-
International Journal of Radiation... Aug 2023Victims of acute radiation exposure are susceptible to hematopoietic toxicity due to bone marrow damage and loss of mature blood elements. Here, we evaluated cord...
PURPOSE
Victims of acute radiation exposure are susceptible to hematopoietic toxicity due to bone marrow damage and loss of mature blood elements. Here, we evaluated cord blood-derived endothelial progenitor cells (CB-EPCs) as a potential cellular therapy for mitigation of hematologic acute radiation syndrome. CB-EPCs express endothelial cell markers and maintain their growth characteristics beyond 10+ passages without diminishing their doubling capacity. Further, CB-EPCs can be cryopreserved in vapor-phase liquid nitrogen and easily recovered for propagation, making them an attractive nonimmunogenic cellular therapy for off-the-shelf use. Importantly, we show CB-EPCs have the capacity to potently expand adult human bone marrow hematopoietic progenitor cells both in vitro and in vivo.
METHODS AND MATERIALS
To demonstrate the role of CB-EPCs in promoting in vivo human immune reconstitution after irradiation, we employed a novel humanized mouse model established by transplant of CD34 bone marrow cells from 9 unique adult organ donors into immunocompromised NSG-SGM3 mice. The response of the humanized immune system to ionizing irradiation was then tested by exposure to 1 Gy followed by subcutaneous treatment of CB-EPCs, Food and Drug Administration-approved growth factor pegfilgrastim (0.3 mg/kg), or saline.
RESULTS
At day 7, total human bone marrow was decreased by 80% in irradiated controls. However, treatment with either growth factor pegfilgrastim or CB-EPCs increased recovery of total human bone marrow by 2.5-fold compared with saline. Notably, CB-EPCs also increased recovery of both human CD34 progenitors by 5-fold and colony-forming capacity by 3-fold versus saline. Additionally, CB-EPCs promoted recovery of endogenous bone marrow endothelial cells as observed by both increased vessel area and length compared with saline.
CONCLUSIONS
These findings indicate the feasibility of using humanized mice engrafted with adult bone marrow for radiation research and the development of CB-EPCs as an off-the-shelf cellular therapy for mitigation of hematologic acute radiation syndrome.
Topics: Adult; Humans; Mice; Animals; Bone Marrow; Hematopoietic Stem Cells; Endothelial Progenitor Cells; Fetal Blood; Acute Radiation Syndrome; Bone Marrow Cells; Intercellular Signaling Peptides and Proteins; Hematopoietic Stem Cell Transplantation
PubMed: 36792018
DOI: 10.1016/j.ijrobp.2023.02.007 -
Drug Safety Apr 2023Evidence highlights the allergenic potential of PEGylated drugs because of the production of anti-polyethylene glycol immunoglobulins. We investigated the risk of...
BACKGROUND AND OBJECTIVE
Evidence highlights the allergenic potential of PEGylated drugs because of the production of anti-polyethylene glycol immunoglobulins. We investigated the risk of hypersensitivity reactions of PEGylated drugs using the Italian spontaneous adverse drug reaction reporting system database.
METHODS
We selected adverse drug reaction reports attributed to medicinal products containing PEGylated active substances and/or PEGylated liposomes from the Italian Spontaneous Reporting System in the period between its inception and March 2021. As comparators, we extracted adverse drug reaction reports of medicinal products containing the same non-PEGylated active substances and/or non-PEGylated liposomes (or compounds belonging to the same mechanistic class). A descriptive analysis of reports of hypersensitivity reactions was performed. Reporting rates and time to onset of hypersensitivity reactions were also calculated in the period between January 2009 and March 2021. As a measure of disproportionality, we calculated the reporting odds ratio.
