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1.
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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2.
The effect of iron overload on the mobilization of peripheral blood hematopoietic stem cells in pediatric patients with thalassemia major
Van Timothee, B. M., Du, J., Ren, Y., He, Y., Ruan, Y., Liu, X., Chen, L., Wen, J., Ding, R., Yu, L., et al
Acta haematologica. 2023
Abstract
INTRODUCTION The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with ꞵ-thalassemia major (TM). METHODS We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload measured by magnetic resonance imaging (MRI) T2*. RESULTS The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI, and lower leukapheresis-product WBC count and and CD34+ cell levels (all, P < 0.05). CONCLUSION Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload , in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs.
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3.
Development and validation of a predictive model to guide the use of plerixafor in pediatric population
Sebastien, B., Cheverton, P., Magnin, C., Aouni, J., Castan, R.
Bone marrow transplantation. 2022
Abstract
Plerixafor, a CXCR4 receptor antagonist, reduces the binding and chemotaxis of hematopoietic stem cells to the bone marrow stroma, resulting in predictable peak of cluster of differentiation 34(+) (CD34(+)) cells in the peripheral blood (PB) approximately 10 h after its administration. We developed a model that could predict the CD34(+) harvest volume on the first day of apheresis (AP-CD34(+)) based on PB-CD34(+) counts immediately prior to commencing apheresis in pediatric population. In all, data from 45 pediatric patients from the MOZAIC study who received either granulocyte colony-stimulating factor (G-CSF) alone or G-CSF plus plerixafor were included. The modeling of the data exhibited a strong and highly predictive linear relationship between the counts of PB-CD34(+) cells on the first day of apheresis and AP-CD34(+) cells collected on the same day. It is predicted that there are approximately 13 new collected CD34(+) cells for 100 new circulating CD34(+) cells before apheresis. Our predictive algorithm can be used to quantify the minimal count of PB-CD34(+) cells that enables to collect at least 2 × 10(6) or 5 × 10(6) AP-CD34(+) cells/kg with sufficient assurance (probability = 0.90) and can guide the use of plerixafor in patients at higher perceived risk for mobilization failure. Trial registration of MOZAIC study: ClinicalTrials.gov, NCT01288573; EudraCT, 2010-019340-40.
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4.
Peripheral blood stem and progenitor cell collection in pediatric candidates for ex vivo gene therapy: a 10-year series
Canarutto, D., Tucci, F., Gattillo, S., Zambelli, M., Calbi, V., Gentner, B., Ferrua, F., Marktel, S., Migliavacca, M., Barzaghi, F., et al
Molecular therapy. Methods & clinical development. 2021;22:76-83
Abstract
Hematopoietic stem and progenitor cell (HSPC)-based gene therapy (GT) requires the collection of a large number of cells. While bone marrow (BM) is the most common source of HSPCs in pediatric donors, the collection of autologous peripheral blood stem cells (PBSCs) is an attractive alternative for GT. We present safety and efficacy data of a 10-year cohort of 45 pediatric patients who underwent PBSC collection for backup and/or purification of CD34(+) cells for ex vivo gene transfer. Median age was 3.7 years and median weight 15.8 kg. After mobilization with lenograstim/plerixafor (n = 41) or lenograstim alone (n = 4) and 1-3 cycles of leukapheresis, median collection was 37 × 10(6) CD34(+) cells/kg. The procedures were well tolerated. Patients who collected =7 and =13 × 10(6) CD34(+) cells/kg in the first cycle had pre-apheresis circulating counts of at =42 and =86 CD34(+) cells/µL, respectively. Weight-adjusted CD34(+) cell yield was positively correlated with peripheral CD34(+) cell counts and influenced by female gender, disease, and drug dosage. All patients received a GT product above the minimum target, ranging from 4 to 30.9 × 10(6) CD34(+) cells/kg. Pediatric PBSC collection compares well to BM harvest in terms of CD34(+) cell yields for the purpose of GT, with a favorable safety profile.
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5.
Single-center results reporting improved hematopoietic stem cell mobilization success in pediatric and young adult patients with solid tumors and lymphoma
Koo, J., Teusink-Cross, A., Davies, S. M., Jodele, S., Dandoy, C. E.
