Mobilization Regimen Research Articles

Mobilities in the Swiss Alps: Circulation and Rootedness

In this contribution, we wish to shed light on narratives and imaginaries of new inhabitants in two Swiss mountain regions, concerning place and belonging, and how these are shaped by concerns of (im)mobilities, circulation and rootedness. Taking into consideration the diverse profiles of people living in the mountains, our aim is to analyse the processes of attachment to place, as enacted both by inhabitants who have migrated for labour reasons and by lifestyle migrants. How do different types of mobilities, and ways of belonging by new inhabitants of urbanised mountain resorts influence their strategies of making sense of place and (local) community? What expectations do both the newcomers and the residents established for several generations carry about each other and the place? How do social processes not only affect people “on the move”, but also the localities that are travelled, visited, inhabited, and invested by these people? We will see that the economic, financial and social backgrounds of the mountain inhabitants have a strong impact on their regimes of mobility, but also that place-attachment, rootedness and commitment to the local community have an influence, and that these vary in the intersection of gender, origin, and social class dimensions.

Where is the child? Refugee narratives in contemporary European popular culture

Abstract Subjected to what has been called a ‘global mobility regime’, refugees will often find that their destination countries have a limited number of pre-cut identities ready for them and allow them little leeway beyond these. In this paper, we will discuss representations of refugees in European popular culture following the so-called 2015 Syrian refugee crisis. We will analyse the narratives in these representations, and how these negotiate both what refugees are and should be, as well as what Europe, and more specifically the EU, is and should be. Through pathos, humour and shock, these works – two pop songs, a concert film, a comic and a cartoon – do not only convey narratives about the plight of refugees, but also work through how Europe experienced the 2015 crisis, and the ensuing, often conflicting, attitudes towards irregular migration that were expressed in European public discourse. We will discuss how this experience can be conceptualised as a ‘boundary experience’ that creates a before and after, as well as the possibility of new forms of identity – a possibility that may be ultimately rejected. As they take up the topic of irregular migration, we find producers of popular culture looking for words, sounds and images to express and address these attitudes, and to remember – or forget – the 2015 refugee crisis.

Stem Cell Mobilization with Ixazomib and G-CSF in Patients with Multiple Myeloma.

(1) Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the standard consolidation strategy for patients with newly diagnosed multiple myeloma (MM) and for a subset of patients with relapsed/refractory disease. For stem cell mobilization, G-CSF alone or in combination with chemotherapy mobilizing agents and/or plerixafor are commonly used. Ixazomib is an oral proteasome inhibitor with less neurotoxic potential, which previously showed the ability to mobilize stem cells in preclinical studies. (2) Methods: Prospective single-center phase 1 study assessing the efficacy and safety of stem cell mobilization with ixazomib and G-CSF in patients with newly diagnosed or relapsed/refractory MM undergoing HDCT and ASCT. Primary endpoint was percentage of patients achieving a yield of at least 6.0 × 106/kg CD34+ cells within the first apheresis. G-CSF (filgrastim) 10 μg/kg/day was administered subcutaneously (s.c.) from day 1 to day 5 (planned apheresis) and ixazomib 4 mg orally at day 4. Plerixafor 24 mg s.c. was administered if the stem cell mobilization with ixazomib and G-CSF was not sufficient. (3) Results: 19 patients were treated within the study between 06/2020 and 02/2021. The primary endpoint was reached in 17 (89%) patients, with a median of 7.1 × 106/kg CD34+ cells collected within the first apheresis, comparable to previously published results, and only 2 (11%) patients required a second apheresis. Median number of circulating CD34+ cells was 14.0 × 106/L (2.0-95.2) before the administration of ixazomib, and 33.0 × 106/L (4.2-177.0) pre-apheresis. However, 9 (47%) patients required the addition of plerixafor to ensure optimal stem cell collection. (4) Conclusions: The combination of ixazomib and G-CSF showed promising stem cell mobilizing activity in patients with MM prior to HDCT and ASCT. Future larger studies might further investigate the role of ixazomib in stem cell mobilization regimens for MM.

