Billing and Coding: Erythropoiesis Stimulating Agents

Title XVIII of the Social Security Act, §1833(e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

Title XVIII of the Social Security Act, §1842(u) Each request for payment, or bill submitted, for a drug furnished to an individual for the treatment of anemia in connection with the treatment of cancer shall include information on the hemoglobin or hematocrit levels for the individual.

Title XVIII of the Social Security Act, §1881(b)(11)(B)(i) allows payment for erythropoietin provided by a physician.

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 6, §10.2 Other Circumstances in Which Payment Cannot Be Made Under Part A and §30 Drugs and Biologicals

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 11, §20.3 Drugs and Biologicals, §30.1 Home Dialysis Items and Services, and §100.6 Applicability of Specific ESRD PPS Policies to AKI Dialysis

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §50.5.2 Erythropoietin (EPO), §50.5.2.1 Requirements for Medicare Coverage for EPO, and §50.5.2.2 Medicare Coverage of Epoetin Alfa (Procrit) for Preoperative Use

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 2, §110.21 Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 4, §10 Hospital Outpatient Prospective Payment System (OPPS), §20 Reporting Hospital Outpatient Services Using Healthcare Common Procedure Coding System (HCPCS), §50.1 Outpatient Provider Specific File, and §200.2 Hospital Dialysis Services For Patients with and without End Stage Renal Disease (ESRD)

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 6, §20 Services Included in Part A PPS Payment Not Billable Separately by the SNF, §20.2.1 Dialysis and Dialysis Related Services to a Beneficiary With ESRD, and §20.2.1.1 ESRD Services

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 7, §100 Epoetin (EPO)

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 8, §10.5 Hospital Services, §40 Acute Kidney Injury (AKI) Claims, §50.2 Drugs and Biologicals Included in the End Stage Renal Disease Prospective Payment System (ESRD)(PPS), §50.3 Required Information for In-Facility Claims Paid Under the End Stage Renal Disease Prospective Payment System ESRD PPS, §60.2 Drugs Furnished in Dialysis Facilities, §60.2.1.1 Separately Billable ESRD Drugs, §60.2.1.2 Facilities Billing for ESRD Drugs and Biologicals Equivalent to Injectable Drugs, §60.4 Erythropoietin Stimulating Agents (ESAs), §60.4.1 ESA Claims Monitoring Policy, §60.4.2 Facility Billing Requirements for ESAs, §60.4.4 Payment Amount for Epoetin Alfa (EPO), §60.4.4.1 Payment for Epoetin Alfa (EPO) in Other Settings, §60.4.4.2 Epoetin Alfa (EPO) Provided in the Hospital Outpatient Departments, §60.4.6.1 Reserved for Future Use, §60.4.6.2 Reserved for Future Use, §60.4.6.3 Payment Amount for Darbepoetin Alfa (Aranesp), §60.4.6.4 Payment for Darbepoetin Alfa (Aranesp) in Other Settings, and §60.4.6.5 Payment for Darbepoetin Alfa (Aranesp) in the Hospital Outpatient Department

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 17, §10 Payment Rules for Drugs and Biologicals, §20.5.8 Injections Furnished to ESRD Beneficiaries, §40.1 Discarded Erythropoietin Stimulating Agents for Home Dialysis, §80.5 Self-Administered Drugs, §80.8 Reporting of Hematocrit and/or Hemoglobin Levels, §80.9 Required Modifiers for ESAs Administered to Non-ESRD Patients, §80.10 Hospitals Billing for Epoetin Alfa (EPO) and Darbepoetin Alfa (Aranesp) for Non-ESRD Patients, §80.11 Requirements for Providing Route of Administration Codes for Erythropoiesis Stimulating Agents (ESAs), and §80.12 Claims Processing Rules for ESAs Administered to Cancer Patients for Anti-Anemia Therapy

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 30 Financial Liability Protections

Medicare Learning Network (MLN) Matters (MM5818); Effective Date July 30, 2007

Medicare Learning Network (MLN) Matters (MM5699); Effective Date January 1, 2008

The information in this article contains billing, coding or other guidelines that complement the Local Coverage Determination (LCD) for Erythropoiesis Stimulating Agents L39237.

