White blood cell growth factors, also known as granulocyte colony stimulating
factors (G-CSF), are administered to enhance recovery of blood related
functions in neutropenia (low white blood count) including febrile neutropenia
(FN).  
  
CSFs are also utilized to decrease the incidence and severity of infection
associated with select disease-related and drug-related myelosuppression
(inhibition of bone marrow function).  
  
G-CSF are glycoproteins which exert major control over the reproduction and
maturation of certain white blood cells, which include the following U.S. Food
& Drug Administration (FDA) approved products:  
  
 Filgrastim
([Neupogen](https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103353s5194lbl.pdf),
Amgen, Thousand Oaks, CA)  
 Filgrastim-sndz biosimilar
([Zarxio](https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125553s017lbl.pdf),
Sandoz, Princeton, NJ)  
 Pegfilgrastim
([Neulasta](https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125031s198lbl.pdf),
Amgen, Thousand Oaks, CA)  
 Tbo-filgrastim
([Granix](https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125294s042lbl.pdf),
Sicor Biotech UAB/Teva Pharmaceuticals North Wales, PA)  
  
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic
growth factor which stimulates proliferation and differentiation of
hematopoietic progenitor cells.  
  
 Sargramostim
([Leukine](https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103362s5240lbl.pdf),
Sanofi-Aventis Bridgewater, NJ and Sanofi-Genzyme Cambridge, MA)  
  
**I. Definitions**  
  
Severe neutropenia is generally defined as an absolute neutrophil count (ANC)
of less than 500 cells per ml.  
  
Primary prophylaxis refers to administration of CSF during the first cycle of
chemotherapy.  
  
Secondary prophylaxis refers to administration of CSF during subsequent cycles
of chemotherapy.  
  
Administration of G-CSF for **primary prophylaxis** should **not be used
routinely** in all chemotherapy patients receiving usual outpatient regimens.
It should be reserved for those patients whose risk of FN is 20% or greater
based upon chemotherapy regimen. In patients whose risk of developing FN is
greater than or equal to 10% and less than 20% based on chemotherapy regimen,
the use of primary prophylaxis should be reserved for those patients with 1 or
more of the following risk factors for FN:  
  
1\. Age greater than 65 years;  
2\. Poor performance status;  
3\. Previous episodes of FN;  
4\. History of previous chemotherapy or radiation therapy;  
5\. After completion of combined chemoradiotherapy;  
6\. Bone marrow involvement by tumor producing cytopenias;  
7\. Preexisting neutropenia;  
8\. Poor nutritional status;  
9\. Poor renal function;  
10\. Liver dysfunction (i.e., elevated bilirubin);  
11\. The presence of open wounds or active infections;  
12\. Recent surgery (generally within the past 12 weeks);  
13\. Advanced cancer; or  
14\. Other serious comorbidities.  
  
Secondary prophylaxis is considered reasonable and necessary after documented
FN from a prior chemotherapy cycle (for which primary prophylaxis was not
received) in which a reduction in dosage of the chemotherapeutic agents or a
delay in treatment may compromise disease-free or overall survival or
treatment outcome.  
  
 **II. FDA Indications**  
  
A. G-CSF pegfilgrastim (Neulasta) and the biosimilar
[Fulphila](https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761075s000lbl.pdf)TM
are indicated for the following:  
  
 ** _ _Patients with Cancer Receiving Myelosuppressive Chemotherapy and/or
Immunotherapy:** to decrease the incidence of infection, as manifested by FN,
in patients with non-myeloid malignancies receiving myelosuppressive anti-
cancer drugs associated with a clinically significant incidence of severe FN.  
  
 ** Patients with Hematopoietic SubSyndrome of Acute Radiation Syndrome:** to
increase survival in patients acutely exposed to myelosuppressive doses of
radiation  
  
Neulasta and biosimilars are **not indicated** for the mobilization of
peripheral blood progenitor cells for hematopoietic stem cell transplantation.  
  
