrathoracic lymph nodes C81.13 Nodular sclerosis classical Hodgkin lymphoma, intra-abdominal lymph nodes C81.14 Nodular sclerosis classical Hodgkin lymphoma, lymph nodes of axilla and upper limb C81.15 Nodular sclerosis classical Hodgkin lymphoma, lymph nodes of inguinal region and lower limb C81.16 Nodular sclerosis classical Hodgkin lymphoma, intrapelvic lymph nodes C81.17 Nodular sclerosis classical Hodgkin lymphoma, spleen C81.18 Nodular sclerosis classical Hodgkin lymphoma, lymph nodes of multiple sites C81.19 Nodular sclerosis classical Hodgkin lymphoma, extranodal and solid organ sites C81.20 Mixed cellularity classical Hodgkin lymphoma, unspecified site C81.21 Mixed cellularity classical Hodgkin lymphoma, lymph nodes of head, face, and neck C81.22 Mixed cellularity classical Hodgkin lymphoma, intrathoracic lymph nodes C81.23 Mixed cellularity classical Hodgkin lymphoma, intra-abdominal lymph nodes C81.24 Mixed cellularity classical Hodgkin lymphoma, lymph nodes of axilla and upper limb C81.25 Mixed cellularity classical Hodgkin lymphoma, lymph nodes of inguinal region and lower limb C81.26 Mixed cellularity classical Hodgkin lymphoma, intrapelvic lymph nodes C81.27 Mixed cellularity classical Hodgkin lymphoma, spleen C81.28 Mixed cellularity classical Hodgkin lymphoma, lymph nodes of multiple sites C81.29 Mixed cellularity classical Hodgkin lymphoma, extranodal and solid organ sites C81.30 Lymphocyte depleted classical Hodgkin lymphoma, unspecified site C81.31 Lymphocyte depleted classical Hodgkin lymphoma, lymph nodes of head, face, and neck C81.32 Lymphocyte depleted classical Hodgkin lymphoma, intrathoracic lymph nodes C81.33 Lymphocyte depleted classical Hodgkin lymphoma, intra-abdominal lymph nodes C81.34 Lymphocyte depleted classical Hodgkin lymphoma, lymph nodes of axilla and upper limb Page 43

44 C81.35 Lymphocyte depleted classical Hodgkin lymphoma, lymph nodes of inguinal region and lower limb C81.36 Lymphocyte depleted classical Hodgkin lymphoma, intrapelvic lymph nodes C81.37 Lymphocyte depleted classical Hodgkin lymphoma, spleen C81.38 Lymphocyte depleted classical Hodgkin lymphoma, lymph nodes of multiple sites C81.39 Lymphocyte depleted classical Hodgkin lymphoma, extranodal and solid organ sites C81.40 Lymphocyte-rich classical Hodgkin lymphoma, unspecified site C81.41 Lymphocyte-rich classical Hodgkin lymphoma, lymph nodes of head, face, and neck C81.42 Lymphocyte-rich classical Hodgkin lymphoma, intrathoracic lymph nodes C81.43 Lymphocyte-rich classical Hodgkin lymphoma, intra-abdominal lymph nodes C81.44 Lymphocyte-rich classical Hodgkin lymphoma, lymph nodes of axilla and upper limb C81.45 Lymphocyte-rich classical Hodgkin lymphoma, lymph nodes of inguinal region and lower limb C81.46 Lymphocyte-rich classical Hodgkin lymphoma, intrapelvic lymph nodes C81.47 Lymphocyte-rich classical Hodgkin lymphoma, spleen C81.48 Lymphocyte-rich classical Hodgkin lymphoma, lymph nodes of multiple sites C81.49 Lymphocyte-rich classical Hodgkin lymphoma, extranodal and solid organ sites C81.70 Other classical Hodgkin lymphoma, unspecified site C81.71 Other classical Hodgkin lymphoma, lymph nodes of head, face, and neck C81.72 Other classical Hodgkin lymphoma, intrathoracic lymph nodes C81.73 Other classical Hodgkin lymphoma, intra-abdominal lymph nodes C81.74 Other classical Hodgkin lymphoma, lymph nodes of axilla and upper limb C81.75 Other classical Hodgkin lymphoma, lymph nodes of inguinal region and lower limb C81.76 Other classical Hodgkin lymphoma, intrapelvic lymph nodes C81.77 Other classical Hodgkin lymphoma, spleen C81.78 Other classical Hodgkin lymphoma, lymph nodes of multiple sites C81.79 Other classical Hodgkin lymphoma, extranodal and solid organ sites C81.90 Hodgkin lymphoma, unspecified, unspecified site C81.91 Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck C81.92 Hodgkin lymphoma, unspecified, intrathoracic lymph nodes C81.93 Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes C81.94 Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb C81.95 Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb C81.96 Hodgkin lymphoma, unspecified, intrapelvic lymph nodes C81.97 Hodgkin lymphoma, unspecified, spleen C81.98 Hodgkin lymphoma, unspecified, lymph nodes of multiple sites C81.99 Hodgkin lymphoma, unspecified, extranodal and solid organ sites C82.00 Follicular lymphoma grade I, unspecified site C82.01 Follicular lymphoma grade I, lymph nodes of head, face, and neck C82.02 Follicular lymphoma grade I, intrathoracic lymph nodes Page 44