Part A and B:

General Information for Erythropoiesis Stimulating Agents (ESA) Claims:

• It is not appropriate to bill Medicare for services that are not covered as if they are covered. When billing for non-covered services, use the appropriate modifier.
• For services requiring a referring/ordering physician, the name and NPI of the referring/ordering physician must be reported on the claim.
• A claim submitted without a valid ICD-10-CM diagnosis code will be returned to the provider as an incomplete claim under Section 1833(e) of the Social Security Act. The diagnosis code(s) must best describe the patient's condition for which the service was performed.
• No ESA should be given within the context of uncontrolled hypertension.
• No ESA should be used to replace red blood cell (RBC) transfusions in patients who need immediate urgent correction of anemia.
• With any ESA, the patient’s medical record should reflect the clinical reason for dose changes and hematocrit (HCT) levels outside the range of 30.0-36.0% (hemoglobin (Hb) levels 10.0-12.0 g/dL). Medicare contractors may review medical records to assure appropriate dose reductions are applied and maintained and hematological target ranges are maintained.
• There may be instances when a patient has a chronic health condition not specifically addressed in this policy for which an ESA is useful treatment. Such scenarios would be expected to demonstrate considerable transfusion dependence and anemia-related symptoms. In the event of denials, an appeals process will allow the opportunity for the provider to substantiate a reasonable and necessary basis for ESA treatment based on medical literature, specialty organization best practice alignment, and the unique clinical circumstances for the beneficiary. Explanatory documentation within the medical record is crucial.

HCPCS Drug Codes:

Healthcare Common Procedure Coding System (HCPCS) codes J0881, J0885, J0888, and Q5106 are for use in patients with non-end stage renal disease (non-ESRD) conditions.

HCPCS codes J0882, J0887, Q4081, and Q5105 are intended for use only with patients who have ESRD and are on dialysis.

Modifiers:

-EA, EB, EC

All non-ESRD claims reporting HCPCS code J0881, J0885, J0888, or Q5106 and ESRD claims reporting J0882, J0887, Q4081, and Q5105 must report 1, and only 1, of the following modifiers:

• EA: ESA administered to treat anemia due to anticancer chemotherapy
• EB: ESA administered to treat anemia due to anticancer radiotherapy
• EC: ESA administered to treat anemia not due to anticancer radiotherapy or anticancer chemotherapy

ESA claims, either institutional or professional, that do not report 1 of the above 3 modifiers will be returned to the provider.

Non-ESRD ESA claims that report the ESA modifier EC and any of the following conditions will be denied as not reasonable and necessary:

• Any anemia in cancer or cancer treatment patients due to:
  • Folate deficiency
  • B-12 deficiency
  • Iron deficiency
  • Hemolysis
  • Bleeding
  • 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
• Prophylactic use to prevent chemotherapy-induced anemia
• Prophylactic use to reduce tumor hypoxia
• Patients with erythropoietin (EPO)-type resistance due to neutralizing antibodies
• Anemia due to cancer treatments if patients have uncontrolled hypertension

Non-ESRD ESA services for J0881, J0885 or Q5106 billed with modifier -EC will be denied in the presence of various secondary ICD-10 codes that are non-covered per CMS.

https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/CR12027.zip

Non-ESRD ESA services for J0881, J0885 and Q5106 are not considered reasonable and necessary within the context of other medical conditions for which resolution would be expected prior to starting or to continue ESA administration. Such conditions would include, but not be limited to: iron/vitamin B12/folate deficiencies, G6PD deficiency, pyridoxine deficiency, various forms of hemolysis, hereditary spherocytosis, and pure red cell aplasias. The presence of any of these conditions would reduce the therapeutic impact and effectiveness of the ESA. Additionally, the presence of an unspecified anemia code suggests appropriate evaluation, to determine the nature of the treated anemia, has not been completed.

Non-ESRD ESA claims that report HCPCS J0881, J0885, J0888 or Q5106 billed with ESA modifier EB (ESA, anemia, radio-induced) will be denied.