Mine Air Makes Free? Rural Liberty, Materiality, and Agency in Europe’s Long Thirteenth Century

Abstract Mines and miners began to proliferate in Europe from the late twelfth century on, in lockstep with the region’s accelerating economic integration and urbanization. Mining communities were often rural and remote, reflecting landlords’ capacity to attract workers through freedoms that echoed the era’s incentives for urban migration. If, according to the adage, “city air makes free,” so apparently did the mine. Yet the specific affordances of mines’ materiality, and the mobility regimes they fostered, shaped distinct social dynamics. These emerge in their complexity when mining ordinances—a new type of legal subgenre—are explored for their handling of matter and movement. Mining legislation attests that the composition of ores, the underground extension of seams, the quality of available tools, and the behavior of gas, water, and air across different topographies were salient factors over which elites had little control. The raw physical constraints on directing the flow of people and matter into, through, and out of mines thus created a network of subterranean agency that translated under certain conditions into exterranean power.

Tejel, Jordi and Öztan, Ramazan Hakkı (eds.). 2022. Regimes of Mobility: Borders and State Formation in the Middle East, 1918–1946

Tejel, Jordi and Öztan, Ramazan Hakkı (eds.). 2022. Regimes of Mobility: Borders and State Formation in the Middle East, 1918–1946

A Multijurisdictional Assessment of the Banking System and Mobile Money Services in Coping with the Pandemic-Triggered Credit Crisis

Although, unlike the 2008 financial crisis that erupted as a result of a corrupt banking system, the Covid-19 pandemic, which is a health crisis, arguably satisfied the regular features of a credit crisis. In its wake, the global economy and its structures were weakened, and made more vulnerable and exploitable. As governments around the world reacted by redirecting more resources in catering for the pandemic and its impacts, the possibility of a lax in regulation of banking activities as a result is high, and might motivate crooks to exploit the gap in financially defrauding citizens. Banks and all entities providing financial services (shadow banks) therefore require a more stringent regulation. Similarly, many governments (including Nigeria and other developing countries) are currently ascertaining ways to tackle the increased level of poverty owing to the pandemic, and towards this aim, have welcomed the proposition that financial technology companies can help achieve financial inclusion and thus reduce poverty. Towards achieving this goal, an effective mobile money services regime has been identified by the Nigerian Central Bank as a critical tool in revitalizing Nigeria’s battered economy. This article argues that the Nigerian regime of mobile money services is still ineffective and it ascertains this through a multijurisdictional assessment of mobile money services: the article makes suitable recommendations for a regulatory reform with lessons from Kenya and other countries.

Huge variability in restrictions of mobilization for patients with aneurysmal subarachnoid hemorrhage - A European survey of practice

IntroductionOne of the major goals of neurointensive care is to prevent secondary injuries following aSAH. Bed rest and patient immobilization are practiced in order to decrease the risk of DCI. Research questionTo explore the current practices in place concerning the management of patients with aSAH, specifically, protocols and habits regarding restrictions of mobilization and HOB positioning. Material and methodsA survey was designed, modified, and approved by the panel of the Trauma & Critical Care section of the EANS to cover the practice of restrictions of patient mobilization and HOB positioning in patients with aSAH. ResultsTwenty-nine physicians from 17 countries completed the questionnaire. The majority (79.3%) stated that non-secured aneurysm and the presence of an EVD were the factors related to the establishment of restriction of mobilization. The average duration of the restriction varied widely ranging between 1 and 21 days. The presence of an EVD (13.8%) was found to be the main reason to recommend restriction of HOB elevation. The average duration of restriction of HOB positioning ranged between 3 and 14 days. Rebleeding or complications related to CSF over-drainage were found to be related to these restrictions. Discussion and conclusionRestriction of patient mobilization regimens vary widely in Europe. Current limited evidence does not support an increased risk of DCI rather the early mobilization might be beneficial. Large prospective studies and/or the initiative of a RCT are needed to understand the significance of early mobilization on the outcome of patients with aSAH.

