Mecapegfilgrastim prophylaxis for neutropenia in patients with non-myeloid malignancies: A Chinese nationwide real-world study.

Introduction

Neutropenia represents a prevalent and grave adverse effect within the chemotherapy regimen for different malignancies, with febrile neutropenia (FN) emerging as a major associated clinical complication [ 1 ]. The manifestation of neutropenia, with or without concurrent FN, critically undermines the delivery of chemotherapeutic agents at the intended relative dose intensity and adherence to planned treatment cycles, consequently diminishing the potential for optimal therapeutic efficacy [ 2 ]. Furthermore, this condition significantly predisposes patients to profound infections that can lead to fatal outcomes [ 3 ]. Epidemiological data suggests the incidence of chemotherapy-induced neutropenia (CIN) to be in the range of 25-30%, carrying a mortality rate that can reach 11% [ 4 ]. Studies illustrates FN rates during solid tumor chemotherapy hovering between 13 and 21%, with an accentuated incidence often witnessed during the first cycle of treatment (23-36%) [ 5 ]. The FN related mortality rates in patients with solid tumors, lymphoma, and leukemia were 8.0%, 8.9%, and 14.3%, respectively [ 6 ]. Those findings highlight the need for management programs aimed at reducing FN related incidence rate and mortality, thereby ensuring the integrity and success of chemotherapy.

Granulocyte colony-stimulating factor (G-CSF), a pivotal hematopoietic growth factor, promotes the maturation of granulocyte progenitors into effector cells, notably neutrophils, and is extensively employed to prevent neutropenia resultant from myelosuppressive chemotherapy [ 7 ]. Originally formulated as a short-acting agent necessitating daily dosing, long-acting formulations, such as pegylated G-CSF, were developed to surmount the associated burdens. Mecapegfilgrastim, a pegylated recombinant human G-CSF (PEG-rhG-CSF), is an exemplar of this prolonged-acting class [ 8 ]. Two pivotal phase III clinical studies have substantiated that mecapegfilgrastim reduces the incidence and duration of severe absolute neutrophil count (ANC) reductions during the first cycle of chemotherapy in patients with non-small cell lung cancer and breast cancer, achieving parity or surpassing the efficacy of its short-acting rhG-CSF counterparts [ 9 , 10 ]. Concomitantly, mecapegfilgrastim has demonstrated a decrement in FN incidence, with a safety profile characterized by predominantly mild adverse effects, such as bone pain, asthenia, and pyrexia [ 9 , 10 ]. Additional small-scale real-world studies (RWS) further demonstrate the reduction in the occurrence of grade ≥ 3 neutropenia and FN [ 11 ]. Moreover, a pharmacoeconomic analysis has illuminated the cost-effectiveness of mecapegfilgrastim in the breast cancer cohort, presenting a more favorable economic profile compared to rhG-CSF [ 12 ]. Endorsed by the National Medical Products Administration of China in May 2018, mecapegfilgrastim has been approved for mitigating the risk of infection manifested by FN in adult patients with non-myeloid malignancies undergoing chemotherapy [ 8 ].

Multiple clinical studies have demonstrated the benefit of mecapegfilgrastim in a variety of cancer types [ 9 , 10 ]. Despite these findings, there remains a gap in evidence from RWS. Thus, this large-scale, prospective RWS aims to evaluate the safety and effectiveness of mecapegfilgrastim in the prophylaxis of moderate to severe CIN in patients with non-myeloid malignancies. This study seeks to substantiate previous clinical outcomes with robust real-world evidence, thereby providing a comprehensive assessment of mecapegfilgrastim as support treatment in routine practice.

Methods

Study design and patients

This was a prospective RWS, conducted across the 46 centers in China, enrolling patients with non-myeloid malignancies. The inclusion criteria were as follows: (1) patients who provided written informed consent and voluntarily participated in the study; (2) pathological or cytohistological confirmation of non-myeloid malignancies, encompassing both solid tumors and hematologic malignancies; (3) eligibility for administration of mecapegfilgrastim as determined by the investigator; and (4) age of 18 years or older. Exclusion criteria included: women who were pregnant or breastfeeding; and patients with known hypersensitivity to mecapegfilgrastim, rhG-CSF, PEG-rhG-CSF, or any other E. coli-derived biologic agents. All patients provided informed consent. The study protocol was approved by the ethics committees of all participating centers, and the study was conducted in accordance with the Declaration of Helsinki.