Non-ESRD ESA claims that report HCPCS J0881, J0885, J0888 or Q5106 billed with modifier EA (ESA, anemia, chemo-induced) for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma, and lymphocytic leukemia when a Hb 10.0g/dL or greater or HCT 30.0% or greater will be denied.

-JA, JB, JE

Route of administration is important information especially with drugs that can be given multiple different ways. All non-ESRD claims reporting HCPCS code J0881, J0885, J0888, or Q5106 and all ESRD claims reporting J0882, Q4081, and Q5105 must also be reported with 1, and only 1, of the following modifiers:

• JA-Administered intravenously (IV)
• JB-Administered subcutaneously (SQ)
• JE-Administered via dialysate

-GA, GX, GY or GZ

An Advance Beneficiary Notice of Noncoverage (ABN) may be used for services which are likely to be non-covered, whether for medical necessity or for other reasons. Non-covered services should be billed with modifier –GA (Waiver of liability statement issued as required by payer policy, individual case) when the provider wants to indicate that it is anticipated Medicare will deny a specific service as not reasonable and necessary and an ABN signed by the beneficiary is on file, with -GX (Notice of liability issued, voluntary under payer policy) when the beneficiary has signed an ABN, and a denial is anticipated based on provisions other than medical necessity, such as statutory exclusions of coverage or technical issues, with -GY (Item or service statutorily excluded, does not meet the definition of any Medicare benefit or, for non-Medicare insurers, is not a contract benefit, or with –GZ (Item or service expected to be denied as not reasonable and necessary) when the provider wants to indicate that it is expected that Medicare will deny a service as not reasonable and necessary and that an ABN has not been signed by the beneficiary, as appropriate.

Claims Reporting-Hemoglobin/Hematocrit

Claims billing for the administration of an ESA (HCPCS codes J0881, J0882, J0885, J0887, J0888, Q4081, Q5105 and Q5106) must report the most recent HCT or Hb reading. Claims not reporting this information will be returned to the provider.

For institutional claims, the Hb reading is reported with a value code 48 and a HCT reading is reported with the value code 49.

For professional paper claims, test results are reported in item 19 of the Form CMS-1500 claim form. For electronic claims (837P), providers report the Hb or Hct readings in Loop 2400 MEA segment. The specifics are mEA01=TR (for test results), MEA02=R1 (for Hb) or R2 (for HCT), and MEA03=the test results.

Documentation Requirements

The medical record documentation for patients receiving ESA therapy must support the reasonable and necessary basis for such therapy.

• All documentation must be maintained in the patient's medical record and made available to the contractor upon request.
• Every page of the record must be legible and include appropriate patient identification information (e.g., complete name, dates of service[s]). The documentation must include the legible signature of the physician or non-physician practitioner responsible for and providing the care to the patient.
• The submitted medical record must support the use of the selected ICD-10-CM code(s). The submitted CPT/HCPCS code must describe the service performed.
• For any ESA, the medical record must reflect that ESA therapy for the individualized patient is reasonable and necessary. The medical record must document the most recent blood pressure and demonstrate reasonable control not in significant excess of a baseline range for a given patient, weight in kilograms, date and results of HCT or Hb level prior to the administration of ESA therapy, evidence of assessment ruling out other causative factors of anemia or, if causative factors are present, that they have been managed and that it is still necessary to initiate ESA. The dosage and route of administration must be documented.

ESRD on Dialysis ESA Claims with Modifier EC

For patients with ESRD who are on dialysis, HCPCS codes J0882, J0887, Q4081, and Q5105 are not paid by Medicare Part B. ESAs for ESRD on dialysis are included in the composite rate for the ESRD facility. If an ESA is administered to a patient with ESRD on dialysis by a provider other than the patient’s ESRD provider, the administering provider must submit a claim to the ESRD provider for the service. The administering provider must not submit a claim to Medicare Part B.

