Pegylated Granulocyte Colony-stimulating Factor Research Articles

Acute Methotrexate Toxicity Managed with Leucovorin and Pegylated Granulocyte Colony-stimulating Factor: A Report of Two Cases and Review of Literature

Acute methotrexate (MTX) toxicity is most commonly due to overdose of the drug, which may be due to the patient's noncompliance to doctor's orders or physician's prescription error. Other causes include acute renal failure, concomitant use of other drugs, and genetic susceptibility. MTX toxicity presents with pancytopenia, mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure. Treatment involves a polypragmatic approach which includes vigorous hydration, urinary alkalinization, administration of leucovorin, and glucarpidase. Administration of granulocyte colony-stimulating factor should be considered in cases of severe neutropenia. Here, we present two cases of acute MTX toxicity in chronic plaque psoriasis presenting with ulceration of psoriatic lesions and mucosal ulceration successfully treated with leucovorin and pegylated granulocyte colony-stimulating factor (G-CSF). This case report demonstrates that G-CSF might be lifesaving by contributing to rapid reconstitution of leukopoiesis.

Optimal timing of prophylactic pegylated G-CSF after chemotherapy administration for patients with cancer: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration. Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data. Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive. Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.

Effectiveness and safety of empegfilgrastim (Extimia®, BIOCAD) in patients with lymphoproliferative diseases receiving cytotoxic therapy: results of LEGERITY, a multicenter retrospective-and-prospective observational post-marketing study

Aim. To evaluate the effectiveness and safety of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) to reduce the incidence and duration of neutropenia, the incidence of febrile neutropenia (FN) and infections associated with FN in patients with lymphoproliferative diseases receiving myelosuppressive therapy.
 Materials and methods. The paper presents the results of a multicenter retrospective-and-prospective observational post-marketing study of the safety and effectiveness of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) in patients with lymphoproliferative diseases receiving cytotoxic therapy. Initially, the study was defined as retrospective-and-prospective. However, only 2 of 671 (0.3%) patients were included retrospectively. Thus, the study is based on the evaluation of prospectively collected data. The analysis describes the characteristics and treatment of 671 patients diagnosed with lymphoma who received one or more cycles of chemotherapy in the LEGERITY study. The endpoints of interest included the incidence of grade 3–4 neutropenia, FN, and grade 3–4 infectious complications, the frequency of antibiotic therapy, and the incidence of all adverse reactions in patients who received at least one dose of the study medication.
 Results. A total of 671 patients were enrolled in the study, the majority having B-cell non-Hodgkin lymphoma (428/671, 64%) and Hodgkin lymphoma (211/671, 31%). The mean age was 54 years (18–84); 35% (236/671) of patients were elderly (over 60). The number of injections of empegfilgrastim for the entire observation period was 3093 (n=671). Adverse events were reported in 57/3093 (1.8%) cases. The most common adverse events were mild to moderate ossalgia and myalgia (27/671, 4%), back pain, and arthralgia (12/671, 1.8%), which did not require drug therapy. Two patients developed serious adverse reactions – CTCAE v.5 grade 4 hypotension events. 529 (78.8%) patients received at least 4 courses of chemotherapy. FN was reported in 14 (2.6%) patients and did not require antimicrobial therapy.
 Conclusion. The final analysis results confirm the high clinical efficacy and safety of the Russian original pegylated granulocyte colony-stimulating factor empegfilgrastim (Extimia®) in patients with indolent and aggressive lymphomas. The data obtained from real-world clinical practice demonstrate a favorable safety and tolerability profile of empegfilgrastim in all age groups, including the elderly population.

Open-labeled, multicenter phase II study of prophylactic administration of pegylated granulocyte colony-stimulating factor in relapsed or refractory multiple myeloma who received pomalidomide-based regimens (KMM170).