Treatment regimens

In this study, all the patients received a subcutaneous injection of mecapegfilgrastim 24 h following the completion of each chemotherapy cycle. The recommended dose was a fixed 6 mg per injection, or alternatively, tailored to the patient’s body weight at 100 µg/kg. Patients were categorized based on the use of mecapegfilgrastim into primary prophylaxis and secondary prophylaxis groups. Primary prophylaxis was defined as intervention for patients without prior history of chemotherapy, or those who have previously undergone chemotherapy but did not experience any neutropenia, or only had grade 1–2 neutropenia. Secondary prophylaxis was defined as intervention for patients with a history of chemotherapy who have previously experienced grade 3–4 neutropenia or FN. Additionally, based on the anti-tumor treatment regimen used in the first cycle, patients were stratified into low, intermediate, and high risk of FN judged by investigators [ 13 ]. In cases where a patient’s neutrophil count remained below 0.5 × 10 9 /L for over 24 h post-mecapegfilgrastim administration, short-acting rhG-CSF was employed as a remedial treatment until normalization of neutrophil levels. The study monitored patients across four chemotherapy cycles. Upon conclusion of the study, subsequent treatment decisions were collaboratively made by the investigators and patients. All adverse events encountered during the treatment were recorded and graded in accordance with the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0.

Study outcomes

The primary outcome of this study was safety, specifically treatment-related adverse events (TRAEs). Secondary outcomes included: the incidence of grade 3 or higher neutropenia during the mecapegfilgrastim treatment (defined as ANC < 1.0 × 10 9 /L); the rate of grade 4 neutropenia (ANC less than 0.5 × 10 9 /L); incidence of FN (defined as an oral temperature > 38.3 °C or axillary temperature > 38.1 °C, or two consecutive measurements within 2 h of oral temperature > 38.0 °C or axillary temperature > 37.8 °C, coupled with an ANC < 0.5 × 10 9 /L or expected to fall below this threshold); the rates of chemotherapy delays > 7 days, infection rates, and antibiotic use.

Statistics analysis

In this study, the primary outcome was evaluated based on the safety set (SS), while secondary outcomes were analyzed using the full analysis set (FAS). The FAS comprised all the patients who signed informed consent, were enrolled in the study, and had at least one record of mecapegfilgrastim administration. The SS consisted of the patients with at least one mecapegfilgrastim administration and safety records.

All statistical analyses were conducted using SAS version 9.4. The primary approach was descriptive analysis. For continuous variables, means and standard deviations were reported, while for categorical variables, the number and percentage were described. Subgroup analyses, including categories such as primary or secondary prophylaxis, age (≤ 65, > 65, and ≥ 75 year old), risk of FN in the first cycle, tumor types, and chemotherapy regimens spanning 1-, 2-, 3-, or 4-week cycles, were conducted for effectiveness outcomes in the first cycle and across all cycles.