B. G-CSF tbo-filgrastim (Granix) is indicated for the following:  
  
 ** _ _Patients with Cancer Receiving Myelosuppressive Chemotherapy and/or
Immunotherapy:** to reduce the duration of severe neutropenia in adult and
pediatric patients 1 month and older with nonmyeloid malignancies receiving
myelosuppressive anticancer drugs associated with a clinically significant
incidence of FN.  
  
C. G-CSF filgrastim (Neupogen) is indicated for the following:  
  
 ** _ _Patients with Cancer Receiving Myelosuppressive Chemotherapy and/or
Immunotherapy: **to decrease the incidence of infection, as manifested by FN,
in patients with nonmyeloid malignancies receiving myelosuppressive anti-
cancer drugs associated with a clinically significant incidence of severe FN.  
  
 ** Patients with Acute Myeloid Leukemia Receiving Induction and/or
Consolidation Chemotherapy:** to reduce the time to neutrophil recovery and
the duration of fever, following induction or consolidation chemotherapy
treatment of patients with acute myeloid leukemia (AML).  
  
 ** Patients with Cancer Undergoing Bone Marrow Transplantation:** to reduce
the duration of neutropenia and neutropenia-related clinical sequelae, e.g.,
FN, in patients with nonmyeloid malignancies undergoing myeloablative
chemotherapy followed by bone marrow transplantation.  
  
 ** Patients Undergoing Autologous Peripheral Blood Progenitor Cell
Collection and Therapy:** for the mobilization of autologous hematopoietic
progenitor cells into the peripheral blood for collection by leukapheresis.  
  
 ** Patients with Severe Chronic Neutropenia:** for chronic administration to
reduce the incidence and duration of sequelae of neutropenia (e.g., fever,
infections, oropharyngeal ulcers) in symptomatic patients with congenital
neutropenia, cyclic neutropenia, or idiopathic neutropenia.  
  
 ** Patients with Hematopoietic Syndrome of Acute Radiation Syndrome:** to
increase survival in patients acutely exposed to myelosuppressive doses of
radiation  
  
D. G-CSF filgrastim-sndz biosimilar (Zarxio) is classified as a biosimilar
and is approved for all indications included in its reference product's
(Neupogen) label (see above listed indications for Neupogen)  
  
E. GM-CSF sargramostim (Leukine) differs from the above listed products in
that it is a recombinant human granulocyte macrophage colony stimulating
factor. GM-CSF is a hematopoietic growth factor which stimulates proliferation
and differentiation of hematopoietic progenitor cells.

Sargramostim is indicated for the following:  
  
 ** _ _Following Induction Chemotherapy in Acute Myelogenous Leukemia _:_**
following induction chemotherapy in older adult patients with acute
myelogenous leukemia (AML) to shorten time to neutrophil recovery and to
reduce the incidence of severe and life-threatening infections and infections
resulting in death. The safety and efficacy of sargramostim have not been
assessed in patients with AML under 55 years of age.  
  
 ** Use in Mobilization and Following Transplantation of Autologous
Peripheral Blood Progentior Cells:** for the mobilization of hematopoietic
progenitor cells into peripheral blood for collection by leukapheresis.
Mobilization allows for the collection of increased numbers of progenitor
cells capable of engraftment as compared with collection without mobilization.
After myeloablative chemotherapy, the transplantation of an increased number
of progenitor cells can lead to more rapid engraftment, which may result in a
decreased need for supportive care. Myeloid reconstitution is further
accelerated by administration of sargramostim following peripheral blood
progenitor cell transplantation.  
  
 ** Use in Myeloid Reconstitution After Allogeneic Bone Marrow
Transplantation:** for acceleration of myeloid recovery in patients undergoing
allogeneic bone marrow transplantation (BMT) from HLA-matched related donors.
Sargramostim has been found to be safe and effective in accelerating myeloid
engraftment, reducing the incidence of bacteremia and other culture positive
infections, and shortening the median duration of hospitalization.  
  
