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 one 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.

  1. The hemoglobin level prior to initiation of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).
  2. Diagnosis of end stage renal disease

**Group B: Chronic Kidney Disease NOT on dialysis**

  1. The hemoglobin level prior to initiation of ESA treatment is less than 10 g/dL (or the hematocrit is less than 30%).
  2. 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**

  1. **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%).  
  

  2. **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%).  
  

  3. **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%).  
  

  4. **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: 
      1. Have a confirmed diagnosis of MDS with a bone marrow biopsy,
      2. the anemia is symptomatic,
      3. there is reasonable expectancy of longer survival,
      4. therapy will end or reduce the need for transfusions,
      5. Anemia with Hgb is less than or equal to 10g/dL **or** HCT is less than or equal to 30%, one week before the initial injection.
      6. pretreatment erythropoietin levels of 500 or less
    * If after two 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.  
  

  5. **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 one of the conditions listed below
in A is met along with both B and C criteria:

    1. At least **one** 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
    2. The pretreatment HCT level is 30 percent or less and/or if the patient has been transfusion dependent.
    3. The pretreatment erythropoietin level is 100 mU/mL or less.  
  

  6. **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.  
  

  7. **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 < 13 gm/dL;
    * are not candidates for autologous blood transfusion.  
  

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.  
  

  8. **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 (<125mU/ml), smaller spleen size, and low RBC transfusion
requirements have been associated with favorable responses.  
  
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.

**Quality** -Moderate  
 **Strength** -Moderate  
 **Weight** -Weak