RESULTS
Overall, 3865 adverse drug reaction reports were related to PEGylated medicinal products and 11,961 to their non-PEGylated comparators. Around two-thirds of patients were female and reports mostly concerned patients aged between 46 and 64 years. The frequency of hypersensitivity reactions reporting was higher among PEGylated versus non-PEGylated medicinal products (11.7% vs 9.4%, p < 0.0001). The hypersensitivity reaction reporting rates were higher for PEGylated medicinal products versus non-PEGylated medicinal products, with reporting rate ratios that ranged from 1.4 (95% confidence interval 0.8-2.5) for pegfilgrastim versus filgrastim to 20.0 (95% confidence interval 2.8-143.5) for peginterferon alpha-2a versus interferon alpha-2a. The median time to onset of hypersensitivity reactions was 10 days (interquartile range: 0-61) for PEGylated medicinal products, and 36 days (interquartile range: 3-216) for non-PEGylated comparators. Statistically significant reporting odds ratios were observed when comparing the reporting of hypersensitivity reactions for PEGylated versus non-PEGylated medicinal products (reporting odds ratio: 1.3; 95% confidence interval 1.1-1.4). However, when using all other drugs as comparators, the disproportionality analysis showed no association with hypersensitivity reactions for PEGylated nor non-PEGylated medicinal products, thus suggesting that many other triggers of drug-induced hypersensitivity reactions play a major role.
CONCLUSIONS
The findings of this analysis of the Italian spontaneous adverse drug reaction database suggest a potential involvement for PEGylation in triggering drug-related hypersensitivity reactions, especially clinically relevant reactions. However, when comparing both PEGylated and non-PEGylated drugs under study to all other drugs no disproportionate reporting of hypersensitivity reactions was observed, probably due to a masking effect owing to the presence in the same database of other medicinal products increasing the threshold required to highlight a safety signal when the entire database is used as a reference.
Topics: Humans; Female; Middle Aged; Male; Adverse Drug Reaction Reporting Systems; Liposomes; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Italy; Databases, Factual
PubMed: 36790561
DOI: 10.1007/s40264-023-01277-5 -
Cancer Reports (Hoboken, N.J.) Apr 2023Pegfilgrastim is recommended in docetaxel plus ramucirumab (DTX + RAM) therapy for recurrent nonsmall cell lung cancer (NSCLC) because of the associated frequency of...
BACKGROUND
Pegfilgrastim is recommended in docetaxel plus ramucirumab (DTX + RAM) therapy for recurrent nonsmall cell lung cancer (NSCLC) because of the associated frequency of febrile neutropenia (FN). However, the FN occurs less frequently when the dose of DTX is reduced because of other adverse events, such as appetite loss and oral mucositis.
METHODS AND RESULTS
Twenty-two patients with recurrent NSCLC who received DTX + RAM therapy at the Hiroshima Prefectural Hospital. The cut-off value which is the most unlikely to cause FN without the combined use of pegfilgrastim was set using a receiver operating characteristic (ROC) curve. This was created according to the dose of DTX and the presence or absence of the onset of FN. We compared the incidence of FN when a DTX dose above and below the cut-off value was used. The ROC curve showed that 48 mg/m was the best cut-off value that predicted whether FN was likely to occur when pegfilgrastim was not used concurrently. The incidence of FN was 26.1% for DTX ≥48 mg/m and 5.1% for DTX <48 mg/m .
CONCLUSIONS
Pegfilgrastim can be discontinued when the dose of DTX is reduced to <48 mg/m due to nonhematological toxicities.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Drug Tapering; Lung Neoplasms; Ramucirumab
PubMed: 36727271
DOI: 10.1002/cnr2.1793 -
Journal of the Advanced Practitioner in... Nov 2022Pegfilgrastim is recommended to be administered at least 24 hours following the completion of chemotherapy, yet some clinicians use a same-day administration protocol.... (Review)
Review
BACKGROUND
Pegfilgrastim is recommended to be administered at least 24 hours following the completion of chemotherapy, yet some clinicians use a same-day administration protocol. In this meta-analysis, we compared the incidence of chemotherapy-induced (febrile) neutropenia (CIN/FN) as well as CIN/FN-related chemotherapy disruptions in cancer patients provided with pegfilgrastim same-day vs. next-day.
