Mecapegfilgrastim for prophylaxis of febrile neutropenia in children and adolescents with rhabdomyosarcoma or Ewing sarcoma: a prospective, single-arm, pilot study.

BACKGROUND: The chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES. METHODS: In this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 µg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 109/L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile. RESULTS: In total, 2 of the 30 (6.7%, 95% CI: 0.82-22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28-45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 109/L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0-5 years and the 13-18 years groups, and 2 patients experienced FN in the 6-12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0-5 years, 6-12 years, and 13-18 years groups, respectively. CONCLUSION: Mecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted. TRIAL REGISTRATION: This clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019.

Effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for invasive breast cancer: a systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022.

INTRODUCTION: Chemotherapy for breast cancer can cause neutropenia, increasing the risk of febrile neutropenia (FN) and serious infections. The use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis has been explored to mitigate these risks. To evaluate the efficacy and safety of primary G-CSF prophylaxis in patients with invasive breast cancer undergoing chemotherapy. METHODS: A systematic literature review was conducted according to the "Minds Handbook for Clinical Practice Guideline Development" using PubMed, Ichushi-Web, and the Cochrane Library databases. Randomized controlled trials (RCTs) and cohort studies assessing using G-CSF as primary prophylaxis in invasive breast cancer were included. The primary outcomes were overall survival (OS) and FN incidence. Meta-analyses were performed for outcomes with sufficient data. RESULTS: Eight RCTs were included in the qualitative analysis, and five RCTs were meta-analyzed for FN incidence. The meta-analysis showed a significant reduction in FN incidence with primary G-CSF prophylaxis (risk difference [RD] = 0.22, 95% CI: 0.01-0.43, p = 0.04). Evidence for improvement in OS with G-CSF was inconclusive. Four RCTs suggested a tendency for increased pain with G-CSF, but statistical significance was not reported. CONCLUSIONS: Primary prophylactic use of G-CSF is strongly recommended for breast cancer patients undergoing chemotherapy, as it has been shown to reduce the incidence of FN. While the impact on OS is unclear, the benefits of reducing FN are considered to outweigh the potential harm of increased pain.

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

[Timing of Administration of Pegfilgrastim and Prophylaxis for Febrile Neutropenia for Patients with Early Breast Cancer Receiving Chemotherapy].

Febrile neutropenia(FN)causes a prolonged treatment schedule and decreased relative dose intensity(RDI)during cancer chemotherapy, which adversely affects prognosis. In recent years, dose-dense(dd)chemotherapy has been used as adjuvant chemotherapy for patients with breast cancer based on the results of improved disease-free survival according to meta-analysis data. Regarding neoadjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer, taxanes and trastuzumab with the addition of pertuzumab have shown higher pathological complete response rates and elevated incidences of FN. One hundred seventy-six patients received pegfilgrastim(PEG)prophylaxis between January 2011 and January 2023. Until 2019, the median day of PEG prophylaxis was day 4 from chemotherapy completion(days 2- 3, 14 cases; day 4, 41 cases; and day 5, 8 cases)with antibiotic prophylaxis in 58 patients(92%). FN was observed in 19 cases(30%). The RDIs of TC and FEC were 96.8% and 96.0%, respectively. Meanwhile, the median day of PEG prophylaxis after 2020 was day 2 from chemotherapy completion(days 2-3, 108 cases; day 4, 4 cases; and day 5, 1 case)without antibiotic prophylaxis. FN was not observed in any of the cases. The RDI of all regimens was 99.7%. Although there were some differences in chemotherapy regimens, an earlier timing of PEG prophylaxis(especially 24-48 hours from chemotherapy completion)has been shown to reduce the incidence of FN and increase the RDI.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Prophylactic pegfilgrastim reduces febrile neutropenia in ramucirumab plus docetaxel after chemoimmunotherapy in advanced NSCLC: post hoc analysis from NEJ051.

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.

Efbemalenograstim alfa, an Fc fusion protein, long-acting granulocyte-colony stimulating factor for reducing the risk of febrile neutropenia following chemotherapy: results of a phase III trial.

PURPOSE: Evaluate the safety and efficacy of efbemalenograstim alfa for reducing the risk of febrile neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy. METHODS: A phase III, randomized, double-blind, placebo-controlled study was conducted. A total of 122 subjects received up to 4 cycles of TA chemotherapy (75 mg/m2 docetaxel + 60 mg/m2 doxorubicin). Patients were randomized in a 2:1 ratio to subcutaneously inject a single 20 mg of efbemalenograstim alfa or placebo on day 2 of cycle 1, and all subjects received efbemalenograstim alfa on day 2 of cycles 2, 3, and 4. Duration of severe (grade 4) neutropenia (DSN), depth of neutrophil nadir, incidence of febrile neutropenia (FN), time to neutrophil recovery, and safety information were recorded. RESULTS: For the primary endpoint, the mean DSN in cycle 1 was 1.3 days and 3.9 days for efbemalenograstim alfa and placebo respectively (95% CI, 2.3, 3.4). As the lower bound of the 95% CI was > 0, superiority of efbemalenograstim alfa over placebo can be declared. In addition, the incidence of FN in Cycle 1 was lower in efbemalenograstim alfa group than in placebo group (4.8% vs. 25.6%; p = 0.0016). Patients in the efbemalenograstim alfa group required less intravenous antibiotics (3.6% vs. 17.9%; p = 0.0119). Most adverse events were consistent with those expected for breast cancer patient receiving TA chemotherapy. CONCLUSION: Efbemalenograstim alfa is effective and safe for significantly decreasing the duration of severe neutropenia and the incidence of febrile neutropenia in breast cancer patients who are receiving TA chemotherapy. TRIAL REGISTRATION: NCT02872103, August 19, 2016.

