correspondence

Comparison between biosimilar filgrastim vs other granulocyte-colony stimulating factor formulations (originator filgrastim, peg-filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network Since the implementation of a biosimilar approval pathway in 2005, several biosimilars including somatotropins, filgrastims and epoietins have been approved and become available in Europe on the basis of comparable quality, safety and efficacy to the originator product (Weise et al, 2012). However, there is still general skepticism in the scientific community about the safety and efficacy of biosimilar granulocyte-colony stimulating factors (G-CSF). The use of G-CSF as a supportive therapy after autologous haematopoietic stem cell transplantation (ASCT) is able to reduce the time of neutrophilis recovery and the incidence of febrile neutropenia and infectious episodes. For this reason, the American Society of Clinical Oncology (ASCO) and the European Group for Blood and Marrow Transplantation recommended the use of GCSF after ASCT (Smith et al, 2006; Apperley et al, 2008). So far, only limited data have been published regarding the use of biosimilar filgrastim in haematological recovery after ASCT (Ferro et al, 2009; Niederwieser & Schmitz, 2011; Ianotto et al, 2012; Rem
enyi et al, 2014). Despite limitations due to retrospective analyses performed on limited numbers of patients, all these studies suggest a substantially similar efficacy of biosimilar products, when compared to originators for prophylaxis of febrile neutropenia in lymphoma and myeloma patients post-ASCT. From March 2013 to June 2014, our Institution used the biosimilar filgrastim (Zarzio
; Sandoz Industrial Products, Rovereto, Italy), at dosage of 5 lg/kg/d from day +3 after stem cell infusion, for febrile neutropenia prophylaxis and haematological recovery in 64 consecutive adult patients who underwent ASCT. These patients were retrospectively compared with three historical cohorts: (i) 99 consecutive adult patients treated with lenograstim (Myelostim
; Italfarmaco, Milan, Italy) at dosage of 5 lg/kg/d from day +3 after stem cell infusion at our Institution from January 2009 to February 2013; (ii) 60 consecutive adult patients treated with peg-filgrastim (Neulasta
; Amgen, Milan, Italy) at a single dose of 6 mg at day +3 after stem cell infusion at our Institution from March 2006 to December 2008; (iii) 79 consecutive adult patients treated with originator filgrastim (Granulokine
; Amgen) at dosage of 5 lg/kg/d from day +3 after stem cell infusion at the Haematology Unit of Campus Bio-Medico University from May 2008 to June 2014. This study aimed to

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

compare Zarzio
with the other available formulations of G-CSF in terms of efficacy and safety. Baseline features of 302 patients are summarized in Table I. There was no statistically significant difference among the four patient cohorts, despite an higher incidence of lymphomas in the group of patients treated with Neulasta
(P = 0
074). In particular, the number of infused CD34+ cells was similar in each cohort (P = 0
834). We analysed the period of haematological recovery after stem cell infusion (defined as an absolute neutrophilis count >0
5 9 109/l and a platelet count >20 9 109/l for three consecutive checks), the occurrence of fever of unknown origin (FUO) in neutropenia, documented infectious episodes and need of intravenous antibiotic treatment, number of red blood and platelet transfusions, days of hospitalization and transplant-related mortality (TRM). The results of the study are shown in Table II. We observed a significantly shorter time to neutrophilis and platelet recovery (P = 0
001 and P = 0
007, respectively) with a consequent lower median number of platelet transfusions (P = 0
001) in the cohort of patients treated with Neulasta
, whereas no difference was observed among the other three groups. Moreover, we did not observe any significant difference among the four patient cohorts for all the other analysed parameters, despite a trend for a shorter period of hospitalization in the patients treated with Zarzio
and Neulasta
(P = 0
095). No difference in terms of drug-related adverse events was observed in the four patient cohorts with no serious adverse events. Similar results were obtained when two separate subanalyses including only lymphoma or myeloma patients were performed (data not shown). Our study shows that biosimilar filgrastim (Zarzio
) has similar efficacy and safety when compared with the other non-peghylated G-CSF formulations in febrile neutropenia prophylaxis and haematological recovery after ASCT. These data confirm previous published evidence that supports the non-inferiority of biosimilar filgrastim in this setting (Ferro et al, 2009; Niederwieser & Schmitz, 2011; Ianotto et al, 2012; Rem
enyi et al, 2014). Moreover, although some preclinical studies highlighted the better efficacy of neutrophilis after stimulation with lenograstim than filgrastim (Ribeiro et al, 2007), we did not find any significant difference between glycosylated and not-glycosylated G-CSF formulations regarding

doi: 10.1111/bjh.13199

Correspondence Table I. Baseline features of 302 patients, according to the received G-CSF formulation.

Parameter Sex, male/female Age, years, median (range) Diagnosis (%) MM NHL/HL ALL Chemotherapy lines prior to ASCT, median (range) Disease status at ASCT (%) CR PR SD/PD Conditioning chemotherapy (%) MEL200/MEL100 BEAM/BEAC/FEAM Others* Infused CD34+ cells, 9 106/kg, median (range)

ZARZIO
N = 64

MYELOSTIM
N = 99

NEULASTA
N = 60

34/30 57 (19–72)

62/37 55 (19–69)

36/24 56 (18–71)

57/22 55 (19–69)

0
127 0
487

41 21 2 1

(64
1) (32
8) (3
1) (1–4)

65 (65
7) 34 (34
3) 0 2 (1–4)

26 (43
3) 34 (56
7) 0 2 (1–4)

50 (63
3) 29 (36
7) 0 1 (1–4)

0
074

33 (52
4) 24 (38
1) 6 (9
5)

63 (63
6) 34 (34
3) 2 (2)