Required Documentation Elements:

• The ESA utilized:
  • Darbepoetin alfa (J0882) or epoetin alfa (Q4081) or epoetin alfa-epbx biosimilar (Q5105) or epoetin beta (J0887)
• Use of the ESA for specific diagnoses indicating symptomatic anemia of chronic kidney disease (CKD) on dialysis 
• For patients with ESRD who are on dialysis, a diagnosis of D63.1 and a diagnosis of N18.6 must be billed with HCPCS code J0882, J0887, Q4081, or Q5105. The EC modifier is also required. A JA, JB or JE modifier is required. Inclusion of any other ICD-10 diagnoses on the claim which are non-covered with an EC modifier per NCD 110.21, will preclude payment for the ESA.
• Use of an appropriate dose, route (IV administration is recommended for use in ESRD), and frequency.
• DOSING:
  • For initial dosing of darbepoetin alfa in ESRD: 0.45 mcg/kg weekly or 0.75 mcg/kg every 2 weeks.
  • For initial dosing of epoetin alfa/epoetin alfa-epbx biosimilar in ESRD: 50-100 u/kg three times per week (TIW) or if appropriate for the patient, a weekly dose of 75-150 u/kg SQ/IV every week
  • A typical therapeutic dose range would be 50-300 u/kg TIW.
  • Maintenance dosing range: 12.5-525 u/kg TIW
  • For initial dosing of epoetin beta in ESRD: 6 mcg/kg body weight administered as a single IV or SQ injection once every 2 weeks.
  • Maintenance dosing: Once the Hb has been stabilized, epoetin beta may be administered once monthly using a dose that is twice that of the every 2-week dose and subsequently titrated as necessary.

• A pre-initiation Hb level < 10 g/dL with ongoing individualized dosing to achieve and maintain Hb levels between 10-12 g/dL.
• Documentation of dose reduction should be evident as the Hb level approaches 12 (11 in the case of epoetin beta or darbepoetin alfa) or when the Hb level rises by more than 1 g/dL within a 2-week period. During therapy, hematological parameters should be monitored at least weekly until the Hb is stable and sufficient to minimize the need for transfusion. Thereafter, monitor Hb at least monthly.
• For patients whose Hb does not attain a level within the range of 10 to 12 g/dL despite appropriate dose titrations over a 12-week period, documentation should not demonstrate further increases in dose amounts but rather continuation of the lowest dose that will avoid the need for recurrent RBC transfusions. When recurrent RBC transfusions become necessary within the setting of ESA use exceeding 12 weeks, the ESA therapy should be stopped due to lack of responsiveness.
• Increases in dose should not be made more frequently than once a month. 
• The maximum number of administrations of epoetin alfa/biosimilar for a billing cycle is 13 times in 30 days and 14 times in 31 days. The maximum number of administrations of darbepoetin for a billing cycle is 5 times in 30/31days.
• Evaluation and treatment of other causes of anemia (and documentation thereof) must occur pre-ESA initiation and at any time thereafter as needed for lack of responsiveness.
• Prior to and during ESA therapy, the patient’s iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, must be evaluated. Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL. Iron stores must also be checked prior to dosage increases. Due to the frequency of concomitant iron deficiency in these patients, even without dosage adjustments iron storage must be checked at least every 3 months during ongoing ESA therapy.
• If the initial dose of an ESA was administered in another setting (i.e. hospital, in a state outside our jurisdiction, or in another facility); subsequent office-administered ESA claims may prompt a Medicare Administrative Contractor (MAC) request for documentation regarding the clinical criteria supporting the initial administration as well as the need to continue the ESA. This may require review of outside medical records and confirmation that needed pre-treatment lab results and evaluation were completed appropriately.

For CKD NOT on Dialysis with Modifier EC ESA Claims:

The term “without dialysis” refers to patients that are not on a regular course of maintenance dialysis. For patients who need occasional “rescue dialysis”, it would be appropriate to bill HCPCS code J0881, J0885, J0888, or Q5106 since these patients are not on a regular course of maintenance dialysis.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) guidelines rely on the third National Health and Nutrition Examination Survey (NHANES III) data analysis regarding a relationship of HCT levels with stage of CKD. Based on this analysis, patients with glomerular filtration rate (GFR) < 30 mL/min/1.73 m² commonly demonstrated severe anemia with HCT levels < 33%. Thus, a GFR < 45 mL/min/1.73m² is a reasonable threshold to support ESA administration in conjunction with sufficiently low and symptomatic Hb/HCT levels.