45 C82.03 Follicular lymphoma grade I, intra-abdominal lymph nodes C82.04 Follicular lymphoma grade I, lymph nodes of axilla and upper limb C82.05 Follicular lymphoma grade I, lymph nodes of inguinal region and lower limb C82.06 Follicular lymphoma grade I, intrapelvic lymph nodes C82.07 Follicular lymphoma grade I, spleen C82.08 Follicular lymphoma grade I, lymph nodes of multiple sites C82.09 Follicular lymphoma grade I, extranodal and solid organ sites C82.10 Follicular lymphoma grade II, unspecified site C82.11 Follicular lymphoma grade II, lymph nodes of head, face, and neck C82.12 Follicular lymphoma grade II, intrathoracic lymph nodes C82.13 Follicular lymphoma grade II, intra-abdominal lymph nodes C82.14 Follicular lymphoma grade II, lymph nodes of axilla and upper limb C82.15 Follicular lymphoma grade II, lymph nodes of inguinal region and lower limb C82.16 Follicular lymphoma grade II, intrapelvic lymph nodes C82.17 Follicular lymphoma grade II, spleen C82.18 Follicular lymphoma grade II, lymph nodes of multiple sites C82.19 Follicular lymphoma grade II, extranodal and solid organ sites C82.20 Follicular lymphoma grade III, unspecified, unspecified site C82.21 Follicular lymphoma grade III, unspecified, lymph nodes of head, face, and neck C82.22 Follicular lymphoma grade III, unspecified, intrathoracic lymph nodes C82.23 Follicular lymphoma grade III, unspecified, intra-abdominal lymph nodes C82.24 Follicular lymphoma grade III, unspecified, lymph nodes of axilla and upper limb C82.25 Follicular lymphoma grade III, unspecified, lymph nodes of inguinal region and lower limb C82.26 Follicular lymphoma grade III, unspecified, intrapelvic lymph nodes C82.27 Follicular lymphoma grade III, unspecified, spleen C82.28 Follicular lymphoma grade III, unspecified, lymph nodes of multiple sites C82.29 Follicular lymphoma grade III, unspecified, extranodal and solid organ sites C82.30 Follicular lymphoma grade IIIa, unspecified site C82.31 Follicular lymphoma grade IIIa, lymph nodes of head, face, and neck C82.32 Follicular lymphoma grade IIIa, intrathoracic lymph nodes C82.33 Follicular lymphoma grade IIIa, intra-abdominal lymph nodes C82.34 Follicular lymphoma grade IIIa, lymph nodes of axilla and upper limb C82.35 Follicular lymphoma grade IIIa, lymph nodes of inguinal region and lower limb C82.36 Follicular lymphoma grade IIIa, intrapelvic lymph nodes C82.37 Follicular lymphoma grade IIIa, spleen C82.38 Follicular lymphoma grade IIIa, lymph nodes of multiple sites C82.39 Follicular lymphoma grade IIIa, extranodal and solid organ sites C82.40 Follicular lymphoma grade IIIb, unspecified site Page 45

46 C82.41 Follicular lymphoma grade IIIb, lymph nodes of head, face, and neck C82.42 Follicular lymphoma grade IIIb, intrathoracic lymph nodes C82.43 Follicular lymphoma grade IIIb, intra-abdominal lymph nodes C82.44 Follicular lymphoma grade IIIb, lymph nodes of axilla and upper limb C82.45 Follicular lymphoma grade IIIb, lymph nodes of inguinal region and lower limb C82.46 Follicular lymphoma grade IIIb, intrapelvic lymph nodes C82.47 Follicular lymphoma grade IIIb, spleen C82.48 Follicular lymphoma grade IIIb, lymph nodes of multiple sites C82.49 Follicular lymphoma grade IIIb, extranodal and solid organ sites C82.50 Diffuse follicle center lymphoma, unspecified site C82.51 Diffuse follicle center lymphoma, lymph nodes of head, face, and neck C82.52 Diffuse follicle center lymphoma, intrathoracic lymph nodes C82.53 Diffuse follicle center lymphoma, intra-abdominal lymph nodes C82.54 Diffuse follicle center lymphoma, lymph nodes of axilla and upper limb C82.55 Diffuse follicle center lymphoma, lymph nodes of inguinal region and lower limb C82.56 Diffuse follicle center lymphoma, intrapelvic lymph nodes C82.57 Diffuse follicle center lymphoma, spleen C82.58 Diffuse follicle center lymphoma, lymph nodes of multiple sites C82.59 Diffuse follicle center lymphoma, extranodal and solid organ sites C82.60 Cutaneous follicle center lymphoma, unspecified site C82.61 Cutaneous follicle center lymphoma, lymph nodes of head, face, and neck C82.62 Cutaneous follicle center lymphoma, intrathoracic lymph nodes C82.63 Cutaneous follicle center lymphoma, intra-abdominal lymph nodes C82.64 Cutaneous follicle center lymphoma, lymph nodes of axilla and upper limb C82.65 Cutaneous follicle center lymphoma, lymph nodes of inguinal region and lower limb C82.66 Cutaneous follicle center lymphoma, intrapelvic lymph nodes C82.67 Cutaneous follicle center lymphoma, spleen C82.68 Cutaneous follicle center lymphoma, lymph nodes of multiple sites C82.69 Cutaneous follicle center lymphoma, extranodal and solid organ sites C82.80 Other types of follicular lymphoma, unspecified site C82.81 Other types of follicular lymphoma, lymph nodes of head, face, and neck C82.82 Other types of follicular lymphoma, intrathoracic lymph nodes C82.83 Other types of follicular lymphoma, intra-abdominal lymph nodes C82.84 Other types of follicular lymphoma, lymph nodes of axilla and upper limb C82.85 Other types of follicular lymphoma, lymph nodes of inguinal region and lower limb C82.86 Other types of follicular lymphoma, intrapelvic lymph nodes C82.87 Other types of follicular lymphoma, spleen C82.88 Other types of follicular lymphoma, lymph nodes of multiple sites Page 46

