1. Tbo-filgrastim for Neutrophil Count Recovery Following Acute Myeloid Leukemia Induction Therapy and Melphalan Conditioning in Autologous Hematopoietic Stem Cell Transplantation
NJSHP Residency Forum
June 9, 2016
Binni M. Kunvarjee, PharmD
PGY-1 Pharmacy Resident
Hackensack University Medical Center
Hackensack, NJ

2. Granulocyte-Colony Stimulating Factor
Used to reduce duration of severe neutropenia in patients receiving myelosuppresive chemotherapy
Stimulates proliferation of neutrophil progenitor cells and promotes their differentiation
Causes premature release of neutrophils from bone marrow
Short Acting Granulocyte-Colony Stimulating Factors (G-CSF)
Filgrastim (Neupogen®)
Tbo-filgrastim (Granix®)
Filgrastim-sndz (Zarxio®)
Let’s begin with an introduction to G-CSF. It is a recombinant form the glycoprotein that work to promote proliferation, differentiation of mature granulocytes from the bone marrow and hematopoietic stem cells. Currently the three short-acting formulations are filgrastim, tbo-filgrastim, and the recently approved biosimilar filgrastim-sndz.
Benett Cl, et al. N Engl J Med. 2013; 386:
Metcalf D, et al. Nature. 2010; 10:

3. Guideline Recommendations
Primary prophylaxis for adult patients with solid tumors and myeloid malignancies
Risk based on disease state & chemotherapy regimen
CHEMOTHERAPY INTENT
Curative/Adjuvant
Prolong Survival/QOL
Symptom Management/QOL
CHEMOTHERAPY RISK OF FEBRILE NEUTROPENIA
High (>20%)
CSF
(Category I for G-CSF)
Intermediate (10-20%)
Consider CSF
Low (<10%)
No CSF
NCCN and ASCO provided recommendation on the use of colony stimulating factors in adult patients with solid tumors and myeloid malignancies. In this table, you see that the recommendation for primary prophylaxis is determined by a number of factors, however the recommendation to use G-CSF is consistent for patients with a high risk of febrile neutropenia.
Smith TJ, et al. J Clin Oncol. 2015; 33: 1-14.
NCCN. Myeloid growth factors. V
QOL = quality of life; CSF = colony stimulating factor

4. Febrile Neutropenia Major dose-limiting toxicity
Occurs in 25-40% of treatment-naïve patients
Chemotherapy-induced leukopenia causes induction of endogenous cytokines (IL-6, TNF) which results in fever in absence of infection
Documented infection occurs in 20-30% of patients
Mortality higher for gram-negative (18%) versus gram-positive (5%) bacteremia
Febrile neutropenia is one of the major-dose limiting toxicities of chemotherapy which occurs in up to 40% of all treatment-naïve patients
The leukopenia-induced fever can occur even in the absence of infection, however documented infections which occur in roughly a quarter of the patients can have large impacts on the morbidity and mortality.
Smith TJ, et al. J Clin Oncol. 2015; 33: 1-14.
Freifeld AG, et al. Clin Infec Dis. 2011; 52: e56-93.
Benett Cl, et al. N Engl J Med. 2013; 386:

5. Filgrastim, filgrastim-sndz
Approved Indications
Filgrastim, filgrastim-sndz
(Neupogen®, Zarxio®)
Non-myeloid malignancies
Acute myeloid leukemia
Hematopoietic stem cell transplant
Peripheral blood progenitor cell mobilization
Acute hematopoietic radiation injury syndrome
Severe chronic neutropenia
Tbo-filgrastim
(Granix®)
Listed here are the current FDA-approved indications for the three short-acting agents. Zarxio, as biosimilar shares all the same indications as the originator product, including use in solid tumors, myeloid malignancies, and progenitor cell mobilization. Meanwhile tbo-filgrastim, which is a competitive biologic product to filgrastim is only approved for use in non-myeloid malignancies.
Neupogen [package insert]. Thousand Islands, CA: Amgen, Inc
Granix [package insert]. North Wales, PA: Cephalon, Inc

