Abstract
No consensus has been made on the use of PEG-modification recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in patients receiving autologous peripheral blood stem cell transplantation (PBSCT). To evaluate the efficacy and safety of PEG-rhG-CSF in provision of neutrophil support for lymphoma patients receiving autologous PBSCT. This retrospective study included lymphoma patients receiving either PEG-rhG-CSF or rhG-CSF after autologous PBSCT from 2018 to 2021 in two clinics. Hematologic recovery time, incidence of infectious complications and toxicity were compared between these two rhG-CSFs and among different initiation time of PEG-rhG-CSF. Of the 139 subjects included, 93 received PEG-rhG-CSF and 46 received rhG-CSF after transplantation. Compared with rhG-CSF, PEG-rhG-CSF marginally but significantly accelerated the neutrophil engraftment by 1 day (10 vs. 9 days, respectively) with no increasing on the risk of infectious complication and toxicity. In the PEG-rhG-CSF group, 50 patients received the growth factor on day 1, 19 received on day 3 and 24 received on day 5. The neutrophil engraftment was significantly shorter in day 1 and day 3 subgroup (9, 9, and 10 days, respectively), with a lower incidence of febrile neutropenia (82%, 100%, 100%) and documented infections (76%, 100%, 100%) in day 1 subgroup. PEG-rhG-CSF might be an alternative to rhG-CSF for lymphoma patients received autologous PBSCT. Administrating PEG-rhG-CSF on day 1 can achieve both faster hematologic recovery and lower infectious complications.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12288-023-01704-8.
Keywords: Autologous stem cell transplantation, PEG-rhG-CSF, rhG-CSF, Hematopoietic engraftment, Lymphoma
Introduction
Polyethylene glycol-recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) has a similar biological activity to rhG-CSF. But with the covalent attachment of PEG, the half-life has been largely extended to 42–62 h [1]. As a result, a single dose of PEG-rhG-CSF can achieve the same effect as multiple daily injections of rhG-CSF [1, 2]. At present, PEG-rhG-CSF can replace rhG-CSF and is widely used in the provision of neutrophil support for patient receiving chemotherapy [3, 4]. However, the efficacy, safety, and optimal timing of PEG-rhG-CSF in patients receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) remains unclear.
The aim of this study was to evaluate the efficacy and safety of fixed 6 mg dose of PEG-rhG-CSF, compared with daily administration of rhG-CSF, in provision of neutrophil support for lymphoma patients receiving high-dose chemotherapy and autologous PBSCT.
Patients and Methods
Patients
This was a retrospective study of patients who underwent autologous PBSCT for lymphoma from January 2018 to January 2021 in two clinics, Peking University Third Hospital (PUTH) and Beijing Hospital (BH). Patients who underwent a second transplant were excluded. The data were obtained from patients’ medical records. This study was approved by the Institutional Review Boards of both PUTH and BH.
Study Design
A total of 139 eligible patients were enrolled in this study, with 93 subjects receiving PEG-rhG-CSF and 46 receiving rhG-CSF after transplant. In the PEG-rhG-CSF group, a single, fixed dose of 6 mg was given on day 1, day 3 or day 5 after autologous PBSCT. In the rhG-CSF arm, the drug was given 5 μg/kg daily starting on day 3 or day 5 post-transplant till neutrophil engraftment. Neutrophil engraftment was defined as the first 3 consecutive days when absolute neutrophil count (ANC) was > 0.5 × 109/L, and platelet engraftment was defined as the first 3 consecutive days when the platelet count was > 20 × 109/L without transfusions for the previous 3 days. Febrile neutropenia was defined as a fever > 38℃ with an ANC of < 0.5 × 109/L. Documented infections was made when an infectious agent was isolated in culture with a strong clinical and laboratory suspicion. Engraftment syndrome was defined by the presence of noninfectious fever and one other syndrome (i.e., skin involvement, diarrhea, or pulmonary manifestations) during the peri-engraftment period [5].
Statistical Analysis
Data were initially analyzed descriptively. Continuous variables were expressed as medians with ranges. Categorial variables were expressed as frequencies and percentages. Independent sample t tests/Mann–Whitney U test and Fisher’s exact chi-square test were used to detect differences between PEG-rhG-CSF group and rhG-CSF group. One-way ANOVA and Fisher’s exact chi-square test were used to analyze differences among the three subgroups of PEG-rhG-CSF. A P value ≤ 0.05 was considered to be statistically significant. Bonferroni t test was used as the multiple comparison test to detect the difference between each 2 subgroups of PEG-rhG-CSF, with a P value ≤ 0.017 considered as statistically significant. Kaplan–Meier estimates were used to summarize the distributions of engraftment. The software package SPSS 26.0 (SPSS Inc) was used for statistical analysis.