Pegylated granulocyte colony-stimulating factor (G-CSF) has been widely used for preventing febrile neutropenia in various types of cancer treatment. In the present study, we prospectively evaluated the safety and efficacy of pegfilgrastim as a primary prophylaxis of febrile neutropenia and infection among patients with relapsed refractory multiple myeloma (RRMM) treated with pomalidomide-based regimens. Thirty-three patients with RRMM who received pomalidomide and dexamethasone (Pd) with or without cyclophosphamide (PCd) were enrolled in this study. Twenty-eight patients were treated with PCd and 5 patients were treated with Pd. All patients were given pegfilgrastim subcutaneously with a single administration performed on the first day of each cycle as primary prophylaxis until the fourth cycle. The median age of the patients was 75 (range 56-85), and the median prior line of therapy was 2 (range 2-6). Seventeen patients (51.5%) had any grade of neutropenia and 20 (60.6%) had any grade of thrombocytopenia before starting pomalidomide treatment. During the 4 cycles of treatment, grade 3 or more neutropenia occurred in 17 patients (51.5%), and 4 (12.1%) experienced grade 3 or more febrile neutropenia. Grade 3 or more infections occurred in 5 patients (15.2%). Interestingly, the patients with markedly increased ANC of more than 2 x 109/L compared to baseline ANC after 7 days of pegfilgrastim at 1st cycle of treatment showed a significantly lower incidence of grade 3-4 neutropenia. The most common adverse event of pegfilgrastim was fatigue, and all the adverse events caused by pegfilgrastim were grade 1 or 2. And there was no significant change in the immune cell population and cytokines during the administration of pegfilgrastim. Considering that this study included elderly patients with baseline neutropenia, pegylated G-CSF could be helpful to prevent severe neutropenia, febrile neutropenia, or infection in patients with RRMM.

Prevention and treatment of neutropenia in routine clinical practice. How to improve the quality of cancer care and reduce treatment costs?

Neutropenia is a common complication during anti-cancer therapy. Risk factors for febrile neutropenia, its diagnostic criteria, and methods of its prevention and treatment have been well described. In this article, we demonstrated the need to assess cost effectiveness of primary prevention of complications associated with polychemotherapy and treatment of neutropenia, as well as the need to analyze their incidence. Individual risk assessment of febrile neutropenia, implementation of the antimicrobial drug registry, and administration of pegylated granulocyte colony-stimulating factor reduced the incidence of neutropenia, its duration, and the number of antimicrobial drugs used. This, in turn, improved the quality of healthcare and optimized the use of hospital resources.

Clinical Impact of Antipolyethylene Glycol (PEG) Antibody in Hematological Patients Administered PEGylated-Granulocyte Colony-Stimulating Factor.

Polyethylene glycol (PEG) is a polymer covalently attached to proteins to improve their half-life and efficacy. We previously reported that the PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) is immunogenic, which could adversely impact drug efficacy and safety in animal models. Here, we analyzed the relationship between anti-PEG antibody titers and the clinical impact of PEG-G-CSF in 19 hematological patients. A gradual decrease of anti-PEG antibody titers from baseline was observed after PEG-G-CSF administration. Of the 19 participants, 10 were assessed for noninfectious fever after the first administration of PEG-G-CSF and three experienced this reaction. The receiver operating characteristic curve revealed that the cut-off values of pretreated anti-PEG IgM and IgG titers for noninfectious fever were set at 5.0 and 96.6U/mL, respectively. All patients who experienced noninfectious fever had anti-PEG antibody titers above this cut-off value (P=.033). An enzyme-linked immunosorbent assay revealed that some anti-PEG antibodies in patients with anti-PEG antibody titers above the cut-off value reacted with the PEGylated liposome. These results indicate the reactivity of the anti-PEG antibodies to PEGylated therapeutics observed in hematologic patients and the possibility of the relationship between high titers of anti-PEG antibodies and the development of adverse events after PEG-G-CSF administration.

Evaluation of mammary gland health in dairy cows treated by pegylated granulocyte colony-stimulating factor

The study aimed to determine the effect of the treatment by pegbovigrastim on the health of the mammary gland in dairy cows. Experimental animals were successively treated with 15 mg of pegylated bovine granulocyte colony-stimulating factor (bG-CSF, pegbovigrastim, PEG, Imrestor, Elanco) 10 ± 3 days before expected parturition and 1 day after actual parturition. Cows in the control group remained without treatment. The occurrence of clinical and subclinical mastitis in dairy cows during the first three months postpartum, and bacteriological findings in milk and milk yield were evaluated after preventive pegbovigrastim treatment. The influence of pegbovigrastim, as an additional treatment of mastitis caused by Streptococcus uberis in dairy cows on the standard course of treatment, was evaluated. The average number of antimicrobial (AML) interventions necessary for healing, the proportion of cows with 1, 2, 3 and more AML interventions, milk somatic cell count before treatment, 1 and 2 months after treatment and average milk withdrawal time were evaluated between groups. The results of the study did not find positive effects of pegbovigrastim on any evaluated variables.