Results

Baseline characteristics of patients

Between June 2019 and March 2022, this study initially screened 2,935 patients, of which 2,859 were successfully enrolled and included in both the FAS and the SS. The cohort’s mean age was 56.3 years. Notably, patients aged over 65 years constituted 27.0% of the study population. Female patients represented a higher proportion at 60.0%, compared to males at 40.0%. The Eastern Cooperative Oncology Group performance status (ECOG PS) scores indicated that the majority (94.4%) of the patients had a score of 0 to 1. Breast cancer was the most common (820 cases, 28.7%), followed by small cell lung cancer (449 cases, 15.7%), and non-small cell lung cancer (260 cases, 9.1%). Of the 191 patients with hematologic malignancies, 190 were diagnosed with lymphoma and 1 with multiple myeloma. The lymphoma subtypes included diffuse large B-cell lymphoma ( n = 94), follicular lymphoma ( n = 23), peripheral T-cell lymphoma ( n = 20), NK/T-cell lymphoma ( n = 6), marginal zone lymphoma ( n = 3), mantle cell lymphoma ( n = 2), Burkitt lymphoma ( n = 3), primary mediastinal large B-cell lymphoma ( n = 4), Hodgkin lymphoma ( n = 4), and chronic lymphocytic leukemia/small lymphocytic lymphoma ( n = 2). An additional 29 cases were categorized as lymphoma of unspecified subtype. Regarding clinical staging, 48.5% of the patients were categorized as stages III-IV. Risk stratification for FN in the first cycle of chemotherapy was classified as low for 13.4% of patients, intermediate for 56.0%, and high for 28.6%. Our study involved 2,293 patients in the primary prophylaxis group and 420 in the secondary prophylaxis group. The baseline characteristics were generally consistent across the primary prophylaxis and secondary prophylaxis groups (Table 1 ). Patient monitoring continued over four chemotherapy cycles, with 2,318 patients progressing to the second cycle, 1,490 to the third, and 1,096 to the fourth cycle. The total number of cycles observed was 7,763.

Safety profiles

A total of 329 patients (11.5%) experienced TRAEs. The most common TRAEs included white blood cell count increased (3.6%), neutrophil count increased (1.6%), and white blood cell count decreased (1.3%). The incidence of grade 3 or higher TRAEs was 1.0%, specifically including neutrophil count decreased (0.3%), white blood cell count decreased (0.3%), and lymphocyte count decreased (0.2%) (Table 2 ). Additionally, treatment-related serious adverse events (TRSAEs) were recorded in four patients (0.1%), comprising one case of hyperhidrosis, allergic dermatitis, asthenia, and allergic gastroenteritis each.

Effectiveness outcomes in cycle 1 and across all cycles

In cycle 1 of our study, which included 2,859 patients, grade ≥ 3 neutropenia was observed in 236 patients (8.3%), grade 4 neutropenia in 125 patients (4.4%), and FN in 24 patients (0.8%). The infection rate was recorded at 2.0%, and antibiotic use was necessary for 5.1% of patients (Table 3 ).

Patients aged ≤ 65 years showed an incidence of grade ≥ 3 neutropenia at 8.8%, grade 4 neutropenia at 4.8%, and FN at 1.1%. In contrast, the > 65 years age group had lower incidences of grade ≥ 3 and grade 4 neutropenia at 6.7% and 3.1%, respectively, and a notably lower FN occurrence at 0.3%. Within the subset aged ≥ 75 years, consisting of 132 patients, only one (0.8%) developed grade ≥ 3 neutropenia, with no occurrences of grade 4 neutropenia or FN. Stratification by FN risk in the first cycle indicated that low-risk patients had a 6.0% incidence of grade ≥ 3 neutropenia and 2.6% for grade 4, whereas high-risk patients showed higher incidences at 10.5% and 6.6%, respectively. Hematologic malignancies were associated with the highest incidences of both grade ≥ 3 and grade 4 neutropenia at 16.2% and 10.5%, in contrast to gastric cancer, which exhibited markedly lower rates at 1.2% and 0.6% (Table 3 ).

Across all cycles, the rates of grade ≥ 3 neutropenia was 5.8%, grade 4 neutropenia was 2.7%, and FN was 0.3%. Concurrently, the overall infection rate and antibiotic use across all cycles were 1.5% and 3.4%, respectively (Table 3 ). Incidences of grade ≥ 3 neutropenia reduced to 4.3% in cycle 2, 4.9% in cycle 3, and 4.0% in cycle 4, while grade 4 neutropenia fell to 1.9%, 2.0%, and 1.4% across these cycles. FN was most prevalent in the first cycle (0.8%) and showed a marked decrease in subsequent cycles, with no cases reported in cycles 2 and 4, and only one case in cycle 3 (Table S1 ). In addition, the mean ANC values remain within normal levels throughout the treatment duration (Fig. 1 ).