Results
Baseline Characteristics
The demographic and clinical data of 93 patients receiving PEG-rhG-CSF and 46 receiving rhG-CSF are summarized respectively in Table 1. The basic characteristics were comparable between PEG-rhG-CSF and rhG-CSF group except earlier initiation of PEG-rhG-CSF than rhG-CSF (median day of 1 versus 5, P < 0.01). In PEG-rhG-CSF group, 50 patients received on day 1, 19 patients on day 3, and 24 patients on day 5. In rhG-CSF group, no patients received on day 1, while 13 patients on day 3 and 33 patients on day 5.
Table 1.
Patient characteristics
| PEG-rhG-CSF (n = 93) |
rhG-CSF (n = 46) |
P value | |
|---|---|---|---|
| Age (median, range) | 44.0 (18, 66) | 39.5 (20, 64) | 0.689 |
| Sex | |||
| Male (%) | 49 (52.7%) | 28 (60.9%) | 0.361 |
| Female (%) | 44 (47.3%) | 18 (39.1%) | |
| Disease | |||
| Non-Hodgkin lymphoma (%) | 86 (92.5%) | 38 (82.6%) | 0.141 |
| Hodgkin lymphoma (%) | 7 (7.5%) | 8 (17.4%) | |
| Others (%) | 1 (1.1%) | 0 (0.0%) | |
| Number of prior regimens (median, range) | 7 (5, 14) | 7 (5, 13) | 0.292 |
| Remission status | |||
| Complete remission (%) | 89 (95.7%) | 40 (87.0%) | 0.261 |
| Partial remission (%) | 3 (3.2%) | 6 (13.0%) | |
| Disease progression or relapse (%) | 1 (1.1%) | 0 (0.0%) | |
| CD34+ cells × 106/kg infused (median, range) | 6.84 (0.81, 77.59) | 6.38 (1.19, 25.29) | 0.662 |
| Day of rhG-CSF initiation (median, range) | 1 (1, 5) | 5 (3, 5) | < 0.01 |
PEG-rhG-CSF PEG-modification recombinant human granulocyte colony stimulating factor; rhG-CSF Recombinant human granulocyte colony stimulating factor
Engraftment Data
Compared with patients receiving rhG-CSF, the patients receiving PEG-rhG-CSF after transplant has significantly shorter days reaching ANC of 0.5 × 109/L (median days of 10 versus 9, P < 0.01) and WBC of 2 × 109/L (median days of 11 versus 10, P < 0.01) (Table 2). As shown in Fig. 1A, B, the ANC and WBC recovery of both groups followed a similar pattern except from day 8 to day 12. Meanwhile, there was no significant difference in the platelet recovery between PEG-rhG-CSF and rhG-CSF groups (median days of 9.5 versus 9, P = 0.196) (Fig. 1C).
Table 2.
Hematologic recovery
| PEG-rhG-CSF (n = 93) |
rhG-CSF (n = 46) |
P value | |
|---|---|---|---|
| Days to ANC ≥ 0.5 × 109/L (median, range) | 9 (7, 13) | 10 (6, 13) | < 0.01 |
| Days to WBC ≥ 2 × 109/L (median, range) | 10 (7, 16) | 11 (6, 20) | 0.005 |
| Days to platelets ≥ 20 × 109/L (median, range) | 9.5 (5, 19) | 9 (4, 24) | 0.196 |
| Maximum WBC (median, range) | 6.21 (1.25, 66.27) | 6.30 (2.53, 22.02) | 0.993 |
| Days to maximum WBC (median, range) | 12 (9, 19) | 12 (9, 20) | 0.562 |
ANC Absolute neutrophil count; WBC White blood cell; PEG-rhG-CSF PEG-modification recombinant human granulocyte colony stimulating factor; rhG-CSF Recombinant human granulocyte colony stimulating factor
Fig. 1.
Hematologic recovery after transplant. Kaplain-Meier plot of time to ANC of 0.5 × 109/L (A), WBC of 2 × 109/L (B) or platelet count of 20 × 109/L (C) in PEG-rhG-CSF group and rhG-CSF group. PEG-rhG-CSF PEG-modification recombinant human granulocyte colony stimulating factor; rhG-CSF recombinant human granulocyte colony stimulating factor
Infectious Complication and Toxicities
There was no significant difference in the incidence of febrile neutropenia between PEG-rhG-CSF and rhG-CSF group (90.3% versus 84.8%, P = 0.336). And the median duration of febrile neutropenia in these two groups were also similar (median days of 3). The grade III or IV toxicities, including bone pain and engraftment syndrome, were also comparable between these two groups (Table 3).
