Cycles Of Granulocyte Colony-stimulating Factor Research Articles

Multiple cycles of granulocyte colony-stimulating factor in decompensated cirrhosis: a double-blind RCT.

BackgroundLiver transplant, the definitive treatment of decompensated cirrhosis (DC), is constrained by donor shortage and long-term complications. Granulocyte colony-stimulating factor (G-CSF) has been explored as an alternative option in open-label studies. This double-blind, randomized, placebo-controlled trial was designed to elucidate the efficacy of G-CSF in DC.MethodsSeventy patients were randomized to either G-CSF plus standard medical therapy (group A, n = 35) or placebo plus standard medical therapy (group B, n = 35). Primary outcome was 12-month overall survival in patients who received at least one cycle of intervention. Secondary outcomes were mobilization of CD34+ cells at day 6, improvement in Child–Turcotte–Pugh (CTP), and model for end-stage liver disease (MELD), liver stiffness measurement, quality of life, nutrition, hepatic decompensation, infection, hospitalization, and acute kidney injury.ResultsSurvival in group A was higher than that in Group B although the difference was not statistically significant (87.9% vs 66.7%; p = 0.053). CD34+ cells at day 6 were significantly higher in group A as compared to baseline (p < 0.001). Ascites control (p = 0.03) and CTP score improvement (p = 0.02) were better in group A at 12-months. Encephalopathy episodes (p = 0.005), infections (p = 0.005) were fewer in group A than group B at 12 months. Other secondary outcomes did not improve post-therapy. There were no treatment-related discontinuations or severe adverse events.ConclusionsG-CSF therapy is safe. The improvement in survival at 12 months is not statistically significant. Better control of ascites, improvement of CTP score, fewer encephalopathy episodes and decreased rate of infections were observed with G-CSF therapy (NCT03911037).Trials Registration NCT03911037Supplementary InformationThe online version contains supplementary material available at 10.1007/s12072-022-10314-x.

Multiple Cycles of Granulocyte Colony-Stimulating Factor Increase Survival Times of Patients With Decompensated Cirrhosis in a Randomized Trial

There is controversy regarding the inclusion of granulocyte colony stimulating factor (G-CSF) in the treatment of decompensated cirrhosis. Previous studies tested only a single cycle of G-CSF administration or were underpowered to detect changes in survival time. We performed an adequately powered study to determine whether multiple cycles of G-CSF increased the survival of patients 1 year after the start of therapy. We conducted an open-label trial of 100 patients with decompensated cirrhosis without acute-on-chronic liver failure at a tertiary center from July 2016 through June 2018. The patients were assigned randomly to a group given 5 days of G-CSF every 3 months, with standard medical therapy, in 4 cycles (group A, n=50), or standard medical therapy alone (group B, n=50). The primary outcome was survival for 12 months after treatment began. Secondary outcomes were an increase in the number of CD34+ cells at day 6 compared with day 0, along with reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased control of ascites, reduced decompensation and episodes of infection, fewer hospitalizations, lower liver stiffness measurements, increased quality of life and nutrition, fulfilment of liver transplant criteria, and fewer adverse events at 12 months after the start of treatment. Groups A and B were comparable at baseline. Survival at 12 months after initiation of treatment was significantly higher in group A (74%) than in group B (42%) (P<.001). Blood samples from patients in group A had significantly more CD34+ cells on day 6 than on day0 (P<.001); there was no significant change in group B. Compared with patients in group B, patients in group A had significant reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased ascites control, fewer infections and hospitalizations, lower liver stiffness measurements, an increased quality of life, and a lower number fulfilled the liver transplant criteria (P<.05). There was no improvement in nutrition in either group compared with baseline. G-CSF was safe and well tolerated. Administration of multiple cycles of G-CSF increases the numbers of hematopoietic stem cells and survival of patients with decompensated cirrhosis receiving standard medical treatment. The addition of G-CSF to medical treatment might provide a bridge to liver transplantation for these patients. ClincialTrials.gov no: NCT03415698.

Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study

ObjectiveWe performed a randomized, double-blind, cross-over study to assess the neuroregenerative potential of intravenous granulocyte colony-stimulating factor (G-CSF) followed by infusion of mobilized peripheral blood mononuclear cells (mPBMCs) in children with cerebral palsy (CP).MethodsChildren with non-severe CP were enrolled in this study. G-CSF was administered for 5 days, then mPBMCs were collected by apheresis and cryopreserved. One month later (M1), recipients were randomized to receive either mPBMCs or a placebo infusion, and these treatment groups were switched at 7 months (M7) and observed for another 6 months (M13). We assessed the efficacy of treatment by evaluating neurodevelopmental tests, as well as by brain magnetic resonance imaging-diffusion tensor imaging (MRI-DTI) and 18F-fluorodeoxyglucose (FDG) brain positron emission tomography-computed tomography (PET-CT) scanning to evaluate the anatomical and functional changes in the brain.ResultsFifty-seven patients aged 4.3 ± 1.9 (range 2–10) years and weighing 16.6 ± 4.9 (range 11.6–56.0) kg were enrolled in this study. The administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. The yield of mPBMCs was comparable to that reported in studies of pediatric donors without CP and patients with nonhematologic diseases. 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. In addition, larger changes in neurodevelopment test scores were observed in the 1 month after G-CSF administration (M0–M1) than during the 6 months after reinfusion with mPBMCs or placebo (M1–M7 or M7–M13). Patients who received G-CSF followed by mPBMC infusion at 7 months (T7 group) demonstrated significantly more neurodevelopmental improvement than patients who received G-CSF followed by mPBMC infusion at 1 month (T1 group). In contrast to the results of neurodevelopment tests, the results of MRI-DTI at the end of this study showed greater improvement in the T1 group. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo group or between the T1 and T7 group.ConclusionsNeurodevelopmental improvement was seen in response to intravenous G-CSF followed by mPBMC reinfusion, particularly to the G-CSF alone even without mPBMC reinfusion. Further studies using a larger number of mPBMCs for the infusion which could be collected by repeated cycles of apheresis or using repeated cycles of G-CSF alone, are needed to clarify the effect of mPBMC reinfusion or G-CSF alone (Trial registration: ClinicalTrials.gov, NCT02983708. Registered 5 December, 2016, retrospectively registered).

Assessing alternative dosing strategies for granulocyte-colony stimulating factor (G-CSF) use with FOLFOX6 therapy for treatment of colorectal cancer in a prospective cohort.

771 Background: While clinical guidelines recommend an average of 11 injections of granulocyte-colony stimulating factor (G-CSF) per cycle of chemotherapy, few studies support alternative dosing strategies for G-CSF use by cancer type and chemotherapy regimen. Methods: From 2004 to 2013, 63 colon and 47 rectal cancer patients were recruited and monitored throughout the course of their FOLFOX6 therapy. G-CSF use was determined by a clinical pharmacist and tracked every week to ensure patients received an adequate number of injections and were compliant with each cycle. All patients received at least two cycles of G-CSF. Occurrence of neutropenia, febrile neutropenia, and thrombocytopenia were compared between patients receiving four and five injections per cycle. Results: There were 54 males and 56 females with a median age of 56. 104 patients received adjuvant chemotherapy with the remaining six being in the metastatic setting. 83 of 110 (75%) patients experienced no delays after initiation of G-CSF with 67 (61%) of those patients receiving four or five injections per cycle. The remaining 27 of 110 (25%) patients experienced a delay in treatment after at least one cycle of G-CSF completed (15 neutropenic delays, four FN delays, and 12 thrombocytopenic delays). Significantly, only seven of those 27 (26%) patients had a neutropenic delay that occurred as a result of a failed dosing strategy after G-CSF was initiated. Of these seven neutropenic delays, five (71%) were the result of a four dose injection pattern, but none were the result of the five dose injection pattern scheme. All other delays, after at least one cycle of G-CSF (74%), were caused by patients’ non-compliance The overall compliance rate with G-CSF injections was 93%. Conclusions: Only 7 of 110 (6.4%) patients experienced a G-CSF failure. It is recommended that G-CSF be administered on day 4, 6, 8, 10, and 12 of each FOLFOX6 cycle to maintain absolute neutrophil counts and prevent treatment delays.

