Sargramostim (GM-CSF, Leukine®)

Date of Revision: 9/20/02

 CMS National Coverage Policy

Description:Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) is an antineutropenic, hematopoietic growth factor, which supports survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GMCSF is also capable of activating mature granulocytes and macrophages. This drug is not a cancer chemotherapy agent.

The drug appears to elicit the pharmacologic effects usually produced by endogenous human GM-CSF. Endogenous GM-CSF is a multilineage colonystimulating factor that principally affects the proliferation, differentiation, and activation of granulocytes and macrophages by inducing partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways.

Endogenous GM-CSF acts on various progenitor target cells by binding to GM-CSF specific receptors on their cell surfaces. Biosynthetic GM-CSF principally affects cells in the granulocyte-macrophage lineage. In patients receiving low doses of biosynthetic GM-CSF, the leukocyte response is composed principally of neutrophils; at higher concentrations, the leukocyte response also involves proliferation of monocytes and eosinophils.

 Indications and Limitations of Coverage and/ or Medical Necessity

The carriers  will consider GM-CSF medically reasonable and necessary for the treatment of the following FDA approved indications when it is not self/caregiver administered:

Promotion of myeloid engraftment following bone marrow transplant (BMT): 

a) For acceleration of myeloid recovery in patients with non-Hodgkin’s lymphomas, acute lymphoblastic leukemia, and Hodgkin’s disease undergoing autologous BMT.

b) For acceleration of myeloid recovery in patients undergoing autologous     or allogenic BMT following myeloablative chemotherapy for nonmyeloid malignancies.

c) For acceleration of myeloid recovery in patients undergoing allogenic    BMT following myeloablative chemotherapy for myeloid malignancies.

d) For treatment of failure or delay of myeloid engraftment following autologous or allogenic BMT, in the presence or absence of infection.

Enhancement of peripheral blood progenitor cell (PBPC) collection when the bone marrow transplant procedure itself is a covered benefit.

For acceleration of myeloid recovery in patients undergoing hematopoietic stem cell transplantation following myeloablative chemotherapy.

To reduce the duration of neutropenia, following induction chemotherapy treatment of adults with acute myelocytic leukemia (AML).

The carriers will consider GM-CSF medically reasonable and necessary       for the treatment of the following off-label indications when it is not self/    caregiver administered:

• Failure or delay of myeloid engraftment in patients who have undergone autologous or allogenic hematopoietic stem cell transplantation, in the presence or absence of infection.

• To decrease the incidence of infection, as manifested by febrile  neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence  of severe febrile neutropenia.

• Acquired immunodeficiency syndrome (AIDS)-associated neutropenia caused by the disease (AIDS) itself or infection with opportunistic organisms (such as cytomegalovirus), or antiretroviral agents (zidovudine, ganciclovir).

• Intermittent administration of GM-CSF for a subset of patients with Myelodysplastic syndromes (MDS) who have severe neutropenia and recurrent infections.

 Limitations

A physician is not to bill for a supply of GM-CSF given to the patient for self-administration at home. The following off-labeled uses of GM-CSF        have not been shown to be safe and effective and are noncovered by the carriers:

• aplastic anemia,
• hairy cell leukemia,
• severe chronic neutropenia which includes congenital (Kostmann’s syndrome), idiopathic and cyclic.
• Treatment of drug-induced neutropenia, except when associated with the use of antiretroviral agents is an off labeled indication and non-covered .
• There is no evidence that GM-CSF is an important benefit in patients with refractory or relapsed myeloid leukemia.
• Therapeutic initiation of GM-CSF does not add significantly to the antibiotic treatment outcome of established febrile neutropenia.

CSFs should not be routinely used as adjunct therapy for the treatment of uncomplicated fever and neutropenia.  

Uncomplicated fever and neutropenia are defined as follows:

• Fever of < 10 days in duration, and

• No evidence of pneumonia, cellulitis, abscess, sinusitis, hypotension, multi-organ dysfunction, or invasive fungal infection, and

• No uncontrolled malignancies.

There is inadequate data to support the use of GM-CSF for patients with afebrile neutropenia. GM-CSF is contraindicated in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (> 10%).

In general, for previously untreated patients receiving a chemotherapy regimen, primary prophylactic administration of GM-CSF is not considered medically necessary.

Due to the potential sensitivity of rapidly dividing hematopoietic cells, GM-CSF should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy.

There is no evidence of benefit from the use of GM-CSF to increase chemotherapy dose-intensity.

