G-CSF Administration Research Articles

The effect of granulocyte colony‐stimulating factor dose and administration interval after allogeneic hematopoietic cell transplantation on early engraftment of neutrophil and platelet

BackgroundHematopoietic stem cell transplantation (HSCT) is one of the treatments for hematologic malignancies. Numerous factors affect the HSCT outcome. The purpose of this study was to investigate the effect of post‐HSCT administration of granulocyte colony‐stimulating factor (post‐G‐CSF) on early neutrophil and platelet engraftment in allogeneic HSCT (allo‐HSCT).Material & methodsThe study was performed on 76 patients diagnosed with AML and ALL. All patients underwent allo‐HSCT at Taleghani stem cell transplantation center, Tehran, Iran, from February 2016 to December 2018. Chemotherapy regimens based on patients' conditions were selected between myeloablative and reduced‐intensity regimens.ResultsStatistical analysis revealed that the number of administered G‐CSF units after HSCT was a time‐dependent variable. Statistical analysis before day +11 reported that patients who received G‐CSF <14 units had three times better early neutrophil engraftment than those with G‐CSF ≥14 (CI 95%, AHR = 3.03, p:0.002). CD3+ cells count <318.5 × 106/kg was associated with fast platelet engraftment (CI 95%, AHR 2.28, p:0.01).ConclusionIn this study, post‐G‐CSF stimulation was associated with early engraftment in a time‐ and dose‐dependent manner. Administration of G‐CSF beyond 14 units resulted in adverse effects on neutrophil early engraftment. It also appeared that with a reduction in CD3+ cell counts, the likelihood of GVHD decreases, and platelet engraftment occurs earlier. Further investigations in the future are required to determine the factors affecting the process of early engraftment.

Systematic review and meta-analysis of febrile neutropenia risk with TCH(P) in HER2-positive breast cancer.

Docetaxel, carboplatin and trastuzumab, with or without pertuzumab (TCH(P)), has become the preferred (neo)adjuvant regimen for HER2-positive breast cancer. However, its associated febrile neutropenia (FN) risk is unclear: pivotal studies reported FN risks < 10%, but in clinical practice, a high FN rate (> 20%) was observed. This systematic review and meta-analysis determine the FN risk associated with TCH(P) and the indication for primary prophylactic granulocyte colony-stimulating factor (PP G-CSF). The MEDLINE, Embase, Web of Science and Cochrane databases were searched for full-text English articles reporting the FN incidence in early breast cancer patients receiving (neo)adjuvant TCH(P). The primary endpoint was the pooled crude FN incidence in patients treated without PP G-CSF using the random effects method. Secondary endpoints were the FN risk with PP G-CSF support, age-related differences in FN and differences in risk with TCH versus TCHP. Seventeen studies were included in the systematic review. The pooled estimates of FN incidences were 27.6% (95% CI 18.6 to 37.1) in patients who did not receive PP G-CSF (primary meta-analysis, 9 studies, n = 889) versus 5.0% (95% CI 2.6 to 8.0) in patients administered PP G-CSF (secondary meta-analysis, 7 studies, n = 445). Two studies reported non-significant age-related differences in FN. The risk comparison between TCH and TCHP was inconclusive. The crude FN risk associated with (neo)adjuvant TCH(P) is over 20%, the upper limit above which the international guidelines unanimously advise PP G-CSF administration. G-CSF prophylaxis effectively reduces FN risk and should become the standard of care with (neo)adjuvant TCH(P).

TCL-361: Bendamustine as Front-Line Therapy in T-Cell Prolymphocytic Leukemia: A Monocentric Experience

