LCD L34633: Erythropoiesis Stimulating Agents (ESAs)

Naturally occurring human erythropoietin (EPO) is a glycoprotein produced mainly in the kidneys. It stimulates the division and differentiation of committed erythroid progenitors in bone marrow. A number of chronic conditions, especially chronic renal failure, result in decreased production of or relative resistance to erythropoietin, often causing anemia. Supplementation by synthetic drugs with structures identical or similar to naturally occurring erythropoietin has been proven safe and effective in correcting anemia in certain groups of patients. Normal plasma erythropoietin levels may vary from 0.01 to 0.03 U/ml (10-30 mU/mL). These levels may increase 100 to 1000 - fold during hypoxia or anemia, and one may see levels from 1,000 to 30,000 mU/mL. Certain conditions blunt this normal physiological response to anemia and so erythropoietin levels do not rise. This causes or aggravates anemia. Anemia of chronic renal failure, as well as certain other anemias, despite adequate erythropoietin levels, may respond to supplemental erythropoietin administration.

Erythropoietin stimulating agents (ESAs) are a covered benefit to treat patients who have 1 of the FDA approved conditions, and have either symptomatic anemia or are transfusion dependent:

Group A: End Stage Renal Disease (ESRD) ON Dialysis

Group B: Chronic Kidney Disease (CKD) NOT on Dialysis

Group C: Indications other than Renal Disease

Group A: End Stage Renal Disease (ESRD) ON dialysis

The likelihood of anemia associated with erythropoietin deficiency increases as renal failure progresses, because the diseased kidneys are unable to produce sufficient quantities of erythropoietin. The anemia of Chronic Renal Failure (CRF) should not be confused with the anemia of chronic disease. In the latter, inflammatory cytokines suppress the endogenous production of erythropoietin and erythropoiesis directly. Measurable levels of circulating cytokines may be found in stable dialysis patients, but, in the absence of inflammation, do not adversely affect the action of ESAs. In patients with impaired renal function and a normochromic, normocytic anemia, it is rare for the serum erythropoietin level to be elevated. Therefore, measurement of erythropoietin levels in such patients is not likely to guide clinical decision making or ESA therapy. Anemia can develop relatively early in the course of CRF and has been associated with a serum creatinine as low as 2.0 mg/dL.

• The hemoglobin level prior to initiation of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).

• Diagnosis of end stage renal disease

Group B: Chronic Kidney Disease NOT on dialysis

• The hemoglobin level prior to initiation of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).

• Serum creatinine equal to or greater than 3, creatinine clearance less than 60 ml/min, or glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2.

This local policy defines the potential eligibility for coverage of ESAs in the treatment of anemia in patients with chronic renal failure/insufficiency. For this purpose, WPS adopts the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommendation, derived largely from the NHANES III analysis. Patients with glomerular filtration rate (GFR) Grade III or higher, a GFR less than 60 ml/min/1.73m 2, should be evaluated for anemia and treated with an erythropoietic agent if appropriate and in accordance with the NKF Guidelines for Anemia of Chronic Kidney Disease.

Group C: Indications other than Renal Disease

• Anemia associated with cancer and related Neoplastic conditions.

This policy does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) and does not contain specific diagnosis codes related to CMS Pub 100-03 Medicare National Coverage Determination (NCD) Manual , Chapter 1 – Coverage Determinations, Part 2 Section 110.21 – Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions.

• The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).

• Anemia related to therapy with Zidovudine (AZT) and/or other Nucleoside Reverse Transcriptase Inhibitors (NRTI) therapy for acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) must meet the coverage requirements in CMS Pub 100-02 Medicare Benefit Policy Manual , Chapter 15 – Covered Medical and Other Health Services, Section - 50.5.2. – Erythropoietin (EPO) (Rev. 1, 10-01-03).

• The hemoglobin level prior to initiation of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).

• Anemia associated with chemotherapeutic medications when medically necessary for a non-cancer diagnosis or following stem cell transplantation and associated immunosuppression.

• The hemoglobin level prior to initiation of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).

• Myelodysplastic Syndrome (MDS )

Anemia is observed in 90 percent of individuals with MDS. Those MDS patients with an endogenous erythropoietin level of less than 500 mU/mL are more likely to respond to ESA therapy.

• ESA therapy is indicated for patients who meet the following:

• Have a confirmed diagnosis of MDS with a bone marrow biopsy,

• the anemia is symptomatic,

• there is reasonable expectancy of longer survival,

• therapy will end or reduce the need for transfusions,

• Anemia with Hgb is less than or equal to 10g/dL or HCT is less than or equal to 30%, 1 week before the initial injection.

• pretreatment erythropoietin levels of 500 or less

• If after 2 months of treatment, there is no significant increase in Hgb/HCT and/or a significant decrease in transfusion requirements, erythropoietin analogs therapy should be stopped.

• Anemia of Chronic disease (Anemia of inflammatory disease)

In anemia of chronic disease, inflammatory cytokines suppress the endogenous production of erythropoietin and erythropoiesis directly. This anemia usually results from a combination of slightly shortened red blood cell survival, the sequestration of iron in the reticuloendothelial systems, and erythropoietin levels that are less than expected for the degree of anemia. The diagnosis is usually exclusionary, meaning other causes of the anemia have been ruled out.

