Efficacy and Safety of Pegfilgrastim in Patients With Severe Congenital Neutropenia.

Introduction

Severe congenital neutropenia (SCN) is a group of rare inherited hematological disorders characterized by defects in the maturation of neutrophil granulocytes, and the absolute neutrophil count (ANC) is lower than 0.5 × 10 9 /L [ 1 ]. As a result, the patients are at risk of recurrent and often lethal infections [ 2 ]. This disorder exhibits both clinical and genetic diversity, characterized by a failure in the proper maturation of neutrophil granulocytes. Autosomal dominant or recessive mutations in several genes such as ELANE, HAX‐1 , G6PC3 , SRP54 , SRP19 , CLBP , and JAGN1 can lead to SCN. The most common mutation for SCN is in the ELANE gene that encodes neutrophil elastase [ 1 , 3 ]. However in Iran, HAX1 is the most prevalent mutation due to the high rate of consanguinity and relative marriage [ 4 ].

In patients with SCN, the long‐term use of filgrastim as a granulocyte colony‐stimulating factor (G‐CSF) is recommended, as it can effectively improve neutropenia and reduce the incidence of infections [ 5 ]. Although G‐CSF has a transient effect, it requires prolonged administration [ 6 ]. Pegfilgrastim is a compound of filgrastim and polyethyleneglycol (PEG) and has a longer half‐life (50–80 h) compared to filgrastim (3–6 h). Therefore, the dosing intervals are significantly extended with pegfilgrastim (10–14 days) [ 6 ]. Consequently, this leads to a decreased infection rate and improved adherence to therapy among patients using pegfilgrastim [ 7 ].

Previous studies have shown that patients with multiple myeloma [ 8 ] and chemotherapy‐induced neutropenia [ 5 ] may benefit from pegfilgrastim to reduce the incidence of febrile neutropenia following myelosuppressive chemotherapy regimens [ 9 ].

However, due to the limited number of studies on the long‐term use of pegfilgrastim in patients with SCN [ 5 , 7 ], there is some controversy surrounding its application. One study found that pegfilgrastim is more challenging to use than conventional G‐CSF, citing more frequent adverse events and sometimes poor efficacy [ 6 ]. In contrast, other studies reported that pegfilgrastim increased ANC, reduced infection rates, and improved quality of life over an extended follow‐up period. [ 5 , 7 ].

The current investigation aimed to evaluate the long‐term efficacy and safety of pegfilgrastim administration on morbidity, compliance, and quality of life in patients diagnosed with SCN.

Material and Method

This observation was conducted from 2019 to 2024 at the Immunology, Asthma, and Allergy Research Institute (IAARI) in Tehran University of Medical Sciences (TUMS), Iran, on eight patients with SCN.

Ethical Approval Statement

This trial has been approved by the IAARI. This trial is registered at https://irct.behdasht.gov.ir/ in Iranian Registry of Clinical Trials (IRCT) # IRCT20150125020786N3.

Patients and Criteria

Patients with poor compliance to G‐CSF due to side effects such as bone pain and frequent injections were voluntarily enrolled in the study if they met the following criteria: (1) Adult patients and children with SCN aged over 12 years old. (2) Myeloid maturation arrest in bone marrow before treated with filgrastim. (3) Negative mutation in G‐CSF receptor.

Patients with any of the following criteria were excluded from the study: (1) Refractory to G‐CSF treatment. (2) Secondary neutropenia due to chemotherapy or other diseases. (3) Uncooperative patient for close follow up. (4) Life threatening complications, such as anaphylaxis or splenic rupture. (5) Late complications such as acute myeloid leukemia (AML). (6) Patients with other chronic diseases such as heart or hepatic disease.

Primary and Secondary Endpoints

The primary goal of the study was to achieve and sustain an ANC greater than 1000 cells/µL. Secondary objectives included reducing the frequency of oral ulcers, preventing infections, and hospital admissions, and enhancing treatment adherence and quality of life by extending the intervals between pegfilgrastim injections.

Medical Interventions

All patients had been on a regimen of G‐CSF (PDgrastim, Pooyesh Darou) at an average dose of 10 mcg/kg every other day for a minimum of 5 years, with consistent clinical monitoring, before transitioning to pegfilgrastim (PDlasta, Pooyesh Darou). Following a 72‐h washout period, pegfilgrastim was initiated via subcutaneous injection at a starting dose of 0.1 mg/kg per week (equivalent to 100 mcg/kg/week), to reach an ANC of at least 1000 cells/µL for each person and infection control. The optimal dose, based on body weight, did not exceed 6 mg /7 days. Initial administrations took place in an outpatient hospital setting under close observation, with patients monitored for 2 h post‐injection to detect any serious adverse reactions, such as anaphylaxis.