Introduction T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell-neoplasm that is characterized by uncontrolled proliferation of mature T-cell lymphocytes with a very poor prognosis. Nowadays, alemtuzumab as a single agent is the best available option for both treatment-naive and relapsed/refractory patients; however, its efficacy is hampered by various adverse events (AEs) such as infusion-associated reactions, autoimmune AEs, and opportunistic infections. Objective We conducted a monocentric, retrospective study to evaluate the safety and efficacy of bendamustine, which is a bifunctional mechlorethamine derivative with alkylating and antimetabolite activities, as first-line therapy in patients unfit for alemtuzumab. Patients and Methods We collected clinical and biological data of 7 T-PLL patients treated with bendamustine between 2014 and 2020 in our institution. Four out of seven (57%) were males, the median age at diagnosis was 73 years (65–83 years). The median time from diagnosis to treatment was 15 months. Bendamustine was administered intravenously (90 mg/m2 on days one and two, every four weeks) for up to six cycles. Results Overall response rate was 57%, 3 patients achieved complete response (43%), and one partial response (14%). One patient experienced stable disease, and two patients progressed during treatment. Five patients (71%) experienced a relapse. Median overall survival (OS) was 63.7 months (19–108); median OS for responding patients was 187 months versus 24 months for non-responding patients (p=0.093). Median progression-free survival (PFS) was 12 months (11–13). Three patients received second-line therapy: one patient was treated with gemcitabine; the others received a second bendamustine course. Two patients received a third-line therapy with combination chemotherapy: COMP (prednisone, cyclophosphamide, vincristine, myocettm) and CVP (cyclophosphamide, vincristine, prednisone). Two patients experienced infusion-associated reactions. Four patients experienced hematological toxicities: one thrombocytopenia G3, 3 neutropenia G3 requiring G-CSF administration. Four patients received co-trimoxazole prophylaxis, one received acyclovir prophylaxis. One patient experienced herpetic retinitis. Premature termination ( Conclusions Our data are consistent with scientific literature. This treatment is feasible and safe, with an acceptable toxicity profile. Although alemtuzumab remains the standard of care of this rare disease, bendamustine might be a valid option either for unfit patients or for undeferrable disease.

Diffuse alveolar hemorrhage in a healthy stem cell donor following administration of granulocyte colony – stimulating factor

BackgroundGranulocyte colony - stimulating factor (G-CSF) is frequently used in healthy adults prior to stem cell donation in order to mobilize stem cells to peripheral blood. Adverse events of G-CSF occur in about 30% and mainly include bone pain, fatigue, and headache. Pulmonary adverse events are rare. Case presentationHere, we describe a case of a healthy donor who developed diffuse alveolar hemorrhage after G-CSF administration. We suggest the underlying mechanism of this injury. ConclusionDiffuse alveolar hemorrhage can occur following G-CSF administration. Treating physicians should be aware of this infrequent but often life-threatening pulmonary side effect of G-CSF.

Abstract 228: A precision dosing application for patients treated with docetaxel and G-CSF

Abstract Purpose Produce a precision dosing application for clinicians to control neutropenia in patients treated with both docetaxel and G-CSF. Context Chemotherapy induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual's dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk averse environment to infections, raising the prospects that a clinician will administer G-CSF. MethodsAiming to predict the level of neutropenia after the first cycle we draw from models in the literature of CIN for G-CSF treated patients [2,3,4]. We adapt the G-CSF induced feedback effect on neutrophil development in these models to account for features specific to docetaxel patients; notably the rebound in neutrophils above baseline seen after nadir [5], and the apparent short maturation time of neutrophils [4]. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (clinical trial number NCT00617669), we identify 27 patients treated with docetaxel and G-CSF with weekly blood tests in the first and second cycle. We calibrate our model by minimising a Bayesian objective function to establish a model that predicts the neutrophil count in the second docetaxel cycle from the first. We then simulate the effect of different combinations of docetaxel, G-CSF, and the timing of G-CSF administration. Conclusions Current progress includes a model which captures the rebound above baseline in neutrophil count seen in docetaxel patients. We will show that our model captures the effect of filgrastim and pegfilgrastim on neutrophil counts, and can determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel.

The Combination of GROβ and AMD3100 Leads to Rapid and Robust Mobilization of Hematopoietic Stem Cells in Nonhuman Primates

