UNASSIGNED: Autologous hematopoietic stem cell transplantation (ASCT) has become the mainstay treatment for many hematological malignancies and solid tumors. An adequate number of stem cells must be collected for better ASCT outcomes, which is challenging in 5%-30% of patients. To improve mobilization, plerixafor is used along with granulocyte colony-stimulating factor (G-CSF).
UNASSIGNED: We conducted a retrospective single center study involving patients who received plerixafor pre-ASCTs between January 2013 and December 2020 at a tertiary care center in Lebanon. We identified a total of 84 consecutive adult patients. All patients identified were poor mobilizers and have eventually received plerixafor either as pre-emptive use before first apheresis in those with peripheral CD34 + of less than 20 cells/ul, or after failure of first apheresis in those with peripheral stem cells (PSC) >2.0 × 106 cells/Kg.
UNASSIGNED: The median age at ASCT was 52.7 years (22-74) with 61% male predominance. Multiple myeloma was the most prevalent disease 64% followed by Lymphoma 32%. The majority of patients were in complete remission 64% at the time of ASCT. Most patients received proteasome inhibitor-based induction therapy 67% and Melphalan-based conditioning therapy 68%. The median follow-up from ASCT was 9 months (1-59). It was noted that greater body mass index (BMI) is a significant factor for better PSC collection whether premobilization (P = 0.003), or post plerixafor mobilization (P = 0.024). Moreover, Multiple Myeloma patients showed better mobilization using Plerixafor (P = 0.049). Using Plerixafor along with G-CSF in poor mobilizers post G-CSF alone showed a statistically significant increase in the collected PSC mean from 0.67 × 106 cells/Kg to 4.90 × 106 cells/Kg (P < 0.001) with a failure rate only for 12 patients (15%). The infusion of PSC > 2.5 × 106 cells/Kg has shown 3 days decrease in time to platelet engraftment (P = 0.021) and a 36% decrease in progression/relapse rate (P = 0.025).
UNASSIGNED: Plerixafor is effective in increasing the PSC yield in poor mobilizers. Low BMI and hematologic malignancies other than Multiple Myeloma are risk factors for poor mobilization. More studies should be performed to establish more risk factors, helping us to identify poor mobilizers more accurately and initiate plerixafor mobilization early on.

BACKGROUND: Febrile Neutropenia (FN) is a common and serious condition related to cancer chemotherapy. Human recombinant Granulocyte-Colony Stimulating Factor (G-CSF) prevents and attenuates the severity and duration of FN. We evaluated the use and predictors of G-CSF adherence among women with breast cancer with a high risk of FN in Puerto Rico.
METHODS: This retrospective cohort study used the Puerto Rico Central Cancer Registry-Health Insurance Linkage Database. Women with invasive breast cancer diagnosed during 2009-2015 who received selected chemotherapy regimens (n = 816) were included. The risk of FN was categorized as high and low risk based on the chemotherapy regimens according to the National Comprehensive Cancer Network guidelines and literature. Adherence was defined as the use or no use of G-CSF at the start of the first chemotherapy cycle among women with breast cancer based on the risk of developing FN. We used a multivariate logistic model to identify factors associated with G-CSF use in women classified at high risk for FN.
RESULTS: Adherence to G-CSF clinical practice guidelines was low (38.2%) among women with a high risk of FN. Women at high risk of FN with Medicaid (aOR: 0.14; CI 95%: 0.08, 0.24) and Medicare/Medicaid (aOR: 0.33; CI 95%: 0.15, 0.73) were less likely to receive G-CSF than women with private health insurance. Women with regional stage (aOR: 1.82; CI 95%: 1.15, 2.88) were more likely to receive G-CSF than women with localized cancers.
CONCLUSIONS: Adherence to clinical practice guidelines was poor among women with a high risk of FN. Furthermore, disparities in the adherence to G-CSF use in terms of health insurance, health region, and cancer stage granted the opportunity to implement strategies to follow the recommended guidelines for using G-CSF as part of cancer treatment.