 ** Use in Bone Marrow Transplantation Failure or Engraftment Delay:** in
patients who have undergone allogeneic or autologous BMT in whom engraftment
is delayed or has failed. Sargramostim has been found to be safe and effective
in prolonging survival of patients who are experiencing graft failure or
engraftment delay, in the presence or absence of infection, following
autologous or allogeneic BMT. Survival benefit may be relatively greater in
those patients who demonstrate one or more of the following characteristics:
autologous BMT failure or engraftment delay, no previous total body
irradiation, malignancy other than leukemia or a multiple organ failure (MOF)
score = 2. Hematologic response to sargramostim can be detected by complete
blood count (CBC) with differential performed twice per week.  
  
 **III. Off-Label Indications**  
  
In addition to the FDA-approved uses, coverage will be extended when any of
the drugs- Filgrastim (Neupogen) or Filgrastim-sndz biosimilar (Zarxio),
Pegfilgrastim (Neulasta), Sargramostim (GM-CSF, Leukine), or Tbo-Filgrastim
(Granix) and biosimilars are used as adjunctive treatment when any of the
conditions listed below are present.  
  
Any of the following conditions may be an indication for adjunctive treatment:  
  
1\. Expected prolonged (greater than 10 days) and profound (less than 0.1 x
109/L) neutropenia;  
2\. Age greater than 65 years;  
3\. Uncontrolled primary disease;  
4\. Pneumonia;  
5\. Hypotension and multi organ dysfunction (sepsis syndrome);  
6\. Invasive fungal infection; or  
7\. Hospitalized at the time of the development of fever.  
  
 **Filgrastim (Neupogen ) or Filgrastim-sndz biosimilar (Zarxio):**  
  
A. In an individual with acute lymphocytic leukemia (ALL) after completion of
the first few days of initial induction chemotherapy or first post-remission
course of chemotherapy; or  
  
B. Use in adult individuals with AML shortly after the completion of induction
or repeat induction chemotherapy, or after the completion of consolidation
chemotherapy for AML; or  
  
C. Treatment of severe neutropenia in individuals with hairy cell leukemia; or  
  
D. In an individual with myelodysplastic syndromes (MDS) with severe
neutropenia (ANC less than or equal to 500 mm3) or experiencing recurrent
infection; or  
  
E. In an individual receiving dose dense therapy (treatment given more
frequently, such as every 2 weeks instead of every 3 weeks) for adjuvant
treatment of breast cancer, or other malignancies for which dose dense
chemotherapy is an accepted treatment option; or  
  
F. Chronic administration to reduce the incidence and duration of sequelae of
neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic
individuals with congenital neutropenia, cyclic neutropenia, or idiopathic
neutropenia; or  
  
G. Treatment of (non-chemotherapy) drug-induced neutropenia; or  
  
H. Treatment of low neutrophil counts in individuals with glycogen storage
disease type 1b; or  
  
I. Treatment for neutropenia associated with human immunodeficiency virus
(HIV) infection and antiretroviral therapy; or  
  
J. In individuals receiving radiation therapy in the absence of chemotherapy
if prolonged delays secondary to neutropenia are expected; or  
  
K. After a hematopoietic progenitor stem cell transplant (HPCT/HSCT) for the
following indications:  
  
 To promote myeloid reconstitution; or  
  
 When engraftment is delayed or has failed; or  
  
 To mobilize progenitor cells into peripheral blood for collection by
leukapheresis, as an adjunct to peripheral blood/hematopoietic stem cell
transplantation (PBSCT/PHSCT); or  
  
 Use as an alternate or adjunct to donor leukocyte infusions (DLI) in
individuals with leukemic relapse after an allogeneic hematopoietic stem cell
transplant.  
  