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits. Japanese White rabbits (n=8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 microg/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 microg/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding. Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p<0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment. Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.

Safety and efficacy of consecutive cycles of granulocyte-colony stimulating factor, and an intracoronary CD133 + cell infusion in patients with chronic refractory ischemic heart disease: The G-CSF in Angina patients with IHD to stimulate Neovascularization (GAIN I) trial

Preclinical studies suggest granulocyte-colony stimulating factor (G-CSF) holds promise for treating ischemic heart disease; however; its clinical safety and efficacy in this setting remain unclear. We elected to evaluate the safety and efficacy of G-CSF administration in patients with refractory "no-option" ischemic heart disease. Twenty patients (18 males, 2 females, mean age 62.4 years) were enrolled and underwent baseline cardiac ischemia assessment (CA) (angina questionnaire, exercise stress test [EST], technetium Tc 99m sestamibi and dobutamine-stress echocardiographic imaging). Patients then received open-label G-CSF commencing at 10 microg/kg SC for 5 days, with an EST on days 4 and 6 (to facilitate myocardial cytokine generation and stem cell trafficking). After 3 months, CA and the same regimen of G-CSF+ESTs were repeated but, in addition, leukapheresis and a randomized double-blinded intracoronary infusion of CD133+ or unselected cells were performed. Final CA occurred 3 months thereafter. There were no deaths, but only 16 patients were permitted to complete the study. Eight events fulfilled prespecified "adverse event" criteria, including 4 troponin I-positive events and 2 episodes of thrombocytopenia. Also, frequent minor troponin I-positive events (troponin I<0.9 microg/L) were observed, which did not meet adverse event criteria. The administration of consecutive cycles of G-CSF resulted in stepwise improvements in anginal frequency, EST performance, and Duke treadmill scores (all P<.005). However, from baseline to final follow-up, technetium Tc 99m sestamibi and dobutamine-stress echocardiographic results were unchanged. Granulocyte-colony stimulating factor administration was associated with improvement in a range of subjective outcomes. However, adverse events were common, and objective measures of cardiac perfusion/ischemia were unchanged.

Repeated Courses of Bone Marrow-Derived Cell Mobilization Induced by Granulocyte-Colony Stimulating Factor (G-CSF) in Amyotrophic Lateral Sclerosis: Interim Analysis of a Prospective Multicenter Trial.

Background. Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder of the adult life, characterized by the progressive loss of cortical and spinal motor neurons and an outcome usually fatal within 3 to 5 yrs, due to respiratory failure, with no effective therapies presently available. Efforts are needed in ALS to find novel treatments, able to reduce or block neuronal loss and/or to rebuild damaged neuronal circuits. Recent studies have raised the interest for the use of bone marrow-derived cells (BMCs) to repair damaged nervous system; this approach seems particularly attractive in ALS, which is characterized by neuronal degeneration. Aims of the study. To evaluate, at the multicenter setting, feasibility, safety and tolerability, and possible benefit of repeated procedures of G-CSF-induced BMC mobilization in ALS patients.Patients and methods. Seven Neurology Centers, along with seven Hematology Centers, are participating to the multicenter “STEMALS” trial, that started in June 2006 and will enrol a total of 28 patients, with 4 mobilization procedures for each patients; this is the interim analysis, after 42 mobilization procedures performed on a total of 22 patients. Patient median age is 56 yrs (range 40–64), 14 are male. The protocol includes four cycles of G-CSF, scheduled at 3 mos. intervals. In each cycle, G-CSF is administered at the dose of 5 μg/kg s.c., twice a day, for 4 consecutive days. At each cycle, CBCs and circulating CD34+ cells are determined, since day 0 through day 6.Results. Overall, 18 patients completed the first G-CSF cycle and all displayed good response; peak values were for WBCs: 41 x103/μL (range 24– 71) at day 3, and for CD34+ve cells: 52/μL (range 8.4–156), at day 4; 16 patients have already completed the second mobilization course, with values of circulating cells matching those of the first cycle (median WBCs/μL: 42x103; median CD34+ve/μL: 60.7); a few patients have undergone the third and fourth cycle, again they consistently displayed high levels of mobilization. Overall, the mobilization procedures were well tolerated, with the exception of a transient increase of growth hormone level in one patient, and a deep venous thrombosis in one patient, both complications did not preclude to conclude the treatment.Conclusion. The STEMALS trial indicate that: i. the use of G-CSF to induce BMC mobilization is safe, well tolerated and feasible in ALS, even at the multicenter level; ii. so far, few and reversible adverse effects have been recorded; iii. peak values of circulating CD34+ve cells indicate that BMC mobilization capacity in ALS is analogous to that commonly observed in the healthy population; iv. there are no signs of impaired mobilization, after repeated courses of G-CSF administration, performed at few month intervals. A longer follow up is still required to verify possible benefits of the repeated BMC mobilization program in ALS.