▪Introduction: Mobilized peripheral blood grafts are currently the predominant source of hematopoietic stem and progenitor cells (HSPC) for both autologous and allogeneic transplantation. The most common clinical hematopoietic stem cell mobilization protocol is five days of Filgrastim (G-CSF). This regimen requires daily injections, has been associated with bone pain and often results in unpredictably low yields. A rapid mobilization method that ideally only required a single treatment and had robust and predictable kinetics would be a significant improvement over the current standard of care. In mice, a unique CXCR2 agonist, GROβ, induces rapid mobilization of stem and progenitor cells 15 minutes after a single injection. When co-administered with plerixafor (AMD3100), an inhibitor of CXCR4, a synergistic increase in mobilization results, with a graft enriched in highly engraftable hematopoietic stem cells (Hoggatt et al., Blood 2016 128:368). Here, we present data demonstrating that combination treatment with GROβ and AMD3100 synergistically mobilizes CD34+ cells and colony forming units (CFU) in nonhuman primates (NHP).Methods: Cynomolgus macaques were injected with G-CSF (10 µg/kg/day, s.c. for four days), AMD3100 (1 mg/kg, s.c. once) or GROβ (various doses and routes) alone and in combination with AMD3100. Blood was collected at various times post treatment and analyzed by multicolor flow cytometry to quantitate HSPC numbers. Additional aliquots of mobilized blood were plated in methylcellulose and CFU were enumerated seven days later.Results: We tested the effect of GROβ alone or in combination with AMD3100 in Cynomolgus monkeys. As published previously, administration of G-CSF, AMD3100 or G-CSF+AMD3100 induced significant mobilization of hematopoietic stem and progenitor cells. In comparison, a single injection each of GROβ+AMD3100 yielded 4-fold more CD34+ cells compared to four days of G-CSF (p < 0.01). While the combination of G-CSF+AMD3100 mobilized significantly more CD34+ cells compared to GROβ+AMD3100 (p < 0.0001), the numbers of CD34+ CD90+ CD45RA- cells, representing the most primitive of hematopoietic stem and progenitor cells, were equivalent between treatment groups. Similarly, GROβ+AMD3100 treatment elicited 7-fold more CFU compared to animals treated with G-CSF (p < 0.01), 3.5-fold more CFU compared to AMD3100 (p < 0.01) and equivalent CFU compared to G-CSF+AMD3100. Importantly, the frequency of CFU among the CD34+ cells was significantly greater with GROβ+AMD3100 (1 in 4) compared to G-CSF (1 in 10) or G-CSF+AMD3100 (1 in 25). In contrast to the increased CD34+ numbers and CFU, white blood cell (WBC) and neutrophil counts were significantly lower with GROβ+AMD3100 compared to AMD3100 alone or G-CSF+AMD3100.Conclusions: We describe a rapid mobilization method that within four hours of a single treatment results in robust hematopoietic mobilization in nonhuman primates. The GROβ+AMD3100 regimen enriches for primitive CD34+ CD90+ CD45RA- stem and progenitor cells with increased colony forming capacity compared to CD34+ cells mobilized with G-CSF+AMD3100, suggesting a significant graft quality difference with the new regimen. The ability to rapidly mobilize primitive HSC with increased CFU frequency may allow effective single day mobilization of HPSCs for patients requiring a HSCT and be especially useful for HSC based gene therapy and gene editing protocols where HSPC grafts enriched for primitive HSC may reduce manufacturing costs and ensure durability of the gene modified HSC. The ability to achieve increased HSPC numbers without dramatically increasing WBC and neutrophils may be especially advantageous in patient populations where G-CSF mobilization is not well tolerated such as Sickle Cell Disease, or where G-CSF leads to increased disease activity such as in autologous transplant for Multiple Sclerosis. A single treatment that results in robust mobilization that is equivalent to G-CSF may allow for a one-day collection method of donor stem cells, and these findings in nonhuman primates support clinical exploration. DisclosuresFalahee:Magenta Therapeutics: Employment, Equity Ownership. Goncalves:Magenta Therapeutics: Employment, Equity Ownership. Hyzy:Magenta Therapeutics: Employment, Equity Ownership. Proctor:Magenta Therapeutics: Employment, Equity Ownership. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.

G-CSF Signaling Counteracts TGF-β—PAI-1-Dependent Retention of Hematopoietic Stem Cells in the Niche