Anemia of cancer is not considered a chronic disease for this purpose and should not be billed as such. Medicare will cover the use of epoetin alfa or darbepoetin alfa for the refractory anemia of chronic disease for patients with Rheumatoid Arthritis, Systemic Lupus Erythematosis, Chronic Hepatitis C, Crohn's Disease and Ulcerative Colitis when 1 of the conditions listed below in A is met along with both B and C criteria:

• At least 1 of the conditions below:

• low or normal serum iron

• low or normal iron binding capacity

• normal or elevated serum ferritin

• adequate iron stores in bone marrow

• The pretreatment HCT level is 30 percent or less and/or if the patient has been transfusion dependent.

• The pretreatment erythropoietin level is 100 mU/mL or less.

• Prophylactic pre-operative use for reduction of allogenic blood transfusions prior to elective hip and knee replacement surgery. (CMS Pub 100-02 Medicare Benefit Policy Manual , Chapter 15 – Covered Medical and Other Health Services, Section - 50.5.2.2 - Medicare Coverage of Epoetin Alfa (Procrit) for Preoperative Use (Rev. 1, 10-01-03).).

Epoetin alfa or Darbepoetin alfa are covered for use in specific patients prior to surgery to reduce risk of transfusion:

• who are undergoing hip or knee surgery;

• have an anemia with a hemoglobin between 10 and 13 gm/dL. (this indication requires a lead time of at least 3 weeks prior to surgery);

• are not candidates for autologous blood transfusion;

• are expected to lose more than 2 units of blood; and

• have had a work-up so that their anemia appears to be that of chronic disease.

A weekly dosage regimen for 3 weeks prior to surgery (e.g., days 21, -14, -7) and on the day of surgery will be covered. The components listed above must be documented in the medical record. Patients receiving ESAs pre-operatively for reduction of allogeneic red blood cell transfusions: A higher incidence of deep venous thrombosis was documented in patients receiving ESAs who were not receiving prophylactic anticoagulation.

• Prophylactic pre-operative use for reduction of allogenic blood transfusions prior to elective noncardiac or nonvascular surgery.

Epoetin alfa-epbx (biosimilar) is covered for use in specific patients who are at high risk for perioperative blood loss prior to surgery to reduce risk of transfusion:

• who are undergoing elective, noncardiac or nonvascular surgery;

• have an anemia with a hemoglobin > 10 to

The recommended Epoetin alfa-epbx (biosimilar) regimens are:

• 300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before

surgery, on the day of surgery, and for 4 days after surgery.

• 600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.

The components listed above must be documented in the medical record.

Deep venous thrombosis prophylaxis is recommended during Epoetin alfa-epbx (biosimilar) therapy.

• Myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) associated with bone marrow fibrosis, cytopenias, constitutional symptoms, hepatosplenomegaly, and/or extramedullary hematopoiesis.

Anemia is considered a negative prognostic risk factor for survival in patients with PMF. Symptomatic anemia is observed in more than 50% of the patients at the time of diagnosis. It is essential to rule out and treat the most commons cause of anemia before considering other treatment options.

Leukoreduced RBC transfusion support is recommended for symptomatic anemia, EPO-stimulating agents (ESAs), danazol and immunomodulatory agents (lenalidomide, thalidomide, and pomalidomide) have also been evaluated for the management of PMF-associated anemia.

The use of recombinant human EPO or darbepoetin alfa has resulted in anemia responses (transfusion independence with normal hemoglobin levels, sustained increase in hemoglobin level s[>2g/dl] within 12 weeks, or >50% reduction in transfusion requirements within 12 weeks) in 45% to 60% of patients. Lowered serum EPO levels ( Primary myelofibrosis is overlapping with Myelodysplastic Syndrome (MDS) on the spectrum, and like MDS, diagnosed by bone marrow pathology.

Goals of ESA Therapy

The goals of ESA Therapy are based on the medication used and the condition being treated as well as individual response to the medication. Doses must be titrated according to the patient’s response. ESA therapy need not be stopped completely simply due to the achievement of the target Hgb and/or Hct. However, judicious, appropriately timed dose adjustments are expected to prevent inappropriate increases in Hgb and Hct levels. Continued use and determination of dosage level must be medically reasonable and necessary.

Review of Management of Primary Myelofibrosis (PMF)in UpToDate authored by Ayalew Tefferi, MD suggests that anemia in PMF is a significant source of impaired quality of life, and may cause fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of well-being. Patients should be evaluated for bleeding, hemolysis, and nutritional deficiencies, and other remediable causes. Most reported responses to erythropoietin stimulating agents (ESA) in patients with PMG were noted in those patients not requiring transfusion support and/or those with inappropriately low serum erythropoietin levels.

NCCN Version 2.2019 Myeloproliferative Neoplasms suggest using ESA in the management of myelofibrosis associated anemia after ruling out coexisting causes and treating those coexisting causes in anemic patients with serum erythropoietin levels under 500mU/ml.