 **Pegfilgrastim (Neulasta ) and Biosimilars:**  
  
A. In an individual with ALL after completion of the first few days of initial
induction chemotherapy or first post-remission course of chemotherapy; or  
  
B. In an individual with MDS with severe neutropenia (ANC less than or equal
to 500 mm3 or experiencing recurrent infection; or  
  
C. In an individual receiving dose dense therapy (treatment given more
frequently, such as every 2 weeks instead of every 3 weeks) for adjuvant
treatment of breast cancer, or other malignancies for which dose dense
chemotherapy is an accepted treatment option. If a patient is on a dose dense
14-day chemotherapy cycle, it would be acceptable to administer Neulasta
outside of the 14-day before and 24-hour after rule for chemotherapy.
Neulasta would typically be administered on the second day of a 14-day dose
dense chemotherapy cycle. The medical record should clearly indicate that the
patient is on a 14-day dose dense chemotherapy cycle regimen; or  
  
D. After HPCT/HSCT for the following indications:  
  
 To promote myeloid reconstitution; or  
  
 When engraftment is delayed or has failed.  
  
 **Sargramostim (GM-CSF, Leukine ):**  
  
A. In an individual receiving dose dense therapy (treatment given more
frequently, such as every 2 weeks instead of every 3 weeks) for adjuvant
treatment of breast cancer; or  
  
B. In an individual with ALL after completion of the first few days of initial
induction chemotherapy or first post-remission course of chemotherapy; or  
  
C. For administration shortly after the completion of induction or repeat
induction chemotherapy of AML for individuals over 55 years of age; or  
  
D. In an individual with MDS with severe neutropenia (ANC less than or equal
to 500 mm3) or experiencing recurrent infection; or  
  
E. In individuals receiving radiation therapy in the absence of chemotherapy
if prolonged delays secondary to neutropenia are expected; or  
  
F. After accidental or intentional total body radiation of myelosuppressive
doses (greater than 2 Grays [Gy]) (such as Hematopoietic Syndrome of Acute
Radiation Syndrome); or  
  
G. After HPCT/HSCT for the following indications:  
  
 To promote myeloid reconstitution; or  
  
 When engraftment is delayed or has failed; or  
  
 To mobilize progenitor cells into peripheral blood for collection by
leukapheresis, as an adjunct to PBSCT/PHSCT; or  
  
 **IV. Uses for which efficacy and safety have not been established**  
  
 Administration of G-CSF in cancer patients in order to increase chemotherapy
dose-intensity except as noted above.  
  
 Routine, continuous use of G-CSF in patients with MDS or Felty's syndrome
without infections.  
  
 Given the concerns for adverse events, avoidance of G-CSFs in patients
receiving concomitant chemoradiotherapy for either head and neck cancer or
lung cancer may be warranted.  
  
 Chemo sensitization of myeloid leukemias.  
  
 Continued use if no response is seen within 28-42 days (individuals who have
failed to respond within this time frame are considered non-responders).  
  
 Administration of G-CSF in patients with chronic aplastic anemia. Growth
factors, as single agents, have not been shown to be effective in severe
aplastic anemia. Their use in combination with other agents such as a
cyclosporine and/or antilymphocyte globulin (ALG) is still investigational.  
  
For uses not meeting the criteria noted above in the LCD.  
  
 **V. Coverage Requirements for Chemotherapy and/or Immunotherapy Related
Uses**  
  
The patient must be receiving a drug known to be associated with the
development of severe neutropenia. The drug must be covered by Medicare.  
  
 **G-CSF 's and GM-CSF's will be covered when administered under direct
supervision of the physician in the office (Part B) or hospital setting (Part
A). When administered by the patient or caregiver, this drug will be
considered self-administered and not payable by this A/B MAC. **

Pegfilgrastim is a white blood cell growth factor with labeled use to decrease
the incidence of infection (as manifested by febrile neutropenia), in patients
with nonmyeloid malignancies receiving myelosuppressive cancer therapy
associated with a clinically significant incidence of FN.1 The FDA label
recommends administration starting at least 24 hours after the completion of
chemotherapy.