Hematopoietic stem cells (HSCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but are usually stayed in the niche. Recently, we have reported that niche cell-producing TGF-β induces intracellular PAI-1 expression in HSCs, which inhibits the proteolytic activity of proprotein convertase Furin-dependent maturation of MT1-MMP, a protease involved in the mobilization of HSPCs, thereby keeping HSCs retaining in the BM niche. Pharmacological inhibition or genetic disruption of the TGF-β−PAI-1 signal increased MT1-MMP-dependent cellular motility, causing a detachment of HSCs from the TGF-β-expressing niche cells, demonstrated a crucial role for TGF-β−PAI-1 signal in the retention of HSCs in the BM. On the other hand, HSCs frequently egress from the BM to circulation and replenish blood supply in order to maintain the homeostasis of blood system. At this moment, however, how environmental stimuli, such as a blood G-CSF concentration rise, counteract the TGF-β-PAI-1 signaling and releases the motility restriction of HSCs remains unknown.To identify the molecular mechanism that govern the dynamic motion of HSCs in the niche, we chose to investigate the cellular activities of HSCs in response to G-CSF. Here, we provide evidence that G-CSF inhibits Smad-dependent signaling by regulating cAMP-PKA-dependent signaling pathway in HSCs. G-CSF-induced activation of this pathway inhibits Smad-dependent expression of PAI-1 through an increase in phosphorylation levels of CREB protein. Mechanistically, increased pCREB competitively inhibited the Smad from binding to the p300/CBP, which ultimately resulting in a transcriptional suppression of Smad-p300/CBP transcription regulatory complex-dependent PAI-1 gene expression. In line with this, administration of G-CSF to mice strongly downregulated intracellular PAI-1 expression in HSCs, which resulted in enhanced Furin-dependent MT1-MMP maturation. The enhanced expression of MT1-MMP results in MT1-MMP-mediated CD44 cleavage as well as CXCR4 and VLA-4 activation, which in turn stimulates detachment of HSPCs from the niche and active trafficking into the blood stream. Expectedly, pharmacological inhibition of intracellular PAI-1 activity synergized with G-CSF-induced HSC mobilization.Our study reveals a novel role for G-CSF signaling in controlling TGF-β−PAI-1-dependent retention of HSCs to recruit them into the circulation, which potentially improve clinical HSC mobilization and transplantation protocols. DisclosuresAndo:CHUGAI PHARMACEUTICAL: Other: Donation to institute; Meiji Seika Pharma: Other: Donation to institute; NOVARTIS: Other: Donation to institute; TOYAMA CHEMICAL: Other: Donation to institute; MOCHIDA PHARMACEUTICAL: Other: Donation to institute; Sumitomo Dainippon Pharma: Other: Donation to institute; Eisai: Other: Donation to institute; Bristol-Myers Squibb: Other: Donation to institute; MSD: Other: Donation to institute; Kyowa Hakko Kirin: Other: Donation to institute; ALEXION: Other: Donation to institute; Takeda: Other: Donation to institute; Japan Blood Products Organization: Other: Donation to institute; Nippon Shinyaku: Other: Donation to institute; NIHON PHARMACEUTICAL: Other: Donation to institute; TAIHO: Other: Donation to institute; Asahi KASEI: Other: Donation to institute.

Effect of Different Treatment Patterns to Cost Effectiveness in Chronic Lymphocytic Leukemia Patients, Turkish CLL Study Group

AimThe data of CLL patients from 12 centers were recorded with an aim of constructing a nationwide CLL registry. We present the retrospective arm of the data obtained, with an emphasis on analysis of cost related parameters.Method761 patients included in the retrospective arm. SAS 9.4 was used to analyze data.Results63.34 % of patients were male, and the median age at diagnosis was 62.37 (25-92). Median follow up of all patients was 42 months. Overall 7.75 percent of patients died during follow up. Among 252 (35.14% of all patients) patients who required CLL specific therapy, rate of death was 12.5%. Among patients who required therapy 70% received one line, 18% received two lines and 13% received three or more lines of therapy. Fludarabin based therapies leaded front-line therapies by 47.60%, chlorambucil followed fludarabin based therapies by 26.2%. Considering the second line therapies most patients received either bendamustine based therapies or novel agents. Overall response achieved by front line therapies was 84% with a CR rate of 48%. Remission rates declined by further lines of therapy. In patients undergoing front-line therapy, del17p rate was %5.3, and del17p was the worst prognostic factor regarding therapy response and outcome. Among all patients median OS was not achieved, and 10 years OS rates for patients requiring therapy was 63,5% which was significantly less than patients who did not require therapy (p=0.027).Cost analysis data, which included duration of hospitalization, total number of specialist visits and G-CSF use, was available for 115 patients. Treatments were classified as fludarabine (FCR- fludarabine, cyclophosphamide, rituximab), bendamustine (benda) and chlorambucil (clb) based. Benda and clb chemotherapy consisted of anti CD20 treatment or not. Median treatment durations were 6 cycles for FCR, 6 cycles for benda and 7.4 months for clb arm. Hospitalization days and G-CSF administration rate was significantly higher in FCR arm compared to benda and clb arms altough mean age in FCR arm was lower. There was a slight significance in terms of specialist visits between FCR and benda arms. No statistical significance was noted between benda and clb regarding age and other cost related parameters (Table 1).ConclusionThis study confirms that the costs for FCR therapy is higher due to its toxicity. Lack of statistical significance between FCR and Clb regarding hospitalization duration and specialist visits might be related with older age of Clb arm. Cost related information in CLL treatment is becoming more important for reimbursement decisions of new generation expensive drugs. Cost effectiveness ratios should be calculated both in daily practice and clinical trial setting using data from prospective patient registries. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chimeric Antigen Receptor Induced Cytopenia Differs from Chemotherapy Induced Myelosuppression