Intermittent Exposure of Primitive Quiescent Chronic Myeloid Leukemia Cells to Granulocyte-Colony Stimulating Factor In vitro Promotes their Elimination by Imatinib Mesylate

Primitive quiescent chronic myeloid leukemia (CML) cells are biologically resistant to imatinib mesylate, an inhibitor of the p210(BCR-ABL) kinase. The present study was designed to investigate whether either continuous or intermittent exposure of these cells to granulocyte-colony stimulating factor (G-CSF) in vitro can overcome this limitation to the effectiveness of imatinib mesylate therapy. CD34(+) leukemic cells were isolated from six newly diagnosed chronic phase CML patients and cultured for 12 days in serum-free medium with or without G-CSF and/or imatinib mesylate present either continuously or intermittently (three cycles of G-CSF for 0, 1, or 4 days +/- imatinib mesylate for 0, 3, or 4 days). Every 4 days, the number of residual undivided viable cells and the total number of viable cells present were measured. Intermittent but not continuous exposure to G-CSF significantly accelerated the disappearance in vitro of initially quiescent CD34(+) CML cells. This resulted in 3- and 5-fold fewer of these cells remaining after 8 and 12 days, respectively, relative to continuous imatinib mesylate alone (P < 0.04). Cultures containing imatinib mesylate and intermittently added G-CSF also showed the greatest reduction in the total number of cells present after 12 days (5-fold more than imatinib mesylate alone). Intermittent exposure to G-CSF can enhance the effect of imatinib mesylate on CML cells by specifically targeting the primitive quiescent leukemic elements. A protocol for treating chronic-phase CML patients with imatinib mesylate that incorporates intermittent G-CSF exposure may offer a novel strategy for obtaining improved responses in vivo.

Granulocyte-Colony Stimulating Factor Decreases Angina and Improves Exercise Capacity in Patients with Chronic Refractory ‘No Option' Ischemic Heart Disease.

Granulocyte-Colony stimulating factor (G-CSF) is widely used in the treatment of hematological malignancies. The administration of G-CSF is a novel therapy for ischemic heart disease (IHD), but current data are controversial and the safety and efficacy of G-CSF in acute or chronic IHD is unclear.Aim: to assess safety and efficacy of G-CSF administration and stem cell mobilization in patients with chronic refractory ‘no option' IHD.Methods: After baseline cardiac assessment (CA) [Seattle Angina Questionnaire (SAQ), Bruce exercise stress test (EST), persantin-Sestamibi and dobutamine-echocardiographic imaging], stable ‘no option' IHD patients received open-label G-CSF 10μg/kg for 5 days, with an EST (to facilitate myocardial cytokine generation and stem cell trafficking) on the 4th and 6th days. After 3 months, CA and the same regimen of G-CSF and ESTs was repeated, but in addition, leucopheresis and a randomized double-blinded intracoronary infusion of either CD133+ or unselected cells was performed (randomized data remains blinded). Final CA was 3 months thereafter.Results: Thirteen patients (12 male, 1 female, mean age 62) received 21 cycles of G-CSF. There were no deaths, Q-wave AMIs or any complications with long-term sequelae, although, transient troponin-I elevation (n = 3) and thrombocytopenia (n = 2) were observed. Mean CD133+ cell count rose from 1.28 to 56.12 x1012/L (p = 0.001). There was no age-related trend towards lower numbers of G-CSF mobilized CD34+ cells in the IHD patients, as compared to a group of younger (<60 y.o) normal male donors (n = 66). After the first cycle of G-CSF, SAQ angina frequency and physical limitation scores improved, and EST time increased (all p < 0.01). There was further but less marked improvement in each of these parameters after the second cycle of G-CSF and cell infusion. Overall, SAQ angina frequency score improved 46 points (95% CI +22 to +70, p = 0.003). This was reflected by reduced anginal frequency and nitrate use (both p < 0.005). Overall, SAQ physical limitation score improved 26 points (95% CI +17 to +35, p = 0.0003), EST time improved 97 seconds (95% CI +41 to +153, p = 0.005) and Duke Treadmill Score improved 4.3 points (95% CI −0.2 to +8.8, p = 0.058).Conclusions: G-CSF and intracoronary cell infusion is safe in chronic ‘no option' IHD patients. In this phase I study G-CSF improved anginal frequency, nitrate use and EST performance. A placebo controlled phase II trial investigating G-CSF with an appropriate cytokine stimulus is warranted.