Pediatric blood & cancer. 2021;:e29319
Abstract
BACKGROUND High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is an established treatment for pediatric and young adult patients with solid tumors and lymphomas. Plerixafor is a CXC chemokine receptor type 4 (CXCR4) antagonist that can be used with granulocyte colony stimulating factor (G-CSF) to amplify the mobilization of hematopoietic stem cells (HSCs). METHODS We performed a retrospective analysis of 167 pediatric solid tumor and lymphoma patients from January 2010 to July 2020 in whom HSCs were mobilized using G-CSF alone or with plerixafor. RESULTS Thirteen heavily pretreated patients (33.3%) required twice-daily dosing of G-CSF compared to five patients (3.9%) in the not heavily pretreated group (p = .0005). Fourteen heavily pretreated patients (35.9%) required plerixafor compared to four patients (3.1%) in the comparison cohort (p = .0002). The number of mobilization days was similar between both cohorts, with 5 days (range 3-11 days) in the heavily pretreated group and 5 days (range 3-13 days) in the not heavily pretreated group (p = .55). The number of harvest days was 2 days (range 1-5 days) in the heavily pretreated group and 1 day (range 1-4 days) in the not heavily pretreated group (p = .0025). The final cluster of differentiation (CD)34(+) /kilogram (kg) count was 9.52 × 10(6) /kg among heavily pretreated patients compared to 34.99 × 10(6) /kg CD34(+) cells in the comparison group (p < .0001). Three heavily pretreated patients (7.7%) failed HSC mobilization. CONCLUSIONS Patients at the highest risk for poor HSC mobilization can be successfully treated with more frequent G-CSF dosing or G-CSF with plerixafor in a large majority of cases.
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6.
A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders
Bhunia, N., Abu-Arja, R., Stanek, J. R., Shaw, P. J., Kang, H. J., Stein, J., O'Brien, T. A., Roberts, C. H., Lee, A. C., Loeb, D. M., et al
Transfusion. 2021
Abstract
BACKGROUND Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34?+?2?×?10(6) /kg) (Group B2) following failed SM and first apheresis attempts. RESULTS The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.
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Plerixafor-based mobilization in pediatric healthy donors with unfavorable donor/recipient body weight ratio resulted in a better CD34(+) collection yield: A retrospective analysis
Zubicaray, J., Galvez, E., Sebastian, E., Molina, B., González-Vicent, M., Castillo, A., Ramírez, M., Madero, L., Díaz, M. A., Sevilla, J.
Journal of clinical apheresis. 2020
Abstract
INTRODUCTION In order to propose risk-adapted mobilization algorithms, several authors have tried to look for predictive factors of the CD34(+) yield in healthy pediatric donors. Donor recipient body weight ratio (D/R ratio) was identified as one of the main variables related with the success to achieve the target cell dose for transplantation. According to this variable we modified the mobilization schedule. MATERIAL AND METHODS We report the results of 46 mobilizations and apheresis procedures performed in our center with unfavorable D/R ratio. Mobilization was attempted by the standard regime of G-CSF (10 mcg/kg/24 hours) in 28 cases (60.9%), with high dose G-CSF (10 mcg/kg/12 hours) in 9 cases (19.6%), and with plerixafor and G-CSF single dose regime in 9 cases (19.6%). RESULTS CD34(+) cell quantification before apheresis is closely related to CD34(+) yield, being the only factor related to collected CD34(+) cells (beta .71; P < .0001). The mobilization efficiency was higher in plerixafor group compared to the other two schedules (P < .0001). By using plerixafor for mobilization, we achieved the target CD34(+) cell dose of ≥2 × 10(6) /kg per recipient body weight in all cases with unfavorable D/R ratio. It was observed that 17.4% of cases that not reached the established target cell dose were located in the standard or high-dose mobilization regimes. This difference is even greater for optimal collections (≥5 × 10(6) /kg), since of the 54.3% cases that did not reach this goal none was mobilized by plerixafor. CONCLUSION Tailoring the mobilization regime we can reach the target cell dose, even in those cases with the worst D/R ratio.
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8.