47 C82.89 Other types of follicular lymphoma, extranodal and solid organ sites C82.90 Follicular lymphoma, unspecified, unspecified site C82.91 Follicular lymphoma, unspecified, lymph nodes of head, face, and neck C82.92 Follicular lymphoma, unspecified, intrathoracic lymph nodes C82.93 Follicular lymphoma, unspecified, intra-abdominal lymph nodes C82.94 Follicular lymphoma, unspecified, lymph nodes of axilla and upper limb C82.95 Follicular lymphoma, unspecified, lymph nodes of inguinal region and lower limb C82.96 Follicular lymphoma, unspecified, intrapelvic lymph nodes C82.97 Follicular lymphoma, unspecified, spleen C82.98 Follicular lymphoma, unspecified, lymph nodes of multiple sites C82.99 Follicular lymphoma, unspecified, extranodal and solid organ sites C83.00 Small cell B-cell lymphoma, unspecified site C83.01 Small cell B-cell lymphoma, lymph nodes of head, face, and neck C83.02 Small cell B-cell lymphoma, intrathoracic lymph nodes C83.03 Small cell B-cell lymphoma, intra-abdominal lymph nodes C83.04 Small cell B-cell lymphoma, lymph nodes of axilla and upper limb C83.05 Small cell B-cell lymphoma, lymph nodes of inguinal region and lower limb C83.06 Small cell B-cell lymphoma, intrapelvic lymph nodes C83.07 Small cell B-cell lymphoma, spleen C83.08 Small cell B-cell lymphoma, lymph nodes of multiple sites C83.09 Small cell B-cell lymphoma, extranodal and solid organ sites C83.10 Mantle cell lymphoma, unspecified site C83.11 Mantle cell lymphoma, lymph nodes of head, face, and neck C83.12 Mantle cell lymphoma, intrathoracic lymph nodes C83.13 Mantle cell lymphoma, intra-abdominal lymph nodes C83.14 Mantle cell lymphoma, lymph nodes of axilla and upper limb C83.15 Mantle cell lymphoma, lymph nodes of inguinal region and lower limb C83.16 Mantle cell lymphoma, intrapelvic lymph nodes C83.17 Mantle cell lymphoma, spleen C83.18 Mantle cell lymphoma, lymph nodes of multiple sites C83.19 Mantle cell lymphoma, extranodal and solid organ sites C83.30 Diffuse large B-cell lymphoma, unspecified site C83.31 Diffuse large B-cell lymphoma, lymph nodes of head, face, and neck C83.32 Diffuse large B-cell lymphoma, intrathoracic lymph nodes C83.33 Diffuse large B-cell lymphoma, intra-abdominal lymph nodes C83.34 Diffuse large B-cell lymphoma, lymph nodes of axilla and upper limb C83.35 Diffuse large B-cell lymphoma, lymph nodes of inguinal region and lower limb C83.36 Diffuse large B-cell lymphoma, intrapelvic lymph nodes Page 47