6. Product Comparison Filgrastim Tbo-filgrastim Product
Non-glycosylated, recombinant, methionyl form of human G-CSF from E. coli
Approval
1991
2012
Dose
5 mcg/kg SQ or IV daily
5 mcg/kg SQ daily
Onset
1-2 days
3-5 days
Time to peak
2-8 hours
4-6 hours
Half-life
~3.5 hours
hours
Bioavailability
SubQ: 60% to 70%
SubQ: 33%
Approval for pediatric use
Yes No
Filgrastim and tbo-filgrastim are both non-glycosylated forms of G-CSF produced in the bacteria E. coli. Filgrastim was originally approved in 1991 and tbo-filgrastim in Both are administered at the same dose of 5 mcg/kg daily. Additionally, the PK parameters, shown here, are similar for both products.
Neupogen [package insert]. Thousand Islands, CA: Amgen, Inc
Granix [package insert]. North Wales, PA: Cephalon, Inc

7. Previous Trials Study Population Results del Giglio A, et al 2008
Stage II, III, IV breast cancer
(n=348)
Duration of severe neutropenia was not significantly different in groups receiving
tbo-filgrastim versus filgrastim
Gatzemeier U, et al
2009
Non-small cell lung cancer
(n=240)
Engert A, et al
Aggressive non-Hodgkin’s lymphoma
(n=92)
Tbo-filgrastim was originally only studied in high risk breast cancer, non-small cell lung cancer, and non-Hodgkin’s lymphoma. In all three of these studies, the efficacy of tbo filgrastim, as evaluated by the primary outcome of duration of severe neutropenia was not significantly different than that of filgrastim.
Gatzemeier U, et al. J Thor Oncol. 2009; 4(6):
del Giglio A, et al. BMC Cancer. 2008; 8(332): 1-7.
Engert A, et al. Leuk Lymphoma. 2009; 50(3):
Engert A, et al. Onkologie. 2009; 32:

8. Study Rationale
Clinical trials for tbo-filgrastim efficacy & safety are in patients with lung cancer, breast cancer, and non-Hodgkin’s lymphoma limiting the use of tbo-filgrastim to non-myeloid malignancies
Lack of data in AML patients and HSCT patients limits the use of tbo-filgrastim to non-myeloid malignancies
Tbo-filgrastim was incorporated in the management of all adult oncology inpatients at HackensackUMC beginning January 2014
Due to the studies that were just presented, and the lack of data in myeloid malignancies and HSCT patients, the indication of tbo-filgrastim is currently limited to non-myeloid malignancies. Because it is not technically a biosilimiar, and slight differences in that may occurs in manufacturing process of the protein, there has been hesitancy to use this product for these off-label indications. Due to the similar efficacy, safety, and PK compared to filgrastim demonstrated in these studies, tbo-filgrastim was incorporated into the management of all adult oncology inpatients at our institution in January Now following this change in practice, we wanted to evaluate the efficacy of this product with that of filgrastim.

9. Study Objective Cohort Cohort 2 1
Compare the efficacy of tbo-filgrastim to filgrastim in patients with myeloid malignancies
Cohort 1
AML patients receiving induction chemotherapy
Cohort 2
Multiple myeloma patients receiving autologous HSCT with melphalan conditioning regimen
The objective of the study was to compare the efficacy of tbo-filgrastim to filgrastim in two distinct populations. Our first cohort of patient were those receiving induction therapy for AML and out second cohort were multiple myeloma patients undergoing autologous stem cell transplantation with melphalan condition.