METHODS
Six databases were searched for comparative studies of same-day vs. next-day pegfilgrastim administration. Fixed or random-effects meta-analyses were conducted to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS
Thirteen studies were included in this meta-analysis. The FN OR for same-day vs. next-day administration was 1.48 (95% CI = 1.06-2.08) across all cycles, attributable mainly to studies of high FN risk (OR = 2.46, 95% CI = 1.04-5.83) vs. intermediate FN risk regimens (OR = 1.41, 95% CI = 0.95-2.10), and breast cancer (OR = 3.15, 95% CI = 1.24-8.01) vs. non-Hodgkin lymphoma (NHL; OR = 1.48, 95% CI = 0.98-2.23) and gynecologic cancers (OR = 0.64, 95% CI = 0.11-3.85). Where available, ORs for first cycle of chemotherapy, grades 3 and/or 4 CIN, and chemotherapy dose delays or reductions were in line with these findings.
CONCLUSION
In this independent study, same-day pegfilgrastim administration may or may not increase the likelihood of FN, grades 3 and/or 4 CIN, and chemotherapy dose reductions or delays; and this may be a function of the myelotoxicity of the regimens (elevated in high-risk but not intermediate-risk regimens) and tumor type (elevated in breast but not in NHL or gynecologic cancers). With due caution, same-day pegfilgrastim administration may be safe and beneficial in intermediate-risk regimens and selected tumor types.
PubMed: 36727017
DOI: 10.6004/jadpro.2022.13.8.6 -
Journal of Managed Care & Specialty... Feb 2023Real-world evidence on the comparative effectiveness of pegfilgrastim biosimilars compared with the originator product is limited. To compare the risk of febrile... (Comparative Study)
Comparative Study
Real-world evidence on the comparative effectiveness of pegfilgrastim biosimilars compared with the originator product is limited. To compare the risk of febrile neutropenia (FN) among users of pegfilgrastim biosimilars (pegfilgrastim-jmdb and pegfilgrastim-cbqv) and the originator product. A retrospective cohort study was conducted using 2019 IBM MarketScan databases to assess comparative effectiveness of pegfilgrastim originator and biosimilars for prevention of FN among patients receiving myelosuppressive chemotherapy. Patients with cancer, including breast, lung, colorectal, esophageal and gastric, pancreatic, prostate, ovarian, and non-Hodgkin lymphomas, initiating myelosuppressive chemotherapy courses were selected. We further selected patients who used pegfilgrastim originator and biosimilars within 3 days of chemotherapy completion. FN-associated hospitalizations were measured by diagnosis codes. After 1:1 propensity score matching, we used equivalence (with a margin of 6%) hypothesis tests to compare FN-related hospitalization risk in the first cycle and across all cycles between biosimilars and originator users. A total of 2,045 patients were included, of which 445 (21.8%) used pegfilgrastim-jmdb, 636 (31.1%) used pegfilgrastim-cbqv, and 964 (47.1%) used pegfilgrastim originator. After matching, 13 out of 445 originator users and 17 out of 445 pegfilgrastim-jmdb users developed FN after the first chemotherapy cycle (risk difference was 0.9%; < 0.001 for equivalence test indicating statistical equivalence). After matching, 14 out of 633 originator users and 16 out of 633 pegfilgrastim-cbqv users developed FN (risk difference was 0.32%; < 0.001 for equivalence test indicating statistical equivalence). Results across all cycles (including the first cycle) were consistent with that in the first cycle. In this real-world study of patients with cancer receiving myelosuppressive chemotherapy, there was no difference in FN risk between patients receiving pegfilgrastim originator and biosimilars in the first cycle and across all cycles. These results add further to the current evidence on pegfilgrastim biosimilars and support wider adoption of pegfilgrastim biosimilars among payers, providers, and patients. Future studies assessing the tolerability, side effects, and other safety issues of pegfilgrastim biosimilars are needed.
Topics: Humans; Male; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Febrile Neutropenia; Granulocyte Colony-Stimulating Factor; Neoplasms; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Comparative Effectiveness Research; Antineoplastic Agents; Filgrastim
PubMed: 36705287
DOI: 10.18553/jmcp.2023.29.2.119 -
Cancer Research and Treatment Jul 2023We investigated the consistent efficacy and safety of eflapegrastim, a novel long-acting granulocyte-colony stimulating factor (G-CSF), in Koreans and Asians compared...
Eflapegrastim versus Pegfilgrastim for Chemotherapy-Induced Neutropenia in Korean and Asian Patients with Early Breast Cancer: Results from the Two Phase III ADVANCE and RECOVER Studies.
