Mobilization Regimen Research Articles

West-African Modes of Mobilisations Confronting EU Mobility Regimes

This article explores West-African modes of mobilisations confronting the externalisation of European borders. At the hands of a secondary data analysis, this article critically examined the most recent publications in relation to this topic, guided by the following research question: How do West-African modes of mobilisations challenge EU mobility regimes? This research identified governments, local organisations, (potential) migrants, expelled migrants, media, academia and writers and transnational social movements as relevant actors with different modes of action. This research suggests that there are multiple West-African modes of mobilisations that challenge EU mobility regimes, confront the problematisation of non-sedentary lifestyles and see mobility as a strategy and a solution for a bottom-up process of globalisation and as an inherent part of West-African mobile societies; existing next to African modes of mobilisations that have become part of EU mobility regimes. The objective of this research is to promote future research by increasing the visibility and political agency of the transformative possibilities of African modes of mobilisations.

A Novel Hematopoietic Progenitor Cell Mobilization Regimen Comprising Bortezomib, G-CSF, and Preemptive Plerixafor for Multiple Myeloma.

Adequate hematopoietic progenitor cell collection is critical for autologous peripheral blood stem cell transplantation. Conventionally, patients with multiple myeloma are treated with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) or G-CSF alone to mobilize their peripheral blood stem cells. However, some patients exhibit insufficient stem cell recruitment in response to these regimens. Recently, plerixafor has been approved for coverage by insurance in Japan. Combination treatment with plerixafor and G-CSF is now a standard procedure. In addition, treatment with bortezomib and G-CSF results in efficient stem cell recruitment. On the basis of the results from mouse studies, we hypothesized that combination treatment with bortezomib ensures efficient mobilization and mediates in vivo purging of malignant cells. Therefore, we administered a regimen of bortezomib, G-CSF, and preemptive plerixafor to 10 patients with multiple myeloma, and analyzed its efficacy and safety. The median patient age was 68 years. We collected CD34-positive cells (median: 4.9×106/kg) in a single session of apheresis from all patients. We observed no obvious myeloma cell contamination in the collected product or serious toxicity during treatment and collection. After collection, we performed autologous peripheral blood stem cell transplantation and confirmed engraftment in all patients (median: day 10). We found that the regimen is safe and reliably facilitated the collection of sufficient autologous peripheral blood stem cells by apheresis from all patients in a single day. Despite the small patient group size, we conclude that the regimen is promising for safe and efficient collection of peripheral blood stem cells for autologous transplantation in patients with multiple myeloma.

Interplay of Policy Experimentation and Institutional Change in Transformative Policy Mixes: The Case of Mobility as a Service in Finland

Calls have been made for new ways of thinking about innovation policy to address pressing global sustainability problems. ‘Transformative innovation policy’ (TIP) is proposed as one such way. Given the newness of thinking on TIP, empirical insights are needed into how ongoing efforts by public administrations link to TIP, and how policy experimentation connecting to TIP intertwines with formal institutional change and policy mixes. We connect literatures on policy experimentation, institutional change and policy mixes for sustainability transitions to create an analytical framework on the interplay between these elements, which we apply to an in-depth case study of the development of Mobility as a Service (MaaS) in Finland. The findings show how a potentially disruptive innovation, MaaS, can be traced back to a longer process of administrative reorientation and restructuring, i.e. gradual transformation in formal institutions, and has benefitted from cycles of policy experimentation, new vision building and learning, combined with a sequence of policy strategies and major regulatory change. The evolving ‘transformative’ policy mix has influenced transition by supporting niche development through policy experimentation as well as changing the established mobility regime through formal institutional change.

Tournament Mobility in Mathematics Course-Taking Pathways.

This visualization represents the structure of mathematics course opportunities as seen in the progress through middle and high school for one cohort of students in Texas. Trajectories are consistent with a tournament mobility regime in which there are repeated opportunities to fall behind but almost none to catch up. Pathways are also characterized by staggered starts, with differences in when students begin the mathematics sequence that have consequences for ultimate attainment. The structure of mathematics opportunities provides many points where trajectories diverge, and these branching points disproportionately sort economically disadvantaged students into less advanced pathways.

Vulnerability and Housing Policies through the Lens of Anthropology. An Introduction

The Dossier «Vulnerability and Housing Policies. Anthropological insights across Europe» is the result of a panel organized by the editors at the 15th EASA Biennial Conference hosted by Stockholm University in August 2018. In this context, we proposed to explore ethnographically housing policies as peculiar and paradigmatic forms of contemporary «regimes of mobility». Coherently to the panel target, the main theme of this Dossier is the anthropological analysis of the production of social and political vulnerability in Europe through housing policies. In particular, the ethnographies hosted in this Dossier explore the dense intersection between different configurations of social and political action, such as housing rights, residents’ responses to public policies, vulnerability, real estate politics, migration, forced evictions, infrastructures. It is impossible to understand contemporary Europe, we argue, without understanding what is going on with housing policies. Anthropology may give a fundamental contribution in this sense.

