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Effectiveness of single-dose 6 mg pegfilgrastim in mobilizing peripheral blood stem cells in allogeneic hematopoietic cell transplantation donors
Cao, J., Li, A., Pei, R., Lu, Y., Chen, D., Du, X., Liu, X., Li, S., Ye, P.
Annals of hematology. 2023
Abstract
A single injection of 12 mg pegfilgrastim was used to mobilize peripheral blood progenitor cells (PBPCs) from healthy donors in some studies. The purpose of this study was to determine if 6 mg of pegfilgrastim was effective and safe for mobilizing CD34+ cells in donors for allogeneic hematopoietic stem cell transplantation. We conducted a retrospective case-matched design. A single dosage of 6 mg pegfilgrastim was used to mobilize PBPCs from 60 healthy donors. Granulocyte colony-stimulating factor (G-CSF, 10 μg/kg) was administered daily to the matched donors. Leukapheresis was scheduled to commence on day 4 of the mobilization regimen. The median yielded CD34+ cell in the pegfilgrastim group was higher than those in the G-CSF group, at 5.06 × 10(6)/kg recipient weight. The 73.3% of donors mobilized with pegfilgrastim yielded >4 × 10(6) cells/kg CD34+ cells in a single apheresis procedure when compared to the 33.3% of donors mobilized with G-CSF (P < 0.001). The myeloid-derived suppressor cells (MDSC) proportion in the pegfilgrastim group was significantly higher than that in the G-CSF group (P < 0.001). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was higher in the G-CSF group than that in the pegfilgrastim group (26.7% vs. 11.7%), without statistical difference. In comparison to the G-CSF group, the pegfilgrastim group had a reduced median pain intensity numerical rating scale score (1 vs. 2). A single 6 mg dosage of pegfilgrastim is effective and safe for allogeneic PBPCs collection from healthy donors. Pegfilgrastim may decrease the incidence of aGVHD by boosting MDSCs, which need further investigation.
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Feasibility of peripheral blood stem cell collection from sickle cell trait donors with an intensified G-CSF regimen
Mohrez, M., Troeger, A., Kleinschmidt, K., Alali, T. H., Jakob, M., Brosig, A., Hähnel, V., Kietz, S., Offner, R., Burkhardt, R., et al
European journal of haematology. 2023
Abstract
OBJECTIVES Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCD and bone marrow from an HLA-matched sibling is currently the standard of care. Haploidentical HSCT from a family donor with a TCR αβ/CD19 depleted graft (T-haplo) is an increasingly successful alternative, which requires the generation of G-CSF stimulated peripheral stem cell (PBSC) from haploidentical relatives. These sickle cell trait (SCT) donors reported to develop SCD-related complications in conditions of severe stress. METHODS In this retrospective analysis, we compared the safety and efficacy of PBSC mobilization with a G-CSF intensified mobilization regimen in SCT donors with a conventional G-CSF mobilization regimen in healthy donors. RESULTS The reported adverse events were similar during intensified G-CSF mobilization, apheresis, and shortly after stem cell apheresis in SCT and control donors. In SCT and control donors, we were able to mobilize high yields of CD34(+) stem cells and the harvested CD34(+) cell count was comparable with control donors. CONCLUSIONS Peripheral stem cell mobilization using an intensified G-CSF regimen is safe, and well tolerated among SCT donors. SCT donors are a valid alternative for collection of peripheral CD34(+) stem cells for T-cell-depleted haploidentical stem cell transplantation.