Table 3.
Infectious complications and toxicities
| PEG-rhG-CSF (n = 93) |
rhG-CSF (n = 46) |
P value | |
|---|---|---|---|
| Febrile neutropenia (%) | 84 (90.3%) | 39 (84.8%) | 0.336 |
| Days of febrile neutropenia (median, range) | 3 (1, 13) | 3 (1, 8) | 0.485 |
| Documented infections (%) | 81 (87.1%) | 34 (73.9%) | 0.053 |
| Bone pain (%) | 3 (3.2%) | 3 (6.5%) | 0.648 |
| Engraftment syndrome (%) | 1 (0.01%) | 0 (0.0%) | 0.480 |
PEG-rhG-CSF PEG-modification recombinant human granulocyte colony stimulating factor; rhG-CSF Recombinant human granulocyte colony stimulating factor
Outcome of Using PEG-rhG-CSF on Day 1, 3 or 5 After Autologous PBSCT
As shown in Table 4, the baseline characteristics were comparable among the 3 subgroups in patients receiving PEG-rhG-CSF. Compared with patients given PEG-rhG-CSF on day 5, the neutrophil engraftment was significantly shorter in patients given on day 1 and day 3, with no significant difference between day 1 and day 3 (Fig. 2A, B). No difference was found in the platelet recovery among these 3 subgroups (Fig. 2C). The incidences of febrile neutropenia and documented infections were statistically different among these 3 subgroups. Although day 1 had a better performance on infectious complications, no significant difference was found between day 1 and day 3 subgroup.
Table 4.
Comparison of baseline characteristics, engraftment data, infectious complications and toxicities in patients receiving PEG-rhG-CSF on day 1, 3 or 5 post-transplant
| Day 1 (n = 50) |
Day 3 (n = 19) |
Day 5 (n = 24) |
P value | |
|---|---|---|---|---|
| Age (median, range) | 41.5 (26, 66) | 46 (18, 64) | 41 (24, 63) | 0.635 |
| Sex | ||||
| Male (%) | 26 (52%) | 12 (63.2%) | 11 (45.8%) | 0.523 |
| Female (%) | 24 (48%) | 7 (36.8%) | 13 (54.2%) | |
| Disease | ||||
| Hodgkin lymphoma (%) | 1 (2%) | 0 (0%) | 0 (0%) | 1.000 |
| Non-Hodgkin lymphoma (%) | 49 (98%) | 19 (100%) | 24 (100%) | |
| Number of prior regimens (median, range) | 7 (5, 14) | 7 (6, 10) | 7 (5, 13) | 0.860 |
| Remission status | ||||
| Complete remission (%) | 47 (94%) | 19 (100%) | 23 (95.8%) | 0.809 |
| Partial remission (%) | 2 (4%) | 0 (0%) | 1 (4%) | |
| Disease progression or relapse (%) | 1 (2%) | 0 (0%) | 0 (0%) | |
| CD34+ cells × 106/kg infused (median, range) | 6.03 (0.81, 20.18) | 7.12 (2.42, 77.59) | 7.44 (3.1, 47.01) | 0.062 |
| Days to ANC ≥ 0.5 × 109/L (median, range) | 9 (7, 13) | 9 (8, 10) | 10 (9, 12) | 0.005 |
| Days to WBC ≥ 2 × 109/L (median, range) | 10 (7, 16) | 10 (8, 13) | 10.5 (9, 14) | 0.236 |
| Days to platelets ≥ 20 × 109/L (median, range) | 9 (5, 19) | 10 (7, 13) | 10 (7, 19) | 0.131 |
| Maximum WBC (median, range) | 5.99 (2.56, 26.82) | 6.15 (2.73, 66.27) | 7.37 (1.78, 54.04) | 0.446 |
| Days to maximum WBC (median, range) | 12 (9, 19) | 12 (9, 14) | 11 (10, 17) | 0.673 |
| Febrile neutropenia (%) | 41 (82%) | 19 (100%) | 24 (100%) | 0.013 |
| Days of febrile neutropenia (median, range) | 3 (1, 13) | 3 (1, 9) | 2.5 (1, 9) | 0.698 |
| Documented infections (%) | 38 (76%) | 19 (100%) | 24 (100%) | 0.002 |
| Bone pain (%) | 1 (2.0%) | 0 (0.0%) | 2 (8.3%) | 0.267 |
| Engraftment syndrome (%) | 1 (0.2%) | 0 (0.0%) | 0 (0.0%) | 1.000 |
ANC Absolute neutrophil count; WBC White blood cell
Fig. 2.