Dosage and Frequency

The following is the recommended dosage and frequency when   administering this drug:

• Myelosuppressive chemotherapy - recommended dose is250 mcg/m²/day. Administered no earlier than 24 hours after cytotoxic chemotherapy and not in the 24 hours before administration of chemotherapy.

• BPC - recommended dose is 250 mcg/m²/day. For the mobilization phase, this dosing should continue through the period of PBPC collection.

• For the post transplantation phase, begin the dose immediately          and continue until an ANC > 1500 cells/mm³ for 3 consecutive days is attained.

Myeloid Reconstitution after Autologous or Allogenic

• BMT - recommended dose following BMT is 250 mcg/ m²/day.    Patients should not receive the drug until the post marrow infusion ANC is less than 500 cells/mm³. The drug should be continued until an ANC >1500 cells/mm³ for 3 consecutive days is attained.

• BMT Failure or Engraftment Delay- recommended dose is 250 mcg/m²/day. Repeat dosage after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/ m²/day for 14 days may be tried after another 7 days off therapy.    If there is still no improvement, it is unlikely that further dose escalation will be beneficial.

• If the ANC exceeds 20,000 or the platelet count exceeds 500,000, GM-CSF treatment should be discontinued or the dose reduced by    half. Excessive blood counts usually return to normal or baseline levels    within 3 to 7 days following withdrawal of GM-CSF.

CPT/HCPCS Codes

J2820

Not Otherwise Classified Codes (NOC)

N/A

ICD-9-CM Codes that Support Medical Necessity

238.7, 288.0 , V42.9 , V58.1, V58.69, V59.8

Note: Please refer to coding guidelines for specific requirements regarding the billing of each of these ICD-9-CM codes.

Reasons for Denials

The use of GM-CSF (Sargramostim, Leukine®) for indications other than those listed in the “Indications and Limitations of Coverage and/or Medical Necessity” section of this policy.

Non-covered ICD-9-CM Codes

Any diagnosis codes not listed in the “ICD-9-CM Codes That Support Medical Necessity” section of this policy.

Coding Guidelines

Claims for GM-CSF should be billed using the following diagnosis codes:

238.7 (Neoplasm of uncertain behavior of other lymphatic and hematopoietic tissues) when GM-CSF is used for Myelodysplastic syndrome (MDS).

288.0 (Agranulocytosis) when GM-CSF is used for patients with AIDS-associated neutropenia.

V42.9 (Unspecified organ or tissue replaced by transplant) when GM-CSF is given to stem cell recipients (e.g., BMT).

V58.1 (Encounter for other and unspecified procedures and aftercare, chemotherapy) when GM-CSF is used for febrile neutropenia resulting from myelosuppressive chemotherapy or following induction or consolidation chemotherapy treatment of adults with AML.

V58.69 (Long-term [current] use of other medications) when GM-CSF is used for a patient with AZT or Ganciclovir neutropenia.

V59.8 (Donors, other specified organ or tissue) when GM-CSF is used in priming for autologous peripheral stem cells (e.g., PBPC), as an adjunct to allogeneic and autologous progenitorcell transplantation, or for neutrophil engraftment failure.

Documentation Requirements

Medical record documentation maintained by the physician must clearly indicate:

• The patient’s current absolute neutrophil count (ANC);

• The patient’s weight in kilograms;

• The administration and dosage of the GM-CSF;

• The actual indication for which the drug was given and

accompanying symptomology (e.g., fever); and

• The patient’s response to the treatment.

This information is usually found in the history and physical or the office/progress notes. The ANC may be reported in the patient’s laboratory report. 

Utilization Guidelines

 It is expected that these services would be performed as indicated by   current medical literature and/or standards of practice. When services are performed in excess of established parameters, they may be subject to  review for medical necessity.

Other Comments

The package insert instructions for dosage and duration of treatment      should not be exceeded. The guidelines recommended for adults are generally applicable to the pediatric age group.

Terms Defined:

Absolute neutrophil count (ANC) - a lab test done on blood which counts the neutrophils within the blood specimen. It is represented by the total     WBC x % segmented neutrophils and bands. Normal ANC is considered 3000-7000/mm³.

Dose-intense chemotherapy - treatment given at higher

Neutropenia - an abnormally small number of neutrophil cells in the blood   (an ANC of < 1800/mm³).

Progenitor-cell support - refers to transplantation of hematopoietic cells derived from either bone marrow or the peripheral blood as a means to increase patient safety and tolerance of treatment when very high doses of chemotherapy are administered to increase remission rates and increase disease-free survival (DFS).

Severe chronic neutropenia - ANC less than 500/mm³.