PURPOSE
We investigated the consistent efficacy and safety of eflapegrastim, a novel long-acting granulocyte-colony stimulating factor (G-CSF), in Koreans and Asians compared with the pooled population of two global phase 3 trials.
MATERIALS AND METHODS
Two phase 3 trials (ADVANCE and RECOVER) evaluated the efficacy and safety of fixed-dose eflapegrastim (13.2 mg/0.6 mL [3.6 mg G-CSF equivalent]) compared to pegfilgrastim (6 mg based on G-CSF) in breast cancer patients who received neoadjuvant or adjuvant docetaxel/cyclophosphamide. The primary objective was to demonstrate non-inferiority of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN) in cycle 1, in Korean and Asian subpopulations.
RESULTS
Among a total of 643 patients randomized to eflapegrastim (n=314) or pegfilgrastim (n=329), 54 Asians (29 to eflapegrastim and 25 to pegfilgrastim) including 28 Koreans (14 to both eflapegrastim and pegfilgrastim) were enrolled. The primary endpoint, DSN in cycle 1 in the eflapegrastim arm was non-inferior to the pegfilgrastim arm in Koreans and Asians. The DSN difference between the eflapegrastim and pegfilgrastim arms was consistent across populations: -0.120 days (95% confidence interval [CI], -0.227 to -0.016), -0.288 (95% CI, -0.714 to 0.143), and -0.267 (95% CI, -0.697 to 0.110) for pooled population, Koreans and Asians, respectively. There were few treatment-related adverse events that caused discontinuation of eflapegrastim (1.9%) or pegfilgrastim (1.5%) in total and no notable trends or differences across patient populations.
CONCLUSION
This study may suggest that eflapegrastim showed non-inferior efficacy and similar safety compared to pegfilgrastim in Koreans and Asians, consistently with those of pooled population.
Topics: Female; Humans; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Filgrastim; Granulocyte Colony-Stimulating Factor; Neutropenia; Polyethylene Glycols; Republic of Korea; East Asian People
PubMed: 36701846
DOI: 10.4143/crt.2022.987 -
International Journal of Radiation... 2023A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue...
PURPOSE
A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue toxicities in exposed victims. With the advent of advanced treatment options for the mitigation of hematological injuries, there are likely to be survivors of total body irradiation (TBI) exposures as high as 8-10 Gy. These survivors are at risk for a range of delayed multi-organ morbidities including progressive renal failure.
MATERIAL AND METHODS
Here, we established the WAG/RijCmcr rat as an effective model for the evaluation of medical countermeasures (MCM) for acute hematologic radiation syndrome (H-ARS). The LD dose for adult and pediatric WAG/RijCmcr rats was determined for both sexes. We then confirmed the FDA-approved MCM pegfilgrastim (peg-GCSF, Neulasta®) mitigates H-ARS in adult male and female rats. Finally, we evaluated survival and renal dysfunction up to 300 d post-TBI in male and female adult rats.
RESULTS
In the WAG/RijCmcr rat model, 87.5% and 100% of adult rats succumb to lethal hematopoietic acute radiation syndrome (H-ARS) at TBI doses of 8 and 8.5 Gy, respectively. A single dose of the hematopoietic growth factor peg-GCSF administered at 24 h post-TBI improved survival during H-ARS. Peg-GCSF treatment improved 30 d survival from 12.5% to 83% at 8 Gy and from 0% to 63% at 8.5 Gy. We then followed survivors of H-ARS through day 300. Rats exposed to TBI doses greater than 8 Gy had a 26% reduction in survival over days 30-300 compared to rats exposed to 7.75 Gy TBI. Concurrent with the reduction in long-term survival, a dose-dependent impairment of renal function as assessed by blood urea nitrogen (BUN) and urine protein to urine creatinine ratio (UP:UC) was observed.
CONCLUSION
Together, these data show survivors of H-ARS are at risk for the development of delayed renal toxicity and emphasize the need for the development of medical countermeasures for delayed renal injury.
Topics: Male; Rats; Female; Animals; Humans; Dose-Response Relationship, Radiation; Acute Radiation Syndrome; Disease Models, Animal; Kidney; Survivors; Whole-Body Irradiation
PubMed: 36688956
DOI: 10.1080/09553002.2023.2170491 -
Frontiers in Oncology 2022Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of... (Review)
Review
Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs' structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs' half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination's route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta.