Quantitative cell-cycle progression analysis of the first three successive cell cycles of granulocyte colony-stimulating factor and/or granulocyte-macrophage colony-stimulating factor-stimulated human CD34+ bone marrow cells in relation to their colony formation

The bromodeoxyuridine (BrdU)-Hoechst flow cytometric technique was applied to study the immediate cell kinetic response of highly purified human (h) bone marrow progenitor cells (CD(34+)-sorted fraction) to h granulocyte colony-stimulating factor (G-CSF) and/or h granulocyte-macrophage colony-stimulating factor (GM-CSF). The technique permits us to differentiate cycling from noncycling cells and to make a quantitative assessment of cell cycles after stimulation. Semisolid agar and single-cell liquid cultures were also performed to compare these initial events to the effects observed after 14 days of culture. The combination of G-CSF plus GM-CSF, acting synergistically in day 14 cultures, was found to have a subadditive effect in the first cell cycles, thereby indicating partial overlap of the different target cells. However, this combination accelerated transit through the cell cycle, as could be seen from the higher number of cells in the third cell cycle after 72 hours of stimulation. We conclude that, apart from the unresponsive cells, the CD34+ compartment consists of cells responsive to both G-CSF and GM-CSF, and cells responsive to either one of the CSFs alone, and that the combination of the two CSFs speeds up the cell cycle traverse rate for a significant fraction of the target cells that are initially responsive for both G-CSF and GM-CSF. The latter supports the hypothesis of an overlapping signalling pathway of G-CSF and GM-CSF.

Quantitative Cell-Cycle Progression Analysis of the First Three Successive Cell Cycles of Granulocyte Colony-Stimulating Factor and/or Granulocyte-Macrophage Colony-Stimulating Factor-Stimulated Human CD34+ Bone Marrow Cells in Relation to Their Colony Formation

AbstractThe bromodeoxyuridine (BrdU)-Hoechst flow cytometric technique was applied to study the immediate cell kinetic response of highly purified human (h) bone marrow progenitor cells (CD34+-sorted fraction) to h granulocyte colony-stimulating factor (G-CSF) and/or h granulocyte-macrophage colony-stimulating factor (GM-CSF). The technique permits us to differentiate cycling from noncycling cells and to make a quantitative assessment of cell-cycle progression during the first three consecutive cell cycles after stimulation. Semisolid agar and single-cell liquid cultures were also performed to compare these initial events to the effects observed after 14 days of culture. The combination of G-CSF plus GM-CSF, acting synergistically in day 14 cultures, was found to have a subadditive effect in the first cell cycles, thereby indicating partial overlap of the different target cells. However, this combination accelerated transit through the cell cycle, as could be seen from the higher number of cells in the third cell cycle after 72 hours of stimulation. We conclude that, apart from the unresponsive cells, the CD344+ compartment consists of cells responsive to both G-CSF and GM-CSF, and cells responsive to either one of the CSFs alone, and that the combination of the two CSFs speeds up the cell cycle traverse rate for a significant fraction of the target cells that are initially responsive for both G-CSF and GM-CSF. The latter supports the hypothesis of an overlapping signalling pathway of G-CSF and GM-CSF.