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Hematopoietic Stem Cell Mobilization for Allogeneic Stem Cell Transplantation by Motixafortide, a Novel CXCR4 Inhibitor
Crees, Z. D., Rettig, M. P., Bashey, A., Devine, S. M., Jaglowski, S. M., Wan, F., Zhou, A., Harding, M., Vainstein-Haras, A., Sorani, E., et al
Blood advances. 2023
Abstract
Peripheral blood stem cells are the most common source of hematopoietic stem and progenitor cells (HSPCs) used for hematopoietic cell transplantation (HCT). HSPC mobilization with G-CSF +/- plerixafor results in suboptimal HSPC yields in up to 30% of patients, despite multiple injections and leukapheresis procedures (LP). We evaluated motixafortide (BL-8040), a high-affinity, long-acting CXCR4 inhibitor with rapid mobilizing kinetics, in a multi-center, open-label, single-arm, 2-part, Phase II study to mobilize HSPCs in allogeneic HCT donors (NCT02639559). The primary endpoint was the efficacy of 1 dose of motixafortide to mobilize greater than or equal to 2.0×10^6 CD34+ cells/kg within 2 LPs. Twenty-five donor-recipient pairs were enrolled. Motixafortide was well-tolerated with 22/24 (92%) evaluable donors meeting the primary endpoint, including 11/11 donors receiving motixafortide at 1.25mg/kg. Engraftment and GVHD rates were comparable to historical data. Motixafortide preferentially mobilized large numbers of multipotent HSPCs and a smaller proportion of CD34+ plasmacytoid dendritic cell precursors with high CD123 expression. Motixafortide induced pan-mobilization of all major myeloid and lymphoid subsets, with maximum relative changes in plasmacytoid/myeloid dendritic cells, B-cells, basophils, CD8 T-cells and classical monocytes. In conclusion, a single injection of motixafortide results in rapid and sustained mobilization of multipotent HSPCs for allogeneic HCT.
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Efficacy and Safety of Single-dose Pegfilgrastim for CD34+ Cell Mobilization in Healthy Volunteers: A Phase 2 Study
Goto, H., Sugita, J., Hasegawa, Y., Hayasaka, K., Sunagoya, K., Hatase, R., Nishida, M., Ichihashi, Y., Odera, M., Senjo, H., et al
Transplantation. 2023
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Abstract
BACKGROUND Pegfilgrastim, a long-acting form of granulocyte-colony stimulating factor, with a convenient single-injection dosage, is being investigated for peripheral blood stem cell (PBSC) mobilization in healthy volunteers. However, data on the adequate dose of pegfilgrastim for PBSC mobilization are limited. This phase 2, single-arm study evaluated the efficacy and safety of pegfilgrastim for PBSC mobilization in healthy volunteers. METHODS The study comprised 2 phases: pilot (steps 1-3, dose escalation, a single subcutaneous dose of 3.6, 7.2, and 10.8 mg pegfilgrastim, respectively) and evaluation (step 4, efficacy and safety assessments). The primary endpoint was the proportion of subjects who achieved mobilization of ≥20 × 106/L cluster of differentiation 34 positive (CD34+) cells. RESULTS Thirty-five subjects (6 each in steps 1 and 2 and 23 in step 4) were included. In the pilot phase, step 3 with a 10.8 mg dose was not conducted due to favorable outcomes in step 2 (desired CD34+ cell count), at 7.2 mg pegfilgrastim, which was identified as the optimal dose for the evaluation phase. In the evaluation phase, successful CD34+ mobilization was achieved in all 23 subjects. The mean peripheral blood CD34+ cells count peaked on day 5. Back pain, thrombocytopenia, transient elevations of alkaline phosphatase, and lactate dehydrogenase were the most common adverse events. All adverse events were mild, and none led to study discontinuation. CONCLUSIONS A single-dose pegfilgrastim successfully mobilized an optimal number of CD34+ cells and was well tolerated. Pegfilgrastim could be an alternative option for PBSC mobilization in healthy volunteers. The trial was registered at www.clinicaltrials.gov (NCT03993639).
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A research on the influence of G-CSF mobilization on donor's peripheral blood MDSCs and its relationship with patient prognosis
Wang, R., Chen, M., Fu, M., Zhao, W., Zhou, J., Gong, M., Wu, Q., Wang, H.