48 C83.37 Diffuse large B-cell lymphoma, spleen C83.38 Diffuse large B-cell lymphoma, lymph nodes of multiple sites C83.39 Diffuse large B-cell lymphoma, extranodal and solid organ sites C83.50 Lymphoblastic (diffuse) lymphoma, unspecified site C83.51 Lymphoblastic (diffuse) lymphoma, lymph nodes of head, face, and neck C83.52 Lymphoblastic (diffuse) lymphoma, intrathoracic lymph nodes C83.53 Lymphoblastic (diffuse) lymphoma, intra-abdominal lymph nodes C83.54 Lymphoblastic (diffuse) lymphoma, lymph nodes of axilla and upper limb C83.55 Lymphoblastic (diffuse) lymphoma, lymph nodes of inguinal region and lower limb C83.56 Lymphoblastic (diffuse) lymphoma, intrapelvic lymph nodes C83.57 Lymphoblastic (diffuse) lymphoma, spleen C83.58 Lymphoblastic (diffuse) lymphoma, lymph nodes of multiple sites C83.59 Lymphoblastic (diffuse) lymphoma, extranodal and solid organ sites C83.70 Burkitt lymphoma, unspecified site C83.71 Burkitt lymphoma, lymph nodes of head, face, and neck C83.72 Burkitt lymphoma, intrathoracic lymph nodes C83.73 Burkitt lymphoma, intra-abdominal lymph nodes C83.74 Burkitt lymphoma, lymph nodes of axilla and upper limb C83.75 Burkitt lymphoma, lymph nodes of inguinal region and lower limb C83.76 Burkitt lymphoma, intrapelvic lymph nodes C83.77 Burkitt lymphoma, spleen C83.78 Burkitt lymphoma, lymph nodes of multiple sites C83.79 Burkitt lymphoma, extranodal and solid organ sites C83.80 Other non-follicular lymphoma, unspecified site C83.81 Other non-follicular lymphoma, lymph nodes of head, face, and neck C83.82 Other non-follicular lymphoma, intrathoracic lymph nodes C83.83 Other non-follicular lymphoma, intra-abdominal lymph nodes C83.84 Other non-follicular lymphoma, lymph nodes of axilla and upper limb C83.85 Other non-follicular lymphoma, lymph nodes of inguinal region and lower limb C83.86 Other non-follicular lymphoma, intrapelvic lymph nodes C83.87 Other non-follicular lymphoma, spleen C83.88 Other non-follicular lymphoma, lymph nodes of multiple sites C83.89 Other non-follicular lymphoma, extranodal and solid organ sites C83.90 Non-follicular (diffuse) lymphoma, unspecified, unspecified site C83.91 Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of head, face, and neck C83.92 Non-follicular (diffuse) lymphoma, unspecified, intrathoracic lymph nodes C83.93 Non-follicular (diffuse) lymphoma, unspecified, intra-abdominal lymph nodes C83.94 Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of axilla and upper limb Page 48

49 C83.95 Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of inguinal region and lower limb C83.96 Non-follicular (diffuse) lymphoma, unspecified, intrapelvic lymph nodes C83.97 Non-follicular (diffuse) lymphoma, unspecified, spleen C83.98 Non-follicular (diffuse) lymphoma, unspecified, lymph nodes of multiple sites C83.99 Non-follicular (diffuse) lymphoma, unspecified, extranodal and solid organ sites C84.00 Mycosis fungoides, unspecified site C84.01 Mycosis fungoides, lymph nodes of head, face, and neck C84.02 Mycosis fungoides, intrathoracic lymph nodes C84.03 Mycosis fungoides, intra-abdominal lymph nodes C84.04 Mycosis fungoides, lymph nodes of axilla and upper limb C84.05 Mycosis fungoides, lymph nodes of inguinal region and lower limb C84.06 Mycosis fungoides, intrapelvic lymph nodes C84.07 Mycosis fungoides, spleen C84.08 Mycosis fungoides, lymph nodes of multiple sites C84.09 Mycosis fungoides, extranodal and solid organ sites C84.10 SÃ zary disease, unspecified site C84.11 SÃ zary disease, lymph nodes of head, face, and neck C84.12 SÃ zary disease, intrathoracic lymph nodes C84.13 SÃ zary disease, intra-abdominal lymph nodes C84.14 SÃ zary disease, lymph nodes of axilla and upper limb C84.15 SÃ zary disease, lymph nodes of inguinal region and lower limb C84.16 SÃ zary disease, intrapelvic lymph nodes C84.17 SÃ zary disease, spleen C84.18 SÃ zary disease, lymph nodes of multiple sites C84.19 SÃ zary disease, extranodal and solid organ sites C84.40 Peripheral T-cell lymphoma, not classified, unspecified site C84.41 Peripheral T-cell lymphoma, not classified, lymph nodes of head, face, and neck C84.42 Peripheral T-cell lymphoma, not classified, intrathoracic lymph nodes C84.43 Peripheral T-cell lymphoma, not classified, intra-abdominal lymph nodes C84.44 Peripheral T-cell lymphoma, not classified, lymph nodes of axilla and upper limb C84.45 Peripheral T-cell lymphoma, not classified, lymph nodes of inguinal region and lower limb C84.46 Peripheral T-cell lymphoma, not classified, intrapelvic lymph nodes C84.47 Peripheral T-cell lymphoma, not classified, spleen C84.48 Peripheral T-cell lymphoma, not classified, lymph nodes of multiple sites C84.49 Peripheral T-cell lymphoma, not classified, extranodal and solid organ sites C84.60 Anaplastic large cell lymphoma, ALK-positive, unspecified site C84.61 Anaplastic large cell lymphoma, ALK-positive, lymph nodes of head, face, and neck C84.62 Anaplastic large cell lymphoma, ALK-positive, intrathoracic lymph nodes Page 49