The Post-2015 European Border Regime. New Approaches in a Shifting Field

Against the background of our recent ethnographic research project on the European border regime in South-East Europe in 2016, the article calls for a re-visiting of established paradigms and approaches in border studies. The article assesses established theoretical conceptualisations of border studies, such as securitisation, externalisation, digitalisation, but also internal mobility regimes and humanitarian rationales. Focussing especially on the vast encampment within Europe, the inner-European buffer zoning, shifting legal foundations as well as new infrastructures of migration control, the authors argue for an extension of theoretical and methodological perspectives of border studies by drawing on insights from legal anthropology and camp and infrastructural studies.

Inclusive Political Intersections of Migration, Race, Gender and Sexuality – The Cases of Austria and Denmark

ABSTRACTThe article aims to integrate key concepts from social movement, citizenship and gender theories with afocus on (political) intersectionality at the interface of migration, race, gender and sexuality. It explores the responses from civil society groups to the exclusive intersections of right-wing politics and discourses in Austria and Denmark with afocus on inclusive intersectionality and transversal politics. The article asks if and how the intersectional repertoires of NGOs were able to create transversal politics and joint activities and explains why these NGOs were unable to counter right-wing hegemony. It uses the cases of Austria and Denmark to illustrate the diverse mobilizations of counter-forces against the attempts to forge an anti-migration and anti-Muslim consensus. The focus is on the mobilization of anti-racist and pro-migrant groups, comparing their strategies and inclusionary repertoires including feminist claims, the framing of activist citizenship, acts of citizenship and of solidarity. The article scrutinizes strategies of transversal politics against the exclusionary right in the two countries; shows the influence of the different contexts of civil society mobilization, political cultures, welfare and gender regimes as well as the differences between right-wing forces in the two countries.

Charge diffusion in homogeneous molecular chains based on the analysis of generalized frequency spectra in the framework of the Holstein model

We analyzed numerically computed velocity autocorrelation functions and generalized frequency spectra of charge distribution in homogeneous DNA sequences at finite temperature. The autocorrelation function and generalized frequency spectrum (frequency-dependent diffusion coefficient) are phenomenologically introduced based on the functional of mean-square displacement of the charge in DNA. The charge transfer in DNA was modeled in the framework of the semi-classical Holstein model. In this model, DNA is represented by a chain of oscillators placed into thermostat at a given temperature that is provided by the additional Langevin term. Correspondence to the real DNA is provided by choice of the force parameters, which are calculated with quantum-chemical methods. We computed the diffusion coefficient for all homogenous DNA chains with respect to the temperature and found a special scaling of independent variables that the temperature dependence of the diffusion coefficient for different homogenous DNA is almost similar. Our calculations suggest that for all the sequences, only one parameter of the system is mainly responsible for the charge kinetics. The character of individual motions contributing to the charge mobility and temperature-dependent regimes of charge distribution is determined.

Charge diffusion in homogeneous molecular chains based on the analysis of generalized frequency spectra in the framework of the Holstein model

We analyzed numerically computed velocity autocorrelation functions and generalized frequency spectra of charge distribution in homogeneous DNA sequences at finite temperature. The autocorrelation function and generalized frequency spectrum (frequency-dependent diffusion coefficient) are phenomenologically introduced based on the functional of mean-square displacement of the charge in DNA. The charge transfer in DNA was modeled in the framework of the semi-classical Holstein model. In this model, DNA is represented by a chain of oscillators placed into thermostat at a given temperature that is provided by the additional Langevin term. Correspondence to the real DNA is provided by choice of the force parameters, which are calculated with quantum-chemical methods. We computed the diffusion coefficient for all homogenous DNA chains with respect to the temperature and found a special scaling of independent variables that the temperature dependence of the diffusion coefficient for different homogenous DNA is almost similar. Our calculations suggest that for all the sequences, only one parameter of the system is mainly responsible for the charge kinetics. The character of individual motions contributing to the charge mobility and temperature-dependent regimes of charge distribution is determined.

Charge diffusion in homogeneous molecular chains based on the analysis of generalized frequency spectra in the framework of the Holstein model

We analyzed numerically computed velocity autocorrelation functions and generalized frequency spectra of charge distribution in homogeneous DNA sequences at finite temperature. The autocorrelation function and generalized frequency spectrum (frequency-dependent diffusion coefficient) are phenomenologically introduced based on the functional of mean-square displacement of the charge in DNA. The charge transfer in DNA was modeled in the framework of the semi-classical Holstein model. In this model, DNA is represented by a chain of oscillators placed into thermostat at a given temperature that is provided by the additional Langevin term. Correspondence to the real DNA is provided by choice of the force parameters, which are calculated with quantum-chemical methods. We computed the diffusion coefficient for all homogenous DNA chains with respect to the temperature and found a special scaling of independent variables that the temperature dependence of the diffusion coefficient for different homogenous DNA is almost similar. Our calculations suggest that for all the sequences, only one parameter of the system is mainly responsible for the charge kinetics. The character of individual motions contributing to the charge mobility and temperature-dependent regimes of charge distribution is determined.