Innovations in hematopoietic stem-cell mobilization: a review of the novel CXCR4 inhibitor motixafortide.

Hematopoietic stem-cell transplantation (HCT) and stem-cell-based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells (HSPCs), typically via peripheral blood mobilization. Commonly used HSPC mobilization regimens include single-agent granulocyte colony-stimulating factor (G-CSF), plerixafor, chemotherapy, or a combination of these agents. These regimens, however, frequently require multiple days of injections and leukapheresis procedures to collect adequate HSPCs for HCT (minimum = >2 × 106 CD34+ cells/kg; optimal = 5-6 × 106 CD34+ cells/kg). In addition, these regimens frequently yield suboptimal CD34+ HSPC numbers for HSPC-based gene-edited therapies, given the significantly higher HSPC number needed for successful gene-editing and manufacturing. Meanwhile, G-CSF is associated with common adverse events such as bone pain as well as an increased risk of rare but potentially life-threatening splenic rupture. Moreover, G-CSF is unsafe in patients with sickle-cell disease, a key patient population that may benefit from autologous HSPC-based gene-edited therapies, where it has been associated with unacceptable rates of serious vaso-occlusive and thrombotic events. Motixafortide is a novel CXCR4 inhibitor with extended in vivo activity (>48 h) that has been shown in preclinical and clinical trials to rapidly mobilize robust numbers of HSPCs in preparation for HCT, while preferentially mobilizing increased numbers of more primitive HSPCs by immunophenotyping and single-cell RNA expression profiling. In this review, we present a history of stem-cell mobilization and update of recent innovations in novel mobilization strategies with a specific focus on the development of motixafortide, a long-acting CXCR4 inhibitor, as a novel HSPC mobilizing agent.

Situated researcher: a critical autoethnography on migrant researcher’s mobility, positionality, and agency

Drawing on a critical autoethnography, this essay explores the lived experiences of a Chinese migrant researcher in Belgium and the influence of Belgium as a place of knowledge production on both the researcher and the research itself. First, it highlights the challenges of academic mobility in Europe experienced by migrant researchers in the face of the multiscalar mobility regimes, and underscores how geographic mobility intersects with social class. Second, it reveals the impact of the dual, even plural, scientific socialisation across borders on the self-refashioning and self-evaluation of researchers with migrant backgrounds. Last, the essay argues that the insider/outsider positions of researchers are not static but are constantly (re)shaped by their identities, social positions, and geographic locations – Belgium, in this case, as a place of study, residence, and knowledge production. It further emphasizes the agency of researchers in negotiating complex field relations. This essay contributes to a nuanced understanding of the vulnerability and resilience of migrant researchers in the Global North and sheds light on the role of the place of knowledge production in shaping their ways of doing research and being a researcher.

THz Response of Charge Carriers in Nanoparticles: Microscopic Master Equations Reveal an Unexplored Equilibration Current and Nonlinear Mobility Regimes

Herein, the THz mobility of charge carriers in low‐dimensional semiconductors based on a density matrix approach involving master equations for population and polarization dynamics is modeled. Pulsed THz fields induce intraband transitions between quantized subband states, creating polarization and subsequent charge transport that governs the electron mobility. It is shown that an equilibration current emerges—a purely quantum mechanical contribution understood via the Ehrenfest theorem in 1D—reshaping the low‐frequency mobility. Apart from thermal population, the results further demonstrate that the frequency‐dependent mobility becomes THz field strength and spectrum, as well as pulse width and chirp dependent, already at moderate THz probe fields of 1 kV cm−1, e.g., for 1D CdSe or GaAs nanostructures. The parametric nature of the underlying master differential equations for polarization and population, driving the intraband conductivity, results in a nonlinear, third‐order mobility and susceptibility, causing a nontrivial field dependence as well as power broadening even at moderate field strength. The obtained results are in good agreement with experiments. The observed high nonlinearities strongly impact the design and interpretation of THz charge carrier mobility experiments and further allow applications like coherent control, frequency mixing, or synthesis through a field‐controlled nonlinearity or high harmonics generation, especially interesting for future 6G telecommunication.