50 C84.63 Anaplastic large cell lymphoma, ALK-positive, intra-abdominal lymph nodes C84.64 Anaplastic large cell lymphoma, ALK-positive, lymph nodes of axilla and upper limb C84.65 Anaplastic large cell lymphoma, ALK-positive, lymph nodes of inguinal region and lower limb C84.66 Anaplastic large cell lymphoma, ALK-positive, intrapelvic lymph nodes C84.67 Anaplastic large cell lymphoma, ALK-positive, spleen C84.68 Anaplastic large cell lymphoma, ALK-positive, lymph nodes of multiple sites C84.69 Anaplastic large cell lymphoma, ALK-positive, extranodal and solid organ sites C84.70 Anaplastic large cell lymphoma, ALK-negative, unspecified site C84.71 Anaplastic large cell lymphoma, ALK-negative, lymph nodes of head, face, and neck C84.72 Anaplastic large cell lymphoma, ALK-negative, intrathoracic lymph nodes C84.73 Anaplastic large cell lymphoma, ALK-negative, intra-abdominal lymph nodes C84.74 Anaplastic large cell lymphoma, ALK-negative, lymph nodes of axilla and upper limb C84.75 Anaplastic large cell lymphoma, ALK-negative, lymph nodes of inguinal region and lower limb C84.76 Anaplastic large cell lymphoma, ALK-negative, intrapelvic lymph nodes C84.77 Anaplastic large cell lymphoma, ALK-negative, spleen C84.78 Anaplastic large cell lymphoma, ALK-negative, lymph nodes of multiple sites C84.79 Anaplastic large cell lymphoma, ALK-negative, extranodal and solid organ sites C84.90 Mature T/NK-cell lymphomas, unspecified, unspecified site C84.91 Mature T/NK-cell lymphomas, unspecified, lymph nodes of head, face, and neck C84.92 Mature T/NK-cell lymphomas, unspecified, intrathoracic lymph nodes C84.93 Mature T/NK-cell lymphomas, unspecified, intra-abdominal lymph nodes C84.94 Mature T/NK-cell lymphomas, unspecified, lymph nodes of axilla and upper limb C84.95 Mature T/NK-cell lymphomas, unspecified, lymph nodes of inguinal region and lower limb C84.96 Mature T/NK-cell lymphomas, unspecified, intrapelvic lymph nodes C84.97 Mature T/NK-cell lymphomas, unspecified, spleen C84.98 Mature T/NK-cell lymphomas, unspecified, lymph nodes of multiple sites C84.99 Mature T/NK-cell lymphomas, unspecified, extranodal and solid organ sites C84.A0 Cutaneous T-cell lymphoma, unspecified, unspecified site C84.A1 Cutaneous T-cell lymphoma, unspecified lymph nodes of head, face, and neck C84.A2 Cutaneous T-cell lymphoma, unspecified, intrathoracic lymph nodes C84.A3 Cutaneous T-cell lymphoma, unspecified, intra-abdominal lymph nodes C84.A4 Cutaneous T-cell lymphoma, unspecified, lymph nodes of axilla and upper limb C84.A5 Cutaneous T-cell lymphoma, unspecified, lymph nodes of inguinal region and lower limb C84.A6 Cutaneous T-cell lymphoma, unspecified, intrapelvic lymph nodes C84.A7 Cutaneous T-cell lymphoma, unspecified, spleen C84.A8 Cutaneous T-cell lymphoma, unspecified, lymph nodes of multiple sites C84.A9 Cutaneous T-cell lymphoma, unspecified, extranodal and solid organ sites C84.Z0 Other mature T/NK-cell lymphomas, unspecified site Page 50