Are We Choosing Mobilization Regimens for Autologous Stem Cell Transplantation in Multiple Myeloma Wisely?: A Single Centre Comparison of GCSF+/-Plerixafor Vs Cyclophosphamide/GCSF+/- Plerixafor

Background: Autologous stem cell transplantation (ASCT) as consolidation post induction is standard of care for eligible multiple myeloma patients. Multiple strategies are employed for mobilization of stem cells in ASCT. Cyclophosphamide/GCSF is an effective standard regimen. However there are reported toxicities associated with cyclophosphamide including risk of febrile neutropenia. Since plerixafor was introduced in Canada, this mobilization agent has been increasingly used as needed with GCSF at Kingston Health Science Centre (KHSC), with elimination of cyclophosphamide. There is however high cost associated with plerixafor. To date, there is no standard mobilization regimen across Canada. This retrospective study evaluates mobilization and ASCT outcomes of multiple myeloma patients who had undergone stem cell mobilization with GCSF+/-plerixafor (GP) vs cyclophosphamide/GCSF+/-plerixafor (CyGP) at KHSC. The goal is to analyze the efficacy of each regimen balanced with adverse events to guide optimal mobilization regimen choice. Method: Patient with multiple myeloma who had ASCT at KHSC were selected consecutively based on date of ASCT in a reverse chronological order starting from Jan 2019. From Oct 2015 to March 2018, CyGP was the mobilization regimen used at KHSC. From March 2017 to January 2019, cyclophosphamide was eliminated and GP was used. Both groups could have received plerixafor as needed based on Cancer Care Ontario funding criteria such as failure to achieve target CD34+ cell count. Retrospective chart review was conducted to collect data on demographics, plerixafor use, days of apheresis, total cell collected, rate of febrile neutropenia, length of transplant hospital stay, time to engraftment, and transfusion requirement. Chi-Square, t-test, or Mann Whitney methods were used for test of statistical significance where appropriate. Results: Total 97 patients were included with 47 in the GP group and 50 in the CyGP group (Table 1). Average age was 64 and 63 respectively. 32% of patients in GP group and 36% of CyGP group required plerixafor rescue. No difference in the number of apheresis days were noted in the two groups. Total cell collection was significantly higher in the CyGP group (P<0.001). Day 1 and 2 cell collections were also significantly higher in the CyGP group (P<0.05) (Fig 1). The cell dose target varied in the CyGP group due to changing practices over time which is a confounding factor. There were no cases of febrile neutropenia in the GP group and 3 cases in the CyGP group (P=0.243). All 3 febrile neutropenia patients required hospitalization with 1 requiring ICU. There was no clinically significant difference in transfusion requirement during ASCT (Fig 2). Median time to engraftment of neutrophil and platelet after ASCT were less by 1 day in the CyGP group (P<0.05) (Fig 3), although there was no difference in length of transplant hospital stay. Conclusions: Stem cell mobilization with CyGP resulted in significantly higher total collection cell count, and more efficient collection with higher yield on the first 2 days of apheresis. However, there was no difference in the total number of apheresis days. It also did not lead to less plerixafor usage and was associated with possibly higher rate of febrile neutropenia. There was no clinically significant difference in transplant outcomes in terms of transfusion support required, days to engraftment, or length of hospitalization for ASCT. Mobilization with GCSF+/-plerixafor without cyclophosphamide is a non-inferior regimen. Disclosures Bhella: Celgene: Consultancy, Honoraria.

Trends in Autologous Transplantation for Myeloma in EBMT Centres between 1993 and 2017

Trends in Autologous Transplantation for Myeloma in EBMT Centres between 1993 and 2017

A Randomized Evaluation of Vinorelbine Versus Gemcitabine Chemotherapy Mobilization of Stem Cells in Myeloma Patients