290P Use of PEG G-CSF is associated with decreased myelotoxicity in dexrazoxane-used aggressive non-Hodgkin lymphoma patients

Dexrazoxane (DXZ) is indicated as a cardioprotective agent for elderly aggressive lymphoma receiving doxorubicin. Several studies reported an apparent increase in the severity of myelosuppression when dexrazoxane was used. Prophylactic use of pegylated granulocyte colony stimulating factor (PEG G-CSF) is known to reduce the incidence of both neutropenia and febrile neutropenia. We conducted a retrospective study to evaluate prophylactic effect of PEG G-CSF in elderly aggressive lymphoma treated with CHOP-based regimen and cardioprotective dexrazoxane.

1025P DOcetaxel (DOC) plus RAmucirumab (RAM) with pegylated Granulocyte-colONy stimulating factor (PEG-G-CSF) for elderly patients with advanced non-small cell lung cancer (NSCLC): A phase II trial (DRAGON study: WJOG9416L)

DOC monotherapy is an optional Japanese standard of care for chemo-naïve elderly patients (pts) with advanced NSCLC. DOC+RAM showed superior survival benefit over DOC in second-line for NSCLC. A Japanese phase II study comparing DOC+RAM and DOC showed febrile neutropenia (FN) incidence of one-third in DOC+RAM. DOC+RAM could be a promising candidate for elderly NSCLC pts, but such high FN incidence is a critical concern. We thus adopted a routine primary prophylactic PEG-G-CSF to reduce FN and maximize the efficacy of DOC+RAM in elderly pts.

G-CSF-induced carotid inflammation.

A 58-year-old woman with newly diagnosed metastatic duodenal adenocarcinoma presented at the emergency department of Brigham and Women's Hospital (Boston, MA, USA) in June, 2021, with worsening right-sided neck and jaw pain and difficulty swallowing. 9 days beforehand, the patient had started chemotherapy with FOLFOXIRI (fluorouracil continuous infusion 1600 mg/m2/day for 46 h, folinic acid 200 mg/m2, irinotecan 165 mg/m2, and oxaliplatin 85 mg/m2) and bevacizumab (5 mg/kg). 7 days prior to presentation, the patient was given pegfilgrastim (pegylated granulocyte colony-stimulating factor [G-CSF], 6 mg) for primary prevention of chemotherapy-induced neutropenia.

Effectiveness and safety of empegfilgrastim (Extimia®, BIOCAD) in patients with lymphoproliferative diseases who receive cytotoxic therapy: results of LEGERITY, the second interim analysis of multicenter retrospective-and-prospective observational post-marketing study