▪Background: Cytopenias are a potential complication of chimeric antigen receptor (CAR) therapy. The specific degree, duration, or implication of these cytopenias is not well established, and is further confounded by baseline cytopenias in heavily pre-treated patients with active leukemia. Preclinical models suggest that these cytopenias may be due to a cytokine rich milieu which may contribute to nonspecific suppression of marrow progenitors-independent of the CAR target (Sauter, ASH 2016, abstract 3357); which differs from standard cytotoxic chemotherapy based myelosuppression. We systematically analyzed CAR-related cytopenias on our phase I dose-escalation study of CD22 CAR.Design: Children and young adults with relapsed/refractory CD22+ acute lymphoblastic leukemia (ALL) treated on our phase I dose escalation anti-CD22 CAR therapy protocol (NCT02315612) were evaluated for time to neutrophil and platelet recovery (defined by absolute neutrophil count (ANC) of > 500 k/mcL x 3 days and achievement of transfusion independent platelet count > 20 k/mcL, respectively). All patients had bone marrow evaluations by morphology and flow cytometry at baseline, prior to lymphodepleting chemotherapy (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) and again at day 28 (+/- 4 days) post-CAR. Infections were closely monitored for. All patients were on anti-fungal prophylaxis and were empirically treated for fever during periods of neutropenia.Results: From December 2014 to July 2017, 30 patients with ALL were treated on study at 3 dose levels. All patients had active bone marrow involvement at baseline with the majority (n=21) having an M2 marrow (>5% blasts) or higher. Twenty-six patients had prior transplants, and 21 patients had prior CD19-directed CAR therapy. Cytokine release syndrome (CRS) was seen in 24/30 (80%), with most patients having grade 1-2 CRS. 18/30 patients (60%) attained a complete remission following CD22 CAR therapy. Baseline hematologic parameters for responders prior to lymphodepletion included grade 2-4 neutropenia and grade 2 and 3 thrombocytopenia, with five patients requiring platelet transfusions (Table 1). Amongst complete responders, the bone marrow at day 28 demonstrated a median cellularity of 28% with trilineage hematopoiesis noted in 16/18 patients. The median CAR T cell % in bone marrow at 1 month was 30%. The median time to ANC nadir was 15 days post CAR infusion (range:10-23 days).17/18 patients had ANC recovery >500 k/mcL, at a median of 22 days post-infusion (range: 15-44 days). One patient had ANC recovery to 260 k/mcL but subsequently developed disease relapse. Eight patients received intermittent GCSF, with clinically relevant responses seen in seven of these patients with a median increase in ANC of 2,180 k/mcL (range: 850-4,100 k/mcL) with limited dosing. The median number of days of GCSF administration to time of ANC recovery was 4, with 3 patients requiring only 1 injection to achieve robust ANC response. Interestingly, only 1/18 patient (6%) had a new onset of infection (clostridium difficile colitis) during the period of CAR associated neutropenia, which was confounded by administration of intravenous antibiotic therapy for fevers that was initiated 24 hours prior to onset of diarrhea. There was no new development of fungal infections or worsening of any pre-existing infections. Platelet recovery to > 20 k/mcL was at a median of 36 days (range: 21-55) post-CAR and was seen in 16 of 18 responders. Two patients who remained platelet transfusion dependent post-CAR included one patient who was later found to have donor-cell monosomy 7 MDS and another patient whose disease relapsed prior to recovery.Conclusion: In contrast to chemotherapy associated myelosuppression, CAR-therapy associated peripheral blood cytopenias existed despite evidence for trilineage hematopoiesis on the bone marrow. Although the period of CAR associated neutropenia is substantial, with prophylactic antifungals and intermittent growth factor support, this heavily pre-treated population was not at an increased risk of developing serious bacterial or fungal infections over baseline. The rapid response to G-CSF is suggestive of an alternative modality of bone marrow inhibition distinct from chemotherapy induced cytotoxicity. Further evaluation in the context of multiple CAR targets and constructs are needed to further explore this complication. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low-Dose Plerixafor and Granulocyte Colony-Stimulating Factor for First-Line Autologous Peripheral Blood Stem Cell Mobilization in Lymphoma and Multiple Myeloma