Background: In myeloma patients, a non-myelosuppressive regimen combining a single dose of vinorelbine chemotherapy together with G-CSF is safe and effective to harvest peripheral blood progenitor and stem cells (PBSC) before autologous stem cell transplantation (ASCT). Considering its neurotoxic potential, vinorelbine may aggravate pre-existing bortezomib-induced polyneuropathy, and gemcitabine represents an alternative mobilization regimen. We have reported that monotherapy with gemcitabine together with G-CSF can be used as a promising alternative mobilization chemotherapy to vinorelbine, even more so as gemcitabine avoids neurotoxicity associated with vinorelbine Methods: In this prospective phase-II study (ViGeM Trial; NCT# 02791373), we compared in a 1:1 randomization the efficacy and toxicity of vinorelbine or gemcitabine with G-CSF (and, if needed, plerixafor) in 130 evaluable myeloma patients in first remission. The objective of the study is to demonstrate the non-inferiority of gemcitabine versus vinorelbine. The primary endpoint is mobilization success, which is defined as a collected apheresis product comprising at least 6.0×106 CD34+ cells/kg b.w. at day 8 after chemotherapy (vinorelbine or gemcitabine) together with G-CSF in the absence of plerixafor. Results: We observed successful CD34+ mobilization in 75% [95% confidence interval (CI): 63%-85%] of patients in the vinorelbine group versus 49% [95% CI: 36%-62%] with gemcitabine; the pre-specified non-inferiority margin -15% was not reached. More vinorelbine recipients achieved the collection goal in a single-day procedure (78% vs 60%). The median CD34+ yield was 11.4×106/kg b.w. in vinorelbine versus 8.7×106/kg in gemcitabine (P=0.001). At apheresis as well as day +100 following ASCT, polyneuropathy occurred more frequent in vinorelbine recipients. Special attention should be given to the fact that no patients with gemcitabine was observed with grade ≥ 3 polyneuropathy (Table 1). Finally, less patients in the vinorelbine group (1%) needed two apheresis days as compared to 14% in the gemcitabine group, respectively (P=0.007), whereas the use of rescue plerixafor was similar (11% versus 10%). Conclusion: This prospective comparison indicated that non-inferiority of gemcitabine as compared to vinorelbine chemotherapy together with G-CSF stimulation regarding CD34+ mobilization was not reached. Polyneuropathy was aggravated in the vinorelbine cohort, but not in gemcitabine recipients. Our study allows individualization of CD34+ mobilization regimens in myeloma patients. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Vinorelbine and gemcitabine are used for stem cell mobilization in this study and, thus, off-label.

A Retrospective Record Review of Mobilization Strategies with and without Plerixafor for Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Background: Autologous hematopoietic stem cell transplantation (ASCT) is the current standard of care in patients with multiple myeloma (MM) to support reconstitution of the bone marrow after myeloablative chemotherapy. Mobilization of blood progenitor cells to the peripheral circulation is stimulated via administration of granulocyte colony-stimulating factor (G-CSF) with or without chemotherapy. The addition of chemotherapy, typically cyclophosphamide, increases the yield of peripheral blood stem cells (also known as CD34+ cells) at the expense of additional toxicity. The unpredictability of harvest yield and the potential need for weekend apheresis sessions complicates mobilization planning when using chemotherapy. Plerixafor, a CXCR4 antagonist, in combination with G-CSF has been shown to be superior to G-CSF alone, leading to higher CD34+ yields in fewer apheresis sessions [Giralt et al, 2014]. However, the advantage of the combination of plerixafor with G-CSF is less well described in the context of new treatment options that can impair stem cell harvest yields when using G-CSF as the sole mobilization agent. Objective: The primary objective of this study was to determine clinical outcomes associated with G-CSF alone vs G-CSF + chemomobilization vs G-CSF + plerixafor from initiation of mobilization until 6 to 12 months after ASCT. Method: This is a retrospective study in patients with MM, carried out at 10 centers in the US. Patients were eligible if ≥ 18 years and undergoing first ASCT (≤ 12 months from initial diagnosis and no disease progression). Eligible patients were identified through a database query of hospital records of oncology patients diagnosed with MM and eligible for ASCT before June 2016. Patients fulfilling inclusion and exclusion criteria were attributed to three treatment arms depending on the mobilization regimen received:Arm 1: G-CSF + plerixaforArm 2: G-CSF + chemomobilizationArm 3: G-CSF Patients will be selected until 170 patients are assigned to each treatment arm or patient records are exhausted. Demographics, induction regimen, mobilization regimens and outcomes, apheresis, transplantation outcomes and survival status were extracted from medical charts and entered in the electronic case report form. Here, we present interim results from data collected at three centers as of June 24, 2019. Results: At the interim analysis cut-off date, 130 patients were included in the database (G-CSF: 52; G-CSF + plerixafor: 78; G-CSF + chemomobilization: 0). Demographic and baseline characteristics were comparable between the two treatment arms. More male patients were included (male: 63%, female: 37%) and the mean age was 58 and 59 years in the G-CSF and G-CSF + plerixafor groups, respectively (Table 1). Disease stage and the proportion of patients with poor-, intermediate- and high-cytogenetic risk status were similar in the two treatment groups. Few patients had a complete response (CR) after chemotherapy, but response rate (CR + partial response) was 91% in both treatment arms. The burden of apheresis in terms of number of sessions and blood volume processed was lower in patients receiving G-CSF + plerixafor compared with patients receiving G-CSF only (Table 2). CD34+ yield was higher in the G-CSF + plerixafor treatment arm, especially after the first apheresis session (Table 2). There was no difference in ASCT outcome between the two treatment groups. All patients had neutrophil engraftment except for one patient in the G-CSF only group, and all patients had platelet engraftment except one patient in each treatment group. There was no significant difference in the proportion of patients experiencing relapse between the two treatment groups at 6 and 12 months of follow-up. Overall, ≥ 90% of patients avoided relapse at 12 months. 96% and 93% of patients were still alive at 12 months in the G-CSF only and G-CSF + plerixafor treatment groups, respectively (Table 3). For the purpose of this study, safety data was not reviewed [Mozobil PI, 2019]. Conclusions: Per interim results, plerixafor reduced the burden of apheresis and increased CD34+ yields. Transplantation outcomes, relapse and overall survival at 6 and 12 months were not significantly different between the two treatment arms. Therefore, plerixafor could increase apheresis efficiency without compromising ASCT success in the context of currently used chemotherapy regimens. Disclosures Mark: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Bubalo:Sanofi: Other: Research and writing support. Barnes:Sanofi: Employment. Drea:Sanofi-Genzyme: Employment. Fausel:Sanofi-Genzyme: Other: Grant to cover costs of data collection.