Engraftment after transplant. Kaplain-Meier curves of time to ANC of 0.5 × 109/L (A), WBC of 2 × 109/L (B) and platelet count of 20 × 109/L (C) in the subjects receiving PEG-rhG-CSF on day 1, 3 or 5 post-transplant. ANC Absolute neutrophil count; WBC White blood cell; PEG-rhG-CSF PEG-modification recombinant human granulocyte colony stimulating factor
Discussion
Several studies have demonstrated the advantages of G-CSF in accelerating neutrophil engraftment, reducing the incidence of bacterial infection and durations of antibiotics use in patients with high-dose chemotherapy followed by ASCT [4, 6–8]. The 2015 American Society of Clinical Oncology Clinical Practice Guideline recommends the administration of WBC Growth factors to shorten the duration of neutropenia after ASCT [4]. However, only filgrastim, a short-acting rhG-CSF, is recommended in setting of high-dose therapy and autologous stem-cell rescue. No consensus has been made on the administration of PEG-rhG-CSF.
In the present study, our data show that compared with rhG-CSF, PEG-rhG-CSF can marginally accelerate the neutrophil engraftment by 1 day. Few studies conducted this comparison with different results [9, 10]. A meta-analysis conducted by Ziakas included 4 randomized controlled trails and other 8 relevant studies. They found the same advantage of PEG-rhG-CSF in neutrophil engraftment by 1 day [9]. However, another randomized phase II study demonstrated similar hematologic recovery and incidence of infection between pegfilgrastim and filgrastim. Considering the convenience of a single dose administration, better compliance, and decreased burden for both patients and healthcare professionals, PEG-rhG-CSF might be an alternative to rhG-CSF for lymphoma patients received autologous PBSCT.
To our best knowledge, the present study firstly analyzed the optimal timing of PEG-rhG-CSF after autologous PBSCT. Ferrara et al. [11] chose to give pegfilgrastim on day 5 after autologous PBSCT deriving by pharmacokinetic consideration. Since the clearance of pegfilgrastim is strictly related to the level of circulating neutrophils, they speculated that delaying pegfilgrastim at day 5, when neutrophil begin to decrease, would achieve a higher efficacy. However, in their study, the median day to neutrophil engraftment was 12, which seems later than our study. In the last two decades, there was a greater trend of using pegfilgrastim on day 1 after transplant [12]. Our data also suggest that administrating on the first day after transplantation can achieve better performance with faster hematologic recovery and lower infectious complications.
There are two main limitations in our study. First, considering the retrospective design, this study subjects our results to the usual restrictions and bias of this type of analyses. Second, the median initiation time of rhG-CSF is significantly later than the median time of PEG-rhG-CSF, which might play a part in the difference we found between these two groups. We further compared hematological recovery, infectious complications and toxicities between PEG-rhG-CSF and rhG-CSF by initiation time. Since no patient received rhG-CSF on day 1, comparison was only made between subgroups of day 3 and day 5 (Supplementary table 1 and 2), with no significant difference was found. Maybe use of rhG-CSF from day 1 could have nullified this 1-day advantage on ANC and WBC recovery. However, this discrepancy in timing is not expected to significantly affect the comparison. The meta-analysis conducted by Ziakas [9] also did an adjusted (meta regression) analysis for delayed versus concurrent use of filgrastim and pegfilgrastim. No significant effect was found on neutrophil engraftment, while an overestimation of the protective effect on the risk of duration of febrile neutropenia was found in the delayed filgrastim.
Conclusion
In the present study, we show that PEG-rhG-CSF can marginally accelerate the neutrophil engraftment than rhG-CSF and might be an alternative to rhG-CSF for lymphoma patients received autologous PBSCT. The administration of PEG-rhG-CSF on day 1 can achieve both faster hematologic recovery and lower infectious complications.
Supplementary Information
Below is the link to the electronic supplementary material.
Declarations
Conflict of interest
The authors stated that they had no interests which might be perceived as posing a conflict or bias.
Footnotes
Publisher's Note
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Sen Li and Jiangtao Li contributed equally to this work.
Contributor Information
Hui Liu, Email: liuhui8140@126.com.
Hongmei Jing, Email: hongmeijing@bjmu.edu.cn.
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