The role of biosimilar granulocyte colony stimulating

The role of biosimilar granulocyte colony stimulating
factor (GCSF) Zarzio for progenitor cell mobilization
and the treatment of therapy-induced neutropenia in
adult hematopoietic stem cell transplantation
by Cherie C. Severson
ABSTRACT
Originator GCSF (Neupogen) has been
used to mobilize progenitor stem cells
and treat therapy-induced neutropenia
in Canadian stem cell transplant settings
for years. Although its benefit is not in
question, viable alternatives are available.
Biosimilar GCSF (Zarzio) is widely in
use in Europe since 2009 and was recently
approved in the U.S. for the same five indications as Neupogen. Zarzio is reported
as safe, equally efficacious, more accessible and cost effective without negatively
impacting patient outcomes. This paper
summarizes the supporting evidence.
Key words: biosimilar GCSF, Zarzio,
autologous transplant, mobilization,
neutropenia, cost
A
s Canadian cancer statistics continue to rise and cancer facilities overflow with patients, the need
to investigate novel approaches and
cost-effective strategies is required
(Canadian Cancer Society’s Advisory
Committee [CCSAC], 2015). Canadian
hematopoietic stem cell transplant
(HCT) programs grapple with budgetary restraints on a daily basis. Measures
that facilitate the achievement of budgetary goals are needed to ensure
patients receive affordable health care,
and HCT programs continue to thrive.
One such cost-effective strategy, which
can achieve both safety and efficacy
while still showing a cost benefit, is the
use of a biosimilar granulocyte colony
stimulating factor (GCSF), also known
as Zarzio (Gascon et al., 2013; Ianotto
et al., 2014). The purpose of this manuscript is to introduce biosimilar Zarzio
as a cost-effective alternative to the originator Neupogen and compare the two
in relation to safety, efficacy, and cost in
the setting of hematopoietic stem cell
transplant.
Biosimilars are biologics with comparable safety, efficacy and quality as the
originator GCSF known as Neupogen
(Bonig, Becker, Schwebig & Turner,
2015; Gascon, 2012; Remenyi, et al.,
2014; Ianotto et al., 2014). As they are
produced by living organisms, biosimilar agents are stringently evaluated on a case-by-case basis prior to
approval by regulatory bodies such as
the European Medicines Agency, the
US Food and Drug Administration
(FDA), and the Australian Therapeutic
Goods Administration (Bonig et
al., 2015; Gascon, 2012; Lefrere et al.,
2011). These regulatory bodies provide
approval based on robust comparability
exercises demonstrating similarity with
the originator GCSF Neupogen (Bonig
et al., 2015; Gascon, 2012; Lefrere et
al., 2011). Similarity is demonstrated
through biochemical characterization
(i.e., purity, chemical identity, protein
structure and receptor on/off kinetics),
biologic activity and clinical similarity for at least one indication (Bonig et
al., 2015). Biosimilars cannot automatically claim all indications of the originator product (Bonig et al., 2015). They
ABOUT THE AUTHOR
Cherie C. Severson, RN, MN, CON(C), BMTCN, Alberta Blood and Marrow Transplant Clinic,
Tom Baker Cancer Centre, Calgary, AB
Email: [email protected]
Canadian Oncology Nursing Journal • Volume 25, Issue 4, Fall 2015
Revue canadienne de soins infirmiers en oncologie
must demonstrate that the mechanism
of action and the receptor involved to
be identical to those of the originator
(Bonig et al., 2015). In this case, both
Neupogen and Zarzio have the same
mechanism of action, which is direct
stimulation of the bone marrow cells
through the GCSF surface receptor
(Gascon et al., 2013). Bioequivalence
of Zarzio and Neupogen was demonstrated in four comparative phase I studies where 146 healthy volunteers were
administered either product (Gascon
et al., 2013). In tests for efficacy using
absolute neutrophil count (ANC) and
CD34+ cell count as surrogate markers,
both products show comparable effect
(Gascon, 2012; Gascon et al., 2013).
Zarzio was initially approved in the
European market in 2009. In 2015, it
was approved by the FDA for use in the
U.S. for the same five indications as its
originator Neupogen (Gascon, 2012;
Hamburg, 2015; McBride, 2015). These
indications include patients with cancer who are receiving myelosuppressive or myeloablative chemotherapy,
patients with acute myeloid leukemia
receiving induction or consolidation chemotherapy, patients with cancer undergoing blood and marrow transplantation,
patients undergoing autologous peripheral blood progenitor cell collection and
therapy, and those with severe neutropenia (Hamburg, 2015; Lefrere et al.,
2011). Pharmacokinetics and pharmacodynamics studies performed on biosimilar GCSF Zarzio are comparable to
the originator GCSF Neupogen (Gascon
et al., 2013; Lefrere et al., 2011). Overall,
the safety profile is extremely similar
to Neupogen with the most common
adverse events being headache, bone
pain, muscle aches, flu like symptoms,
febrile neutropenia, and rash. Rare side
effects include splenic rupture, acute
443
FEATURES/Rubriques
clinical practice
FEATURES/Rubriques
respiratory distress syndrome, allergic
reactions including anaphylaxis, fatal
sickle cell crises, capillary leak syndrome,
and thrombocytopenia (USA-FDA, 2015).