Targeting CXCR4, VLA4, and CXCR2 for Hematopoietic Stem Cell Mobilization

Background: Hematopoietic stem cell (HSC) transplant is an essential treatment for a variety of blood disorders and malignancies. A key step in this procedure is the mobilization of donor stem cells. The most commonly used regimen for donor mobilization is a 5-day course of G-CSF. The length of this regimen coupled with the associated side effects emphasizes a need for superior alternatives. In recent years, there has been a growing understanding of mechanisms governing stem cell retention within the bone marrow niche. This has led to the development of new mobilization drugs that specifically target these processes. Two examples of previously described drugs that target mechanisms of stem cell retention are Plerixafor (a CXCR4 inhibitor already in clinical use), and truncated Gro-Beta (tGroβ; a CXCR2 agonist). Another potential target for inducing mobilization is disruption of the interaction between the VLA-4 integrin and its ligand VCAM-1. In this study, we evaluate the efficacy of novel VLA-4 inhibitors (VLA4i) alone and in combination with Plerixafor and/or tGroβ for the purposes of hematopoietic stem cell mobilization. Methods: We synthesized over 15 novel VLA-4 inhibitor molecules and tested their potency using soluble VCAM-1 binding assays. The 5 inhibitors determined to be most potent were then tested in vivo in DBA mice for their ability to mobilize HSCs alone and in combination with tGroβ and/or Plerixafor (n=5). HSC mobilization was measured in wild-type and splenectomized mice via flow cytometry to quantify the proportion of LSK (Lineage- Sca+ cKit+) cells as well as via Colony Forming Unit (CFU) assays. For competitive transplant, mobilized CD45.1+ BALB/c mouse blood (10 uL) was injected into lethally irradiated CD45.2+ BALB/c recipients alongside 2.5x105 CD45.2+ BALB/c bone marrow cells (n=10 / cohort). HSC engraftment was monitored monthly via flow cytometry for ratio of 45.1+ vs. 45.2+ cells in peripheral blood. Results: Firetagrast and BIO5192 are previously characterized VLA4i that have been administered to humans for indications unrelated to HSC mobilization. Our best VLA4i to date, LGB-2019, exhibited similar potency as BIO5192 in preventing the binding of sVCAM-1 to VLA-4 (IC50: 1.7nM) and was >200-fold more potent than firategrast. LGB-2019 showed increased aqueous solubility and mobilized 1.5-fold more murine LSK cells for a longer time period (peak HSC mobilization maintained for 4 hours) than BIO5192 when administered alone. Simultaneous injection of C57BL/6 mice with LGB-2019 (VLA4i), Plerixafor (CXCR4i) and tGro-β (CXCR2a) resulted in a synergistic increase in circulating CFUs (Fig. 1A; 9.8 x 103 CFUs/mL) and LSKs (Fig. 1B; 12.8 LSKs/uL) at 4 hours post-injection. In contrast, 5 days of G-CSF treatment mobilized approximately 3-fold and 8-fold less CFUs and LSKs, respectively (Fig. 1A-B). We saw no significant difference in mobilization for splenectomized vs. wildtype mice (23.4 x 103 CFUs/mL vs. 23.0 x 103 CFUs/mL) when mobilizing DBA/2 mice via VLA4i+CXCR4i+CXCR2a. Three months after competitive transplantation, blood obtained from BALB/c mice mobilized with the triple combination engrafted significantly better than blood obtained from mice treated with G-CSF or the dual combinations (Fig. 1C). Summary: New insights about the stem cell niche have allowed for the development of targeted drugs for the purposes of mobilization. Here, we show that a novel VLA-4 receptor inhibitor in combination with two other known mobilizers induces mobilization of hematopoietic stem and progenitor cells (CFU/LSK) at levels superior to the standard of care G-CSF and in a dramatically shortened time frame. Mouse transplant data also show superior engraftment in lethally irradiated recipients when using the triple cocktail regimen compared to the G-CSF mobilized graft. Secondary transplants are ongoing and will provide a more complete picture of primitive HSC mobilization and serial engraftment properties of the cells. Disclosures Rettig: WashU: Patents & Royalties: Patent Application 16/401,950. Karpova:WashU: Patents & Royalties: Patent Application 16/401,950. Ruminski:WahU: Patents & Royalties: Patent Application 16/401,950. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. DiPersio:Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Equity Ownership; Incyte: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; NeoImmune Tech: Research Funding.