Ideational obstructions to mobility justice in U.S. study abroad

This article examines the experiences of first-generation, low-income, racially minoritized students from the United States who study abroad. I complicate hegemonic understandings of United States study abroad programming through analyses of participant mobility histories and identify the structural dynamics that constrain marginalized students before going overseas. In doing so, this article amplifies the voices of a population that remains largely absent from study abroad literature and forwards an understanding of how mobility regimes function in one educational realm. I draw from interviews with 18 alumni of a nationally led study abroad program to examine how participants make meaning of their study abroad experience and identify barriers to their participation. Study participants completed various short-term study abroad experiences between the years 2000 and 2019. In contrast to universalist and market-driven assumptions in study abroad literature, participant narratives display mobility imaginaries and possibilities of travel as the product of historically differentiated mobilities and inequalities.

Impact of Mobilization Strategies on Peripheral Blood Stem Cell Collection Efficiency and Product Quality: A Retrospective Single-Center Study.

Autologous stem cell transplantation is routinely used in the management of several hematological diseases, solid tumors, and immune disorders. Peripheral blood stem cell (PBSC) collection performed by apheresis is the preferred source of stem cells. In this study, the potential impact of mobilization regimens on the performance of the Spectra Optia® continuous mononuclear cell collection system was evaluated. We performed a retrospective data analysis for patients undergoing autologous PBSC collection at the Medical University Vienna, Vienna General Hospital between September 2016 and June 2018. Collections were divided into two main groups according to the mobilization regimen received: without (210 collections) or with (99 collections) plerixafor. Assessed variables included product characteristics and collection efficiency (CE). Overall, product characteristics were similar between the groups. Median CD34+ CE2 was 50.1% versus 53.0%, and CE1 was 66.9% versus 69.9% following mobilization without and with plerixafor, respectively; the difference was not statistically significant. Simple linear regression showed a very weak positive correlation between the mobilization method and CE1 or CE2 (mobilization with plerixafor increased CE2 by 4.106%). In conclusion, the Spectra Optia® apheresis system led to high CE and a good quality of PBSC products when mobilization regimens with or without plerixafor were used.

Quantitative measurement of the charge carrier concentration using dielectric force microscopy

The charge carrier concentration profile is a critical factor that determines semiconducting material properties and device performance. Dielectric force microscopy (DFM) has been previously developed to map charge carrier concentrations with nanometer-scale spatial resolution. However, it is challenging to quantitatively obtain the charge carrier concentration, since the dielectric force is also affected by the mobility. Here, we quantitative measured the charge carrier concentration at the saturation mobility regime via the rectification effect-dependent gating ratio of DFM. By measuring a series of n-type GaAs and GaN thin films with mobility in the saturation regime, we confirmed the decreased DFM-measured gating ratio with increasing electron concentration. Combined with numerical simulation to calibrate the tip–sample geometry-induced systematic error, the quantitative correlation between the DFM-measured gating ratio and the electron concentration has been established, where the extracted electron concentration presents high accuracy in the range of 4 × 1016 – 1 × 1018 cm−3. We expect the quantitative DFM to find broad applications in characterizing the charge carrier transport properties of various semiconducting materials and devices.