International immunopharmacology. 2023;124(Pt B):110998
Abstract
OBJECTIVE To discuss the effects of mobilization of healthy donors with granulocyte colony-stimulating factor (G-CSF) on the absolute values and functions of myeloid-derived suppressor cells (MDSCs) and subpopulations of M-MDSCs and P-MDSCs in their peripheral blood. In addition, this study also aims to investigate the impacts of the adoptively transferred MDSCs from the grafts to the patients on their prognosis and immune reconstitution. METHODS The selection of 72 donors and 72 patients were conducted for allogeneic hematopoietic stem cell transplantation (allo-HSCT) from August 2022 to December 2022 at Lu Daopei Hospital in Beijing, China. Statistical calculations were performed by Wilcoxon signed-rank test, Kruskal Wallis test, χ(2) test, Kaplan Meier test, and log-rank test to analyze the data. RESULTS & CONCLUSION G-CSF induced significant amplification of MDSCs in the peripheral blood of donors in percentage and absolute values. Whether the level of P-MDSCs in patients conducted for the adoptive transfer of P - MDSCs is higher than 3.7× 10(7)/kg or lower than 1.4× 10(7)/kg leads to a poor prognosis of the patients. Ensuring a balanced state of MDSCs is crucial for effective immunotherapy. Transferring a high level of MDSCs from the graft to the patient's body is advantageous for the development of MDSCs while simultaneously inhibiting the proliferation of lymphocyte subgroups.
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Peripheral Blood Allogeneic Stem Cell Mobilization: Can We Predict a Suboptimal Mobilization?
Piccirillo, N., Putzulu, R., Metafuni, E., Massini, G., Fatone, F., Corbingi, A., Giammarco, S., Limongiello, M. A., Di Giovanni, A., Zini, G., et al
Transfusion medicine reviews. 2023;37(2):150725
Abstract
Allogeneic peripheral blood stem cells mobilization is now the basis of most stem cell transplants. In a very limited number of cases, mobilization is suboptimal leading to further collection procedures, to suboptimal cell doses infusion with delayed engraftment time, increased risks of transplant procedure and of related costs. To date we have no recognized and shared criteria for early estimating the probability of poor mobilization in healthy donors. We then analyzed allogeneic peripheral blood stem cell donations performed at the Fondazione Policlinico Universitario A.Gemelli IRCCS Hospital from January 2013 to December 2021 in order to identify premobilization factors associated with successful mobilization. The following data were collected: age, gender, weight, complete blood cell count at baseline, G-CSF dose, number of collection procedures, CD34+ cell count in peripheral blood on the first day of collection, CD34+ cell dose per kg body weight of recipient. Mobilization efficacy was defined according to the number of CD34+ cells in peripheral blood on day +5 of G-CSF administration. We classified donors as sub-optimal mobilizers or good mobilizers according to the achievement of the 50 CD34+ cell/μL threshold. We observed 30 suboptimal mobilizations in 158 allogeneic peripheral blood stem cell donations. Age and baseline white blood cell count were factors significantly associated with negative or positive impact on mobilization, respectively. We did not find significant differences in mobilization based on gender or G-CSF dose. Using cut-off values of 43 years and 5.5×10(9)/L WBC count, we built a suboptimal mobilization score: donors who reach 2, 1 or 0 points have a 46%, 16% or 4% probability of suboptimal mobilization, respectively. Our model explains 26% of the variability of mobilization confirming that most of the mobilization magnitude depends on genetically determined factors; however, suboptimal mobilization score is a simple tool providing an early assessment of mobilization efficacy before G-CSF administration begins in order to support allogeneic stem cells selection, mobilization and collection. Through a systematic review, we looked for confirmation of our findings. According to the published articles, all the variables we included in our model are confirmed to be strongly related to the success of mobilization. We believe that score system approach could be applied in clinical practice to assess the risk of mobilization failure at baseline allowing for a priori intervention.