Oncostatin M Is a Novel Niche Factor That Restrains Hematopoietic Stem Cell Mobilization in Response to G-CSF and CXCR4 Antagonist Plerixafor

Granulocyte colony-stimulating factor (G-CSF) and the CXCR4 chemokine receptor antagonist Plerixafor are used to mobilize hematopoietic stem and progenitor cells (HSPC). However, in the autologous setting, prior chemotherapy and radiotherapy impair HSPC mobilizing response to G-CSF and Plerixafor thereby precluding autologous HSC transplantation. We now demonstrate in mice that oncostatin M (OSM) production in the bone marrow (BM) is dramatically increased in response to G-CSF and that OSM counteracts the mobilizing effect of G-CSF and Plerixafor indirectly through the BM stroma. Indeed, by immunohistochemistry, a 4-day G-CSF treatment strongly increased OSM protein expression in cell clusters containing F4/80+ macrophages in the endosteal and central region of the mobilized BM. OSM concentration was 7-fold higher in BM fluids of G-CSF mobilized mice compared to control mice as measured by ELISA. To investigate OSM effects on HSPC mobilization, C57BL/6 mice (WT) and mice lacking the OSM receptor gene (OSMR-/-) were treated with 125 μg/kg human G-CSF bidaily for 2-6 days and/or Plerixafor (10 mg/kg) one hour before harvest. Absence of OSMR increased HSPC mobilization with a 4-fold increase in colony forming cells (CFC), phenotypic Lin-Kit+Sca1+ HSPC (LKS+ cells) and LKS+Flt3-CD48-CD150+ HSC into the blood at days 2 and 4 of G-CSF treatment and increased accumulation of HSPC and HSC in the spleen of OSMR-/- mice at day 6 of G-CSF treatment. In a competitive repopulation assay with serial dilutions of mobilized blood, deletion of OSMR gene enhanced ≈4-fold mobilization of functional reconstituting HSC in response to G-CSF as shown by Poisson's distribution analysis. HSPC mobilization in response to Plerixafor was also significantly enhanced with a doubling of CFC, HSPC and HSC into the blood of OSMR-/- mice compared to WT. OSMR gene deletion also significantly enhanced HSPC mobilization (3-fold) in response to G-CSF plus Plerixafor combination, the most effective mobilization regimen currently approved. To further demonstrate that endogenous OSM restrains HSPC mobilization in response to G-CSF, we produced a recombinant mouse OSM-trap, a dimeric protein chimera made of the extracellular domain of mouse OSMR and mouse gp130 fused with a mutant Fc fragment of mouse IgG2a. Co-administration of this OSM-trap together with G-CSF also increased HSPC and HSC mobilization into the blood in response to G-CSF compared to mice treated with G-CSF and control trap construct. This negative effect of endogenous OSM on HSPC mobilization was indirectly mediated by BM stromal cells. qRT-PCR on BM myeloid and stromal cells sorted from steady-state or mobilized mice showed that Osm mRNA is mostly expressed by CD11b+F4/80+CD169+VCAM1+ macrophages and CD11b+F4/80-Ly6G+ neutrophils. In sharp contrast, Osmr mRNA was undetectable in any sorted BM leukocyte population, but abundantly expressed by CD45-Lin-CD31+Sca1+CD105+ endothelial and CD45-Lin-CD31-CD51+PDGFRα+/-Sca-1+/- mesenchymal progenitor cells. OSMR protein was expressed by vascular beds in the BM as detected by IHC. Confirming the indirect effect of OSM, we found that recombinant OSM had no effect on HSPC chemotaxis in response to CXCL12, or HSPC adhesion to immobilized VCAM-1 or selectins in vitro. However, HSPC freshly isolated from the BM of OSMR-/- mice had enhanced chemotaxis in response to CXCL12 compared to HSPC isolated from WT mice. In conclusion, G-CSF increases OSM expression in the BM, and this appears to restrain HSPC mobilization in response to G-CSF via OSMR-expressing endothelial and mesenchymal cells that decreases HSPC responsiveness to CXCL12 gradient. Disclosures Winkler: GlycoMimetics: Patents & Royalties. Levesque:GlycoMimetics: Equity Ownership.