Effectiveness outcomes in patients receiving combined targeted and immunotherapy

In cycle 1, the incidence of grade ≥ 3 neutropenia was 5.9% in patients receiving combined targeted therapy, with a 4.1% incidence of grade 4 neutropenia and a FN rate of 1.3%. Across all cycles, these rates decreased to 4.9% for grade ≥ 3 neutropenia, 2.5% for grade 4 neutropenia, and 0.6% for FN. In patients treated with combined immunotherapy, the incidence of grade ≥ 3 neutropenia in cycle 1 was 6.2%, with 3.5% experiencing grade 4 neutropenia and 0.4% developing FN. Across all cycles, these outcomes improved, with grade ≥ 3 neutropenia occurring in 3.9% of patients, grade 4 neutropenia in 1.9%, and FN in only 0.2% (Table 3 ).

Effectiveness by prophylaxis category in cycle 1

In cycle 1 of our study, the primary prophylaxis group experienced a lower incidence of grade ≥ 3 neutropenia at 7.9% compared to 11.2% in the secondary prophylaxis group. Grade 4 neutropenia was also less prevalent in the primary prophylaxis group at 4.1%, in contrast to 6.7% in the secondary prophylaxis group. The incidence of FN was similar across groups, with the primary prophylaxis group showing a slightly higher rate at 0.9% compared to 0.7% in the secondary prophylaxis group. The infection rates and antibiotic usage were comparable among the different groups, with the primary prophylaxis group reporting an infection rate of 2.0% and antibiotic use at 5.4%. Notably, chemotherapy delays of ≥ 7 days in cycle 2 were less frequent in the primary prophylaxis group at 15.1% versus 16.4% in the secondary prophylaxis group (Table 4 ).

Within the primary prophylaxis group, patients were further categorized based on their prior chemotherapy history and the neutropenia experienced (Table S2). Patients without any history of neutropenia exhibited a 10.2% incidence of grade ≥ 3 neutropenia and a 5.5% incidence of grade 4 neutropenia. FN was present in 1.3% of these patients, with an infection rate of 1.4% and antibiotic use reported at 6.2%. Conversely, patients who had previously experienced grade 1–2 neutropenia had lower incidences of grade ≥ 3 and grade 4 neutropenia, at 5.8% and 2.9%, respectively. FN occurred in 0.6% of these patients, with a slightly higher infection rate at 2.6% and antibiotic use at 4.6%. Notably, chemotherapy delays of ≥ 7 days in cycle 2 were reported at 10.7% for patients without prior neutropenia, whereas those with a history of grade 1–2 neutropenia had a significantly higher delay rate at 19.1%.

Discussion

In this large-scale RWS, 2859 patients from 46 hospitals nationwide were enrolled to evaluate the safety and efficacy of mecapegfilgrastim in preventing moderate to severe CIN in patients with non-myeloid malignancies. To the best of our knowledge, this investigation stands as the first large-scale study examining the long-acting G-CSF in a real-world setting within a Chinese population. Our findings indicate that mecapegfilgrastim offers favorable safety and efficacy in the prophylaxis of CIN among patients with non-myeloid malignancies. These results not only corroborate previous clinical trial data [ 9 , 10 ], but also extend the evidence into the broader, more variable context of routine clinical practice, thereby reinforcing the role of mecapegfilgrastim as a key regimen in the supportive care management for oncology patients.

In the current study, the incidence of TRAEs associated with mecapegfilgrastim was documented at 11.5%, with the most frequently reported TRAEs being white blood cell count increased (3.6%), neutrophil count increased (1.6%), and white blood cell count decreased (1.3%). The incidence of TRSAEs was minimal, representing a mere 0.1% of the cohort. This TRSAE profile is consistent with previous study, while the TRAE frequency is comparatively lower. Contrastingly, a phase III randomized controlled trial focusing on mecapegfilgrastim for patients with advanced non-small cell lung cancer reported TRAE rates between 27% and 32%, with no patient experiencing TRSAE [ 9 ]. Furthermore, a RWS by Fontaine et al. on the efficacy and safety of lipegfilgrastim reported TRAE and TRSAE frequencies of 39.6% and 6.5%, respectively [ 14 ]. Among the AEs associated with G-CSF, the predominant manifestation is mild to moderate bone pain, with an occurrence rate ranging from 10 to 30% [ 15 , 16 ]. Contrasting with the broader data, our study observed a markedly lower incidence of bone pain at 1.0%. Notably, none of the patients reported experiencing bone pain of grade 3 or higher severity. The lower incidences in our study may be attributable to the high percentage of patients receiving concomitant medications (97.3%), which potentially obfuscates the causal relationship between mecapegfilgrastim and AEs. Despite these considerations, our findings and previous studies underscores the substantial safety profile of mecapegfilgrastim.

