Biosimilar filgrastim (Zarzio^®) vs. lenograstim (Myelostim^®) for peripheral blood stem cell mobilization in adult patients with lymphoma and myeloma: a single center experience

The combination of chemotherapy and granulocyte-colony stimulating factor (G-CSF) in patients with hematologic malignancies is considered the best regimen to mobilize peripheral blood hematopoietic stem cells (PBSC). Lenograstim and filgrastim, the glycosylated and non-glycosylated form of recombinant human G-CSF, are both approved in Western countries for PBSC mobilization, with a recommended daily dose of at least 5 μg/kg body weight (b.w.) [1]. Data from the comparison between lenograstim and originator filgrastim in PBSC mobilization are so far not conclusive in the autologous setting [2–5], suggesting a substantial uniformity in retrospective [2] and randomized [3] studies, but also a greater efficacy of lenograstim in other randomized [4] and retrospective [5] published reports. Since the implementation of a biosimilar approval pathway in 2005, several biosimilars of filgrastim have become available in Europe on the basis of comparable quality, safety and efficacy as the originator product in any of the approved indications. However, biosimilar filgrastim is still regarded with general skepticism by the scientific community in this type of setting and its use is not recommended in the current guidelines of the American Society for Blood and Marrow Transplantation (ASBMT) [1]. So far, the published data from prospective randomized [6,7] and retrospective studies [8–11] about the use of biosimilar filgrastim in comparison with the originator one for the PBSC mobilization in the autologous setting, suggest a substantially similar efficacy and safety. Yet, to our knowledge, only one retrospective study has compared lenograstim with biosimilar filgrastim in patients with hematologic malignancies undergoing PBSC mobilization, indicating no greater efficacy of lenograstim over filgrastim [8]. In the present non-randomized single-center study, we compared the efficacy and safety of biosimilar filgrastim with lenograstim utilized at the same dosage for PBSC mobilization in 97 consecutive patients with lymphoma (n = 54) and myeloma (n = 43). The dose of G-CSF was established on the basis of our previous experience indicating that 5 and 10 μg/kg/day were the optimal dose to reach a CD34 + cell collection dose of at least 4 and 8 × 10⁶/kg, for lymphoma and myeloma patients respectively [12]. Therefore, we used a dose of 5 μg/kg/day for lymphoma patients with a harvest target of 4 × 10⁶ CD34+/Kg (single transplant), and of 10 μg/kg/day for myeloma patients with a target of 8 × 10⁶ CD34+/Kg (double transplant). Twenty-eight consecutive adult lymphoma and 23 myeloma patients underwent PBSC mobilization after administration of chemotherapy plus lenograstim (Myelostim^®, Italfarmaco Spa, Milan, Italy) at the daily dose of 5 and 10 μg/kg respectively from March 2011 to February 2013, and were compared with 26 consecutive adult lymphoma and 20 myeloma patients who underwent PBSC mobilization after administration of chemotherapy plus biosimilar filgrastim (Zarzio^®, Sandoz Industrial Products Spa, Rovereto, Italy) at the same dosage from March 2013 (date on which the regional regulatory authority recommended the use of biosimilar filgrastim in all the approved indications for purposes of spending review) to February 2015. All patients had signed an informed consent granting the use of sensitive data for scientific purposes.