Evaluation of the Role of Plerixafor in Peripheral Blood Progenitor Cell Mobilization and Collection in Autologous Donors with Multiple Myeloma and Non-Hodgkin Lymphoma

Purpose Autologous hematopoietic stem cell transplantation is commonly used as treatment for patients with Multiple Myeloma (MM) or Non-Hodgkin Lymphoma (NHL). The mobilization and collection of peripheral blood progenitor cells (PBPC) to reach the required cell dose for transplantation is problematic for some patients when standard mobilization agents such as G-CSF, alone or combined with chemotherapy, are used. These patients are considered poor mobilizers with < 20 CD34+ cells /μl on the planned day of collection and the optimal strategy to collect a sufficient number of PBPC in poor mobilizers is still not fully known. Plerixafor, a CXCR4 inhibitor, when added to the standard mobilization regimen, has been shown to improve mobilization and increase the probability of collecting a PBPC graft > 2 X106CD34 /kg in standard mobilizers. In our center, Plerixafor became available in October 2012. However, how best to use plerixafor to improve care for poor mobilizers while ensuring the most cost-effective use of health care resources for this patient population remains an important question. To begin answering this question, we evaluated the impact of plerixafor usage in our population of poor mobilizers in our institution using a historical cohort for comparison. Material and method The population of poor mobilizers in the setting of MM or NHL (defined as < 20 CD34 / μl on the planned day of collection) between January 2009 and December 2017 at Hôpital de l'Enfant Jesus (HEJ) du CHU de Québec was retrospectively studied and analyzed. To ensure that all poor mobilizers were included, we screened all flow cytometry CD34+ cell count results < 50 /μl on the planned day of collection and reviewed all the charts of patients with < 20 CD34 / μl regardless of whether they were collected or not. This chart review allowed a comprehensive description of the characteristics of our poor mobilizers, a comparison of the capacity to collect an adequate PBPC with or without plerixafor and to evaluate its impact on different variable with regard to PBPC collection and subsequent engraftment. The data were compiled in an ACCESS database using a retrospective review of digital patient charts. The data was analyzed by the Centre de Recherche du CHU de Quebec (CRCHUQ). Data were stratified by disease type and CD34 level on the planned day of PBPC collection. Results 207 patient charts were reviewed; 70 poor mobilizers with 95 mobilizations attempts, 30 of them using plerixafor, were included. The baseline characteristics of both groups were similar as well as the length of hospitalization for transplant and relapse free survival at one year. The addition of Plerixafor to our management of poor mobilizers did not significantly increase the proportion of patients proceeding to autologous PBPC transplant (80,4 vs 75% p=0,7599). During the mobilization attempts, the maximal CD34 /μl reached was similar in both groups (18,86 vs 15,4 p=0,1541). Plerixafor was associated with a superior collection efficiency (% of CD34 collected) (40,85 vs 60,91% p=0,007), but this can be explained by a greater use of central venous catheters for collection in this group (70 vs 95,1% p = 0,0275). Data stratified by initial diagnosis and CD34 level on the planned day of PBPC collection (<10 c/μl versus [10c/μl - 20c /μl [) showed the same tendency. The collection duration was not significantly reduced in the plerixafor group, but there was a trend for a shorter mean duration of 22 minutes also explained by a greater use of central venous catheters in this group. The preplanned subgroups analyses have shown the same trend when stratified by diagnosis, with a reduction of 53 minutes in the multiple myeloma subgroup with a greater total CFU-GEM / kg per collect (46,35 vs 70,55 p=0,0163). Conclusion The use of plerixafor at HEJ did not improve significantly the proportion of poor mobilizers reaching an adequate PBPC graft and did not improve transplant outcomes compared to a historical control. Better strategies are needed to improve care for true poor mobilizers. The optimal use of plerixafor needs to be further studied. Table. Disclosures Blais-Normandin: Sanofi: Other: unrestricted research grant. Laroche:Sanofi: Other: unrestricted research grant.

Engraftment Syndrome in the Setting of Autologous Stem Cell Transplantation for Multiple Myeloma-a Single Institution Review of over 600 Patients

Engraftment Syndrome in the Setting of Autologous Stem Cell Transplantation for Multiple Myeloma-a Single Institution Review of over 600 Patients

Incorporating Reduced-Dose Plerixafor to a Preemptive Mobilization Algorithm Increases Access to Autologous Transplantation in a Limited-Resource Setting