Required Documentation Elements:

• Serum creatinine and/or GFR
• The ESA utilized:
  • Darbepoetin alfa (J0881) or epoetin alfa (J0885) or epoetin alfa-epbx biosimilar (Q5106) or epoetin beta (J0888)
• Use of the ESA for specific diagnoses indicating symptomatic anemia of CKD not on dialysis
• For patients with CKD who are not on dialysis, a diagnosis code of D63.1 and a diagnosis of I12.0, I13.11, I13.2, N18.32, N18.4, or N18.5 must be billed with HCPCS code J0881, J0885, J0888, or Q5106. The EC modifier is also required. A JA or JB modifier is required. Inclusion of any other ICD-10 diagnoses on the claim which are non-covered with an EC modifier per NCD 110.21, will preclude payment for the ESA.
  • Note: Patients with stage I and II and IIIa CKD do not meet the GFR requirements in coverage criteria for the following combination ICD-10 codes:
    • I12.9
    • I13.0

• Use of an appropriate dose, route, and frequency.
• DOSING:
  • For initial dosing of darbepoetin alfa in non dialysis CKD: 0.45 mcg/kg IV or SQ every 4 weeks
  • For initial dosing of epoetin alfa/epoetin alfa-epbx biosimilar in non dialysis CKD: 50-100 u/kg TIW or, if appropriate for the patient, a weekly dose of 75-150 u/kg SQ/IV every week.
  • Maintenance dosing range: A therapeutic dose range would be 50-300 u/kg TIW and more typically, 75 to 150 units/kg/week.
  • For initial dosing of epoetin beta in CKD NOT on dialysis CKD in adult CKD patients who not currently treated with an ESA: 0.6 mcg/kg body weight administered as a single IV or SQ injection once every 2 weeks.
  • Maintenance dosing range: Once the Hb has been stabilized, epoetin beta may be administered once monthly using a dose that is twice that of the every-2-week dose and subsequently titrated as necessary.
• A pre-initiation Hb level < 10 g/dL with ongoing individualized dosing to achieve and maintain Hb levels between 10-12 g/dL.
• Documentation of dose reduction should be evident as the Hb level approaches 12 (11 in the case of epoetin beta or 10 with darbepoetin alfa) or when the Hb level rises by more than 1 g/dL within a 2-week period. During therapy, hematological parameters should be monitored at least weekly until the Hb is stable and sufficient to minimize the need for transfusion. Thereafter, monitor Hb at least monthly.
• For patients whose Hb does not attain a level within the range of 10 to 12 g/dL despite appropriate dose titrations over a 12-week period, documentation should not demonstrate further increases in dose amounts but rather continuation of the lowest dose that will avoid the need for recurrent RBC transfusions. When recurrent RBC transfusions become necessary within the setting of ESA use exceeding 12 weeks, the ESA therapy should be stopped due to lack of responsiveness.
• Increases in dose should not be made more frequently than once a month.
• Evaluation and treatment of other causes of anemia (and documentation thereof) must occur pre-ESA initiation and at any time thereafter as needed for lack of responsiveness.
• Prior to ESA therapy, the patient’s iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, must be evaluated. Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL. Iron stores must also be checked prior to dosage increases. Due to the frequency of concomitant iron deficiency in these patients, even without dosage adjustments, iron storage must be checked at least every 3 months during ongoing ESA therapy.
• If the initial dose of an ESA was administered in another setting (i.e. hospital, in a state outside our jurisdiction, or in another facility); subsequent office-administered ESAs must still meet all the above-mentioned requirements. This may require review of outside medical records and confirmation that needed pre-treatment lab results and evaluation were completed appropriately.

Anemia Due to Antineoplastic Chemotherapy

This policy does not replace or supersede existing Medicare applicable National Coverage Determination (NCD) 110.21.

Epoetin beta is NOT indicated or covered for treatment of anemia due to cancer chemotherapy.