Aim. To assess effectiveness and safety of Extimia BIOCAD (INN: empegfilgrastim) used to decrease the rate and duration of neutropenia, the rate of febrile neutropenia and infections that manifest in febrile neutropenia in patients with lymphoproliferative diseases who receive myelosuppressive therapy.
 Materials and methods. The paper presents the results of the second interim analysis of multicenter retrospective-and-prospective observational post-marketing study of effectiveness and safety of Extimia BIOCAD (INN: empegfilgrastim) in patients with lymphoproliferative diseases who receive cytotoxic therapy. The second stage of the interim analysis describes patient characteristics, therapy used in 221 patients with morphologically confirmed lymphoma who received one or more cycles of chemotherapy as part of LEGERITY study. The endpoints of interest included the rate of Grade 3/4 neutropenia in patients, after the first cycle of any therapy line; the rate of febrile neutropenia; the rate of Grade 3/4 infectious complications; the rate of antibacterial therapy prescriptions; and the assessment of the relative dose-intensity of received chemotherapy. Additionally, the incidence rate of all adverse drug reactions (ADRs) was assessed in patients who received at least one dose of the study drug; the incidence rate of all serious ADRs was assessed in patients who received at least one dose of the study drug; the incidence rate of Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 3/4 ADRs in patients who received at least one dose of the study drug; the rate of study drug discontinuations due to ADRs was also assessed.
 Results. As of the second interim analysis, LEGERITY included 221 patients with various indolent and aggressive lymphomas. Median age of the patients was 53 years (1982). A group of older patients (over 60 years of age) accounted for 34% of the study population. Patients received 1 injection of Extimia per chemotherapy cycle. Grade 3/4 neutropenia was registered in 6.7% (n=14) patients. Overall, all-grade neutropenia was reported in 21.4% (n=44) patients. Febrile neutropenia was reported in 2.9% cases. Severe infections and the use of antimicrobials were reported in no patients throughout the CT period and after each cycle of therapy. Most commonly reported adverse reactions included mild-to-moderate ossalgias (6.8%) and myalgias, back pain, and arthralgias (3.2%), that did not require pharmaceutical therapy. One (0.5%) patient had a severe adverse drug reaction a CTCAE 5.0 Grade 4 hypotension episode.
 Conclusion. Interim analysis results support high effectiveness and safety of the Russian original pegylated granulocyte colony-stimulating factor of empegfilgrastim (Extimia) in patients both with indolent and aggressive lymphomas. Real world evidence demonstrates a favourable safety and tolerability profile of empegfilgrastim in all age groups, including in the aging population. As of the moment of the interim analysis publication, the study is ongoing. Final conclusions on the safety and effectiveness of empegfilgrastim (Extimia) are to be drawn upon the study completion.

339 A serum exocrine enzyme as a biomarker of response to immunotherapy in type 1 diabetes.

OBJECTIVES/GOALS: We assessed the relationship between C-peptide preservation and a serum exocrine pancreatic enzyme (trypsin) in a recently concluded clinical trial. We hypothesized that immunomodulatory treatment resulting in improved beta-cell function would be associated with improved trypsin levels in subjects with recent-onset type 1 diabetes (T1D). METHODS/STUDY POPULATION: In a three-arm, randomized, double-masked, placebo-controlled trial 'Antithymocyte Globulin (ATG) and pegylated granulocyte colony stimulating factor (GCSF) in New Onset Type 1 Diabetes’ 89 subjects with recent-onset T1D (duration <100 days) were enrolled and randomized to 3 groups: low-dose ATG (2.5 mg/kg IV) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), low-dose ATG alone, and placebo. We compared longitudinal serum levels of an exocrine enzyme (trypsin) in a subset of responders to therapy (defined as subjects with at least 60% of baseline area under the curve (AUC) C-peptide levels at 96 weeks, n=4) versus placebo 'responders’ (n=2) and non-responders (n=25), and treated (n=19) versus placebo (n=12) subjects at baseline, 2 weeks, and 6 months after treatment. RESULTS/ANTICIPATED RESULTS: There was no observed difference in treated (n=20) versus placebo (n=12) longitudinal trends in trypsin levels when compared to baseline levels. However, responders to immunotherapy (n=4) had 6 month trypsin levels that were 114% of baseline whereas placebo subject 'responders’ (n=2), placebo subjects (n=10), and non-responders to immunotherapy (n=15) had trypsin levels that were 81-93% of baseline (unpaired T test p=0.05). Overall, we found that serum trypsin, a marker of exocrine pancreatic function, had a normal upward trend in new-onset T1D subjects who responded clinically to immunotherapy but declined in subjects who did not respond or who were not treated. These results were bordering on statistical significance but did not reach significance, likely due to the small sample size. DISCUSSION/SIGNIFICANCE: An improvement in trypsin, a marker of exocrine function, after response to immunotherapy in new-onset T1D may be due to a direct impact on exocrine function versus an indirect effect from improved beta cell function. Future studies will be needed to confirm our findings in a larger sample and evaluate the mechanism for improved exocrine function.

Granulocyte colony-stimulating factor-associated aortitis.