To improve compliance and convenience for patients by not having to return 24
hours after chemotherapy for administration there is an interest in same day
administration. A survey of physicians who administer pegfilgrastim reported
that 31.6% were treated on a "same-day" schedule utilizing patient related
considerations in the decision such as patient/caregiver travel distance and
practice related consideration such as burden on the practice for next day
administration as determining factors.2

Burris et al3 conducted a study to compare data on severe (grade 4)
neutropenia duration and FN incidence in patients receiving chemotherapy with
pegfilgrastim administered the same day or 24 hours after chemotherapy. These
were similar, randomized, double-blind phase II noninferiority studies of
patients with lymphoma or non-small-cell lung (NSCLC), breast, or ovarian
cancer. Each study was analyzed separately. The primary end point in each
study was cycle-1 severe neutropenia duration. Approximately 90 patients per
study were randomly assigned at a ratio of 1:1 to receive pegfilgrastim 6 mg
once per cycle on the day of chemotherapy or the day after (with placebo on
the alternate day). In 4 studies, 272 patients received chemotherapy and 1 or
more doses of pegfilgrastim (133 same day, 139 next day). Three studies
(breast, lymphoma, NSCLC) enrolled an adequate number of patients for
analysis. However, in the NSCLC study, the neutropenic rate was lower than
expected (only 2 patients per arm experienced grade 4 neutropenia). In the
breast cancer study, the mean cycle-1 severe neutropenia duration was 1.2 days
(95% confidence limit [CL], 0.7 to 1.6) longer in the same-day compared with
the next-day group (mean, 2.6 v 1.4 days). In the lymphoma study, the mean
cycle-1 severe neutropenia duration was 0.9 days (95% CL, 0.3 to 1.4) longer
in the same-day compared with the next-day group (mean, 2.1 v 1.2 days). In
the breast and lymphoma studies, the ANC profile for same-day patients was
earlier, deeper, and longer compared with that for next-day patients, although
the results indicate that same-day administration was statistically
noninferior to next-day administration according to neutropenia duration. The
authors concluded that pegfilgrastim administered at least 24 hours after
chemotherapy completion is recommended.

A retrospective study of patients who received chemotherapy and prophylactic
same-day or next-day pegfilgrastim found that in cycle 1, 117 patients
received same-day pegfilgrastim and 180 patients received next-day
pegfilgrastim. FN episodes in cycle 1 occurred in 6.0% versus 6.7% of patients
with same-day versus next-day pegfilgrastim, respectively (p = 0.814). Across
all cycles, 8.5 and 9.4% of patients experienced >/=1 FN episode after same-
day versus next-day pegfilgrastim, respectively (p = 0.793). In the breast
cancer patient subgroup, FN occurred 3.2% of same-day pegfilgrastim cycles
versus 1.8% of next-day pegfilgrastim cycles (p = 0.938). The authors reached
the conclusion that there was no significant difference between same-day and
next-day pegfilgrastim administration.4

McBride et. al.5 looked at 93 patients who received 460 cycles of CHOP-like
chemotherapy. The incidence of FN and grade 3/4 chemotherapy-induced
neutropenia was 5% and 16.5%, respectively. In 401 cycles, pegfilgrastim was
administered same-day versus 12 cycles next-day. FN occurred in 17 cycles
versus 0 cycles (p = 1.00) and grade 3/4 chemotherapy-induced neutropenia in
65 cycles (16.2%) versus 1 cycle (16.7%; p = 1.00) with same-day versus next-
day pegfilgrastim administration, respectively. They concluded that
pegfilgrastim may be safely administered on the same day as chemotherapy in
patients with lymphoma receiving CHOP-like chemotherapy.