Required Documentation Elements:

• The ESA utilized:
  • Darbepoetin alfa (J0881) or epoetin alfa (J0885) or epoetin alfa-epbx biosimilar (Q5106)
• Use of the ESA for symptomatic anemia due to antineoplastic chemotherapy
• A diagnosis of a non-myeloid malignancy (solid tumor, multiple myeloma, lymphoma, or lymphocytic leukemia)
• For HCPCS codes J0881, J0885 or Q5106: ICD-10-CM code D64.81 or D61.810 AND 1 of the malignancy codes listed in ICD-10 Group 3 MUST be billed together. The EA modifier is also required. A JA or JB modifier is required. Inclusion of any other ICD-10 diagnoses on the claim which are non-covered with an EC modifier per NCD 110.21, except for ICD-10 codes strictly indicating a relationship to adverse effect of antineoplastic drugs or chemotherapy, will preclude payment for the ESA.
• DOSING:
  • For darbepoetin alfa therapy in anemia due to antineoplastic chemotherapy: 2.25 mcg/kg every week SQ or 500 mcg every 3 weeks until completion of the chemotherapy course.
  • If Hb increases more than 1 g/dL in any 2-week period or if a Hb level is reached that will avoid RBC transfusion, then the dose of darbepoetin alfa should be decreased by 40%.
  • During treatment, if Hb increases by less than 1 g/dL and remains below 10 g/dL after 4 weeks of therapy, the dose of darbepoetin alfa may be increased once by 25%.
  • If there is no response as measured by Hb levels or if RBC transfusions are still required after 8 weeks of therapy, darbepoetin therapy should be stopped. Darbepoetin therapy must cease following completion of a chemotherapy course.
  • For epoetin alfa/epoetin alfa-epbx biosimilar in anemia due to antineoplastic chemotherapy:
  • Initial dosing: 150 Units/kg SC TIW or 40,000 units SC weekly
  • Reduce dose by 25% when Hb reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-week period.
  • Increase dose by 25%, if there is no reduction in transfusion requirements or the Hb level does not rise > 1 g/dL after 4 weeks of therapy.
  • If after 8 weeks of therapy there is no response as measured by Hb levels or if transfusions are still required, epoetin alfa should be discontinued. Epoetin alfa therapy must cease following completion of a chemotherapy course.

• ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.
• Any ESA administered for anemia in association with cancer chemotherapy will only be covered if the Hb level immediately prior to initiation or maintenance of the ESA treatment is less than 10 g/dL (or the HCT < 30%).
• An ESA should only be started if there is a minimum of 2 additional months of planned chemotherapy.
• ESAs should not be used in a patient with cancer receiving myelosuppressive chemotherapy when the anticipated outcome for the cancer is cure.
• Hb levels should be monitored on a weekly basis in patients receiving ESA therapy until Hb becomes stable. ESA doses should be titrated as low as possible for each patient to achieve and maintain the lowest Hb level sufficient to avoid the need for blood transfusion.
• Although no specific serum EPO level can be stipulated above which patients would be unlikely to respond to ESA therapy, treatment of patients with grossly elevated serum EPO levels (e.g., > 200 mUnits/mL) is not recommended.
• Evaluation and treatment of other causes of anemia must occur pre-ESA initiation and at any time thereafter as needed for lack of responsiveness.
• Prior to ESA therapy, the patient’s iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, must be evaluated. Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL. Iron stores must also be checked prior to dosage increases. Even without dosage adjustments, iron storage must be checked at least every 3 months during ongoing ESA therapy.
• If the initial dose of an ESA was administered in another setting (i.e., hospital, in a state outside our jurisdiction, or in another facility); subsequent office-administered ESAs must still meet all the above-mentioned requirements. This may require review of outside medical records and confirmation that needed pre-treatment lab results and evaluation were completed appropriately.

Anemia in Zidovudine Treated HIV Infection

Darbepoetin alfa and epoetin beta are NOT indicated for this condition.

For epoetin alfa/epoetin alfa-epbx biosimilar in anemia related to Zidovudine treated HIV:

Epoetin alfa is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding, which should be managed appropriately.