51 C84.Z1 Other mature T/NK-cell lymphomas, lymph nodes of head, face, and neck C84.Z2 Other mature T/NK-cell lymphomas, intrathoracic lymph nodes C84.Z3 Other mature T/NK-cell lymphomas, intra-abdominal lymph nodes C84.Z4 Other mature T/NK-cell lymphomas, lymph nodes of axilla and upper limb C84.Z5 Other mature T/NK-cell lymphomas, lymph nodes of inguinal region and lower limb C84.Z6 Other mature T/NK-cell lymphomas, intrapelvic lymph nodes C84.Z7 Other mature T/NK-cell lymphomas, spleen C84.Z8 Other mature T/NK-cell lymphomas, lymph nodes of multiple sites C84.Z9 Other mature T/NK-cell lymphomas, extranodal and solid organ sites C85.10 Unspecified B-cell lymphoma, unspecified site C85.11 Unspecified B-cell lymphoma, lymph nodes of head, face, and neck C85.12 Unspecified B-cell lymphoma, intrathoracic lymph nodes C85.13 Unspecified B-cell lymphoma, intra-abdominal lymph nodes C85.14 Unspecified B-cell lymphoma, lymph nodes of axilla and upper limb C85.15 Unspecified B-cell lymphoma, lymph nodes of inguinal region and lower limb C85.16 Unspecified B-cell lymphoma, intrapelvic lymph nodes C85.17 Unspecified B-cell lymphoma, spleen C85.18 Unspecified B-cell lymphoma, lymph nodes of multiple sites C85.19 Unspecified B-cell lymphoma, extranodal and solid organ sites C85.20 Mediastinal (thymic) large B-cell lymphoma, unspecified site C85.21 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of head, face, and neck C85.22 Mediastinal (thymic) large B-cell lymphoma, intrathoracic lymph nodes C85.23 Mediastinal (thymic) large B-cell lymphoma, intra-abdominal lymph nodes C85.24 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of axilla and upper limb C85.25 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of inguinal region and lower limb C85.26 Mediastinal (thymic) large B-cell lymphoma, intrapelvic lymph nodes C85.27 Mediastinal (thymic) large B-cell lymphoma, spleen C85.28 Mediastinal (thymic) large B-cell lymphoma, lymph nodes of multiple sites C85.29 Mediastinal (thymic) large B-cell lymphoma, extranodal and solid organ sites C85.80 Other specified types of non-hodgkin lymphoma, unspecified site C85.81 Other specified types of non-hodgkin lymphoma, lymph nodes of head, face, and neck C85.82 Other specified types of non-hodgkin lymphoma, intrathoracic lymph nodes C85.83 Other specified types of non-hodgkin lymphoma, intra-abdominal lymph nodes C85.84 Other specified types of non-hodgkin lymphoma, lymph nodes of axilla and upper limb C85.85 Other specified types of non-hodgkin lymphoma, lymph nodes of inguinal region and lower limb C85.86 Other specified types of non-hodgkin lymphoma, intrapelvic lymph nodes C85.87 Other specified types of non-hodgkin lymphoma, spleen C85.88 Other specified types of non-hodgkin lymphoma, lymph nodes of multiple sites Page 51

52 C85.89 Other specified types of non-hodgkin lymphoma, extranodal and solid organ sites C85.90 Non-Hodgkin lymphoma, unspecified, unspecified site C85.91 Non-Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck C85.92 Non-Hodgkin lymphoma, unspecified, intrathoracic lymph nodes C85.93 Non-Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes C85.94 Non-Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb C85.95 Non-Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb C85.96 Non-Hodgkin lymphoma, unspecified, intrapelvic lymph nodes C85.97 Non-Hodgkin lymphoma, unspecified, spleen C85.98 Non-Hodgkin lymphoma, unspecified, lymph nodes of multiple sites C85.99 Non-Hodgkin lymphoma, unspecified, extranodal and solid organ sites C86.0 Extranodal NK/T-cell lymphoma, nasal type C86.1 Hepatosplenic T-cell lymphoma C86.2 Enteropathy-type (intestinal) T-cell lymphoma C86.3 Subcutaneous panniculitis-like T-cell lymphoma C86.4 Blastic NK-cell lymphoma C86.5 Angioimmunoblastic T-cell lymphoma C86.6 Primary cutaneous CD30-positive T-cell proliferations C88.2 Heavy chain disease C88.3 Immunoproliferative small intestinal disease C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma] C88.8 Other malignant immunoproliferative diseases C88.9 Malignant immunoproliferative disease, unspecified C90.00 Multiple myeloma not having achieved remission C90.01 Multiple myeloma in remission C90.02 Multiple myeloma in relapse C90.10 Plasma cell leukemia not having achieved remission C90.11 Plasma cell leukemia in remission C90.12 Plasma cell leukemia in relapse C90.20 Extramedullary plasmacytoma not having achieved remission C90.21 Extramedullary plasmacytoma in remission C90.22 Extramedullary plasmacytoma in relapse C90.30 Solitary plasmacytoma not having achieved remission C90.31 Solitary plasmacytoma in remission C90.32 Solitary plasmacytoma in relapse C91.00 Acute lymphoblastic leukemia not having achieved remission C91.01 Acute lymphoblastic leukemia, in remission C91.02 Acute lymphoblastic leukemia, in relapse Page 52

53 C91.10 Chronic lymphocytic leukemia of B-cell type not having achieved remission C91.11 Chronic lymphocytic leukemia of B-cell type in remission C91.12 Chronic lymphocytic leukemia of B-cell type in relapse C91.30 Prolymphocytic leukemia of B-cell type not having achieved remission C91.31 Prolymphocytic leukemia of B-cell type, in remission C91.32 Prolymphocytic leukemia of B-cell type, in relapse C91.40 Hairy cell leukemia not having achieved remission C91.41 Hairy cell leukemia, in remission C91.42 Hairy cell leukemia, in relapse C91.50 Adult T-cell lymphoma/leukemia (HTLV-1-associated) not having achieved remission C91.51 Adult T-cell lymphoma/leukemia (HTLV-1-associated), in remission C91.52 Adult T-cell lymphoma/leukemia (HTLV-1-associated), in relapse C91.60 Prolymphocytic leukemia of T-cell type not having achieved remission C91.61 Prolymphocytic leukemia of T-cell type, in remission C91.62 Prolymphocytic leukemia of T-cell type, in relapse C91.90 Lymphoid leukemia, unspecified not having achieved remission C91.91 Lymphoid leukemia, unspecified, in remission C91.92 Lymphoid leukemia, unspecified, in relapse C91.A0 Mature B-cell leukemia Burkitt-type not having achieved remission C91.A1 Mature B-cell leukemia Burkitt-type, in remission C91.A2 Mature B-cell leukemia Burkitt-type, in relapse C91.Z0 Other lymphoid leukemia not having achieved remission C91.Z1 Other lymphoid leukemia, in remission C91.Z2 Other lymphoid leukemia, in relapse C92.00 Acute myeloblastic leukemia, not having achieved remission C92.01 Acute myeloblastic leukemia, in remission C92.02 Acute myeloblastic leukemia, in relapse C92.10 Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission C92.11 Chronic myeloid leukemia, BCR/ABL-positive, in remission C92.12 Chronic myeloid leukemia, BCR/ABL-positive, in relapse C92.20 Atypical chronic myeloid leukemia, BCR/ABL-negative, not having achieved remission C92.21 Atypical chronic myeloid leukemia, BCR/ABL-negative, in remission C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative, in relapse C92.30 Myeloid sarcoma, not having achieved remission C92.31 Myeloid sarcoma, in remission C92.32 Myeloid sarcoma, in relapse C92.40 Acute promyelocytic leukemia, not having achieved remission C92.41 Acute promyelocytic leukemia, in remission Page 53