Plerixafor combined with standard regimens for hematopoietic stem cell mobilization in pediatric patients with solid tumors eligible for autologous transplants: two-arm phase I/II study (MOZAIC)
Morland, B., Kepak, T., Dallorso, S., Sevilla, J., Murphy, D., Luksch, R., Yaniv, I., Bader, P., Rossler, J., Bisogno, G., et al
Bone marrow transplantation. 2020
Abstract
This study (NCT01288573) investigated plerixafor's safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics (PD), and safety of plerixafor + standard mobilization (G-CSF +/- chemotherapy). The stage 2 primary endpoint was successful mobilization (doubling of peripheral blood CD34+ cell count in the 24 h prior to first apheresis) in patients treated with plerixafor + standard mobilization vs. standard mobilization alone. In stage 1, three patients per age group (2-<6, 6-<12, and 12-<18 years) were treated at each dose level (160, 240, and 320 microg/kg). Based on PK and PD data, the dose proposed for stage 2 was 240 microg/kg (patients 1-<18 years), in which 45 patients were enrolled (30 plerixafor arm, 15 standard arm). Patient demographics and characteristics were well balanced across treatment arms. More patients in the plerixafor arm (24/30, 80%) met the primary endpoint of successful mobilization than in the standard arm (4/14, 28.6%, p = 0.0019). Adverse events reported as related to study treatment were mild, and no new safety concerns were identified. Plerixafor + standard G-CSF +/- chemotherapy mobilization was generally well tolerated and efficacious when used to mobilize CD34+ cells in pediatric cancer patients.
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Peripheral Blood Stem Cell Mobilization and Collection in Pediatric Healthy Sibling Donors Weighing 20 Kilograms or Less; Algerian Experience
Benakli, M., Ahmed Nacer, R., Mehdid, F., Belhadj, R., Rahmoune, N., Baazizi, M., Ait Ouali, D., Harieche, F., Hamladji, R. M.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2020;:102987
Abstract
Peripheral blood stem cells (PBSC) are the source of allogeneic hematopoietic stem cell transplants currently used for malignant and non-malignant hematological diseases. PBSC harvest may be difficult in young children who are donors. Extracorporeal separator line priming by red blood cells or albumin alone is usually required to improve haemodynamic tolerance and efficacy of collection. We present our experience with 29 children weighing 20 kg or less mobilised between January 2005 and June 2018. The median age and weight at the time of apheresis were 5 years and 18 kg, respectively. A total of 54 PBSC were performed. The median cell yield per apheresis was 5.9 × 10(6) CD34(+)cells/kg (2,5-13,9) recipient body weight (RBW). Despite their low weight, insertion of a femoral catheter was avoided in 58.6% of children. Nineteen donors required 2 or 3 apheresis sessions without any major complication. Twenty-nine pts with hemopathies have successfully benefited from PBSC except one case of rejection with aplastic anemia.
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10.
EMA Recommendation for the Pediatric Indications of Plerixafor (Mozobil) to Enhance Mobilization of Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Children with Lymphoma or Malignant Solid Tumors
Karres, D., Ali, S., van Hennik, P. B., Straus, S., Josephson, F., Thole, G., Glerum, P. J., Herberts, C., Babae, N., Herold, R., et al
The oncologist. 2020
Abstract
On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony-stimulating factor (G-CSF) to pediatric patients (aged 1 year to <18 years) to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. This treatment is indicated either preemptively, when circulating stem cell count on the predicted day of collection after adequate mobilization with G-CSF (with or without chemotherapy) is expected to be insufficient with regard to desired hematopoietic stem cells yield, or in children who previously failed to collect sufficient hematopoietic stem cells. The efficacy and safety of plerixafor were evaluated in an open label, multicenter, phase I/II, dose-ranging, and randomized controlled study (DFI12860) in pediatric patients with solid tumors, including neuroblastoma, sarcoma, Ewing sarcoma, or lymphoma, who were eligible for autologous hematopoietic stem cell transplantation. Forty-five patients (aged 1 year to <18 years) were randomized, 2:1, using 0.24 mg/kg of plerixafor plus standard mobilization (G-CSF with or without chemotherapy) versus control (standard mobilization alone). The primary analysis showed that 80% of patients in the plerixafor arm experienced at least a doubling of the peripheral blood (PB) CD34+ count, observed from the morning of the day preceding the first planned apheresis to the morning prior to apheresis, versus 28.6% of patients in the control arm (p = .0019). The median increase in PB CD34+ cell counts from baseline to the day of apheresis was 3.2-fold in the plerixafor arm versus by 1.4-fold in the control arm. The observed safety profile in the pediatric population was consistent with that in adults, with adverse events mainly related to injection site reactions, hypokalemia, and increased blood bicarbonate. Importantly, plerixafor exposure did not seem to negatively affect transplant efficiency. This article summarizes the scientific review of the application leading to regulatory approval in the European Union. IMPLICATIONS FOR PRACTICE This review of the marketing authorization of plerixafor will raise awareness of pediatric indication granted for this medicinal product.