Introduction: Approximately 10-30% of candidates to autologous hematopietic stem cell transplant (HSCT) are unable to collect an adequate yield of CD34+ cells/kg to support high-dose chemotherapy and autologous HSCT. Peripheral blood stem cell (PBSC) mobilization strategies vary considerably but the optimal methodology for mobilizing PBSC is not well defined. Plerixafor (Mozobil®) is approved for the mobilization of PBPC in combination with G-CSF at a dose of 0.24 mg/kg once daily for up to 4 consecutive days; however, it is an expensive drug and is expected to increase costs associated with PBSC harvest. Failure of peripheral blood (PB) mobilization and harvest is a critical issue for multiple myeloma (MM) and non hodgkin´s lymphoma (NHL) since the correlation between successful engraftment and the number of CD34+ cells infused is well established. We aim to investigate the safety and efficacy of the administration of low-dose plerixafor in mobilizing CD34+ cells plus G-CSF in MM and NHL.Methods: It is a preliminary report of a single-institution, open-label, phase II trial to test the feasibility and efficacy for mobilization of low-dose plerixafor added to daily G-CSF administration in adult patients with MM or NHL undergoing autologous HSCT. Institution ethic board approved the trial and all patients provided written informed consent. Consecutive patients in autologous transplant protocol with MM or NHL were included. The mobilization protocol consisted of G-CSF (10 μg/kg) subcutaneously daily for 4 days and plerixafor (0.12 mg/kg) administered subcutaneously 11 hours prior to initiation of apheresis. Stem cells collection was performed with a Cobe Spectra® or Spectra Optia® apheresis system. The planned target blood volume to be processed was 4-fold total blood volume calculated according to patients' weight and size. Peripheral blood CD34+ counts were analyzed using flow cytometry. Primary endpoint was the proportion of patients achieving at least 2 x 106 CD34+cells/kg in 1 apheresis harvest. Secondary end points included the rate of successful CD34+ cell mobilization, defined as a peak of CD34+ cells in PB >20 cells/mL. We measure PB CD34+ cells the day 4 and 5 after plerixafor administration. Toxicities and engraftment were documented.Results: Between april 2017 and july 2017, nine patients has been enrolled. Six with MM and 3 with NHL. The median PB CD34+ cell count for patients on day 4 before receiving plerixafor was 12.3/mL (range, 2.2-168.8) and 65.4/mL (range, 8.2-360.7) on day 5 after plerixafor (P=0.103). The median collection yield was 4.9 x 106 CD34+ cells/Kg (range, 1.4 - 24.5 million CD34+ cells/Kg). Plerixafor was well tolerated in most patients, only 2 referred moderate diarrhea. Eight of the 9 patients reached the target cell count (88.8%) with only 1 day of collection. Seven of nine patients had hematopoietic recovery with median neutrophil and platelet engraftment of 14 (range, 10-16) and 12 days (range, 10-16), respectively. Two patients are on day +1 and +5 and waiting for engraftment.Conclusions: Failure of PBSC mobilization is a critical issue for MM and NHL patients undergoing autologous HSCT. The combination of low-dose plerixafor with G- CSF in this study achieved 88% of successful yields, and appears to be an efficient and safe approach in first-line to improve the success of the yield. Aside of the costs related to plerixafor, this strategy can be counterweighed by reducing other resources as reducing number of apheresis and possibly reducing the impact on quality of life for patients. DisclosuresGomez-Almaguer:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The Effect of Neutropenia and Filgrastim (G-CSF) on Cancer Patients With Coronavirus Disease 2019 (COVID-19) Infection.