10. Study Design Retrospective chart review
January 2012-December 2015
Epic® generated report of filgrastim and tbo-filgrastim orders for adult inpatients with diagnosis codes
List of expected HSCT admissions
IRB approved
Hackensack University Medical Center
775 bed hospital
4 oncology units (~75 beds)
Among the top 10 HSCT centers in the US by volume
The study was a retrospective chart review of patients admitted between Jan 2012-Dec I used an Epic generated report of medication orders as will as a list of expected HSCT admissions to identify patients.
As an institution Hackensack UMC is a…

11. Inclusion Criteria AML Autologous HSCT ≥ 18 years of age
Diagnosis of de-novo or secondary AML
Received induction therapy with standard “7+3” regimen
Idarubicin 12 mg/m2 on days 1-3 & cytarabine 100 mg/m2 on days 1-7
Dose adjusted “7+3” regimen
Receipt of filgrastim or tbo-filgrastim mcg/kg/day after day 14 bone marrow is negative for residual leukemia until recovery (ANC > 1000/mm3)
 ≥ 18 years of age
Diagnosis of multiple myeloma
Received an autologous hematopoietic stem cell transplant
Received conditioning therapy with melphalan 200 mg/m2 or 140 mg/m2 on Day -1
Receipt of filgrastim or tbo-filgrastim mcg/kg/day on day +3, day +5, day +7, and daily starting on day +9 until engraftment (ANC > 500/mm3)
ANC= absolute neutrophil count

12. Exclusion Criteria AML Autologous HSCT
Diagnosis of acute promeyelocytic leukemia
Previous treatment for AML or any other malignancy
Requiring re-induction therapy during same admission
Previous treatment for any other malignancy other than multiple myeloma
Receipt of G-CSF for reasons other than neutrophil recovery post chemotherapy
(i.e. support with ganciclovir therapy, treatment of febrile neutropenia)

13. Endpoints Primary Duration of severe neutropenia (ANC < 500/mm3)
Secondary
Time to ANC recovery (days)
Incidence of febrile neutropenia (%)
Incidence of documented infection (%)
Duration of IV antibiotic use (days)

14. Patients Screened 329 AML patients screened from medication report
284 patients excluded
20 patients received filgrastim
25 patients received tbo-filgrastim
148 auto-HSCT patients screened from transplant admission list
68 patients
excluded
40 patients received filgrastim
40 patients received tbo-filgrastim
Reasons for exclusion:
AML
Did not receive (admitted for salvage therapy)
Re-induction during same admission
On trial (i.e. hedgehog inhibitor)
Receipt of ATRA
AutoHSCT
Outpatient transplant
On study (i.e. Mel/Vel)
Received combination of Neupogen/Granix/Leukine

15. Baseline Characteristics AML Induction Therapy
Filgrastim (n = 20)
Tbo-Filgrastim (n = 25)
p-value
Age (mean, yrs) 55 52
0.537
Gender (n, % male)
10 (50)
12(48) 
0.893 
Race
White 15 18
Black 3 1
Hispanic
Other 2
Weight (mean, kg)
85.65
81.70
0.467
BSA (mean, m2)
1.99
1.95
0.552
Cytogenetic Risk 
Favorable 11
Intermediate 5
Poor 9
ECOG 16 20 ≥2
Not assessed
G-CSF Dose
300 mcg
480 mcg 22
Day 1 WBC (x103/mcL)
23.72
26.16
0.819
Day 1 ANC (x103/mcL)
3.48
4.12
0.693
We will review each cohort individually.
Here are the baseline characteristic for patient receiving AML induction therapy. There is no significant differences in demographics.

16. Baseline Characteristics AML Induction Therapy
Filgrastim (n = 20)
Tbo-Filgrastim (n = 25)
p-value
Age (mean, yrs) 55 52
0.537
Gender (n, % male)
10 (50)
12(48) 
0.893 
Race
White 15 18
Black 3 1
Hispanic
Other 2
Weight (mean, kg)
85.65
81.70
0.467
BSA (mean, m2)
1.99
1.95
0.552
Cytogenetic Risk 
Favorable 11
Intermediate 5
Poor 9
ECOG 16 20 ≥2
Not assessed
G-CSF Dose
300 mcg
480 mcg 22
Day 1 WBC (x103/mcL)
23.72
26.16
0.819
Day 1 ANC (x103/mcL)
3.48
4.12
0.693
The average age for both groups is around 53 years, and most patients received the higher weight based dose of 480 mcg.