38 (63
3) 21 (35) 1 (1
7)

47 (59
5) 24 (30
4) 8 (10
1)

0
911

42 19 3 5
67

(65
6) (29
7) (4
7) (2
3–14
2)

65 32 2 5
52

(65
7) (32
2) (2) (3
3–14
5)

26 32 2 5
42

(43
3) (53
3) (3
3) (2
9–14
4)

GRANULOKINE
N = 79

51 22 6 6
03

(64
6) (27
8) (7
6) (1
5–12
6)

P

0
242

0
077

0
834

MM, multiple myeloma; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; ALL, acute lymphoblastic leukaemia; ASCT, autologous stem cell transplantation; CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease; MEL, melphalan; BEAM, Carmustine, Etoposide, Cytarabine, Melphalan; BEAC, Carmustine, Etoposide, Cytarabine, Cyclophosphamide; FEAM, Fotemustine, Etoposide, Cytarabine, Melphalan. *BeEAM: Bendamustine, Etoposide, Cytarabine, Melphalan; MITO-MEL: Mitoxantrone, Melphalan; BU-MEL: Busulfan, Melphalan.

Table II. Clinical results of 302 patients, according to the received G-CSF formulation.

Results

ZARZIO
N = 64

MYELOSTIM
N = 99

Haematological recovery, days (range) ANC >0
5 9 109/l PLT >20 x109/l G-CSF injections, days, median (range) FUO episodes in neutropenia, n (%) Microbiologically-documented infections, n (%) Needed intravenous antibiotics, n (%) Number of RBC transfusions, mean  SD Number of PLT transfusions, median (range) Hospitalization duration, days, median (range) TRM (%)

11 (8–19) 14 (9–120) 9 (7–17) 8 (15
4) 23 (35
9) 31 (51
3) 0
33  0
778 2 (0–7) 21 (15–49) 0

11 (9–29) 14 (10–35) 9 (4–26) 10 (10
1) 43 (43
4) 53 (53
5) 0
78  1
475 2 (0–12) 24 (15–68) 2%

NEULASTA
N = 60

10 (8–18) 12 (9–23) 13 (21
7) 19 (31
7) 32 (53
3) 0
44  0
952 1 (0–6) 21 (6–29) 1
7%

GRANULOKINE
N = 79

P

11 (9–25) 14 (10–100) 10 (5–24) 21 (26
6) 29 (36
7) 50 (63
2) 1
21  1
871 2 (0–11) 23 (15–40) 2
5%

0
001 0
007 0
354 0
097 0
488 0
606 0
121 0
001 0
095 0
675

RBC, red blood cells; PLT, platelet count; ANC, absolute neutrophil count; FUO, fever of unknown origin; TRM, transplant-related mortality; SD, standard deviation. Bold values indicate statistically significant P values.

FUO in neutropenia and occurrence of infections, according to the current ASCO guidelines (Smith et al, 2006) and European Organization for Research and Treatment of Cancer (Aapro et al, 2011). Some recently published data also showed that peg-filgrastim presents similar efficacy and safety profiles when compared with non-pegylated formulations after ASCT (Sebban et al, 2012). Despite the limitation due to its retrospective nature, our study suggests a significantly better time to neutrophilis and platelet recovery in patients treated with peg-filgrastim (Neulasta
). However, this superiority does not determine a better outcome in terms of FUO in neutropenia 2

and infectious episodes, duration of hospitalization and TRM, but only a significant decrease in platelet transfusions. Biosimilar products are characterized by a different method of synthesis compared to originators, because they utilize bacterial support (Weise et al, 2012). This method induces some modifications of the molecules but permits generation of a final product similar to the originator drug with a significant limitation of the costs. Based on this premise, we also analysed the costs relative to G-CSF administration. Considering the median days of G-CSF injections and assuming a patient median body weight of 60 kg, the estimated cost for each patient was significantly lower in the ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Correspondence Zarzio
group (approximately 73€) when compared with the other groups (approximately 732€ for Myelostim
, 649€ for Granulokine
and 660€ for Neulasta
; P < 0
0001). In conclusion, our retrospective analysis indicates that biosimilar filgrastim (Zarzio
) seems to be substantially equivalent in terms of efficacy and safety to other G-CSF formulations when used for febrile neutropenia prophylaxis and haematological recovery after ASCT in adult patients with haematological malignancies. However, the use of biosimilar filgrastim results in significantly lower costs in this setting. Further prospective randomized studies are warranted to confirm these results.

Acknowledgements We thanks Mrs. Caterina Viggiani for data collection about hospitalization duration.

F.P., F.P., A.R., A.S., L.P., O.A., A.L.M.; data analysis and interpretation: F.M., A.M.; manuscript writing: F.M.; final critical revision of the manuscript: W.A., A.M. Francesco Marchesi1 Elisabetta Cerchiara2 Maria Laura Dessanti1 Svitlana Gumenyuk1 Luca Franceschini3 Francesca Palombi1 Francesco Pisani1 Atelda Romano1 Antonio Spadea1 Livio Pupo3 Ombretta Annibali2 Antonella La Malfa4 William Arcese3,5 Andrea Mengarelli1 1

Haematology and Stem Cell Transplantation Unit, Regina Elena

National Cancer Institute, 2Haematology Unit, Campus Bio-Medico

Conflict of interest

University, 3Haematology Unit, Tor Vergata University, 4Pharmacy

The authors declare no financial or other potential conflicts of interest.

Unit, Regina Elena National Cancer Institute, and 5Rome Transplant Network, Rome, Italy E-mail: [email protected]

Author’s contributions Concept and design of the study: F.M., A.M.; clinical management and data collection: F.M., E.C., M.L.D., S.G., L.F.,

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