BackgroundNeutropenia is commonly encountered in cancer patients. Recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim), a cytokine that initiates proliferation and differentiation of mature granulocytes, is widely given to oncology patients to counteract neutropenia, reducing susceptibility to infection. However, the clinical impact of neutropenia and G-CSF use in cancer patients with coronavirus disease 2019 (COVID-19) remains unknown.MethodsAn observational cohort of 379 actively treated cancer patients with COVID-19 was assembled to investigate links between concurrent neutropenia and G-CSF administration on COVID-19-associated respiratory failure and death. These factors were encoded as time-dependent predictors in an extended Cox model, controlling for age and underlying cancer diagnosis. To determine whether the degree of granulocyte response to G-CSF affected outcomes, the degree of response to G-CSF, based on rise in absolute neutrophil count (ANC) 24 hours after growth factor administration, was also incorporated into a similar Cox model.ResultsIn the setting of active COVID-19 infection, outpatient receipt of G-CSF led to an increased number of hospitalizations (hazard ratio [HR]: 3.54, 95% confidence interval [CI]: 1.25–10.0, P value: .017). Furthermore, among inpatients, G-CSF administration was associated with increased need for high levels of oxygen supplementation and death (HR: 3.56, 95% CI: 1.19–10.2, P value: .024). This effect was predominantly seen in patients that exhibited a high response to G-CSF based on their ANC increase post-G-CSF administration (HR: 7.78, 95% CI: 2.05–27.9, P value: .004).ConclusionsThe potential risks versus benefits of G-CSF administration should be considered in neutropenic cancer patients with COVID-19, because G-CSF administration may lead to worsening clinical and respiratory status.

Impact of G-CSF during neoadjuvant therapy on outcomes of operable pancreatic cancer.

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p &lt; 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p &lt; 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.

A precision dosing application for prostate cancer patients treated with docetaxel and G-CSF.

e13585 Background: The aim of this study is to produce a precision dosing application for clinicians to control neutropenia in prostate cancer patients treated with both docetaxel and G-CSF. Chemotherapy-induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual’s dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk adverse environment to infections, raising the prospects that a clinician will administer G-CSF. Methods: We adapted and combined representations of endogenous and exogenous G-CSF action on CIN from the literature [2,3,4] to capture the inherent feedback effect of circulating neutrophils on progenitor proliferation as well as the stimulatory action of G-CSF injection on proliferation and maturation of progenitor cells. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669), we identified 134 patients treated with docetaxel with recorded weekly blood tests in the first and second cycle, including 27 also receiving G-CSF. We calibrated individualised patient models against neutrophil counts measured in the first cycle by minimising a Bayesian objective function and evaluated their ability to predict the levels observed in the second cycle. Results: The model was able to capture the main features of endogenous and exogenous G-CSF action on neutrophil count described in the literature, including endogenous-G-CSF-mediated rebound above baseline after chemotherapy-induced depletion [4], rapid rise in neutrophil count following exogenous G-CSF administration [5], as well as reduced chemotherapy-induced depletion and earlier recovery under G-CSF treatment compared to chemotherapy alone [5]. Conclusions: This tool has the potential to help determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel.

Combining Mobilizing Agents with Busulfan to Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell Transplantation.

In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient’s diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.

One-Year Experience of Cytomegalovirus T Cell Immunity Monitoring in Heart Transplant Recipients

<h3>Purpose</h3> Guidelines suggest optional use of Cytomegalovirus (CMV) T Cell immunity monitoring (TCell) to guide primary prophylaxis duration or need for secondary prophylaxis after infection. This may help balance the negative implications of CMV (rejection, coronary artery vasculopathy) against those of valganciclovir (expense, leukopenia/neutropenia). We present one year of experience to evaluate the potential utility of this test. <h3>Methods</h3> CMV TCell was implemented at our center to assess immunity at end of primary prophylaxis (R+ serostatus) and need for secondary prophylaxis after treatment of CMV. Heart transplant recipients with CMV TCell September 2019 to 2020 were retrospectively reviewed. Primary prophylaxis tests were excluded if R- serostatus or within 6 months of rATG. Tests at time of CMV detection prior to treatment were also excluded. <h3>Results</h3> Table 1 describes requirements for implementation. 24 patients had CMV TCell during study period; 1 never processed. Patients were excluded for: R- serostatus (6), rATG (1), and at time of CMV detection (2). 14 patients were included for analysis; 5 CMV R+ to guide primary prophylaxis discontinuation, 8 for secondary prophylaxis after infection treatment, 1 early for neutropenia. The early test for neutropenia was inconclusive after G-CSF administration. Immunity was noted at first test in 2/5 (40%) of the primary prophylaxis and 4/8 (50%) of the secondary group. Of non-immune in primary prophylaxis group, 2 had inconclusive tests concurrent to non-CMV infection and other in setting of neutropenia. After repeat tests, 9/14 (64%) patients were noted to have immunity. Of those with immunity, 5/9 (55%) had recurrence of low level viremia; 2 treated at detection, 3 self-cleared without treatment. <h3>Conclusion</h3> Early review of our data suggests CMV TCell may serve a role to identify patients who would benefit from secondary prophylaxis after treatment of CMV infection. Additional data over future years will help better define optimal utilization of this test.