17. Duration of Severe Neutropenia AML Induction Therapy
For our primary endpoint, there was an average of days of severe neutropenia in patients receiving filgrastim and days in patients receiving tbo-filgrastim. This difference was not significant with a p value of 0.869

18. Time to ANC Recovery AML Induction Therapy
This graph represents the probability of count recovery, shown on the y-axis, on any given day from start of induction therapy (on the x-axis). 50% of patients in both groups recovered counts by day 23 and > 90% by day 28. The average time to count recovery was 23.6 days in the filgrastim group compared to 24.3 in the tbo-filgrastim group and this difference was not significant.
Filgrastim (n = 20)
Tbo-filgrastim (n = 25) p
Days to ANC Recovery (mean)
23.6
24.3
0.381

19. Secondary Outcomes AML Induction Therapy
For the secondary endpoints, the incidence of febrile neutropenia, incidence of documented infection, and total duration of IV antibiotic use demonstrated no significant differences between patients receiving filgrastim vs tbo figrastim. A majority of patients developed febrile neutropenia, however a lower percent had a documented infection, 25% in the filgrastim group and 8% in the tbo-filgrastim group. Both groups had an average duration of IV antibiotic use of approximately 21 days.
Filgrastim (n = 20)
Tbo-filgrastim (n = 25) p
Days of IV antibiotic therapy (mean)
20.9
20.7
0.932

20. Baseline Characteristics Autologous HSCT
Filgrastim
(n = 40)
Tbo-Filgrastim
p-value
Age (mean, yr) 63 62
0.443
Gender (% male)
47.5
45.0
0.825
Race  
White 22 2
Black 5 6
Hispanic 3 4
Other 10
Weight (mean, kg)
78.9
84.6
0.157
BSA (mean, m2)
1.90
1.95
0.373
Durie-Salmon Stage  1 9 7 28 24
Not Specified
Cytogenetics 
High Risk 8
Standard or Low Risk 12
Unknown 20 19
Filgrastim
(n = 40)
Tbo-Filgrastim
p-value
KPS  
≤ 70 35 32
71-80 3 5
81-90 1
Not assessed
Stem Cell Dose (CD34 e6/kg)
6.23
5.35
0.089
Mobilizing Regimen 
CDE 31 28
Filgrastim + Plerixafor 4 11
VDT/R-PACE
Melphalan Dose
140 mg/m2 2
200 mg/m2 38 40
G-CSF Dose 
300 mcg 7
480 mcg 33 29
Admission WBC (x 103/mcL)
5.15
4.85
0.449
Admission ANC (x 103/mcL)
3.80
3.47
0.382
Moving on to the autologous HSCT cohort.
Here are the baseline characteristics. Again, there is no significant differences in demographics.

21. Baseline Characteristics Autologous HSCT
Filgrastim
(n = 40)
Tbo-Filgrastim
p-value
Age (mean, yr) 63 62
0.443
Gender (% male)
47.5
45.0
0.825
Race  
White 22 2
Black 5 6
Hispanic 3 4
Other 10
Weight (mean, kg)
78.9
84.6
0.157
BSA (mean, m2)
1.90
1.95
0.373
Durie-Salmon Stage  1 9 7 28 24
Not Specified
Cytogenetics 
High Risk 8
Standard or Low Risk 12
Unknown 20 19
Filgrastim
(n = 40)
Tbo-Filgrastim
p-value
KPS  
≤ 70 35 32
71-80 3 5
81-90 1
Not assessed
Stem Cell Dose (CD34 e6/kg)
6.23
5.35
0.089
Mobilizing Regimen 
CDE 31 28
Filgrastim + Plerixafor 4 11
VDT/R-PACE
Melphalan Dose
140 mg/m2 2
200 mg/m2 38 40
G-CSF Dose 
300 mcg 7
480 mcg 33 29
Admission WBC (x 103/mcL)
5.15
4.85
0.449
Admission ANC (x 103/mcL)
3.80
3.47
0.382
The mean age was approximately 63 years. The stem cell dose transplanted was comparable for both groups. Most patients received a melphalan dose of 200 mg/m2 and a G-CSF dose of 480 mcg.