In this investigation, the first chemotherapy cycle witnessed the highest incidences of grade ≥ 3 and grade 4 neutropenia, at 8.3% and 4.4%, respectively. Notably, there was a marked reduction in these incidences over subsequent cycles, with grade ≥ 3 neutropenia diminishing to 4.0% by the fourth cycle and grade 4 neutropenia to 1.4%. Similarly, FN was most prevalent initially at 0.8% but showed a substantial decrease thereafter, indicating a potential cumulative protective effect of mecapegfilgrastim across treatment cycles. This declining pattern in neutropenia rates across treatment cycles concurs with findings from a phase III breast cancer trial, which also noted a decrease in the incidence of grade ≥ 3 and grade 4 neutropenia with successive chemotherapy cycles [ 10 ]. Such data advocate for the sustained administration of mecapegfilgrastim, potentially enhancing patient outcomes through consistent prophylaxis against neutropenia.

The subgroup analysis sheds light on the differential impact of mecapegfilgrastim across various patient demographics. Notably, younger patients (≤ 65 years) experienced higher rates of grade ≥ 3 neutropenia, grade 4 neutropenia, and FN compared to their older patients (> 65 years). This suggests a potential age-related variability in response to prophylactic treatment. Significantly, the subset of patients aged ≥ 75 years showed promising outcomes with only one (0.8%) experiencing grade ≥ 3 neutropenia and no reported cases of more severe complications. The lower incidence of neutropenic complications in elderly patients may be attributable to attenuated chemotherapy intensity, a common approach in geriatric oncology to balance efficacy with tolerability [ 17 ]. Since elderly patients have often been underrepresented in clinical trials [ 9 , 10 ], our findings offer valuable insights into the broader applicability of mecapegfilgrastim, including its potential benefits for older populations.

For FN risk management, this study offers a comprehensive analysis aligned with recent guidelines which advocate for risk assessment and stratified prophylaxis based on individual risk profiles [ 13 ]. Our findings revealed that even among low-risk patients, the occurrence of significant grade ≥ 3 was 6.0%, with grade 4 neutropenia at 2.6%. In high-risk individuals, these figures rose to 10.5% and 6.6%, respectively. Notably, higher incidences were seen in patients with hematologic malignancies and breast cancer, which likely reflects the more intensive chemotherapy regimens associated with these cancers [ 10 , 18 ]. The study highlights the critical need for personalized risk evaluation and indicates that prophylactic intervention is particularly crucial for high-risk patients. It also suggests that even patients considered low-risk could benefit from a reassessment of their risk factors and potential prophylactic measures. Such an individualized approach could enhance patient outcomes by minimizing the interruption of chemotherapy due to neutropenic complications.

In this study, the most patients were treated with mecapegfilgrastim as primary prophylaxis. The primary prophylaxis is often favored for patients who are at a higher risk of developing FN, either due to specific risk factors or because they are receiving high-risk chemotherapy regimens [ 19 ]. Our findings indicate that the use of primary prophylaxis was associated with a notably lower incidence of grade ≥ 3 neutropenia at 7.9% and grade 4 neutropenia at 4.1% during the first cycle, as opposed to the secondary prophylaxis group which exhibited rates of 11.2% and 6.7%, respectively. This trend aligns with other studies, including a retrospective study on lymphoma patients that showed consistently lower rates of grade ≥ 3 neutropenia with primary prophylaxis [ 20 ]. Further supporting this trend, European studies have found that patients receiving primary prophylaxis with PEG-rhG-CSF also had lower instances of grade ≥ 3 neutropenia compared to those receiving secondary prophylaxis [ 14 , 21 ]. These findings suggest that primary prophylaxis with mecapegfilgrastim may be more effective than secondary prophylaxis in preventing neutropenia.