Biosimilar filgrastim and lenograstim were administered subcutaneously as a single dose at a daily dosage of 5 μg/kg and 10 μg/kg starting on day + 1 and + 5 from the chemotherapy, for lymphoma and myeloma, respectively. When the white blood cell (WBC) count returned to at least 1 × 10⁹/L, for each patient circulating CD34 + cells were measured by flow cytometry every day until the number of these cells was considered adequate. The threshold of circulating CD34 + cells for starting leukapheresis was of 20 × 10⁶/L. Proven “poor mobilizers” were defined as patients with a peak of CD34 + circulating cell count ≤ 20 × 10⁶/L up to 20 days after chemotherapy and G-CSF, according to published criteria [13,14]. In our study, patients with a peak (daily monitoring) of circulating CD34 + cells between 5 and 20 × 10⁶/L were considered eligible for “on-demand” plerixafor administration in adjunction to G-CSF (0.24 mg/kg/day 6 hours before leukapheresis), whereas patients with a peak of circulating CD34 + cells lower than 5 × 10⁶/L for three consecutive days were considered not eligible for “on-demand” plerixafor. The target dose of CD34 + cells to be harvested was at least 4 and 8 × 10⁶/kg for lymphoma and myeloma, respectively. The continuous-flow device used for leukapheresis was Fresenius COMTEC (Fresenius KABI AG, Bad Homburg, Germany). The apheresis product obtained was analyzed for the count of CD34 cells by flow cytometry and then cryopreserved within 24 hours from harvest in a 10% dimethyl sulfoxide solution and stored in vapor or liquid nitrogen at temperature lower than − 150°C. Data were analyzed by Statistical Package of Social Sciences software (SPSS, version 17.0, Chicago, USA). Baseline characteristics and PBSC collection data of the two cohorts of patients were compared using the chi-square test and the analysis of variance for dichotomous and continuous variables, respectively. Two-sided p-values ≤ 0.05 were considered as statistically significant. The two cohorts of patients were absolutely comparable for all the considered baseline characteristics for both diagnosis subsets (Table I). Table II shows the PBSC collection data in myeloma and lymphoma patients. Among myeloma patients, we did not observe any statistically significant differences in all the analyzed PBSC collection parameters between the two cohorts. In the contrast, among lymphoma patients, in the lenograstim cohort, we observed a significantly higher rate of patients achieving the required CD34 + cell collection target dose [27/28 (96%) vs. 19/26 (73%); p = 0.022] and an adequate number of circulating CD34 + cells at peak (≥ 20 × 10⁶/L) [26/28 (92%) vs. 19/26 (73%); p = 0.047], and a lower rate of “poor mobilizer” patients needing “on-demand” plerixafor administration in order to reach a sufficient number of circulating CD34 + cells [1/28 (4%) vs. 5/26 (19%); p = 0.05]. The rate of mobilization failures was similar between the two cohorts of patients [1/28 (4%) vs. 2/26 (8%); p = 0.604]. None of myeloma and lymphoma patients treated with plerixafor failed the PBSC collection. Overall, regardless of myeloma or lymphoma diagnosis, all patients undergoing apheresis not achieving the required CD34 + cell collection target dose were in any case able to harvest more than 2 × 10⁶ CD34 + cells/kg b.w. Of the nine lymphoma “poor mobilizer” patients, one patient had a diagnosis of Hodgkin lymphoma (HL), whereas the remaining eight had non-Hodgkin lymphoma (NHL). The median age was 55 years, median number of previous received chemotherapy lines was two and only one patient received a radiotherapy prior mobilization.

Table I. Baseline characteristics of 97 patients according to received G-CSF formulation.

Parameter	Lymphoma			Myeloma
	Lenograstim (n = 28)	Biosimilar filgrastim (n = 26)	p	Lenograstim (n = 23)	Biosimilar filgrastim (n = 20)	p
Median age at mobilization (range)	49 (18 − 69)	51 (25 − 66)	0.296	57 (40 − 66)	57 (51 − 69)	0.952
Sex (M/F)	14/14	12/14	0.793	12/11	11/9	0.883
Diagnosis  NHL  HL	21 (75%) 7 (25%)	23 (88%) 3 (12%)	0.295	−	−	−
Bone marrow involvement at mobilization	1 (4%)	1 (4%)	1	3 (13%)	1 (5%)	0.335
Mobilization  First-line  Salvage	4 (14%) 24 (86%)	10 (39%) 16 (61%)	0.093	23 (100%) 0	20 (100%) 0	1
Median lines of chemotherapy previous mobilization (range)	2 (1 − 3)	2 (1 − 2)	0.939	1	1	1
Radiotherapy previous mobilization	3 (11%)	0	0.237	0	0	−
Median kg body weight (range)	75 (51 − 110)	72 (50 − 120)	0.606	76 (52 − 101)	74 (54 − 103)	0.789
Mobilization chemotherapy*  HD-Cytarabine-based  HD-Ifosfamide-based  HD-Cyclophosphamide and others^†	8 (29%) 14 (50%) 6 (21%)	10 (39%) 11 (42%) 5 (19%)	0.214	0 0 23 (100%)	0 0 20 (100%)	1

NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; HD, high-dose

*Rituximab was administered in association with chemotherapy in CD20 + B-cell lymphomas.

^†Others: BEACOPP, Bendamustine.

Table II. PBSC collection data according to received G-CSF formulation in lymphoma patients.