The biosimilar GCSF Zarzio is reported
to be as safe, equally efficacious, and
more cost effective than the originator
GCSF (Aapro, Cornes & Abraham, 2011;
Gascon et al., 2013; Lefrere et al., 2011). A
review of the pertinent trials regarding
the use of biosimilar GCSF Zarzio in
the setting of hematology and blood and
marrow transplant is on the following
pages (see Table 1).
continued on page 446…
Table 1: Review of the trials
Author
Trial Design
Bassi et al., Single institution,
2015
retrospective study
N=56 minus 1
Noted one patient died
prior to engraftment
because of disease
progression
Eligibility
Results
Adverse Events
Conclusion
Male: 34
Female: 22
Median age 57 (r 23-71
years old)
NHL: 44%, Myeloma: 44%
Hodgkin’s: 12%
1st transplant: 89%
Conditioning:
Melphalan, BEAM-like
regimen ThiotepaMEL
All received daily
biosimilars (Tevagrastim
(17) and Zarzio (39) at
standard dose starting on
day 5 with a median # of
days in duration =7 (range
4-9d)
Median CD34+ cells
infused 4.05x106/kg r
(2.2-7.76x106/kg)
Grade 2 bone
pain, sporadic
headache, febrile
neutropenia
lasting a median
of 2 days=47%
Biosimilar GCSF is
effective and safe for
facilitating bone marrow
recovery in autologous
HCT and costs less than
the originator GCSF
Neupogen
Engraftment 55/56
Median time to
neutrophil recovery is
10 (range 8-11 days)
Median time to platelet
recovery is 12 days
(range 8-23 days)
Mucositis
post high dose
conditioning
Rare side
effects include
a fib, CHF,
toxic hepatitis,
and 2/55 with
erythematous
rash covering
50% of body
surface
No secondary
malignancies
Schmitt et Multicentre analysis
al., 2014
involving 904
adult patients with
hematological
malignancies and healthy
donors who underwent
stem cell mobilization
using a biosimilar agent
(Tevagrastim or Zarzio)
Tevagrastim 520
Zarzio 384
MM 326
NHL 273
HL and other disease
including germ cell tumor
and cardiac failure 79
Healthy donors 156
Headache, bone
and muscle
pain, flu like
symptoms and
mild fever. Rare
The median number
reporting of
of apheresis collection
neutropenic
is 1 with few patients
enterocolitis,
undergoing 2 collections
grade 3 or 4
and even fewer
infection and
undergoing 3
sepsis are of
note
Autologous
Median neutrophil
engraftment time
(>0.5G/L) 11-15 days
(range 7-23 days)
Median platelet
engraftment (>20G/L)
12-14 days (range 6-33
days).
Median CD34+ cell
count is 3-10.2X 106 /
kg body weight (range
1-23X 106 /kg)
Autologous
No significant difference
in the peripheral blood
stem cell yield or toxicity
profile compared with
the historical data of
the originator GCSF
Neupogen
Allogeneic
To ensure the safety of
healthy donors further
long term data regarding
biosimilar use in healthy
donors is needed.
Allogeneic neutrophil
engraftment was similar
however median platelet
recovery was overall
higher at 25 days (range
0-33 days)
continued on page 445…
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Revue canadienne de soins infirmiers en oncologie
Trial Design
Remenyi
et al.,
2014
2 retrospective studies
of observational design
across 2 medical centres
in Hungary.
Eligibility
Study 1: N=70
with hematological
malignancies: MM 59%,
NHL 27%, HL 14%.
Median age 56y 60:40
Study 1: Primary
M/F ratio. ECOG =/<2.
objective was to
Adequate heart, liver and
evaluate the safety
kidney function. Rituximab
and effectiveness of
given to pts with NHL for
engraftment following
in vivo purging. Neupogen
treatment with Zarzio in
2x 5ug/kg admin 24 hr post
Auto HCT.
last day mobilizing chemo.