54 C92.42 Acute promyelocytic leukemia, in relapse C92.50 Acute myelomonocytic leukemia, not having achieved remission C92.51 Acute myelomonocytic leukemia, in remission C92.52 Acute myelomonocytic leukemia, in relapse C92.60 Acute myeloid leukemia with 11q23-abnormality not having achieved remission C92.61 Acute myeloid leukemia with 11q23-abnormality in remission C92.62 Acute myeloid leukemia with 11q23-abnormality in relapse C92.90 Myeloid leukemia, unspecified, not having achieved remission C92.91 Myeloid leukemia, unspecified in remission C92.92 Myeloid leukemia, unspecified in relapse C92.A0 Acute myeloid leukemia with multilineage dysplasia, not having achieved remission C92.A1 Acute myeloid leukemia with multilineage dysplasia, in remission C92.A2 Acute myeloid leukemia with multilineage dysplasia, in relapse C92.Z0 Other myeloid leukemia not having achieved remission C92.Z1 Other myeloid leukemia, in remission C92.Z2 Other myeloid leukemia, in relapse C93.00 Acute monoblastic/monocytic leukemia, not having achieved remission C93.01 Acute monoblastic/monocytic leukemia, in remission C93.02 Acute monoblastic/monocytic leukemia, in relapse C93.10 Chronic myelomonocytic leukemia not having achieved remission C93.11 Chronic myelomonocytic leukemia, in remission C93.12 Chronic myelomonocytic leukemia, in relapse C93.30 Juvenile myelomonocytic leukemia, not having achieved remission C93.31 Juvenile myelomonocytic leukemia, in remission C93.32 Juvenile myelomonocytic leukemia, in relapse C93.90 Monocytic leukemia, unspecified, not having achieved remission C93.91 Monocytic leukemia, unspecified in remission C93.92 Monocytic leukemia, unspecified in relapse C93.Z0 Other monocytic leukemia, not having achieved remission C93.Z1 Other monocytic leukemia, in remission C93.Z2 Other monocytic leukemia, in relapse C94.00 Acute erythroid leukemia, not having achieved remission C94.01 Acute erythroid leukemia, in remission C94.02 Acute erythroid leukemia, in relapse C94.20 Acute megakaryoblastic leukemia not having achieved remission C94.21 Acute megakaryoblastic leukemia, in remission C94.22 Acute megakaryoblastic leukemia, in relapse C94.30 Mast cell leukemia not having achieved remission Page 54

55 C94.31 Mast cell leukemia, in remission C94.32 Mast cell leukemia, in relapse C94.80 Other specified leukemias not having achieved remission C94.81 Other specified leukemias, in remission C94.82 Other specified leukemias, in relapse C95.00 Acute leukemia of unspecified cell type not having achieved remission C95.01 Acute leukemia of unspecified cell type, in remission C95.02 Acute leukemia of unspecified cell type, in relapse C95.10 Chronic leukemia of unspecified cell type not having achieved remission C95.11 Chronic leukemia of unspecified cell type, in remission C95.12 Chronic leukemia of unspecified cell type, in relapse C95.90 Leukemia, unspecified not having achieved remission C95.91 Leukemia, unspecified, in remission C95.92 Leukemia, unspecified, in relapse C96.0 Multifocal and multisystemic (disseminated) Langerhans-cell histiocytosis C96.2 Malignant mast cell tumor C96.4 Sarcoma of dendritic cells (accessory cells) C96.9 Malignant neoplasm of lymphoid, hematopoietic and related tissue, unspecified C96.A Histiocytic sarcoma C96.Z Other specified malignant neoplasms of lymphoid, hematopoietic and related tissue D03.0 Melanoma in situ of lip D03.10 Melanoma in situ of unspecified eyelid, including canthus D03.11 Melanoma in situ of right eyelid, including canthus D03.12 Melanoma in situ of left eyelid, including canthus D03.20 Melanoma in situ of unspecified ear and external auricular canal D03.21 Melanoma in situ of right ear and external auricular canal D03.22 Melanoma in situ of left ear and external auricular canal D03.30 Melanoma in situ of unspecified part of face D03.39 Melanoma in situ of other parts of face D03.4 Melanoma in situ of scalp and neck D03.51 Melanoma in situ of anal skin D03.52 Melanoma in situ of breast (skin) (soft tissue) D03.59 Melanoma in situ of other part of trunk D03.60 Melanoma in situ of unspecified upper limb, including shoulder D03.61 Melanoma in situ of right upper limb, including shoulder D03.62 Melanoma in situ of left upper limb, including shoulder D03.70 Melanoma in situ of unspecified lower limb, including hip D03.71 Melanoma in situ of right lower limb, including hip Page 55