Incidence and risk factors for febrile neutropenia of patients with diffuse large B-cell lymphoma receiving R-CHOP-21 in China.

OBJECTIVE: Febrile neutropenia (FN) is a serious complication of patients with diffuse large B-cell lymphoma (DLBCL) receiving R-CHOP-21. The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) can significantly reduce the risk of FN. International guidelines recommend G-CSFs for patients receiving chemotherapy with FN risk of 20% or 10 to 20% with defined risk factors. However, there are few studies on the incidence and risk factors of FN in patients with DLBCL receiving R-CHOP-21, especially in patients without primary G-CSF prophylaxis. METHODS: We conducted a retrospective analysis for the clinical data of 103 patients with DLBCL who underwent first R-CHOP-21 without primary G-CSF prophylaxis. The objective of the assessment was the incidence and risk factors of FN after the first chemotherapy cycle. RESULTS: After the first chemotherapy cycle, the incidence of FN was 20.4%. Multivariate analysis showed that age ≥ 65 years, bone marrow involvement, albumin < 35 g/L, and average relative dose intensity ≥ 80% were independent risk factors for FN. According to risk factors, we created a risk score system. The incidence of FN in the low-, intermediate- and high-risk groups was 5.6%, 17.2%, and 61.9%, respectively. CONCLUSION: Our data indicated that R-CHOP-21 itself is associated with a high-risk regiment for FN. We recommend that intermediate/high-risk patients should actively consider primary G-CSF prophylaxis to reduce the incidence of FN after chemotherapy.

Profilaxis con levofloxacina en pacientes neutropénicos / Levofloxacin prophylaxis in neutropenic patients

La profilaxis con fluorquinolonas ha demostrado utilidad en la prevención de infecciones en pacientes neutropénicos de alto riesgo. Nuestro objetivo fue describir y comparar las características clínicas, microbiológicas, terapéuticas y la evolución en pacientes durante el primer episodio de neutropenia febril, según hubieran o no recibido profilaxis con levofloxacina. Fue un estudio prospectivo observacional, que incluyó los episodios de internados por neutropenia febril, (febrero 1997 a noviembre 2014), y los primeros episodios en un mismo paciente en diferentes internaciones; en total fueron 946 episodios. En 821 el episodio de neutropenia febril fue de alto riesgo, y en 264 (27.9%) se administró profilaxis con levofloxacina. Este grupo estaba compuesto por mayor proporción de neutropenias febriles de alto riesgo (99.2% vs. 82.3%, p = 0.0001) y casos con trasplante de células progenitoras hematopoyéticas (67.8% vs. 29.3%, p = 0.0001) comparado con los que no recibieron profilaxis, y presentó una frecuencia similar de infecciones clínicamente documentadas pero una menor proporción de infecciones microbiológicamente documentadas (28.8% vs. 37.5%, p = 0.012). Las bacteriemias en el grupo con quimioprofilaxis fueron más frecuentemente causadas por organismos multirresistentes (OMR) (34.5% vs. 17.3%, p = 0.007) y por enterobacterias productoras de beta lactamasas de espectro extendido (19.0% vs. 3.8%, p = 0.0001). En ese grupo con profilaxis la proporción que recibió tratamiento antibiótico empírico adecuado fue menor (69.7% vs. 83.7%, p = 0.009). La evolución fue similar en ambos grupos. Sugerimos que cuando se observe un aumento en la frecuencia de infecciones por OMR en esta población se considere la interrupción de la profilaxis antibiótica con levofloxacina.