HD conditioning chemo
Study 2: primary
objective: retrospective regimens: melphalan, TBI/
CYCLO/R or R-BEAM
analysis of the efficacy
and safety of biosimilar followed by Zarzio 5ug/kg/
GCSF (Zarzio) following day beginning on day 1 post
mobilization chemo in pt Auto.
with lymphoid tumors
Study 2 Lymphoid
malignancies. N=40.
Median age 54y. 57.5%:
42.5% F/M ratio. ECOG
=/<2 with adequate heart,
liver and kidney function.
Diagnosis: MM 52.5%,
NHL 40%, HL 7.5%.
34/40 pts mobilized with
either Cyclo or R-DHAP
followed by Zarzio. 4 failed
to mobilize and needed
Plerixafor
Gascon et Pooled analysis
al., 2013
N=1302 patients
Breast cancer 42%
Lung cancer 16%
Lymphoma/Leukemia
15%
Other: prostate,
bladder, myeloma,
colorectal, endometrial
and ovarian)=27%
Febrile neutropenic risk
>20%=36% of 1302
Febrile neutropenic risk
10-20%=40%
Febrile neutropenic risk
<10%=12%
Unknown= 12%
Adult patients >18y
Confirmed diagnosis of
cancer
Received at least one cycle
of chemotherapy with
Zarzio
Exclusion: Patients
receiving Zarzio for the
treatment of neutropenia
(rather than prophylaxis)
were excluded from the
analysis
Results
Adverse Events
Conclusion
Study 1: Median # of
re-infused CD34+ cells
6.33 X 106/kg.
Time to ANC, WBC
and PLT engraftment:
9days (r 8-11d), 10 days
(r8-12d) and 10.5 days
(r7-19d) respectively.
Study 1:
neutropenic
fever >38.0C
(64%) related to
CVC infection,
pneumonia and
perianal soft
tissue infection.
Mucositis grade
1-4: 78%,
Diarrhea 58%,
Toxicoderma
10%
Engraftment
syndrome:
13%. Poor
graft function
1 Patient. No
treatment
related deaths
before day 100
post Transplant.
Auto transplant only:
Study 1: Time to
engraftment for WBC,
ANC and PLTS are
comparable between
Biosimilar GCSF (Zarzio)
and previous reports of
Neupogen.
No significant
differences between
biosimilar GCSF and
originator GCSF in
the median number of
CD 34+ cells mobilized
or in the number
of GCSF injections
and leukophereses
procedures to harvest the
target CD34+ cell dose.
No major differences
in safety profile with
previous reports of
Neupogen.
Generally well
tolerated
Bone pain (8%)
Overall Zarzio is effective
in the prevention of
chemotherapy-induced
neutropenia in a variety
of different cancers
treated in clinical
practice settings.
Study 2: median time
interval btw day1 of
mobilizing chemo and
first leukophereses:
12 days (r=9-27d).
40 successfully
harvested for a total
of 58 leukophereses
procedure. Median
apheresis procedures
per pt 1.4 (r 1-2)
Median # CD 34 cells
harvested: 5.2X 106 /kg
(r 2.22-57.07 x 106/kg).
Study 2: No
Median yield CD 34+
AE’s mentioned Study 2: Chemotherapy
count 2.47X 106 /kg.
in combination with
Biosimilar GCSF
enables successful
PBSC mobilization and
harvesting in the majority
of patients (91%).
An episode of
febrile neutropenia
N=29/1302=2.2%
Severe grade
4 neutropenia
N=104/1302=8.5%
No risk of
immunogenicity with
Zarzio as no antibodies
have been detected to
date demonstrating no
or low potential for an
immunologic response
continued on page 446…
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Revue canadienne de soins infirmiers en oncologie
445
FEATURES/Rubriques
Author
FEATURES/Rubriques
Author
Trial Design
Verpoort & Single centre
retrospective review
Mohler,
from a large community
2012
oncology practice in
Germany
Biosimilar group
N=77
Originator group
N=25
Eligibility
Results
Adult >18y
Biosimilar GCSF
Median age 67y (range
20-83y)
Female 64%
Male 36%
Primary prophylaxis =52%
of patients
Secondary
prophylaxis=48% of
patients
Originator GCSF
Median age 64y (range
31-81y)
Female 64%
Male 36%
Primary prophylaxis =36%
Biosimilar GCSF
Febrile neutropenia=1 pt
Dose reductions=5 pts
(6.5%)
Dose discontinuation=
2 pts (2.5%)
Adverse Events
No unexpected
safety findings
were observed
with the use of
biosimilar GCSF.
However since
this was not
Originator GCSF
a prospective
Febrile neutropenia=1 pt
study, adverse
Dose reductions=2 pts
events were not
(8%)
recorded
Dose discontinuation=
2 pts (8%).