After 3 months of supervised therapy at the initial dose, maintenance injections were continued at home. Calculated doses ranged from 3 to 6 mg and were given every 7–14 days, adjusted according to each patient's therapeutic response—including infection control, ANC above 1000/µL, body weight, and overall clinical status for at least five years (Figure 1 ; Table 1 ).

Follow‐Ups

Complete blood counts (CBC), including differential and ANC, were assessed twice weekly during the initial two weeks of pegfilgrastim therapy—typically on Days 0, 3, 7, and either Day 10 or 12, based on patient adherence and clinical scheduling. Following this initial monitoring phase, ANC measurements were performed weekly or every 10 to 14 days until the end of the first month of treatment.

From the second month, CBC and a comprehensive panel of biochemical markers—including lactate dehydrogenase (LDH), uric acid, liver function tests, thyroid function tests, lipid profile, and fasting blood sugar (FBS)—were evaluated every month for six months. Thereafter, these parameters were monitored three to four times annually over the five‐year follow‐up period following the initiation of pegfilgrastim therapy.

In this study, the average monthly ANC levels were calculated during the approximately two final years of treatment with G‐CSF prior to initiating pegfilgrastim, as well as before and after pegfilgrastim injections over a five‐year period.

The two‐year average ANC during treatment with G‐CSF (prior to starting pegfilgrastim) was considered the “before treatment” phase and was compared to the five‐year average ANC during pegfilgrastim therapy (the “after treatment” phase) using the t ‐test method (Table 1 ).

Abdominal ultrasound scans were performed at baseline and then annually. The RUNX1 and G‐CSF receptor mutation statuses, along with bone mineral density (BMD), were assessed at baseline and then every two years following the start of pegfilgrastim treatment.

The consistency of follow‐up visits was occasionally affected by the COVID‐19 pandemic, as concerns about health risks and transportation difficulties prevented some patients from attending scheduled in‐person appointments. Nevertheless, all patients were provided with remote monitoring and virtual consultations as needed to maintain continuity of care.

Quality of Life Assessment

Quality of life was evaluated using the validated Farsi version of Functional Assessment of Cancer Therapy‐Neutropenia (FACT‐N) questionnaire. FACT‐N is a self‐report questionnaire specifically developed to assess QoL in patients with neutropenia. [ 10 ] The overall FACT‐N score is derived from five subscales: Physical Well‐Being (PWB), Social/Family Well‐Being (SWB), Emotional Well‐Being (EWB), Functional Well‐Being (FWB), and the Neutropenia Subscale (NS). Assessments were conducted at baseline, every six months, and at the conclusion of the study. A lower score on this scale indicates a better quality of life.

Statistical Analysis

IBM SPSS version 22 (IBM Corporation, NY, USA) and GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA) were used for data analysis and drawing the graphs. The descriptive statistics for quantitative variables were calculated. After calculating the median values of ANC for each patient before and after treatment with pegfilgrastim, a Wilcoxon signed rank test was employed to compare them. Moreover, a repeated measures ANOVA with a Greenhouse‐Geisser correction was utilized to compare the mean quality of life scores among patients. A two‐tailed p ‐value with a statistical significance level < 0.05 was considered.

Result

Eight patients with a history of SCN since the age of 2 months, with a mean age of first dose pegfilgrastim of 17.8 years (range, 13–25 years), were enrolled in the study. Five out of eight patients were male. Four out of the eight patients had a positive family history of SCN, and consanguinity was noted in six out of the eight patients. In genetic analysis, 5 out of 8 patients were diagnosed with a mutation in HAX1 , one had an ELANE gene mutation, one had an SRP19 mutation, and a genetic mutation was not found in one of our patients (Table 1 ).

Variable maintenance dosages were needed for pegfilgrastim based on the patient's therapeutic response and body weight for at least 5 years, including 3 mg every 14 days (for 2 patients), 6 mg every 10 days (for 2 patients), 6 mg every 14 weeks (for 3 patients), and 6 mg every 7 days for one patient (Table 1 ). Following pegfilgrastim treatment, ANC levels showed significant improvement in patients during 5 years of treatment with pegfilgrastim compared to the prior 2 years of assessed ANC on treatment with G‐CSF ( p = 0.008) (Table 1 ). The ANC graph of the patients, during the last 2 years of using G‐CSF and after 5 years of using pegfilgrastim is shown in Figure 2 .

Six patients completed all six scheduled assessments, one completed five assessments due to COVID‐19‐related restrictions, and another completed four assessments because of discontinuation from the study. Improvements across the subscales varied among individuals; however, the overall FACT‐N score showed improvement (lower score) in 6 of the 8 patients. To address missing data, we analyzed the quality of life of patients using two complementary methods. First, we assessed the quality of life of the six patients who completed the questionnaire six times, and their results revealed a significant improvement in quality of life following the intervention ( p = 0.016). Second, we analyzed the quality of life of eight patients who completed four times. Although six of these patients showed improved quality of life after pegfilgrastim, the overall difference did not reach statistical significance ( p = 0.055). Taken together, these results suggest that the intervention likely had a beneficial impact on quality of life (Figure 3 ).