A systematic literature review evaluated the relative merits of same-day
versus next-day dosing of pegfilgrastim. A broad Ovid MEDLINE and Embase
literature search was conducted that examined all publications indexed before
May 9, 2016, that compared same-day versus next-day pegfilgrastim
administration. The first part of the systematic literature search identified
1736 publications. After elimination of duplicates, title/abstract screening
was conducted on 1440 records, and full text review was conducted on 449
publications. Eleven publications met all criteria and are included in this
systematic review; of these, 4 included data from randomized or single arm
prospective studies, and 7 were retrospective studies. In most studies
included in this review and across a variety of tumor types, administration of
pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in
improved patient outcomes. The authors concluded that data from multiple
publications supports administration of pegfilgrastim at least 1 day after
chemotherapy.6

A small study of 46 patients were treated for the following malignancies: 35
(76%) epithelial ovarian, 6 (13%) primary peritoneal, and 5 (11.0%) ovarian
germ cell or stromal cell carcinoma. All patients met the current guidelines
of using CSF for prophylaxis against FN. A total of 269 cycles of chemotherapy
were administered. All patients received pegfilgrastim within 1 hour of the
completion of chemotherapy administration. Grade 1 or 2 neutropenia developed
in 10 cycles (3.7%), and the mean ANC was 4926/uL (range, 1,293-24,300). No
patients had febrile neutropenic episodes, hospitalizations, or antibiotic use
secondary to neutropenia, nor did they have dose reductions or chemotherapy
delays due to neutropenia. The authors felt that administration of
pegfilgrastim on the same day as myelosuppressive chemotherapy in patients
with ovarian or primary peritoneal cancer may be a convenient, safe, and
effective approach.7

Whitworth et.al.8 sought to compare the safety and efficacy of day 1
pegfilgrastim administration to day 2 administration in patients with
gynecologic malignancies. They retrospectively evaluated patients receiving
both chemotherapy and pegfilgrastim from June 1, 2006, to August 31, 2007, for
a gynecologic malignancy. After administration of chemotherapy, all patients
either received 6 mg of pegfilgrastim subcutaneously on day 1 or day 2. 1226
administrations of pegfilgrastim in 230 patients were identified. 490
administrations of pegfilgrastim were given on day 1 compared to 736 on day 2.
70% of patients had ovarian cancer with a median age of 64 years (range
15-88). 79% of patients had stage III, IV, or recurrent disease and 67% were
undergoing primary chemotherapy. The most common chemotherapy was
docetaxel/carboplatin (53%) followed by paclitaxel/carboplatin (19%). The mean
ANC nadir was 4810/mm(3) in the day 1 cohort compared to 4212/mm(3) in the day
2 cohort (p=.004). The incidence of Grade 3/4 neutropenia was similar in both
groups (4.9% in day 1 vs. 5.7% in day 2; p=.63). Grade 3/4 febrile neutropenia
was uncommon in both cohorts (0 episodes vs. 3 episodes; p=.41). Treatment
delays were similar in both cohorts (5.9% vs. 7.5%; p=.35). Dose modifications
were also similar in both cohorts (2.8% vs. 5.3%; p=.06). Their conclusion was
that day 1 administration of pegfilgrastim is as effective as day 2
administration in the prevention of neutropenia in patients with gynecologic
malignancies.

Some retrospective studies support safety and efficacy of same day
administration, but also trend to a non-statistically significant increase in
side effects with same day administration. In addition, other retrospective
studies demonstrate a disadvantage to same day dosing. The National
Comprehensive Cancer Network (NCCN) Guidelines Version 1.2022 state that
pegfilgrastim same day administration is supported by category 1 evidence,
however there is data for and against same day dosing. The FDA approved dosing
schedule is still recommended by NCCN.9

For patients who cannot return to the clinic for next-day administration,
there is an FDA-approved delivery device available that can be applied the
same day as chemotherapy in order to deliver the full dose of pegfilgrastim
the following day (approximately 27 hours after application).

In consideration of the above, Pegfilgrastim should continue to be given
according to FDA approved dosing schedule. This A/B MAC will consider same day
administration when patient/caregiver circumstances create a significant
barrier to compliance, such as lack of transportation to return for dosing
within recommended time frame and inability to tolerate and/or obtain the FDA
approved on-body injector. This A/B MAC expects clear documentation for same
day administration to be in the medical record and available upon request.