A 55-year-old woman presented to the emergency department at a general hospital in Japan with a 3-day history of fever and upper back pain. She was diagnosed with metastatic pancreatic cancer and underwent systemic chemotherapy with a modified FOLFIRINOX regimen (oxaliplatin 65 mg/m2, leucovorin 200 mg/m2, irinotecan 150 mg/m2, fluorouracil 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-h continuous infusion). Following the chemotherapy, she received 3·6 mg of intravenous pegylated granulocyte colony-stimulating factor (PEG-G-CSF) as prophylaxis for febrile neutropenia.

Higher efficacy of oral etoposide for mobilization of peripheral blood stem cells in patients with multiple myeloma

This study compares the efficacy, toxicity, hematopoietic recovery, and cost of stem-cell mobilization using intermediate-dose cyclophosphamide (IDCy) plus granulocyte colony-stimulating factor (G-CSF) compared with etoposide (VP-16) plus pegylated granulocyte colony-stimulating factor (PEG-rhG-CSF) in multiple myeloma (MM) patients. Two hundred forty-four consecutive patients undergoing mobilization with IDCy (3-3.5 g/m2) plus G-CSF (n = 155) were compared with patients receiving VP-16 plus PEG-rhG-CSF (n = 89), including oral etoposide (n = 65) and intravenous etoposide (n = 24). Compared with IDCy, VP-16 use was associated with significantly higher median peak peripheral blood CD34 + cell count (8.20 [range: 1.84-84] × 106/kg vs 4.58 [range: 0.1-27.9] × 106/kg, P= .000), and ideal CD34 + cell yield of more than 6 × 106/kg (56.8% vs 35.1%, P= .001), notably with a higher efficacy in oral VP-16 use compared with IDCy use (CD 34 + cell counts: median peak peripheral blood 5.87 vs 4.58 × 106/kg and ≥6 × 106/kg [48.4% vs 35.1%]). The median number of apheresis courses was reduced from two in the IDCy group to one in the VP-16 group (P = .000). IDCy use was associated with significantly more frequent episodes of neutropenia (70.2% vs 35.2%; P= .000), intravenous antibiotic use (13.2% vs 11.4%; P= .672), and hospitalization (P = .000). The recoveries of neutrophils and platelets after autologous stem-cell transplantation were significantly faster in the VP-16 group compared with the IDCy group (P = .000). Our data indicate robust stem-cell mobilization in MM patients with VP-16 delivered either orally or intravenously. When compared with intravenous VP-16, oral VP-16 mobilization was associated with significantly more convenient, lower average total costs, and especially decreased the risk of hospital visits and exposure.

Intravitreal Injection of Long-Acting Pegylated Granulocyte Colony-Stimulating Factor Provides Neuroprotective Effects via Antioxidant Response in a Rat Model of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) may cause severe visual loss following direct or indirect head trauma which may result in optic nerve injuries and therefore contribute to the subsequent loss of retinal ganglion cells by inflammatory mediators and reactive oxygen species (ROS). Granulocyte colony-stimulating factor (G-CSF) provides the anti-inflammatory and anti-oxidative actions but has a short half-life and also induces leukocytosis upon typical systemic administration. The purpose of the present study was to investigate the relationship between the anti-oxidative response and neuroprotective effects of long-acting pegylated human G-CSF (PEG-G-CSF) in a rat model of optic nerve crush (ONC). Adult male Wistar rats (150–180 g) were chosen to have a sham operation in one eye and have ONC in the other. PEG-G-CSF or phosphate-buffered saline (PBS control) was immediately administered after ONC by intravitreal injection (IVI). We found the IVI of PEG-G-CSF does not induce systemic leukocytosis, but increases survival of RGCs and preserves the visual function after ONC. TUNEL assays showed fewer apoptotic cells in the retina in the PEG-G-CSF-treated eyes. The number of sorely ED1-positive cells was attenuated at the lesion site in the PEG-G-CSF-treated eyes. Immunoblotting showed up-regulation of p-Akt1, Nrf2, Sirt3, and HO-1 in the ON of the PEG-G-CSF-treated eyes. Our results demonstrated that one IVI of long-acting PEG-G-CSF is neuroprotective in the rONC. PEG-G-CSF activates the p-Akt1/Nrf2/Sirt3 and the p-Akt1/Nrf2/HO-1 axes to provide the antioxidative action and further attenuated RGC apoptosis and neuroinflammation. This provides crucial preclinical information for the development of alternative therapy with IVI of PEG-G-CSF in TON.