The clinical usefulness of peripheral blood (PB) mononuclear cell (MNC) transplantation in patients with peripheral arterial disease (PAD), especially in those with mild-to-moderate severity, has not been fully clarified.Methods and Results:A randomized clinical trial was conducted to evaluate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMNC transplantation in patients with PAD (Fontaine stage II-IV and Rutherford category 1-5) caused by arteriosclerosis obliterans or Buerger\'s disease. The primary endpoint was progression-free survival (PFS). In total, 107 subjects were enrolled. At baseline, Fontaine stage was II/III in 82 patients and IV in 21, and 54 patients were on hemodialysis. A total of 50 patients had intramuscular transplantation of PBMNC combined with standard of care (SOC) (cell therapy group), and 53 received SOC only (control group). PFS tended to be improved in the cell therapy group than in the control group (P=0.07). PFS in Fontaine stage II/III subgroup was significantly better in the cell therapy group than in the control group. Cell therapy-related adverse events were transient and not serious.
In this first randomized, large-scale clinical trial of G-CSF-mobilized PBMNC transplantation, the cell therapy was tolerated by a variety of PAD patients. The PBMNC therapy was significantly effective for inhibiting disease progression in mild-to-moderate PAD.

Estimating impact of the various product-related variants and impurities on a biotherapeutic\'s safety and efficacy is an essential requirement in the quality by design paradigm. In view of the limited role that clinical studies offer in this regard, we demonstrate a preclinical approach to achieve this for granulocyte colony-stimulating factor (GCSF). While our repeated-dose toxicity data suggest that these variants do not elicit any adverse effects or histopathological changes, aggregated GCSF impurity caused sluggishness in animal behavior manifested by a possible muscular injury. Cell assay data revealed that the cys-64-cys74 disulfide bond in reduced GCSF imparts stabilization in absence of the cys-36-cys42 bond. PK data demonstrate variability in half lives of different species when compared to the native GCSF. PD data along with differential expression of JAK-2 and STAT5a genes show that all the tested variants triggered the required signal transduction pathways for neutrophil proliferation and activation.

Patients receiving pegfilgrastim (Neulasta®) for the treatment of neutropenia can experience bone pain following the injections required to achieve effective neutrophil levels. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of ANF-RHO™, a novel pegylated granulocyte colony stimulating factor, were assessed in a randomized, controlled, double-blind Phase 1 clinical study in healthy volunteers. Subjects received a single subcutaneous dose of ANF-RHO over a range of 6 doses (5-50 μg/kg), placebo (saline), or the recommended clinical dose of pegfilgrastim administered at the labeled fixed 6 mg dosage (equivalent to 80-100 μg/kg). The primary outcome measure was safety and tolerability. Secondary outcomes included PK and PD effects on absolute neutrophil count (ANC) and number of CD34+ progenitor cells. Severity of bone pain was also assessed. In healthy volunteers, ANF-RHO was administered at ascending doses up to 50 μg/kg without significant adverse effects; appeared to be better (5 to 30 μg/kg) or equally well (50 μg/kg) tolerated, and had lower mean bone pain scores as compared to pegfilgrastim. ANF-RHO achieved CD34+ and ANC numbers at significantly lower doses, and had a significantly longer circulating half-life than pegfilgrastim. These results suggest that ANF-RHO can be provided less frequently, at a lower dose, and with fewer side effects. ANF-RHO had unique, prolonged PK/PD attributes as compared to marketed pegfilgrastim, suggesting that it may provide an improved clinical benefit in further clinical studies in patients with chemotherapy-induced or chronic idiopathic neutropenia.