Parameter	Lymphoma			Myeloma
	Lenograstim (n = 28)	Biosimilar filgrastim (n = 26)	p	Lenograstim (n = 23)	Biosimilar filgrastim (n = 20)	p
Median days of G-CSF administration (range)	8 (6–15)	8 (5–16)	0.884	8 (6–16)	8 (6–11)	0.954
Median peak of WBC (x 10^9/L) (range)	17 (7.4–23.4)	15.7 (4.6–53.4)	0.438	16.1 (5.8–41.4)	18.6 (8.3–51.2)	0.538
Median peak of mobilized PB CD34 + cells (x 10^6/L) (range)	80 (0–267)	66 (1–332)	0.979	98 (25–428)	126 (1–798)	0.479
No. of patients with peak of mobilized PB CD34 + cells (x10^6/L) under G-CSF:  < 5 (no apheresis)  5–19 (plerixafor + G-CSF → apheresis)  ≥ 20	1 (4%) 1 (4%) 26 (92%)	2 (8%) 5 (19%) 19 (73%)	0.09	0 0 23 (100%)	1 (5%) 1 (5%) 18 (90%)	0.269
No. of patients with peak of mobilized PB CD34 + cells (x 10^6/L) under G-CSF:  < 20  ≥ 20	2 (8%) 26 (92%)	7 (27%) 19 (73%)	0.047	0 23 (100%)	2 (10%) 18 (90%)	0.226
No. of mobilization failures (“non mobilizers”)	1 (4%)	2 (8%)	0.604	0	1 (5%)	0.331
No. of patients needing “on demand” plerixafor (“poor mobilizers”)	1 (4%)	5 (19%)	0.050	0	1 (5%)	0.331
Median no. of collected CD34 + cells x 10^6/kg (range)	6.3 (4–18.5)	7.2 (2.8–16.7)	0.830	10.7 (5.8–21.8)	14.3 (8.3–45.7)	0.465
Mean no. of leukapheresis (± SD)	1.32 (± 0.56)	1.25 (± 0.52)	0.714	1.3 (± 0.55)	1.25 (± 0.48)	0.798
No. of patients achieving the CD34 + cell target dose – ITT population	27 (96%)	19 (73%)	0.022	21 (91%)	19 (95%)	0.845
Hematological recovery after first ASCT	n = 22	n = 24	p	n = 21	n = 15	p
Days to ANC > 500/mcL	11 (8–21)	12 (10–30)	0.095	11 (9–21)	12 (10–21)	0.351
Days to PLT > 20.000/mcL	13 (9–120)	15 (12–57)	0.622	15 (11–40)	16 (12–32)	0.578
Hematological recovery after second ASCT				n = 18	n = 5	p
Days to ANC > 500/mcL				11 (9–21)	12 (10–15)	0.905
Days to PLT > 20.000/mcL				15 (10–29)	16 (12–20)	0.824

G-CSF, granulocyte-colony-stimulating-factor; WBC, white blood cells; PB, peripheral blood; SD, standard deviation; ITT, intention-to-treat.

ASCT, autologous hematopoietic stem cell transplant; ANC, absolute neutrophilis count; PLT, platelets.

Table II also shows the post-ASCT hematological recovery data. No difference in terms of drug-related adverse events was observed in the two cohorts of patients, with no reported serious adverse event. So far, to our knowledge, one single study comparing lenograstim with biosimilar filgrastim in PBSC mobilization in an autologous setting has been published [8]. This study included 68 patients treated with originator filgrastim, 16 with biosimilar filgrastim and 12 with lenograstim after chemotherapy with median doses of G-CSF of 10 μg/kg/day, and reported that the collected CD34 + cell count under biosimilar filgrastim was superior to that under originator filgrastim and lenograstim. Our results could suggest a similar efficacy between biosimilar filgrastim and lenograstim in myeloma patients, but a greater efficacy of lenograstim in terms of number of patients achieving both the required CD34 + cell collection target dose and an adequate number of circulating CD34 + cells at peak in patients with lymphoma (Table II). The suggestion of a greater mobilization efficacy of lenograstim over filgrastim could find the basis in in vitro studies. In fact, some previous studies performed by the Italian group of Pisa University, evaluating G-CSF induced cell activation and functions, showed that behavior is significantly different when cells are induced by filgrastim or lenograstim. In particular, filgrastim appears to reduce motility in human neutrophilis, whereas lenograstim is able to preserve the functional status of neutrophilis as in the basal condition. The glycosylation of G-CSF determines a minor activation of the pathway of the RhoA gene, a small G-protein that regulates cell morphology and motility via actin cytoskeleton reorganization in response to extracellular signals [15], supporting the hypothesis of a greater capacity to mobilize hematopoietic progenitor cells from their bone marrow niches towards the circulatory torrent. Based on these findings, we could hypothesize that lymphoma patients are more sensitive to little differences in stem cell mobilization capacity primed by glycosylated or non-glycosylated forms of G-CSF because of the greater chemotherapeutic load behind when compared with myeloma patients.

Despite the limitations due to relatively low number of patients, to date this is the largest non Company-supported report comparing lenograstim and biosimilar filgrastim in the autologous mobilization setting for hematologic patients. Furthermore, the limitations inherent in the non-randomized nature of the study are mitigated from having the patients homogeneously distributed between the cohorts as baseline characteristics and uniformly treated with the same mobilization regimens and under an unchanged and unique mobilization policy over the previous 4 years. In conclusion, at the same doses, biosimilar filgrastim seems to be similarly effective when compared with lenograstim for PBSC mobilization in adult patients with myeloma, but less effective in lymphoma patients, and it is more likely to attribute the lower efficacy of filgrastim vs. lenograstim in this subset to the non glycosylated nature of filgrastim and not to the biosimilar nature of the utilized filgrastim formulation. However, we believe that further randomized controlled studies in a larger cohort of lymphoma patients are highly warranted to confirm these findings.

Potential conflict of interest

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