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Comparing the effectiveness of biosimilar filgrastim (Nivestim®) versus original filgrastim (Neupogen®) for stem cell mobilization in adult and pediatric healthy donors
Muffarrej, D., Hashem, H., Tbakhi, A., Najjar, R.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231171829
Abstract
INTRODUCTION Filgrastim is used for the mobilization of stem cells in healthy donors. Though several biosimilar filgrastim products have been approved, there is limited literature evaluating biosimilar products for stem cell mobilization. Therefore, we conducted this study to compare the effectiveness of the original filgrastim, Neupogen®, to the biosimilar product, Nivestim®, for stem cell mobilization(SCM) in healthy donors. METHODS This was a retrospective study that included all healthy donors: adults and pediatrics, who received Neupogen® or Nivestim® for stem cell mobilization between 2014 and 2016 at a comprehensive cancer center. Donors received filgrastim at a dose of 5 mcg/kg every 12 h for 4 days to achieve the target CD34 + cell count of 5-10 × 10(6) CD34 + /kg of recipient body weight. Additional doses of filgrastim were administered and/or the dose increased if target CD34 + was not achieved. The primary endpoint was the number of doses required to achieve the target CD34 + cell count. RESULTS Over the study period, 89 donors received Neupogen® and 68 received Nivestim®. The median age of donors was 19.5 years (3-64) in the Nivestim® group and 15 years (2-16) in the Neupogen® group. The median number of doses required for SCM was eight doses (6-10) in the Nivestim group and eight (6-16) in the Neupogen® group. CONCLUSION Biosimilar Nivestim® was as effective as the original, Neupogen®, for stem cell mobilization for healthy adult and pediatric donors. Larger randomized studies are necessary to evaluate the safety and transplant outcomes of the use of Nivestim®.
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Predicting the CD34 content of mobilized peripheral blood leukapheresis products: single institution experience over 20 years
Mutlu, Y. G., Sevcik, J., Kiss, J. E., Lister, J., Moore, L. R., Donnenberg, A. D.
Cytotherapy. 2023
Abstract
BACKGROUND AIMS Since the standardization of CD34 measurement by flow cytometry, predictors of leukapheresis CD34 yield have played a pivotal role in planning donor leukaphereses. We describe here a single institution's experience with a multivariate predictor that was used for 2,929 products without alteration for 20 years. METHODS The ordinary least squares regression model variables included log peripheral CD34 count, collection duration (3- versus 4-hours), collection number, donor sex, and transplant type. RESULTS During the study period we changed flow cytometers twice and leukapheresis instruments once. During the Cobe Spectra era the predictor explained 90% of the variability in CD34 collection yield for autologous transplants (r(2) = 0.90), and 70% for allogeneic transplants with an overall sensitivity to predict a CD34 yield of ≥ 1 × 10(6)/kg of 97.7%, and specificity of 81.4%. CONCLUSIONS Implemented prospectively with real-time result reporting, the model allowed us to predict CD34 yield with both 3- and 4-hour collection scenarios. Given this guidance, 3-hour collections were selected by the clinical team 25% of the time, saving patient leukapheresis time and resources. When faced with a prediction of < 1 × 10(6) CD34/kg, the clinical team chose to defer collection 72% of the time. In instances where leukapheresis was performed despite a poor predicted outcome, 85% of patients collected on the Cobe Spectra, and 92% of patients collected on the Optia, failed to collect at least 1 × 10(6) CD34/kg. A revised model is tested retrospectively on Optia data, and suggestions for further improvements are discussed.