PubMed: 36686781
DOI: 10.3389/fonc.2022.1026377 -
World Journal of Oncology Dec 2022Severe neutropenia, including febrile neutropenia, is a major toxicity of systemic chemotherapy that leads to delays in treatment, higher costs, and mortality. Severe...
BACKGROUND
Severe neutropenia, including febrile neutropenia, is a major toxicity of systemic chemotherapy that leads to delays in treatment, higher costs, and mortality. Severe neutropenia may occur during neoadjuvant chemotherapy even when the patients are free from known risk factors. Pegfilgrastim, a covalent conjugant of filgrastim that stimulate the production of neutrophils, is used for prevention. The current study aimed to reveal the characteristics of patients who need pegfilgrastim for primary prophylaxis to prevent severe neutropenia, including febrile neutropenia and grade 3 neutropenia, during neoadjuvant chemotherapy.
METHODS
A retrospective analysis of 83 patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy was performed. The factors which associated with severe neutropenia were examined by univariate and multivariate analyses.
RESULTS
Severe neutropenia developed in one of 22 patients (5%) with pegfilgrastim for primary prophylaxis and in 17 of 61 patients (28%) without it. In 83 patients, the incidence of severe neutropenia was significantly decreased in the patients with pegfilgrastim for primary prophylaxis shown by the univariate analysis (P = 0.023) and multivariate analysis (P = 0.030). In 61 patients without pegfilgrastim for primary prophylaxis, the univariate analysis showed that severe neutropenia was associated with tumor size (P = 0.004), clinical stage (P = 0.009), and cancer antigen 15-3 (CA15-3) (P = 0.026). The multivariate analysis showed that clinical stage was associated with severe neutropenia (P = 0.021).
CONCLUSIONS
The current study demonstrated that advanced stage is a risk for severe neutropenia in patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy. Given that prophylaxis with pegfilgrastim was associated with significantly lower incidence of severe neutropenia, patient with advance stage breast cancer may benefit from pegfilgrastim during neoadjuvant chemotherapy.
PubMed: 36660211
DOI: 10.14740/wjon1530 -
Journal of Pharmaceutical Health Care... Jan 2023Pegfilgrastim is widely used for the prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy for various types of cancer. However,...
BACKGROUND
Pegfilgrastim is widely used for the prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy for various types of cancer. However, pegfilgrastim-induced bone pain (PIBP) is a relevant adverse event occurring during cancer treatment. Thus, we aimed to determine the risk factors for PIBP in real-world clinical practice.
MAIN BODY
We retrospectively collected the clinical records of patients who received pegfilgrastim to support myelosuppressive chemotherapy with at least a 10% risk of FN between 2015 and 2018 at our center. Patients received pegfilgrastim 3.6 mg between days 2 and 7 after chemotherapy administration (day 1) for primary or secondary prophylaxis against FN. All adverse events were recorded according to the Common Terminology Criteria for Adverse Events. Patients who experienced intermittent bone pain in the back, femur, or other anatomic sites after the pegfilgrastim administration were considered to have PIBP. To evaluate the relationship between PIBP incidence and patient characteristics, we performed univariate and multivariate logistic regression analyses to calculate the odds ratios (ORs) of possible risk factors for PIBP. We analyzed the data of 305 patients (median age: 63 years), who underwent 1220 chemotherapy cycles with pegfilgrastim per cycle. Univariate analysis revealed that female sex (vs. male sex), younger age (< 55 years vs. ≥ 55 years), and solid cancers (vs. hematologic cancers) had significantly higher ORs (p < 0.05). However, only younger age (< 55 years) was an independent risk factor for PIBP on multivariate analysis (OR 3.62, 95% confidence interval 1.51-8.69, p = 0.004).
CONCLUSIONS
Younger age (< 55 years) was significantly associated with a higher risk of PIBP among patients receiving chemotherapy with a ≥ 10% risk of FN. Therefore, oncologists should meticulously formulate management plan for PIBP in younger patients after administering pegfilgrastim.
PubMed: 36627672
DOI: 10.1186/s40780-022-00272-9