High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard care provided to patients with relapsed/refractory lymphoma or with newly diagnosed multiple myeloma (MM) [1]. Although the best conditioning regimen for ASCT remains undefined, regimens such as BEAM (carmustine, etoposide, cytarabine, and melphalan) and high-dose melphalan (140–200 mg/m2) are the regimens of choice for lymphoma and myeloma, respectively. Importantly, outpatient transplant programs aim to avoid hospitalization to improve the quality of life of patients, the patient experience, and healthcare expenditure, reducing the total cost of ASCT by up to 50 % [2,3]. However, regardless of the conditioning regimen used and the follow-up model selected, febrile neutropenia (FN) is a common complication in the aplastic phase. During the post-conditioning period, neutropenic patients are at risk of infection, hospitalization, and the need for antibiotic therapy or blood transfusions.

Filgrastim, which is a recombinant granulocyte colony-stimulating factor (G-CSF), has traditionally been used to reduce the duration and severity of neutropenia during ASCT. After administering G-CSF at a dose of 10 mg/kg/day for 6–10 days, hematological recovery (neutrophil count >0.5 × 109/L and platelet count >20 × 109/L) is generally achieved between Day 12 and Day 14 (range: Day 10–25) post-transplant [4,5]. Pegfilgrastim is a long-acting form of G-CSF that was approved in 2002 and has since been widely used for the prophylaxis of chemotherapy-induced FN and, less frequently, in patients receiving ASCT. This study was designed to compare the efficacy of a single dose of either the original (innovator) pegylated filgrastim drug or a biosimilar pegylated filgrastim with the efficacy of daily filgrastim administration in patients who received ASCT as outpatients, with a particular focus on the time to engraftment.

This was a prospective open-label, phase II, single-center study conducted in a public hospital in Monterrey, Mexico. It compared the effectiveness of three treatments for the prophylaxis of FN in patients receiving ASCT for lymphoma or myeloma as outpatients at the study center between March 2022 and November 2022. The treatment regimens consisted of: a single dose of innovator pegfilgrastim (Neulastim, Amgen, Mexico), a single dose of biosimilar pegfilgrastim (Linkix, Teva, Mexico), or daily treatment with biosimilar filgrastim.

Patients were eligible to participate in this study if they were between 18 and 75 years old; had a previous confirmed diagnosis of MM, non-Hodgkin lymphoma (NHL), or Hodgkin’s lymphoma (HL); and were in a first or consecutive remission after receiving an ASCT. Additional inclusion criteria were as follows: patients had an Eastern Cooperative Oncology Group (ECOG) performance status of <2, patients were eligible for ASCT, patients had not undergone chemotherapy as a mobilization regimen; and patients had normal liver function test results. The exclusion criteria comprised having one of the following conditions: fever; an active infection, including viral infections such as hepatitis A, B, or human immunodeficiency virus (HIV); or congestive heart failure with an ejection fraction of <40 %.

The study consisted of two arms: patients in Arm 1 received the innovator pegfilgrastim (Neulastim®, AMGEN, Mexico) for the prophylaxis of FN, whereas patients in Arm 2 received a biosimilar pegfilgrastim (Linkix®, TEVA, Mexico).

Additionally, a historical Control Group of 53 consecutively-treated patients who met the same inclusion criteria and received a biosimilar filgrastim (Biofilgran, Landsteiner Scientific, Mexico) for the prophylaxis of FN were included. Patients in this retrospective cohort received their transplant between January 2020 and December 2021, following the same outpatient follow-up protocols, antimicrobial prophylaxis, and hospitalization criteria established in the institutional standard operating procedure outlined in the unit's FACT (Foundation for the Accreditation of Cellular Therapy) accreditation.