22. Duration of Severe Neutropenia Autologous HSCT
For our primary endpoint, there was an average of 4.85 days of severe neutropenia in patients receiving filgrastim and 5.08 days in patients receiving tbo-filgrastim. This difference was not significant with a p value of 0.304

23. Time to Engraftment Autologous HSCT
In our autologous HSCT group, 50% of patients in both groups recovered counts by day 11 and > 90% by day 13. The average time to count recovery was days in the filgrastim group compared to in the tbo-filgrastim group and this difference was not significant.
Filgrastim (n = 40)
Tbo-filgrastim (n = 40) p
Days to ANC recovery (mean)
11.27
11.57
0.097

24. Secondary Outcomes Autologous HSCT
P= 0.259
P= 0.761
For the secondary endpoints, the incidence of febrile neutropenia, incidence of documented infection, and total duration of IV antibiotic use demonstrated no significant differences between patients receiving filgrastim vs tbo figrastim. The two groups had an average duration of IV antibiotic use of 1.97 and 3.15 days, respectively.
Filgrastim (n = 40)
Tbo-filgrastim (n = 40) p
Days of IV antibiotic therapy (mean)
1.97
3.15
0.101

25. Incidence of Bone Pain AML Auto HSCT Filgrastim 2/20 (10%) 2/40 (5%)
Tbo-filgrastim
7/25 (28%)
0/40 (0%)
p-value
0.133
0.152
The incidence of bone pain related to G-CSF use was evaluated as our safety endpoint. The first graph shows the incidence for both products in each population cohort, for which no significant differences were noted.
The overall incidence of bone pain was 6% for filgrastim and 11% for tbo-filgrastim.
Overall Incidence
Filgrastim (n = 60) 6%
Tbo-filgrastim (n = 65)
11%

26. Study Limitations Retrospective chart review Small sample size
Patients who were discharged before they met definition of ANC recovery were included in the study
Days of IV antibiotic administration prior to start of chemotherapy were counted
G-CSF standard of practice for AML and HSCT may differ from those utilized at other institutions

27. Conclusion
There is no statistically significant difference in duration of severe neutropenia between tbo-filgrastim and filgrastim, when used for neutrophil count recovery in the AML induction population and melphalan autologous HSCT population
Results are similar to a recent study evaluating use of tbo-filgrastim in autologous HSCT patients
First study to our knowledge to compare the efficacy of tbo-filgrastim to filgrastim in AML patients
Trifilio S, et al. Clin Transplant. 2015: 29: 1128–1132.

28. Active Learning Question
Which of the following statements is true for the HSCT population?
There is an average of 5 days of severe neutropenia with both G-CSF products
There is a significant increase in days of severe neutropenia when using tbo-filgrastim versus fillgrastim
There is a significant decrease in days of severe neutropenia when using tbo-filgrastim versus filgrastim
G-CSF is used for treatment of febrile neutropenia in HSCT patients

29. Acknowledgments Christina Howlett, PharmD, BCOP
Maribel A. Pereiras, PharmD, BCPS, BCOP
Scott Rowley, MD, FACP
I would like to thank Drs. Howlett, Pereiras, and Rowley for all of their help on this project.

30. Tbo-filgrastim for Neutrophil Count Recovery Following AML Induction Therapy and Melphalan Conditioning in Autologous HSCT
NJSHP Residency Forum
June 9, 2016
Binni M. Kunvarjee, PharmD
PGY-1 Pharmacy Resident
Hackensack University Medical Center
Hackensack, NJ
Thank you! I will be glad to take any questions at this time.