6 research outputs found
Stability analysis of activity-based models: case study of the Tel Aviv transportation model
The Tel Aviv activity based model structure is similar to other activity based models described in the literature. The model run is supposed to converge to the equilibrium between generated tours and corresponding level of service (LOS) data. However, individual tour generation uses random draws for various choices (activity, time of day, destination, and mode). This introduces simulation errors, which combined with population sampling and limited precision of static traffic assignments, prevents the convergence of the model results. This paper analyses the above uncertainty sources on the basis of multiple model runs conducted for this study. Three averaging procedures are investigated and compared. Practical considerations regarding setting up the averaging procedures required for obtaining stable model results are discussed
Hematopoietic stem cell mobilization for allogeneic stem cell transplantation by motixafortide, a novel CXCR4 inhibitor
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Hematopoietic Cell Transplantation of Higher CD34+ Cell Doses and Specific CD34+ Subsets Mobilized with Motixafortide and/or G-CSF Is Associated with Rapid Engraftment - a Post-Hoc Analysis of the Genesis Trial
Abstract
Background: CD34+ hematopoietic stem and progenitor cell (HSPC) dose during hematopoietic cell transplantation (HCT) remains one of the most reliable clinical parameters to predict quality of engraftment. A minimum HSPC dose of 2-2.5x10 6 CD34+ cells/kg is considered necessary for reliable engraftment, while optimal doses of 5-6x10 6 CD34+ cells/kg are associated with faster engraftment, as well as fewer transfusions, infections, and antibiotic days. CXCR4 inhibition significantly improves the number (#) of CD34+ HSPCs mobilized for HCT, when added to G-CSF (G). Motixafortide (M), a novel CXCR4 antagonist, is a potent mobilizer of HSPCs recently evaluated in the phase 3, double blind, placebo controlled, multicenter GENESIS Trial as a mobilizing agent prior to autologous HCT (ASCT) in multiple myeloma (MM).
Methods: Patients received G (10 mcg/kg) on days 1-5 (and days 6-8, if needed). On day 4 (and day 6, if needed), patients received either M (1.25 mg/kg) or placebo (P). Apheresis began day 5, with up to 4 days of apheresis if needed. The primary and secondary endpoints were collection of ³6x10 6 CD34+ cells/kg in up to 2 days of apheresis or 1 day, respectively. The # of CD34+ cells/kg infused was determined independently by each investigator according to local practice, but a minimum of ³2x10 6 CD34+ cells/kg was required. A post-hoc analysis was performed pooling data from both arms to evaluate time to platelet engraftment (TPE) (≥20x10 9/L without transfusions x7 days) and neutrophil engraftment (TNE) (ANC ≥0.5x10 9/L x3 days) based on total # of CD34+ cells/kg and # of specific CD34+ HSPC subsets infused. CD34+ HSPC immunophenotyping was performed via multicolor fluorescence-activated cell sorting (FACS). TPE/TNE was analyzed using Kaplan-Meier curves and Cox proportional hazards model.
Results: 114 MM patients underwent apheresis, ASCT and were evaluable (M+G N=77; P+G N=37). M+G mobilization yielded a median of 10.8x10 6 CD34+ cells/kg collected in 1 apheresis vs 2.3x10 6 CD34+ cells/kg with P+G (p75 th percentile) of combined CD34+ HSC, MPP, CMP and GMP subsets was associated with faster TPE of 12 days vs 19 days with lower #s of these subsets (p=0.003) (Figure 2A). Furthermore, higher #s (>75 th percentile) of GMPs was individually associated with faster TPE of 13 days vs 19 days with lower GMP cell doses (p=0.0116) (Figure 2C). TNE was not impacted by increasing doses of total CD34+ HSPCs or any specific CD34+ HSPC subset (all p>0.05) (Figures 1B, 2B and 2D).