Patients with lymphoma received a conditioning regimen of bendamustine (180 mg/m2/day for two days) and melphalan (140 mg/m2/day for one day), or of etoposide (450 mg/m2/day for two days) and melphalan (140 mg/m2/day for one day). Patients with myeloma received melphalan (140 or 200 mg/m2/day for one day) (Table 1). The conditioning regimen to be used was chosen according to the availability of the medicines. Peripheral blood was the source of the hematopoietic stem cells in all patients. Hematopoietic stem cells were mobilized by the subcutaneous administration of filgrastim at 10 µg/kg/day for four consecutive days before being collected by apheresis on the fifth day of mobilization. Apheresis was performed as an outpatient procedure for all patients. The objective of this procedure was to obtain at least 2 × 106/kg CD34+ hematopoietic stem cells. Infection prophylaxis for all patients consisted of oral levofloxacin (500 mg/day), acyclovir (400 mg/day), and voriconazole (200 mg/day). This regimen began on Day 0 (transplant day) and continued until absolute neutrophil count exceeded 500 cells/µL, at which point levofloxacin was replaced with trimethoprim-sulfamethoxazole.

The complete ASCT procedure, including cell mobilization, cell collection, administration of the conditioning regimen, stem cell infusion, and post-transplantation follow-up, was performed in an outpatient setting according to institutional guidelines.

Patients were prospectively randomized one-by-one to either Arm 1 or Arm 2 when they underwent an ASCT. On Day +1 after transplantation, patients in Arm 1 received a single subcutaneous dose of 6 mg of the innovator pegfilgrastim whereas patients in Arm 2 received a single subcutaneous dose of 6 mg of a biosimilar pegfilgrastim. Complete blood cell counts were performed every 24 h until engraftment was confirmed. Patients were followed up daily and adverse events were cataloged in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

According to institutional guidelines, the historical Control Group had received a single daily subcutaneous dose of 5 µg/kg of filgrastim, starting on Day +1 post-transplantation and continuing until hematologic recovery was observed.

Neutrophil engraftment was defined as achieving an absolute neutrophil count of at least 0.5 × 109/L for three consecutive days, whereas platelet engraftment was defined as a platelet count of at least 20 × 109/L for three consecutive days without transfusion support.

FN neutropenia was defined as an absolute neutrophil count <0.5 × 109/L with a single oral temperature reading of 38.3 °C or a sustained temperature of ≥38.0 °C over a one-hour period.

Transfusions administered to patients in both the prospective and retrospective groups were performed prophylactically, based on the standard operating procedure of the transplant unit, when the platelet count was less than 20 × 109/L or hemoglobin was <7 g/dL. No patient required a therapeutic transfusion.

This study received approval from the Institutional Ethics Committee (HE22–00006). All procedures were performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, with informed consent obtained in writing from each participant. The privacy rights of patients were always observed. This study was registered on the ClinicalTrials.gov platform under the identifier NCT05338047.

A total of 83 patients were included in the study; 30 patients were recruited prospectively and 53 were analyzed retrospectively (Control Group). Among the prospectively recruited patients, 15 patients received the innovator pegfilgrastim (Arm 1) and 15 patients received a biosimilar pegfilgrastim (Arm 2). The median age of all 83 patients was 50 years (range: 18–70 years) with no significant differences in age between groups (p-value = 0.56). Most of the patients in both Arms 1 and 2 were male (Arm 1: 53 % males; Arm 2: 60 % male). The underlying diseases and the conditioning regimens patients received are shown in Table 1.

FN, a frequent complication in patients undergoing ASCT, increases morbidity, mortality, and hospitalization rates, thereby increasing transplantation costs. Neutropenic sepsis remains a significant life-threatening adverse event and cause of mortality in patients who receive chemotherapy from which patients undergoing transplantation are not exempt [6,7]. Various hematopoietic growth factors have been used, including filgrastim and pegfilgrastim with the aim of accelerating engraftment and reducing the number of days during which a patient is at risk of neutropenia [8]. This study analyzed the effectiveness of three different G-CSF formulations (innovator pegfilgrastim, biosimilar pegfilgrastim, and biosimilar filgrastim) based on the number of days to engraftment in patients undergoing outpatient ASCT.