56 D03.72 Melanoma in situ of left lower limb, including hip D03.8 Melanoma in situ of other sites D03.9 Melanoma in situ, unspecified D45 Polycythemia vera D63.0 Anemia in neoplastic disease D63.1 Anemia in chronic kidney disease D63.8 Anemia in other chronic diseases classified elsewhere D64.81 Anemia due to antineoplastic chemotherapy N18.1 Chronic kidney disease, stage 1 N18.2 Chronic kidney disease, stage 2 (mild) N18.3 Chronic kidney disease, stage 3 (moderate) N18.4 Chronic kidney disease, stage 4 (severe) N18.5 Chronic kidney disease, stage 5 N18.6 End stage renal disease N18.9 Chronic kidney disease, unspecified N19 Unspecified kidney failure Z Encounter for aftercare following bone marrow transplant Z51.11 Encounter for antineoplastic chemotherapy Z51.12 Encounter for antineoplastic immunotherapy Z94.81 Bone marrow transplant status Z94.84 Stem cells transplant status *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. IX. REFERENCES TOP 1. U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS), page last updated: 08/01/ s/ucm htm. Accessed January 12, 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. Accessed January 12, 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 (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No I.) AHRQ Publication No. 13-EHC077-EF. Rockville, MD: Agency for Healthcare Research and Page 56

57 Quality; April Accessed January 12, 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 ;98(10): PMID 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 ) Rockville, MD: Agency for Healthcare Research and Quality; May Accessed January 12, 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):CD PMID 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 ;373(9674): PMID Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;12:CD PMID 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 ;28(33): PMID Centers for Medicare and Medicaid Services (CMS). Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N), July 30, AAAAAIAAA&. Accessed January 12, 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. Accessed January 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): PMID Amgen Inc. Epogen (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, April Accessed January 12, Amgen Inc. Procrit (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, December Accessed January 12, Amgen Inc. Aranesp (darbepoetin alfa) injection for intravenous or subcutaneous use prescribing information, December Accessed January 12, Page 57

58 16. Hoffmann-La Roche, Inc. Mircera (methoxy polyethylene glycol-epoetin beta) solution for injection: intravenous (IV) or subcutaneous (SC) use prescribing information, November Accessed January 12, 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): PMID 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 ;339(9): PMID 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): PMID Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. Nov ;355(20): PMID 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): PMID 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 ;355(20): PMID 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 ;361(21): PMID 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 ;124(25): PMID 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):c PMID 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): PMID Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2014;3:CD PMID Walker RG, Strippoli GF. A pegylated epoetin in anaemia of renal disease: non-inferiority for an unvalidated surrogate. Lancet. Oct ;370(9596): PMID U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Office Director Memo: application number BLA Accessed August Page 58

59 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): PMID 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): PMID 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 ;370(9596): PMID 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): PMID 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): PMID 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): PMID 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:CD PMID 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): PMID 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): PMID 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): PMID 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 PMID 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): PMID Page 59

60 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): PMID Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Specialty Pharmacy Reports Peginesatide: # 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, ucm htm?source=govdelivery. Accessed January 12, 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): PMID 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): PMID 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): PMID 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): PMID 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): PMID 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). cm htm. Accessed January 12, National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: cancer- and chemotherapy-induced anemia, version Accessed January 12, 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, Accessed January 12, Page 60

61 Other: FDA Recall-Firm Press Release. Affymax and Takeda Announce a Nationwide Voluntary Recall of All Lots of OMONTYS (peginesatide) Injection February 23, [Website]: Accessed January 12, Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions. Effective 7/30/07. CMS [Website]: Accessed January 12, Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual. Publication Chapter 15 Covered Medical and Other Services. Effective 01/14/14. [Website]: Accessed January 12, Taber's Cyclopedic Medical Dictionary, 20th edition X. POLICY HISTORY TOP MP 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. 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. Page 61

62 2013 Codes added-12/20/2013-sb Admin posting 2/28/13. Information in policy related to Omontys removed from policy due to product recall. Admin posting Prior auth requirement removed from FEP variation. Code J0890 added sb CAC 7/30/13 Minor review. Added the following: Information on Omontys (peginesatice) recall to Background/Description Policy guidelines Reference to NCD 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. 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 62