Conclusion
Biosimilar GCSF was
effective and prevented
dose reductions/
discontinuations in the
majority of patients. It is
considered comparable to
the originator Neupogen
for the prevention of
neutropenia in patients
with cancer in routine
clinical practice
All patients had a
confirmed diagnosis of
solid tumor (breast, colon)
cancer or hematologic
malignancy (lymphoma)
and received biosimilar
GCSF during at least
one cycle of combination
chemotherapy
Patients were stratified by
risk of febrile neutropenia
based on the chemo
regimen (>20%, 10-20%,
<10%)
COST
Biosimilar products are used widely
across the European market (Verpoort
& Mohler, 2012). In some cases, biosimilars are used more often than the originator product (Bonig et al., 2015). The
benefit to using biosimilar GCSF Zarzio
is increased affordability and improved
access for a hematopoietic stem cell
transplant program (Verpoort & Mohler,
2012, Bonig et al., 2015). Originally, the
cost of Zarzio was reported as 15% lower
than the originator GCSF (Schmitt et al.,
2014). However, in a 2014 report, Zarzio
was variably reported between 25%
and 86% less in cost than Neupogen
(Bassi et al., 2015; Schmitt et al., 2014;
Verpoort & Mohler, 2012) (see Table
2). The second benefit to using biosimilar GCSF Zarzio over Neupogen is
access (Verpoort & Mohler, 2012). Due
to Zarzio’s affordability, access is easier
(Verpoort & Mohler, 2012) This allows
446
physicians to follow the recommended
European Organization for Research
and Treatment of Cancer (EORTC)
clinical guidelines including wider
use of GCSF as a primary prophylaxis
(Verpoort & Mohler, 2012). It is of note
that global hospitalization costs may not
be significantly impacted by the use of
biosimilars taking into consideration
the total cost of a transplant procedure
(Ianotto et al., 2012).
IMPLICATIONS FOR
CLINICAL PRACTICE
Biosimilar Zarzio formulation comes
in a prefilled syringe (300ug/0.5ml
and 480ug/0.8ml) and is administered
subcutaneously (US Food and Drug
Administration [FDA], 2015). Patient
teaching is expected to take the same
amount of time, as the side effect profile is similar to the originator product
Neupogen. Since the safety, efficacy, and
method of administration are comparable between the two, the change to biosimilar Zarzio does not have great impact
on frontline staff nurses. The greatest implication for clinical practice in a
hematopoietic stem cell program is cost
and access. This is significant to ambulatory clinic nurses and physicians who
grapple with getting approval for cancer treatments due to high costs (Turner
& Associates, 2008). If drugs are more
expensive, in general, they are more difficult to access and have fewer indications
approved for use (Turner & Associates,
2008). According to the EORTC guidelines, both the biosimilar GCSF and the
originator GCSF are recommended for
prevention of febrile neutropenia, but the
choice of which formulation to use is left
with the individual provider (Verpoort &
Mohler, 2012). Due to the high expense
of Neupogen for transplant programs,
health care providers are not using it as
Volume 25, Issue 4, Fall 2015 • Canadian Oncology Nursing Journal
Revue canadienne de soins infirmiers en oncologie
Authors
Zarzio (300ug SC)
Neupogen (300ugSC)
Aapro et al, 2011
€95.45/1day€1336.46/14 days
€128.16/1day€1794.30/14days
Bassi et al, 2015
€10.85/13.50 USD/one vial €77.53/96.65 USD/one vial
Mean cost per pt for one
Mean cost per patient not
total treatment=€76.22
reported
(USD=95)
Scottish Medicines
Consortium, 2011
One course=10d/tx and 5
cycles/course
£3,442/course
£3,047/course
Ianotto et al., 2012
127 €/pt in lymphoma
140€/pt in myeloma
617€/pt in lymphoma
564€/pt in myeloma
127€/pt vs. 42838€
total cost of transplant in
lymphoma
140€/pt vs. 32894€
total cost of transplant in
myeloma.
95€/300ug dose
150€/480ug dose
119€/300ug dose
187€/480ug dose
Lefrere et al., 2011
€=Euro; USD= United States Dollar; pt=patient
widely as its approval would implicate
(Verpoort & Mohler, 2012). If biosimilar Zarzio is less expensive, it could be
argued that it should be easier to access
and, logically, be utilized more widely in
accordance with the EORTC guidelines
(Verpoort & Mohler, 2012). Further, it is
significant to patients who should benefit
if physicians could more widely prescribe
for indications where they may have hesitated before, such as primary prophylaxis
(Verpoort and Mohler, 2012).
CONCLUSION
Although originator GCSF (Neupogen)
is the current drug of choice for stem cell
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