505 - G-CSF Administration Post Transplant Does Not Accelerate Neutrophil Engraftment or Delay Platelet Engraftment in Recipients Undergoing Auto-HCT Regardless of CD34 Dose

505 - G-CSF Administration Post Transplant Does Not Accelerate Neutrophil Engraftment or Delay Platelet Engraftment in Recipients Undergoing Auto-HCT Regardless of CD34 Dose

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration.

Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study, we aimed to explore the role of GCSF in nonalcoholic fatty liver disease (NAFLD). Male GCSF-/- mice were used to investigate the function of GCSF in vivo after high-fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF-/- mice exhibited alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD.NEW & NOTEWORTHY We found GCSF was involved in lipid metabolism and NAFLD development. GCSF administration increased serum triglyceride levels in patients. GCSF deficiency alleviated HFD-induced insulin resistance and hepatic steatosis in mice. GCSF could directly act on hepatocytes through GCSFR-SOCS3-JAK-STAT3 pathway, and regulate the infiltration of immune cells into the liver to indirectly modulate NAFLD. Our finding indicates that GCSF may provide new strategies for the treatment of NAFLD.

Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis

The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58–3.00; p < 0.00001; OR 2.03; 95% CI 1.22–3.36; p = 0.006) and LBR (RR 2.41; 95% CI 1.40–4.16; p = 0.002; OR 3.73; 95% CI 1.13–12.29; p = 0.03), of subcutaneous G-CSF administration on CPR (RR 2.29; 95% CI 1.58–3.31; p < 0.0001) and of intrauterine PRP infusion on CPR (RR 2.45; 95% CI 1.55–3.86; p = 0.0001). Observational studies also demonstrated a positive effect of IVIG and intrauterine hCG infusion on both CPR and LBR and of atosiban on CPR. Studies investigating intrauterine G-CSF infusion, LMWH, intravenous intralipid, hysteroscopy, blastocyst-stage ET, ZIFT, PGT-A and AH failed to observe an impact on IVF outcome. The quality of the evidence that emerged from RCTs focused on intrauterine PBMC infusion and subcutaneous G-CSF administration was moderate. For all other therapies/interventions it varied from low to very low. In conclusion, intrauterine PBMC infusion and subcutaneous G-CSF administration are the most promising therapeutic options for RIF. However, further well conducted RCTs are necessary before their introduction into clinical practice.

Effect of Intra Uterine Granulocyte Colony Stimulating Factor vs. Human Chorionic Gonadotropin at Ovum Pick Up Day on Pregnancy Rate in IVF/ICSI Cases With Recurrent Implantation Failure.

ObjectiveRecurrent implantation failure is defined as failure to achieve clinical pregnancy after the transfer of four or more good-quality embryos in a minimum of three fresh or frozen cycles in a woman aged less than 40 years. The objective is to compare between the effect of intrauterine G-CSF, hCG, and saline solution injection (as placebo) at the day of ovum pick-up on clinical pregnancy, chemical pregnancy, implantation, and miscarriage rates in patients with recurrent implantation failure undergoing IVF/ICSI.MethodsThis prospective, double blind, parallel, randomized controlled trial included 150 patients equally divided into 3 groups, each containing 50 individuals. Subjects in Group 1 received intrauterine injections of G-CSF; Group 2: received intrauterine injections of 500 IU of hCG; and Group 3 received intrauterine injections of saline solution as placebo. The primary outcome measure is clinical pregnancy rate. Secondary outcomes are biochemical pregnancy, implantation, and miscarriage rates.ResultsClinical pregnancy, biochemical pregnancy, and implantation rates were highest in the group given G-CSF and lowest in the group administered saline solution; miscarriage rates were not significantly different between the groups.ConclusionsIntrauterine administration of G-CSF at a dose of 100 µg/1.0 cc at the time of ovum pick-up is associated with better clinical pregnancy, chemical pregnancy, and implantation rates as compared with intrauterine saline solution administration. Further studies are needed to determine the optimum timing of intrauterine administration of G-CSF that achieves the best results, and longer follow-up is needed to determine take-home baby percentages.