A Comparative Study of Biosimilar Filgrastim Versus Originator G-CSF for CD34+ Cells Mobilization and Autografting in Hematological Malignancies
Authors: Brunello Lucia , Giaccone Luisa , Fornaro Maria Josè , Scaldaferri Matilde , Redoglia Valter , Omedè Paola , Festuccia Moreno , Ciccone Giovannino , Massaia Massimo , Ferrero Dario , Cavallo Federica , Palumbo Antonio , Cattel Francesco , Evangelista Andrea , Boccadoro Mario , Bruno Benedetto 
Published: October 2019

Abstract
INTRODUCTION: Autografting (auto-HSCT) is widely used for the treatment of hematological malignancies. Since 2010, Biosimilar Filgrastim (Nivestim™, Pfizer Inc.) (BioG-CSF) has been approved and introduced into clinical practice to mobilize hematopoietic stem cells (CD34+cells) and to reduce the duration of chemo-induced neutropenia. This single institution study was designed to evaluate its safety and efficacy in the setting of "real life" medical practice.
METHODS: We designed a "mixed retrospetive-prospective study" to evaluate the impact of BioG-CSF on CD34+ cells collections and engraftment kinetics after autografting. Patients who received BioG-CSF were compared with a historical cohort treated with Originator G-CSF (Filgrastim or Lenograstim). Primary endopoints were CD34+ mobilizations and post auto-HSCT engraftment kinetics. Secondary objectives included transfusions requirements, duration of hospitalization and 1-year overall survival (OS). Leukapheresis (LA) was initiated when circulating CD34+ count was at least 20/uL. Day of neutrophil engraftment was defined as the first of 3 consecutive days of absolute neutrophil count (ANC) ≥ 500/ul whereas day of platelet engraftment was defined as the first of 7 consecutive days without transfusion support.
RESULTS: Initially,187 patients (137/187 affected by multiple myeloma) have been enrolled in the cohort under evaluation for CD34+ mobilization kinetics. Overall, 138 and 49 patients received originator and BioG-CSF (5-10 ug/kg/day) to collect CD34+cells. All but two patients underwent chemotherapy for mobilization (high-dose cyclophosphamide in 157/187 patients). Less than 3% of patients were poor mobilizers in both cohorts. No differences between Originator and BioG-CSF cohort were observed in time from chemotherapy to first day of LA (median day 11 vs day 11 p=0.473), CD34+/ul (mean 157.3/ul vs 166.2/ul, p=0.59) and CD34+*10^6/kg recipient harvested on the first day of LA (mean 10.5*10^6/kg vs 11.1*10^6/kg, p=0.323). A higher count of white blood cells on the first day of LA was observed in patients treated with BioG-CSF (mean originator 18.6*10^9/L vs BioG-CSF 27.1*10^9/L, p=0.001).
A further analysis was conducted on 175 patients (126/175 affected my multiple myeloma) for a total of 220 auto-HSCTs, evaluable for hematological recovery and clinical outcomes. Overall, 137 and 83 patients received Originator and BioG-CSF, respectively. All patients were hospitalized and prepared for the autograft with a high-dose conditioning (Melphalan 200mg/sqm in 171/220 auto-HSCTs). Infused CD34+ cells were 5*10^6/kg recipient (IQR 3.8-5.1) and 4.1*10^6/kg recipient (IQR 3.5-5.3) in the Originator and BioG-CSF cohorts. After the autograft, patients were prescribed 30-34 milliion units (MU) of Originator G-CSF and 30 MU dose of BioG-CSF starting on day +1/+3. Day +25 cumulative incidences of ANC and platelets recovery were 99.3% and 98.5% and 97.6% and 90.2% in the Originator and BioG-CSF groups, respectively (p=0.786, p=0.006). Of note, by Mann-Whitney test, no differences between cohorts were found in a)median duration of neutropenia (median 7 and 6 days, p=0.355), platelets (median 1 pool/patient in both, p=0.894) and red blood cells (median 0/patient in both, p=0.704) transfusion requirements, hospital stay (median 20 days and 21 days, p=0.33). Serial measurements of complete blood counts were performed from discharge to day +90 post auto-HSCT; no significant differences were found at any time point between the two groups. No severe adverse reactions attributable to G-CSFs were documented. Thrombocytopenia lasted longer for patients treated with BioG-CSF, however this finding did not translate into a higher transfusion requirement or bleeding episodes. Finally, 1-year OS was comparable between cohorts (p=0.699).
CONCLUSIONS: In this sizable study, BioG-CSF was as effective as Originator G-CSF in mobilizing CD34+ cells as well as in treating post-transplant neutropenia in patients with hematological malignancies. Moreover, the extensive use of BioG-CSF led to a significant cost containment.

Disclosures
Massaia: Janssen: Other: advisory board; Gilead: Other: advisory board; Roche: Other: advisory board, research support. Cavallo:JANSSEN: Honoraria; CELGENE: Honoraria; ONYX: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; Abbivie: Honoraria; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.