Common side effects, including bone pain, were reported by three patients within the first days of treatment. The treatment was discontinued for one patient due to severe bone pain (No. 8) and G‐CSF was substituted. No cases of acute respiratory distress syndrome (ARDS), thrombocytopenia, splenic rupture, skin rash, or headache were reported. Furthermore, no malignancies or cancers were observed in any of the patients. Two patients required hospitalization and intravenous antibiotic therapy during the five‐year treatment with pegfilgrastim (Table 1 ). Overall, the patients' hospitalization duration did not show a significant difference before and after treatment with pegfilgrastim. However, oral ulcers were decreased in two patients (Table 1 ).

Biochemical tests were normal in all patients except one patient who experienced an increase in uric acid levels during the study, rising from 3.4 to 7.1 mg/dL.

Of the eight patients, one patient with a prior history of splenomegaly (138–146 mm over three years of treatment with G‐CSF) continued to exhibit an increase in spleen size, progressing from 146 to 194 mm over five years of receiving pegfilgrastim. In addition, another patient with a history of hepatosplenomegaly showed no signs of liver or spleen enlargement during pegfilgrastim treatment, as evidenced by physical examinations and routine ultrasound assays.

Before starting pegfilgrastim, 3 out of 8 patients had hip osteopenia, and 4 patients had spine osteopenia. However, two patients developed hip osteopenia after receiving the medication (Table 1 ). There were no G‐CSF receptor and RUNX1 mutations detected in any of the patients.

Discussion

This study evaluated eight patients with SCN, five males and three females, with varied genetic backgrounds ( HAX1 , ELANE , SRP19 , and unidentified mutations), offering valuable insights into transitioning from daily G‐CSF to long‐acting pegfilgrastim. We observed a statistically significant improvement in ANC during pegfilgrastim therapy, with median post‐treatment ANC levels ranging from 1432 to 2106 cells/µL. This benefit is likely due to pegfilgrastim's prolonged half‐life (15–80 h vs. 3.5–3.8 h for filgrastim), which allows for sustained stimulation of myeloid progenitor cells.

A maintenance calculated dose of 3–6 mg every 7–14 days effectively maintained therapeutic ANC levels (>1000 cells/µL) in all but one patient, who discontinued treatment. This longer dosing interval presents a significant practical advantage over daily G‐CSF injections by lowering treatment burden. However, responses varied among patients, influenced by genetic differences. For instance, HAX1 mutation carriers required more frequent dosing, likely due to enhanced neutrophil apoptosis. [ 11 ]. In contrast, a patient with an ELANE mutation maintained stable ANC levels, though some ELANE variants can lead to treatment resistance [ 12 ]. The patient with an SRP19 mutation exhibited fluctuating ANC levels, likely due to ribosomal stress impairing neutrophil maturation, a phenomenon also noted in SRP54 ‐deficient models [ 13 ]. These findings support individualized dosing based on ANC monitoring rather than a uniform weight‐based protocol [ 14 ].

Previous studies have also documented the benefits of pegfilgrastim in SCN. For example, Fioredda et al. reported improved ANC, reduced infections, and enhanced quality of life in two pediatric cases. [ 5 ] Similarly, Beaupain et al. found pegfilgrastim resulted in higher ANC levels than traditional G‐CSF, although the difference was not statistically significant [ 6 ]. These studies suggest pegfilgrastim offers similar efficacy with the added convenience of extended action.

In comparison to these studies, our findings indicate that pegfilgrastim not only improves ANC levels but also improves quality of life metrics among SCN patients. Despite observed improvements in ANC, the observation that overall hospitalization duration and infection frequency were not significantly different before and after pegfilgrastim. Two patients required hospitalization after starting pegfilgrastim, one due to peritonitis and the other for pneumonia. The remaining patients did not experience any severe infections. Oral ulcers were decreased in two patients and remained unchanged in one patient. (Table 1 ) This could be attributed to the relatively small sample size, the specific types and severity of infections experienced by the patients, or the implementation of stringent infection prevention protocols regardless of treatment.

If such a difference between the two treatments does indeed exist, it might be linked to a potential smaller effect on neutrophil chemotaxis or to a lack of complete understanding of how pegfilgrastim works and the best way to use it to prevent infections [ 15 , 16 ].

The potential side effects of G‐CSF and pegfilgrastim necessitate careful monitoring, as they can range from mild symptoms, like headaches and bone pain and asymptomatic splenomegaly, to more severe complications, including ARDS [ 17 , 18 ], aortitis, and haematological malignancies [ 19 , 20 ]. In addition, sporadic studies have documented bone pain, myalgia, erythema, dyspnea, hypotension, sweating, and flushing as potential side effects of this therapy [ 19 , 21 ]. Furthermore, filgrastim can induce platelet aggregation, petechiae, and anemia [ 17 ].