Conclusions: M+G mobilization enabled significantly more CD34+ cells to be collected in 1 apheresis (median 10.8x10 6 CD34+ cells/kg) vs P+G (2.3x10 6 CD34+ cells/kg), as well as 3.5-5.6 fold higher #s of HSCs, MPPs, CMPs and GMPs (all p-values <0.0004). This high # of CD34+ cells/kg mobilized with M+G enables the potential infusion of ≥6x10 6 CD34+ cells/kg and cryopreservation of cells for later use. A dose response was observed with significant correlation between faster TPE and infusion of higher #s of total CD34+ HSPC doses (³6x10 6 CD34+ cells/kg) and combined HSC, MPP, CMP and GMP subsets. Additionally, infusion of higher #s of CD34+ GMP subsets was independently associated with faster TPE, suggesting these more committed progenitors may play a critical role in early engraftment.
Figure 1 Figure 1.
Disclosures
Crees: BioLineRx Ltd.: Research Funding. Retting: BioLineRx Ltd.: Research Funding. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Abbvie, Bioline, BMS, Celgene, GSK, Janssen, Juno, Novartis, Pfizer, Takeda: Research Funding. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding. Sborov: SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pereira: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Mikala: Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Krka: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Qazilbash: Janssen: Research Funding; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding. Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Sorani: BioLineRx LTD: Current Employment. Shemesh-Darvish: BioLineRx LTD: Current Employment. Vainstein: BioLineRx LTD: Current Employment; Enlivex: Consultancy. Kadosh: StatExcellence: Current holder of individual stocks in a privately-held company; BioLineRx: Honoraria
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Motixafortide Enables Consistent, Robust Hematopoietic Stem Cell Collection (HSC) across Populations with Increased Impaired HSC Mobilization: A Sub-Group Analysis of the Genesis Study
The clinical benefit of autologous hematopoietic stem cell transplant (ASCT) for multiple myeloma (MM) partly depends on the ability to collect sufficient hematopoietic stem cells (HSCs) from peripheral blood (PB). Risk factors for impaired HSC mobilization are increasingly common in patients with MM undergoing ASCT in the current treatment landscape, including advanced age, presence of cytopenias and prior exposure to radiation, lenalidomide and/or anti-CD38 monoclonal antibodies (mAb). Motixafortide is a novel high affinity CXCR4 antagonist indicated, in combination with G-CSF, for mobilization of HSCs to the PB for collection and subsequent ASCT in MM. In the GENESIS trial (NCT03246529), a single dose of motixafortide, in combination with G-CSF, enabled a significantly greater proportion of subjects to mobilize ≥6 × 106 CD34+ cells/kg in up to 2 aphereses. Here we report the results of subgroup analyses of the GENESIS trial evaluating baseline characteristics and risk factors for impaired mobilization.
The GENESIS trial was a multicenter, randomized, double-blind, placebo-controlled Phase 3 study. The primary endpoint was % of subjects mobilizing ≥6 × 106 CD34+ cells/kg after a single dose of motixafortide in up to 2 aphereses. CD34+ cell enumeration was assessed by both central and local laboratories. Central lab results enabled standardization across sites, while local lab results were used for clinical decisions; such as determining if a subject reached the collection goal. Pre-planned subgroups included gender, age, response status at randomization, and baseline platelets. A post-hoc subgroup analysis based on prior radiation, lenalidomide and/or anti-CD38 mAb prior to mobilization was performed.
A total of 122 patients were enrolled. Demographics were comparable between arms, including for risk factors of impaired mobilization (Table 1). Overall, 70.0% (central lab) and 92.5 % (local lab) of subjects in the motixafortide arm met the primary endpoint vs 14.3% (central lab) and 26.2 % (local lab) with G-CSF alone. Sub-analysis of the efficacy of motixafortide in subgroups at increased risk of impaired mobilization demonstrated consistently higher collection rates compared to G-CSF alone (Table 2) including: age >65 years (motixafortide+ G-CSF: 70.4%, G-CSF alone: 16.7%), prior RT (motixafortide+ G-CSF: 55.6%, G-CSF alone: 0%), and prior lenalidomide (motixafortide+ G-CSF: 73.7%, G-CSF alone: 10.7%) . Figure 1 shows the Cochran-Mantel-Haenszel common proportions difference of the different sub-groups.
Taken together, these data demonstrate a consistent benefit of motixafortide + G-CSF over G-CSF mobilization for all patients, including those at risk for impaired HSPC mobilization
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Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial
Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34
hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10
CD34
cells kg
within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34
HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529