In the MONITOR-GCSF study of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim, 56.6% of patients were prophylacted according to amended EORTC guidelines, but 17.4% were prophylacted below and 26.0% above guideline recommendations.
MONITOR-GCSF is a prospective, observational study of 1447 evaluable patients from 140 cancers centers in 12 European countries treated with myelosuppressive chemotherapy for up to 6 cycles receiving biosimilar GCSF prophylaxis. Patients were classified as under-, correctly-, or over-prophylacted with GCSF relative to guideline recommendations based on their chemotherapy risk, individual risk factors, and type of GCSF prophylaxis (primary versus secondary).
Differences between under- (17.4%), correctly- (56.6%), or over-prophylacted (26.0%) groups were found in terms of patient risk factors (age, performance status, history of FN, comorbid conditions) as well as prophylaxis patterns (type of prophylaxis, day of GCSF initiation, and GCSF duration). Rates of chemotherapy-induced neutropenia (CIN) (all grades), FN, and CIN-related hospitalizations were consistently lower in over-prophylacted patients relative to under- and correctly-prophylacted patients. No differences were observed between under- and correctly-prophylacted patients except for CIN/FN-related chemotherapy disturbances. No GCSF safety differences were found between groups (except for headaches).
The real-world evidence provided by the MONITOR-GCSF study indicates that providing GCSF support may yield better CIN, FN, and CIN/FN-related hospitalization outcomes if patients are prophylacted at levels above guideline recommendations. Patients who are under-prophylacted are at higher risk for disturbances to their chemotherapy regimens. Our findings support the guideline recommendation that CIN/FN risk be assessed at the beginning of each chemotherapy cycle.

The biosimilar industry is witnessing an unprecedented growth with the newer therapeutics increasing in complexity over time. A key step towards development of a biosimilar is to establish analytical comparability with the innovator product, which would otherwise affect the safety/efficacy profile of the product. Choosing appropriate analytical tools that can fulfil this objective by qualitatively and/or quantitatively assessing the critical quality attributes (CQAs) of the product is highly critical for establishing equivalence. These CQAs cover the primary and higher order structures of the product, product related variants and impurities, as well as process related impurities, and host cell related impurities. In the present work, we use such an analytical platform for assessing comparability of five approved Granulocyte Colony Stimulating Factor (GCSF) biosimilars (Emgrast, Lupifil, Colstim, Neukine and Grafeel) to the innovator product, Neupogen(®). The comparability studies involve assessing structural homogeneity, identity, secondary structure, and product related modifications. Physicochemical analytical tools include peptide mapping with mass determination, circular dichroism (CD) spectroscopy, reverse phase chromatography (RPC) and size exclusion chromatography (SEC) have been used in this exercise. Bioactivity assessment include comparison of relative potency through in vitro cell proliferation assays. The results from extensive analytical examination offer robust evidence of structural and biological similarity of the products under consideration with the pertinent innovator product. For the most part, the biosimilar drugs were found to be comparable to the innovator drug anomaly that was identified was that three of the biosimilars had a typical variant which was reported as an oxidized species in the literature. But, upon further investigation using RPC-FLD and ESI-MS we found that this is likely a conformational variant of the biotherapeutic been studied.

OBJECTIVE: In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI).
METHODS: After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6 months of follow-up (ΔLVEF, ΔRVEF), as determined by cardiac MRI.
RESULTS: At follow-up ΔLVEF as well as ΔRVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12 months of follow-up as compared to patients under GS.
CONCLUSIONS: Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12 months. (EudraCT: 2007-003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation).

The objective of this study was to assess the impact of the primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) in the management of childhood B-cell non-Hodgkin lymphoma (B-NHL). Patients with advanced-stage mature B-NHL were randomized to receive prophylactic G-CSF (G-CSF+) or not receive G-CSF (G-CSF-) based on protocols of the B-NHL03 study. The G-CSF group received 5 μg/kg/d Lenograstim from day 2 after each course of six chemotherapy courses. Fifty-eight patients were assessable, 29 G-CSF + and 29 G-CSF-. G-CSF + patients showed a positive impact on the meantime to neutrophil recovery and hospital stay. On the other hand, they had no impact in the incidences of febrile neutropenia, serious infections, stomatitis and total cost. Our study showed that administration of prophylactic G-CSF through all six chemotherapy courses for childhood B-NHL showed no clinical and economic benefits for the management of childhood B-NHL treatment.