In our study, two out of eight patients experienced self‐limited bone pain after starting pegfilgrastim. For one patient, the pain was effectively managed with nonsteroidal anti‐inflammatory drugs (NSAIDs), while the other required a switch back to G‐CSF. Also, one patient had bone pain with both G‐CSF and pegfilgrastim and he had pre‐existing spine osteopenia and hip osteoporosis before pegfilgrastim. Among the three patients who experienced bone pain, two were receiving 6 mg of pegfilgrastim every 14 days, while one patient was on a maintenance dose of 6 mg /7 days. In contrast, patients receiving doses ranging from 6 mg every 10 days to 3 mg every 14 days did not report bone pain. Our study found no clear association between bone pain and either the dosage of pegfilgrastim or the patients' BMD profile.

Splenic enlargement is frequently present at pretreatment baseline in SCN patients and is common early in the course of treatment with filgrastim [ 22 , 23 ]. In our study, one patient with baseline splenomegaly experienced spleen enlargement over a seven‐year period of combined G‐CSF and pegfilgrastim use, while another patient with hepatosplenomegaly had stable organ size during pegfilgrastim treatment. We observed no serious adverse events (e.g., ARDS, thrombocytopenia, or splenic rupture).

Some patients in this study also had pre‐existing osteopenia or osteoporosis, though the role of long‐term pegfilgrastim in bone density loss remains unclear [ 19 , 24 ]. With limited sample size, no correlation between G‐CSF or pegfilgrastim dosing and osteopenia risk could be established, warranting further research.

While there is concern about G‐CSF potentially contributing to transformation of SCN to myelodysplastic syndrome (MDS) or AML [ 5 , 25 ], no direct link has been established for pegfilgrastim [ 26 ]. Mutations in RUNX1 and the G‐CSF receptor (CSF3R), both of which are associated with hematologic malignancies [ 27 ], were absent in all patients at baseline and during follow‐up, and no cases of cancer were observed.

Anaphylaxis due to pegfilgrastim, though rare, can occur within 10 min of administration and may require repeated epinephrine due to its prolonged systemic presence [ 28 , 29 ]. However, no hypersensitivity or anaphylactic reactions occurred among our patients during outpatient treatment.

Conclusion

Pegfilgrastim demonstrates positive outcomes in SCN patients by significantly improving ANC levels and enhancing quality of life. Despite some limitations, such as unchanged hospitalization rates and a small sample size, these findings support pegfilgrastim as a viable alternative to daily G‐CSF. Continued larger scale researches are needed to refine dosing strategies, evaluate long‐term safety, and explore its impact on infection risk and bone health across broader and more diverse patient populations.

Study Limitations

The main limitations of our study are the small number of patients, which reflects the rarity of SCN, and the limited availability of complete documentation regarding the duration of G‐CSF treatment prior to the last two years assessed. In addition, the COVID‐19 pandemic affected some follow‐up visits, which had to be conducted remotely rather than on site.

Authors Contributions

Mahdiyeh Movahedi : project administration, writing – original draft, writing – review and editing, project administration. Leila Moradi : project administration, writing, review, and editing. Zahra Alizadeh : genetic analysis. Mojtaba Tabatabaei Yazdi : investigation. Shirin Dehbashi : resources. Raheleh Shokouhi Shoormasti : formal analysis. Marzieh Maddah : project administration. Anahita Razaghian : resources. Amir Ali Hamidieh : resources. Mansoureh Shariat : resources. Massoud Houshmand : review and editing. Atefe Alirezaee : genetic analysis. Maryam Akbari : genetic analysis. Mohammad Reza Fazlollahi : project administration, writing – review and editing, validation. Zahra Pourpak : conceptualization, supervision, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

This trial has been approved by the Ethics Committee of the Immunology, Asthma and Allergy Research Institute (IAARI).

Consent

Informed consent was obtained from both the patients and their parents before enrolment.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

We would like to sincerely thank Dr. Rozita Akramian, Prof. Anoshirvan Kazemnejad, Dr. Parichehr Bahreini, and Dr. Nastaran Sabetkish for their valuable support. Also, we thank Pooyesh Darou for providing the medications required for patients during the 5‐year study. We acknowledge the use of ChatGPT (OpenAI, https://openai.com/chatgpt ) and Sider ( https://sider.ai/ ) for grammatical checks and minor paraphrasing during manuscript preparation. All scientific content, analyses, and conclusions remain the sole responsibility of the authors. Finally, we appreciate the FACIT system for its contribution to the validation of the Farsi version of FACT‐N and for granting us permission to use it.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

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