Peripheral blood stem cell mobilization with pegylated granulocyte colony stimulating factor in children.

Background and AimWe report here our experience of using pegylated granulocyte colony stimulating factor (peg‐GCSF) for peripheral blood stem cell (PBSC) mobilization in children.Methods and resultsA total of nine children suffering from high‐risk/relapsed solid tumors were mobilized with chemotherapy and peg‐GCSF (100 microgram/kg single dose). Mean age was 7.7 years (range 2–15 years).The mean time from peg‐GCSF administration to PBSC harvest was 9.7 days. Adequate stem cells (median dose 26.9 million/kg) could be harvested in all children by a single apheresis procedure. No major adverse events observed.ConclusionIt is feasible and safe to mobilize PBSC with peg‐GCSF in children with cancer.

A Prospective Registry Study of Peg-G-CSF Prophylaxis for Patients with Diffuse Large B-Cell Lymphoma (CISL 1403)

BackgroundFebrile neutropenia (FN) is the most important side effect of chemotherapy in diffuse large B cell lymphoma (DLBCL) causing not only treatment-related morbidity but also suboptimal chemotherapy delivery. Prophylactic use of granulocyte colony stimulating factor (G-CSF) or pegylated G-CSF (PEG-G-CSF) is known to reduce the incidence of both neutropenia and FN. We conducted a prospective registry study to evaluate prophylactic effect of PEG-G-CSF in DLBCL patients treated with R-CHOP regimen (ClinicalTrials.gov Identifier: NCT02474550).Patients and MethodSince January 1st 2015, after written informed consent, patients receiving R-CHOP therapy with curative intent were registered and prospectively monitored. All patients were pathologically confirmed with DLBCL according to World Health Organization Classification 2008. Prophylactic Peg-G-CSF was given 24 hours after R-CHOP chemotherapy subcutaneously. The incidence of neutropenia and neutropenic fever were studied. Febrile neutropenia (FN) is defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2h and an absolute neutrophil count <0.5 × 109/l, or expected to fall below 0.5 × 109/l. This interim-analysis was performed as of 1st June 2017.ResultsA total of 2957 cycles in 694 patients were included in the analysis. Base-line characteristics are summarized in Table 1. Median age at diagnosis was 62 (10-86) with a predominance of males (67%). Most patients had extranodal involvement (90.7%) and 257 patients (37%) had two or more extra-nodal involvements. The most common extranodal involvement sites were stomach (16.6%), bone (11.7%), intestine (11.4%) and lung (8.8%). Bone marrow involvement was observed in 281 patients (40.5%). At the time of analysis 407 (58.6%) patients completed 6 cycles of R-CHOP therapy. Forty-three patients (6%) experienced primary failure with R-CHOP treatment. Treatment related mortality occurred in 41 patients (5.9%). Grade III/IV neutropenia was developed with the incidence of 13.6% (402/2957 cycles) in the patients. FN developed in 74 (10.7%) patients with the overall incidence of 4.2% (124/2957) in the cycles (Table 2.). Twenty-five patients (33.7%) had multiple episodes of FN. Most patients (78.9%) experienced the first episode of FN within three cycles. Among pretreatment clinical factors analyzed, age, ECOG performance status and LDH level were related with the development of FN (Table 3.). Vitamin D deficiency at diagnosis was observed in 74.6% (347/501) of the patients but not associated with the development of FN. Deranged Light chain level is detected in 23.3% (112/479) of the patients, but not associated with the development of FN as well.ConclusionThis interim analysis showed clinical feature of FN with PEG-G-CSF prophylaxis in DLBCL patients. Peg-G-CSF prophylaxis was effective in reducing the incidence of neutropenia and FN. However, the patients who were elderly, with poor performance status or high LDH level still had high incidence of FN. We will further study whether this result could be translated into better treatment outcomes in the patients. [Display omitted] DisclosuresKim:Celltrion, Inc: Consultancy, Honoraria; Takeda: Research Funding; Kyowa-Kirin: Research Funding; J&J: Research Funding; Novartis: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Roche: Research Funding.