Background: Patients with lymphoma and myeloma undergoing autologous hematopoietic stem cell transplantation (ASCT) are at risk for mobilization failure, defined as the inability to harvest the minimum recommended 2x106/kg CD34+ cells prior to conditioning. This limitation can be surpassed by combining multiple apheresis sessions, cryopreservation and adding plerixafor to filgrastim. However, these strategies substantially increase transplant costs and are unaffordable for many patients in low and middle-income countries (LMIC). Furthermore, standard doses of plerixafor can lead to unnecessarily high CD34+ cell yields, leading to resource waste. We have previously shown that a reduced dose of plerixafor at 0.12 μg/kg is effective in a pilot trial. Consequently, we have incorporated RD-plerixafor to a mobilization algorithm using peripheral CD34+ cell analysis to be used in a setting with limited resources. Objective: To evaluate the efficacy of a decision-making mobilization algorithm in patients with lymphoma or myeloma defined by our ability to harvest at least 2x106Kg CD34+ cells in a single apheresis session. Methods: We performed a single-arm prospective study including consecutive adults diagnosed with lymphoma or myeloma undergoing ASCT in our institution. Patients received a mobilization regimen consisting of filgrastim 5 μg/kg BID for 4 days. On day 4 peripheral blood CD34+ cell flow cytometry analysis was performed. We designed a mobilization algorithm hypothesizing that if the day 4 CD34+ pre-count was 5-10 cells/μL, a single RD-plerixafor dose at 0.12 mg/kg (11 hours prior to apheresis) would be sufficient to achieve a successful harvest (≥2x106/kg CD34+) in one large-volume apheresis session based on a prior local study (Panel B). Patients with <5 cells/μL received filgrastim plus a single dose of plerixafor 0.24 mg/kg and those with ≥10 cells/μL received filgrastim alone. Plerixafor vials were shared between 2 patients when possible. Day 5 peripheral CD34+ cell analysis was also performed. Cells were not frozen but were stored at 4ºC. Adverse effects, final CD34+ yield and probability of engraftment using 1-survival Kaplan Meier analysis were determined. This study was performed in accordance to the Declaration of Helsinki. Results: Twenty-nine patients were included. Baseline characteristics and outcomes are shown in Table 1. Median day 4 CD34+ cell pre-count was 15 cells/μL (range, 1.4-88.7). Following our algorithm n=19 patients received filgrastim (65.5%), n=6 received RD-plerixafor (20.7%) and n=4 full-dose plerixafor (13.8%). Median day 5 peripheral blood CD34+ increased to 34.3 cells/μL (range, 10.8-107) (Wilcoxon signed ranked p<0.001), with a median increase of +28 cells/μL (+16.77-55.8) in the RD-plerixafor group. No severe adverse events were observed. We were able to successfully harvest 89.7% of patients using our algorithm with median final yield of 3.9x106 (1.7-12.3) CD34+cells/kg. Mobilization success rates were 94.7% for patients who recieved filgrastim alone, 83.3% for RD-plerixafor and 75% for full-dose plerixafor-treated patients. Optimal yields (≥5x106/kg) were achieved by 31% of patients using our strategy. Only three required a second apheresis session, and all underwent successful outpatient transplantation. One patient died due to hemorrhagic stroke on day +7. All remaining patients engrafted. Median probability of engraftment was estimated at 12 days for both neutrophils (95% CI 11.4-12.6) and platelets (95% CI 11.1-12.9) (Panel C). Female sex and prior treatment lines (continuous) were significantly associated to plerixafor requirement in a univariate regression analysis. Our strategy led to savings of $22,000 USD by lowering the plerixafor dose alone. Conclusion: Incorporating RD-plerixafor into a mobilization algorithm is a safe and effective strategy that increases access to transplantation in patients with lymphoma and myeloma at risk of harvesting failure. External validation of our decision-making algorithm is warranted. Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

MIGRATION, MOBILITY, AND PURSUIT OF GOOD OLD AGES: NARRATIVES OF OLDER PUERTO RICAN ADULTS WHO MIGRATE

Migration research has articulated “regimes of mobility,” or multi-scalar movements (within and across households, communities, and borders) that are interconnected and embedded in unequal power relations. Research on late-life migration has been limited by: (1) simplistic conceptualizations of mobility as adaptive or traumatic; and (2) a focus on transnationalism. The migration of older adults between Puerto Rico and US mainland presents a new frontier for examining mobility in aging. Puerto Rico’s population is rapidly aging and out-migrating. Moreover, as US citizens, Puerto Ricans experience no legal restrictions on migration typical of transnationalism. Yet little is known about their migration patterns and associated narrated meanings. I conducted semi-structured interviews and participant observation among older Puerto Ricans who migrated to the US mainland in late-life. Preliminary findings suggest that older Puerto Ricans negotiate competing definitions of “good” old ages based on residential context. They report migrating to the mainland to pursue “good” old ages defined in material terms, namely access to social and medical services. Post-migration, however, older Puerto Ricans report experiences of confinement and loneliness, due to language barriers and familial separation. In narrating hopes for the future, they describe an alternative “good” old age in Puerto Rico, emphasizing belonging and familial connection. As older Puerto Ricans negotiate multiple definitions of “good” old ages through circular mobility, the social and economic inequalities which first necessitated migration reproduce disadvantage in the new location. This study highlights the need to conceptualize multi-scalar mobilities that intersect with inequality to shape aging among migrant populations.