Epoetin alfa therapy for anemia related to Zidovudine therapy for HIV must not target a Hb > 12 g/dL.

Required Documentation Elements:

• Use of the ESA for symptomatic anemia due to AZT therapy
• Zidovudine therapy at a dose < 4200 mg/week
• An endogenous baseline pre-transfusion serum EPO level < 500 mUnits/mL
• A dose titrated to the individual need to achieve and maintain the lowest Hb level needed to avoid RBC transfusions.
• The ESA Utilized: 
  • Epoetin alfa (J0885) or epoetin alfa-epbx biosimilar (Q5106)
• For patients with symptomatic anemia due to adverse impact of AZT, a diagnosis of D61.1 and either B20 or B97.35 must be billed with HCPCS codes J0885 or Q5106. A JA or JB modifier is required. The EC modifier is also required. Inclusion of any other ICD-10 diagnoses on the claim which are non-covered with an EC modifier per NCD 110.21, will preclude payment for the ESA.
• DOSING:
  • Initial dosing: 100 Units/kg TIW for 8 weeks.
  • Maintenance dosing: After 8 weeks of initial therapy, if the response has not been satisfactory in terms of decreasing RBC transfusion or the Hb level, then the dose may be increased by 50-100 units/kg TIW.
  • Response should be evaluated and documented every 4-8 weeks thereafter with the dose adjusted accordingly by 50 to 100 Units/kg increments TIW. If the Hb exceeds 12 g/dL then the ESA should be stopped until the Hb drops below 11 g/dL at which time it can be restarted at a dose reduced by at least 25%. During maintenance, dosage variations will depend on the presence of intercurrent infections and variances in Zidovudine dosing.
  • Dosing should never exceed 300 units/kg TIW as further improvements in response are unlikely.

For Anemia in Myelodysplastic Syndromes (MDS)

MDS comprises a range of hematologic malignancies characterized by isolated or multiple cytopenias accompanied by abnormal cellular maturation. Much of the morbidity and death from MDS is due to the cytopenia impacts rather than transformation to acute myeloid leukemia (AML). There are well supported scenarios in which ESAs can be used as part of the therapeutic regimen in a very low, low or intermediate risk MDS population. These scenarios, for which coverage can be considered, presuming the reasonable and necessary use of ESAs is well documented, are noted below.

Epoetin beta is NOT indicated for treatment of anemia in MDS.

ESA use for symptomatic anemia in MDS can be considered for the following categories:

• Patients with MDS with very low, low risk (score < 3) per the Revised International Prognostic Scoring System (IPSS-R), or
• Patients with intermediate risk (IPSS-R score < 3.5), or
• Patients with MDS with low or intermediate- 1 risk (score of 0-1) per the International Prognostic Scoring System (IPSS), or
• Patients with very low, low or intermediate risk (score of 0-2) per the WHO Prognostic Scoring System (WPSS)

AND

• Without del(5q) and serum EPO < 500 mU/mL, or
• With del(5q) and no chromosome 7 associated abnormalities, on or before starting Lenalidomide with serum EPO < 500 mU/mL

Required Documentation Elements:

• Symptomatic anemia or transfusion dependence and a Hb < 10 g/dL within 1 week of the initial ESA treatment
• The ESA utilized:
  • Epoetin alfa (J0885) or epoetin alfa-epbx biosimilar (Q5106) or darbepoetin (J0881)
• Weight in kilograms
• MDS diagnostic bone marrow biopsy with cytogenetic analysis
• Documented evaluation for other anemia contributing factors such as blood loss, hemolysis, renal failure, medications, nutritional deficiencies, thyroid dysfunction, autoimmune disorders and anemia of chronic disease
• Evaluation and treatment of other causes of anemia must occur pre-ESA initiation and at any time thereafter as needed for lack of responsiveness.
• Iron store results pre-ESA use: serum iron/TIBC (TSAT) and ferritin and at least every 3 months during treatment
• Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL to start or continue ESA without correction of iron deficiency.
• Serum EPO result < 500 mU/mL
• Documented IPSS-R result of 3 or less for very low, low risk MDS or documented IPSS-R result of 3.5 or less for an intermediate risk MDS or IPSS score of 0-1 or WPSS score of 0-2.
• Narrative regarding ongoing response to therapy
• If the initial dose of an ESA was administered in another setting (i.e., hospital, in a state outside our jurisdiction, or in another facility); subsequent office-administered ESAs must still meet all the above-mentioned requirements. This may require review of outside medical records and confirmation that needed pre-treatment lab results and evaluation were completed appropriately.
• For patients with symptomatic anemia due to low-risk categories of MDS (Very low, Low or intermediate risk IPPS-R score < 3.5), 1 of the following diagnosis codes should be present on the claim; D46.0, D46.1, D46.20, D46.21, D46.22, D46.A, D46.B, D46.C or D46.Z. In the rare case of essential thrombocythemia progressing to refractory anemia due to secondary myelofibrosis, the dual diagnoses of D47.3 and D75.81 should be reported. Waldenstrom macroglobulinemia cases complicated by neoplastic bone marrow infiltration resulting in symptomatic anemia should simply be reported with C88.0. Inclusion of any other ICD-10 diagnoses on the claim which are non-covered with an EC modifier per NCD 110.21, will preclude payment for the ESA. A JA or JB modifier is required.

ESA use for 6-12 weeks would be expected as would RBC transfusion use for symptom management while awaiting an erythroid response.

The ESA regimen should be adjusted to maintain the lowest level of Hb/HCT that is sufficient to avoid RBC transfusions. If the rise of Hb is adequate to avoid transfusions or increases > 1 g/dL in any given 2-week period, the dose of epoetin alfa should be reduced by 25% or the dose of darbepoetin alfa can be reduced by 40%. Less frequent dosing would also be an acceptable alternative.

If the response is not adequate after 4 weeks, dose escalation, an increase in dose frequency or addition of a myeloid growth factor would be acceptable.

ESAs should not be continued for more than 12 weeks if no response is observed.

Before beginning ESA therapy, risk of thrombosis should be considered. Hypertension must be controlled.

Much higher doses of ESAs are utilized as compared to all the uses noted otherwise in this article. Dosing for epoetin alfa/epoetin alfa-epbx often is in a range of 40,000-60,000 units SQ 1-2 times per week and darbepoetin alfa often in a range of 150-300 mcg SQ every other week.

There is currently no consensus regarding an optimal dose/schedule for ESA administration. This decision is left to the treating oncologist.

Prophylactic Allogeneic Transfusion Reduction Intent in Presurgical Anemia

Darbepoetin alfa and epoetin beta are NOT indicated for this condition.

For epoetin alfa/epoetin alfa-epbx biosimilar in anemia in a presurgical setting:

• For HCPCS codes J0885 or Q5106: ICD-10-CM codes D63.8 and Z01.818 MUST be billed along with 1 of the osteoarthritis codes listed in ICD-10 Group 6. The EC modifier is also required. A JA or JB modifier is required; a JB modifier would be consistent with the FDA label indication. Inclusion of any other ICD-10 diagnoses on the claim which are non-covered with an EC modifier per NCD 110.21, will preclude payment for the ESA.

Required Documentation Elements:

• A presurgical Hb greater than 10 but less than 13 g/dL.
• A high risk for perioperative blood loss related to planned elective orthopedic hip or knee surgery with an expectation for more than 2 units of blood loss
• Inability or unwillingness by the patient to donate autologous blood
• A workup for anemia that suggests anemia of chronic disease
• Iron supplementation ongoing during the entire course of the ESA
• Deep vein thrombosis (DVT) prophylaxis ongoing during the entire course of the ESA
• Dosing: 300 u/kg/day SQ daily for 10 days prior to surgery, on the day of surgery and daily for 4 days following surgery. The other dosing option would be 600 units/kg SQ once weekly for 3 weeks prior to the surgery (21, 14 and 7 days before surgery) plus a 4^th dose on the day of surgery.

• Erythropoiesis Stimulating Agents
• ESAs