Allogeneic Hematopoietic Stem Cell Transplantation Mobilized With Pegylated Granulocyte Colony-Stimulating Factor Ameliorates Severe Acute Graft-Versus-Host Disease Through Enrichment of Monocytic Myeloid-Derived Suppressor Cells in the Graft: A Real World Experience.

We compared the effectiveness and safety of pegylated granulocyte colony-stimulating factor (peg-G-CSF) vs. non-peg-G-CSF for hematopoietic stem cell mobilization in allogeneic hematopoietic stem cell transplantation in a real-world setting. We included 136 consecutive healthy donors treated with non–peg-G-CSF (n = 53) or peg-G-CSF (n = 83), and 125 consecutive recipients (n = 42 and 83, respectively) in this study. All harvesting was completed successfully. No significant difference in leukapheresis number and adverse events frequency was observed, nor were there severe adverse events leading to discontinuation of mobilization. The leukapheresis products mobilized by peg-G-CSF had higher total nucleated cells (p < 0.001), monocytic myeloid-derived suppressor cells (p < 0.001), granulocytic myeloid-derived suppressor cells (p = 0.004) and B cells (p = 0.019). CD34+ cells and other lymphocyte subsets (T cells, regulatory T cells, natural killer [NK] cells, etc.) were similar in both apheresis products. Patients who received grafts mobilized by peg-G-CSF exhibited a lower incidence of grade III-IV acute graft-versus-host disease (p = 0.001). The 1-year cumulative incidence of chronic graft-versus-host disease and relapse, 1-year probability of graft-versus-host disease-free relapse-free survival, and overall survival did not differ significantly between subgroups. Our results suggest that collecting allogeneic stem cells after the administration of peg-G-CSF is feasible and safe. Peg-G-CSF mobilized grafts may reduce severe acute graft-versus-host disease compared with non-peg-G-CSF mobilized grafts after allogeneic stem cell transplantation. The beneficial effects of a peg-G-CSF graft might be mediated by increased numbers of monocytic myeloid-derived suppressor cells.

Interim results of a multicenter retrospective-prospective observational post-marketing study of Extimia® BIOCAD (INN: empegfilgrastim) to evaluate safety and efficacy in patients with lymphoproliferative diseases receiving cytotoxic therapy

Aim. To assess the efficacy and safety of using the drug Extimia BIOCAD (international nonproprietary name INN: empegfilgrastim) in order to reduce the frequency and duration of neutropenia, the frequency of febrile neutropenia (FN) and infections manifested by FN in patients with lymphoproliferative diseases receiving myelosuppressive therapy.&#x0D; Materials and methods. This publication presents the interim results of a multicenter retrospective prospective observational post-marketing study of the safety and efficacy of the drug Extimia BIOCAD (INN: empegfilgrastim) in patients with lymphoproliferative diseases receiving cytotoxic therapy (LEGERITY). The interim data analysis included 40 patients with lymphoproliferative diseases (Hodgkins lymphoma, diffuse large B-cell lymphoma, multiple myeloma, primary mediastinal large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, splenic marginal zone lymphoma), who were treated in ten research centers of the Russian Federation (Moscow, St. Petersburg, regional clinics). The median age of patients was 48 (2172) years, 13/40 (32.5%) patients belonged to the older age group (60 years). Patients had functional status on the ECOG scale of 02 and received at least 2 chemotherapy injections against the background of prophylaxis with empegfilgrastim. Empegfilgrastim was administered at a dose of 7.5 mg subcutaneously once 24 hours after the end of the administration of cytotoxic chemotherapeutic agents. Primary endpoint: frequency of neutropenia 35 degrees of severity; secondary endpoints: frequency of FN; frequency of severe infections (34 stages); frequency of antibiotic prescription; relative dose intensity of therapy of the conducted chemotherapy courses; the incidence of all adverse reactions in patients who received at least one dose of the study drug empegfilgrastim; the incidence of all serious adverse reactions in patients who received at least one dose of the study drug empegfilgrastim; the incidence of CTCAE 5.0 grade 34 HP in patients who received at least one dose of the study drug empegfilgrastim; discontinuation rate of study drug empegfilgrastim due to adverse reactions.&#x0D; Results. The results of this study demonstrate that the incidence of neutropenia of 3 degree of severity after the 1st cycle of chemotherapy developed in 2/40 patients (5%) and as a result of high-dose therapy (R-DHAP). Neutropenia of any severity was reported in 5/40 patients (12.5%). Cases of FN development have not been registered. Severe infections (mucositis, enteropathy, pneumonia, etc.), as well as the use of antibacterial and antifungal drugs during 1 cycle of chemotherapy and in the inter-course period after 1 cycle of therapy were not recorded in any patient. The next course of myelosuppressive therapy was not delayed due to the development of neutropenia in any of the patients during the study. Adverse events, according to the researcher, associated with the use of empegfilgrastim, were registered in 2/40 patients (5%): moderate generalized pain syndrome (diffuse pain) of 1 severity and in one case ossalgia of 2 severity. No serious adverse reactions were reported.&#x0D; Conclusion. The results of the interim analysis of the study demonstrate the high efficacy of the first Russian original pegylated granulocyte colony-stimulating factor empegfilgrastim after a single administration of a fixed dose in the treatment of patients with aggressive and indolent lymphomas. The drug has a favorable tolerance profile in any age group of patients, especially in elderly patients. Administration of empegfilgrastim as a prophylaxis of neutropenia in patients with lymphoproliferative diseases receiving myelosuppressive therapy of varying intensity can reduce the burden on medical personnel, improve patient adherence to treatment, and contribute to the implementation of the therapeutic plan.