Fluorquinolone-prophylaxis has proven useful in preventing infections in high risk neutropenic patients. The objective of this study was to describe the clinical, microbiological and therapeutic characteristics, and outcome of patients in the first episode of febrile neutropenia, comparing those who received levofloxacin prophylaxis with those who didn't. It was a prospective observational study that included all the episodes of inpatients with febrile neutropenia (February 1997- November 2014), also including the first episode in a same patient in different hospitalizations. Of 946 episodes here included, 821 presented high risk febrile neutropenia. A total of 264 cases (27.9%) received levofloxacin prophylaxis. This group consisted of a higher proportion of high risk febrile neutropenia (99.2% vs. 82.3%, p = 0.0001) and patients that had received an hematopoietic stem cell transplant (67.8% vs. 29.3%, p = 0.0001) compared to those who didn't receive prophylaxis. Those who received levofloxacin prophylaxis presented a similar frequency of clinically diagnosed but a lower proportion of microbiologically documented infections (28.8% vs. 37.5%, p = 0.012) than those who didn´t receive prophylaxis. The episodes of bacteremia that occurred in the first group were more frequently caused by multidrug resistant bacteria (MDRB) (34.5% vs. 17.3%, p = 0.007) and by extended spectrum beta lactamase producing Enterobacteriaceae (19% vs. 3.8%, p = 0.0001). The group that received prophylaxis had a lower proportion of adequate empirical antibiotic treatment (69.7% vs. 83.7%, p = 0.009), with similar outcomes in both groups. We suggest that levofloxacin prophylaxis should be stopped whenever there is a rise in the frequency of MDRB infections in this population.

Evaluación de efectividad y seguridad comparativas del filgrastim para la prevención de neutropenia febril, en pacientes con cáncer sometidos a quimioterapia citotóxica / Comparative effectiveness and safety assessment of filgrastim for the prevention of febrile neutropenia in cancer patients undergoing cytotoxic chemotherapy

Introducción: la neutropenia febril es una complicación frecuente en pacientes con cáncer sometidos a quimioterapia citotóxica. Entre las opciones para prevenir esta complicación está el filgrastim. Esta evaluación de tecnología se desarrolló para informar la toma de decisiones en el marco de la actualización integral del Plan Obligatorio de Salud para Colombia. Objetivo: examinar la efectividad y seguridad comparativas del filgrastim para la prevención de neutropenia febril, en pacientes con cáncer sometidos a quimioterapia citotóxica. Metodología: se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS. La tamización de referencias se realizó por dos revisores de forma independiente y la selección de estudios fue hecha por un revisor, aplicando los criterios de elegibilidad predefinidos en el protocolo de la evaluación. La calidad de las revisiones sistemáticas se valoró con la herramienta AMSTAR. Se realizó una síntesis narrativa y meta-analítica de las estimaciones del efecto para las comparaciones y desenlaces de interés. Resultados: los hallazgos de efectividad y seguridad de la presente evaluación se basan en tres revisiones sistemáticas de calidad media, tres meta-análisis de comparaciones directas (dos publicados y uno de novo) y ocho ensayos clínicos cabeza a cabeza, siete de ellos aleatorizados, incluyendo dos estudios de no inferioridad, para un total aproximado de 1072 pacientes. Se identificó evidencia de los efectos del filgrastim comparado con pegfilgrastim para una variedad de desenlaces incluyendo, neutropenia febril, hospitalización asociada, mortalidad, retraso en la quimioterapia, eventos adversos globales, serios y específicos. La evidencia disponible corresponde a adultos con cáncer de mama, linfoma no Hodgkin y enfermedad de Hodgkin, y población pediátrica con sarcomas. También se presentan los eventos adversos reportados en la etapa post-clínica con el uso del filgrastim. Conclusiones: la evidencia identificada en esta evaluación de tecnología, muestra efectos mixtos en la efectividad y seguridad del filgrastim para la prevención de neutropenia febril, en pacientes con cáncer sometidos a quimioterapia citotóxica: los resultados de efectividad indican que este medicamento puede ser similar o menos efectivo frente a su comparador y para algunos desenlaces existe incertidumbre. Respecto a la seguridad comparada del filgrastim, esta puede ser similar o incierta. A juicio de los expertos clínicos, el balance entre los beneficios y riesgos no favorece al filgrastim ni a su comparador.(AU)

Neutropenia inducida por fármacos antineoplásicos: utilización de los factores estimulantes de colonias de granulocitos / Antineoplastic drug-induced neutropenia: use of granulocyte colony stimulating factors

Los tratamientos farmacológicos del cáncer cursan con neutropenia en un elevado porcentaje de casos. La utilización de factores estimulantes de colonias de granulocitos (G-CSF) puede evitar las complicaciones asociadas a la neutropenia. Las guías clínicas europeas y americanas recomiendan su uso profiláctico cuando se espera una incidencia de neutropenia febril (NF) mayor del 20 % con el tratamiento antineoplásico, o cuando existen factores de riesgo adicionales. Su utilización se recomienda para tratar episodios de NF pero no episodios neutropénicos afebriles. Otras indicaciones aprobadas son la movilización de células madre previa al tratamiento quimioterápico de altas dosis y para la correcta cumplimentación de la farmacoterapia programada en términos de densidad de dosis e intensidad de dosis (AU)

Neutropenia is a frequent adverse event of the pharmacologic treatment of cancer. Morbidity and mortality-associated neutropenia can be successfully treated and prevented with granulocyte-colony stimulating factors (G-CSF). European and American Guidelines recommend their prophylactic use when the expected percentage of febrile neutropenia exceeds 20 % or there are concomitant risk factors. Afebrile neutropenia is not considered to benefit from G-CSF treatment. Other approved indications include stem cell mobilization, and an adequate delivery of dose-intense and dose-dense chemotherapy regimens (AU)