A comparison between the innovator and biosimilar pegfilgrastim groups revealed no significant differences in demographic characteristics, underlying diseases, or conditioning regimens. (Table 1). Furthermore, there were no differences according to the type of G-CSF treatment received for the following variables: time to neutrophil engraftment (p-value = 0.14), time to platelet engraftment (p-value = 0.81), transfusion rate (p-value = 1.0), hospitalization rate (p-value = 1.0), FN frequency (p-value = 1.0), and frequency of adverse events (p-value = 0.45); this demonstrated the comparable effectiveness of a biosimilar pegfilgrastim and the innovator pegfilgrastim (Table 2). However, there was a difference between the costs of these medications (p-value = 0.001). Although this is not a phase III clinical trial and the number of patients is limited, in this study the effects of the two different pegfilgrastim products were comparable. In a previous study, Wong et al. compared the effectiveness of the innovator pegfilgrastim with a biosimilar pegfilgrastim to prevent FN in patients who had received chemotherapy for breast cancer; these authors observed no differences in the incidence of FN between treatments, but there was a significantly higher cost when the innovator medication was used [9].

On the other hand, differences in some variables were observed when comparing patients who received pegfilgrastim versus filgrastim including time to engraftment. Patients who received pegfilgrastim achieved neutrophil and platelet recovery two days faster than those who received filgrastim (p-value = 0.0001; Table 4). In the pegfilgrastim group, a greater number of patients required platelet transfusion support (86 % versus 73 %); however, the number of platelet units that were transfused was greater in the filgrastim group (p-value = 0.029) as many of the patients in the filgrastim group required more than one platelet transfusion.

The incidences of FN post-ASCT reported in the literature vary widely, ranging from 20–80 % [8,10]. Patients who receive an ASCT are considered to be at high risk for FN and for fatal complications with a combined mortality rate of up to 10 %; therefore, previous studies have recommended the use of filgrastim or pegfilgrastim for primary prophylaxis [11,12]. Some reports have shown that patients receiving pegfilgrastim have a lower incidence of FN and others have shown no differences in the incidence of FN when using filgrastim [8,13,14].

In the present study, the incidence of FN was significatively lower in patients who received pegfilgrastim (6.7 %) than in those who received filgrastim (24.5 %; p-value = 0.04). Similar results were observed in previous studies evaluating pegfilgrastim versus filgrastim for FN prophylaxis; these studies demonstrated that pegfilgrastim significantly reduced the risk of FN and its associated complications in chemotherapy patients [6,8].

The most common causes of hospitalization in patients receiving high doses of chemotherapy include mucositis and FN. The study center of this research is a FACT-accredited unit that has operated an outpatient autologous and allogeneic transplant program since 1998 [15]; the entire ASCT procedure is performed in the outpatient clinic. After chemotherapy administration and cell infusion, patients are discharged home and are then followed up in the outpatient clinic every day until engraftment. Patients are admitted to hospital if they develop FN or any other complication that requires in-hospital treatment; this does not include transfusions, which are performed in an outpatient setting. In the present study, we did not observe significant differences between the three groups of patients with respect to their hospitalization rate or length of hospital stay. The differences in the FN incidence and the hospitalization rate that were observed in the current study can be explained by the rapid response to outpatient antibiotic treatment that occurred in some patients such that they were not hospitalized.

The limitations of the present study are the small number of patients who were included, the lack of blinding, and the inclusion of a retrospective Control Group; however, it is important to highlight that there is little existing information on the outcomes of these patients in an outpatient setting.

The two pegfilgrastim formulations demonstrated similar effects on time to engraftment and FN incidence. Compared to daily filgrastim, pegfilgrastim treatment resulted in faster engraftment, fewer platelet transfusions, and a lower incidence of FN. While pegfilgrastim was associated with a higher product cost, these clinical advantages may provide significant value in an outpatient setting.

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The study drug was funded by the institution where the research was conducted.

Informed consent was obtained in writing from each participant

approval from the Institutional Ethics Committee (HE22–00006).

Identifier NCT05338047

CHGA: Design the protocol and writing the manuscript. FGS: Design the protocol and follow-up. DGA: Revising the work for intellectual content. JCJP: Writing the manuscript. CMG: Interpreting the results and Data analysis. AGL: Interpreting the results and Data analysis. PCP: Clinical follow-up of patients. MJMM: Data acquisition. VCER: Data acquisition. OGCR: Revising the work and final approval.

The data that support the findings of this study are available from the corresponding author upon reasonable request.