Co-Therapy of Pegylated G-CSF and Ghrelin for Enhancing Survival After Exposure to Lethal Radiation.

Exposure to ionizing radiation (radiation injury, RI) in nuclear-related episode is evident to be life-threatening. RI occurs at levels of organs, tissues, cytosols, or nucleus. Their mechanisms are still not fully understood. FDA approves pegylated granulocyte colony-stimulating factor (Neulasta™, Peg-G-CSF) for acute hematopoietic syndrome and has been shown to save lives after lethal RI. We aimed to test whether Ghrelin enhanced Peg-G-CSF’s efficacy to save more lives after lethal RI. B6D2F1/J female mice were used for the study. They received 9.5 Gy (LD50/30 at 0.4 Gy/min) emitted from the 60Co-γ-photon radiation facility. Peg-G-CSF was injected subcutaneously at 1 mg/kg once on days 1, 8, and 15 after irradiation. Ghrelin contains 28 amino acid and is a hunger peptide that has been shown to stimulate food intake, promote intestinal epithelial cell proliferation, elevates immunity, inhibits brain hemorrhage, and increases stress-coping. Ghrelin was injected subcutaneously at 113 μg/kg once on days 1, 2, and 3 after irradiation. Survival, body weight, water consumption, hematology, spleen weight, splenocytes, bone marrow cells, and histology of bone marrow and ileum were performed. We observed that radiation resulted in 30-days survival by 30%. RI decreased their body weights and water consumption volumes. On the 30th day post-RI, platelets and WBCs such as basophils, eosinophils, monocytes, lymphocytes, neutrophils and leukocytes were still significantly decreased in surviving mice. Likewise, their RBC, hemoglobin, hematocrit, and splenocytes remained low; splenomegaly was found in these mice. Bone marrow in surviving RI animals maintained low cellularity with high counts of fat cells and low counts of megakaryocytes. Meanwhile, ileum histology displayed injury. However, mice co-treated with both drugs 24 h after RI resulted in 30-days survival by 45% above the vehicle group. Additionally, the body-weight loss was mitigated, the acute radiation syndrome was reduced. This co-therapy significantly increased neutrophils, eosinophils, leukocytes, and platelets in circulation, inhibited splenomegaly, and increased bone marrow cells. Histopathological analysis showed significant improvement on bone marrow cellularity and ileum morphology. In conclusion, the results provide a proof of concept and suggest that the co-therapy of Peg-G-CSF and Ghrelin is efficacious to ameliorate RI.