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Stem Cells mobilization and collection in allogeneic related and unrelated donors: a single center experience with focus on plerixafor
Marcon, C., Bertone, A., Mauro, S., Mestroni, R., Battaglia, G., Pizzano, U., Facchin, G., De Martino, M., Isola, M., Patriarca, F., et al
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103845
Abstract
INTRODUCTION Poor CD34 + cells mobilization in allogeneic donors could affect transplant outcome. In a subgroup of patient mobilization with granulocyte colony-stimulating factor (G-CSF) alone is unsatisfactory, and Plerixafor could be used to enhance CD34 + cells release from bone marrow niche. MATERIALS AND METHODS We conducted a retrospective single-center, cohort study on healthy allogeneic donors both related and unrelated, treated by Udine Transfusion Center over the last 10 years (2012-2022). In the 195 allogeneic donors treated we analyzed age, sex, body weight, BMI, comorbidities, G-CSF dosage and even baseline white blood cell count as possible predictor of insufficient CD34 + cells mobilization on day 5. In the subgroup of related donors we evaluated even baseline CD34 + cells (measured before mobilization start). Processed donor blood volume, collection efficiency and apheresis product were examined. Additionally a comparative analysis was conducted between G-CSF alone treated donors and poor mobilizing ones, in which Plerixafor was administered at a dose of 0.24 mg/kg as a pre-emptive or rescue agent. RESULTS In 9 donors, due to poor mobilization (defined as CD34 + < 20/µL or estimated yield < 1 ×10(6) kg/recipient body weight), the use of plerixafor was necessary. PLX at a dose of 0.24 mg/kg was administered 5 h before collection, inducing an average increase of 5.1 (1.7-12.6) in CD34 + circulating cells. In this subgroup of patients, BMI and weight were significantly lower (p = 0.03). Interestingly, baseline CD34 + cells (measured before the onset of mobilization) also seems to predict poor mobilization (p = 0.003). In donors additionally treated with Plerixafor compared to those who received G-CSF alone, collection efficiency was higher (p = 0.02) and CD34 + cells collected were comparable (p = 0.2). Side effects related to the administration of plerixafor, if they occurred, were well tolerated. CONCLUSIONS Plerixafor is a safe and effective drug in the rescue and prevention of poor mobilization. New prospective studies on allogeneic donors should be performed to increase the treatable population to avoid inadequate collection and mobilization. New laboratory predictors such as baseline CD34 + cells should be investigated in larger cohorts and then used as early screening.
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Is split-dose better than single-dose? Results of Turkish Stem Cell Coordination Center (TURKOK) donors in the era of rising biosimilar G-CSF
Pınar İ, E., Özkocaman, V., Özkalemkaş, F., Durgut, H., Dakiki, B., Ersal, T., Gürsoy, V., Yalçın, C., Orhan, B., Candar, Ö, et al
Journal of clinical apheresis. 2022
Abstract
BACKGROUND Turkish Stem Cell Coordination Center (TURKOK) carries out the procurement process of unrelated allogeneic hematopoietic stem cells in Turkey. This study aims to compare the efficacy of both once-daily and divided-dose G-CSF administration and the original and biosimilar G-CSF use and the frequency and severity of adverse events in TURKOK donors. METHOD The study was conducted retrospectively with 142 healthy TURKOK donors. For PBSC mobilization, two different subcutaneous G-CSF programs were used as 10 μ/kg/day single-dose and 5 μ/kg/12 h. Neupogen (Amgen, Puerto Rico) and Tevagrastim (Teva, Kfar Saba, Israel) were used as G-CSF. All donors started apheresis on the fifth day, and all side effects were recorded during the procedure. RESULTS Stem cell yield was similar between single-dose and divided-doses based on donor weight, favoring the split-dose based on recipient weight (P = .506 and P = .023, respectively). Both G-CSF posologies were comparable if the target CD34+ cell yield was ≥4 × 10(6) /kg. CD34+ cell yield was equivalent when evaluated against recipient weight, significantly favoring Tevagrastim vs Neupogen by donor weight (P = .740 and P = .021, respectively). Side effects, duration of pain, and need for analgesia favor Tevagratim over Neupogen. CONCLUSION Split-dose may be recommended for cases where the need for large numbers of CD34+ cells to be harvested is anticipated due to significant cell yield relative to recipient weight. However, sufficient hematopoietic stem cells can be collected with both posology. Tevagrastim is non-inferiority effective to Neupogen. Side effects during administration are both low-grade and temporary.