The increasing use of novel therapeutic agents, including PD-1/PD-L1 inhibitors, monoclonal and bispecific antibodies, and small molecule targeted therapies, has markedly improved outcomes for cancer patients. However, these advancements often come at the cost of significant hematologic toxicity, particularly neutropenia, which remains a common complication in combination treatments. Despite the growing prevalence of these novel agents, there is a notable lack of data addressing effective strategies to mitigate neutropenia when they are used alongside traditional chemotherapy regimens. Our RWS provides critical insight into the role of mecapegfilgrastim in preventing chemotherapy-induced neutropenia, particularly in patients receiving these newer therapeutic agents. The results of this study demonstrate that mecapegfilgrastim, when used in combination with immunotherapy and targeted therapies, significantly reduces the incidence of severe neutropenia and FN, thus enhancing the overall tolerability of treatment. This enables patients to maintain the intensity of therapy without interruption, which is crucial for achieving optimal therapeutic outcomes.

This multicenter RWS has some limitations. Due to the absence of protocol-driven interventions, reliance on routine clinical care may have resulted in incomplete capture of certain clinical parameters, such as the duration of neutropenia and time to hematologic recovery, which could influence the granularity and precision of outcome assessments. In addition, the patients using various drugs and treatments simultaneously with mecapegfilgrastim may make it complex to attribute adverse events to mecapegfilgrastim. This complexity may lead to an underestimation of the incidence of TRAE. Additionally, although no cases of G-CSF-induced vasculitis were identified, the absence of routine pre- and post-treatment imaging, such as computed tomography scans, may have limited our ability to detect subclinical or radiographically subtle cases.

In summary, this RWS confirms the safety and effectiveness of mecapegfilgrastim in preventing moderate to severe CIN in patients with non-myeloid malignancies. Mecapegfilgrastim is mainly used as a primary prevention drug, which is related to the low incidence rate of neutropenia. This indicates that early implementation of mecapegfilgrastim may be a strategy to reduce hematological adverse reactions to chemotherapy in clinical practice.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We would like to express our gratitude to all patients and their families as well as the investigators and site staff, who participated in this research. We thank Liu Yang and Qiao Xue (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals) for data interpretation, Du Wang and Xinwei Zhong (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals) for statistical support, and Zhongjiang Chen (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals) for medical writing assistance according to Good Publication Practice Guidelines.

Author contributions

Shukui Qin, Ruihua Xu, and Jun Ma were responsible for the conception and design of the study. Shukui Qin, Yanxia Shi, Peifen Fu, Nong Xu, Chenyu Mao, Yong Chen, Yongsheng Wang, Huiqiang Huang, Xin Huang, Yongqing Li, Haijiao Yan, Yumin Yao, Gang Cheng, Zhe Yang, Ningling Zhang, Guifang Zhang, Minbin Chen, Hua Jiang, Zhangxia Ren, Liang Chen, Lifang Ding, Ruihua Xu, and Jun Ma contributed to data collection. Shukui Qin, Ruihua Xu, and Jun Ma directed the statistical analysis. All authors were involved in data interpretation, manuscript writing, and review, and all approved the final manuscript for submission.

Funding

None.

Data availability

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

Declarations

Ethics approval and consent to participate

The study protocol was approved by the ethics committees of Nanjing Tianyinshang Hospital of China Phamaceutical University, Sun Yat-Sen University Cancer Center, and Harbin Institute of Hematology and Oncology, and the study was conducted in accordance with the Declaration of Helsinki. All patients provided informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Ruihua Xu, Email: xurh@sysucc.org.cn.

Jun Ma, Email: drmajun123@163.com.

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Associated Data

Supplementary Materials

Supplementary Material 1

Data Availability Statement

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