Analysis of Related Factors of Autologous Peripheral Hematopoietic Stem Cell Mobilization in Patients with Lymphoma and Myeloma

To explore the related factors affecting of autologous peripheral hematopoietic stem cell mobilization in patients with single center lymphoma and multiple myeloma. The clinical total of 30 patients with lymphoma or multiple myeloma who underwent autologous peripheral hematopoietic stem cell mobilization and transplantation in the Affiliated Hospital of Jiangsu University from March 2012 to December 2021 were retrospectively analyzed, including the patients' age, gender, disease type, chemotherapy course, mobilization scheme, collection times, CD34+ cell count, adverse events, days of neutrophil and platelet implantation after transplantation. The related factors affecting to the mobilization efficiency of peripheral blood stem cells was analyzed. The mobilization scheme had a significant effect on the mobilization success rate of CD34+ cells. The mobilization success rate and optimal mobilization rate of intermediate-dose VP-16+G-CSF were higher than that of high-dose VP-16+G-CSF (P<0.05); the mobilization success rate of patients with previous chemotherapy courses ≤4 was higher than that of patients with chemotherapy courses >4 (100% vs 72.22%, P<0.05); the mobilization success rate of lymphoma patients was lower than that of myeloma patients (66.67% vs 94.44%, P<0.05); the mobilization success rate of lymphoma patients who received intermediate-dose VP-16+G-CSF was higher than that received high-dose VP-16+G-CSF patients (100% vs 42.86%, P<0.05). Patients' gender, age, time from diagnosis to mobilization and disease status had no significant effect on the efficiency of stem cell mobilization. Fifteen patients (50%) had febrile neutropenia during stem cell mobilization. There was no statistical difference in the incidence of febrile neutropenia between the two mobilization schemes (P>0.05); the incidence of severe thrombocytopenia in intermediate-dose VP-16+G-CSF group was higher than that in high-dose VP-16+G-CSF group (P<0.05). There was no statistical difference in the time of granulocyte implantation and platelet implantation after stem cell transplantation in patients with different mobilization schemes (P>0.05). Mobilization regime, the number of previous chemotherapy course and disease type affect the mobilization efficiency of stem cells. Intermediate dose VP-16+G-CSF can improve the mobilization efficiency of stem cell in lymphoma patients, but should pay attention to the risk of bleeding.

Towards an Understanding of Digital Nomadic Mobilities

Abstract This paper instigates a discussion on the applicability of a mobility lens to digital nomadism. Digital nomadism defines the lifestyle of highly mobile professionals, known as digital nomads, who work while traveling on a (semi)- permanent basis. Digital nomads encompass the mobility changes that have taken place both at a personal and at a societal level and serve as an example of the mobility changes brought about by “the mobilities turn.” This article outlines how mobility and immobility are present in digital nomadism, and how mobility regimes shape the digital nomadic lifestyle. It further discusses digital nomadism in relation to work and travel to examine how this phenomenon challenges and broadens our understanding of and perspectives on mobilities.

Effect of Daratumumab on Stem Cell Mobilization and Engraftment Kinetics Post Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma

Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care therapy for patients with newly diagnosed multiple myeloma. Daratumumab, an anti-CD38 monoclonal antibody, is now frequently being incorporated as a part of induction therapy in clinical practice, on the basis of data from several clinical trials.1-3 Few studies have evaluated the impact of daratumumab on stem cell mobilization and engraftment with conflicting results. Delayed neutrophil engraftment was noted in patients who received daratumumab as a part of induction therapy in one study.4 However, no delay was reported in another retrospective study5 and at least one clinical trial.6 Lower numbers of stem cells collected were reported uniformly in all three studies with daratumumab use. We evaluated the impact of daratumumab on stem cell yield with mobilization therapy as well as engraftment kinetics. Methods: We retrospectively evaluated 353 patients with newly diagnosed multiple myeloma treated at Hackensack University Medical Center between 2019-2021, on an IRB approved protocol. As per institutional guidelines, a combination of granulocyte colony stimulating factor (GCSF) with plerixafor was used as the mobilizing regimen for patients >70 yrs; cyclophosphamide, etoposide and dexamethasone (CdE) with GCSF was used for patients <70. Plerixafor could be added after chemotherapy mobilization for patients failing to achieve the desired collection goals. All patients received melphalan at a dose of 200mg/m2 administered intravenously on day -1. Time to engraftment (TTE) was calculated from the day of stem cell infusion to neutrophil and platelet engraftment, each defined as an absolute neutrophil count (ANC) of over 500/uL for three sequential tests and a platelet level over 20,000/uL without transfusion support, respectively. Goal for stem cell collection was defined as >8 x 106 CD34+ cells for patients >65 years, >12 x 106 CD34+ cells for patients <65. Statistical analyses were performed using STATA v16.0 (Stata Corp, TX, USA). The differences in median times to engraftment were analyzed using the Wilcoxon signed-rank test. Neutrophil and platelet recovery over time were calculated and plotted using Kaplan-Meier survival analyses and log-rank test for equality of survival function. Differences were considered significant at p-values <0.05. Results: 47 patients received daratumumab as a part of their induction therapy (Group A) compared with 306 patients who did not (Group B). Both groups were well balanced with regards to number of cycles of remission-induction therapy, age, sex, and mobilization regimens (Table 1). A higher number of CD34+ cells were collected for Group B, compared with Group A (12 x 10^6 vs 9.5 x 10^6, p<0.001); a lower number of collection days were required to reach collection goal for Group B compared with Group A (2 days vs 3 days, p=0.01); more CD34+ cells were collected per day for Group B compared with Group A (4.9 x10^6 vs 3.0 x 10^6, p=0.01). 73.5% patients met their collection goal for Group A, compared with 46% for Group B (p<0.001). A second mobilization attempt was required for 7 (14.9%) of patients in Group A compared to 10 (3.3%) for Group B. No difference was noted with regards to TTE for ANC (11 days for both groups, p=0.005) (Figures A); TTE for platelets was noted to be delayed by 1 day for Group A (14 days vs 13 days, p=0.0168) (Figures B). Rates of bacteremia did not differ between the two groups. Results are summarized in Table 1. Conclusions In our single-center study, a lower number of CD34+ cells were collected for patients who received daratumumab as a part of induction therapy for myeloma despite the use of standard mobilization regimens. No difference was found with regards to ANC engraftment. Platelet engraftment occurred one day earlier for patients who did not receive daratumumab for induction. These observations are consistent with results published in two prior studies.5,6 Depending on the target goal for CD34+ cell collection, daratumumab should be used with caution in the upfront setting for multiple myeloma. This is particularly important if tandem stem cell transplantation, salvage transplantation, or stem cell boost post high dose therapy are being considered as prospective treatment options for patients with multiple myeloma. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Despite Use of Upfront Plerixafor and G-CSF, Daratumumab Exposure Reduces Stem Cell Mobilization in Patients with Multiple Myeloma

Introduction Daratumumab is an anti-CD38 IgG1k monoclonal antibody with direct tumor killing and immunomodulatory mechanisms of action which was shown to have clinical benefits when added to the standard-of-care induction regimen in transplant eligible multiple myeloma (MM) patients. However, prior studies have indicated a potential reduction in stem cell yield in patients exposed to daratumumab prior to stem cell mobilization. Additionally, prior studies have not utilized combination mobilization regimens with G-CSF and the CXCR4 antagonist plerixafor as standard-of-care, which may overcome the deleterious effect of daratumumab. In this study, we investigated the stem cell yield of plerixafor-treated patients with daratumumab exposure compared to those without. Methods We conducted a retrospective study of patients with MM at our institution who underwent autologous stem cell mobilization and collection during first-line treatment over a 15-month period from 2021-2022. Following induction, patients underwent mobilization with a regimen of G-CSF for 5 days with plerixafor on the 4th day. Circulating CD34+ stem cells were enumerated on the 5th day, after which patients underwent approximately 20L apheresis with a collection goal of 5x106 CD34+ cells/kg of body weight. The primary endpoint of this study was the comparison of circulating CD34+ cells between patients who received daratumumab during induction and those who did not. Secondary endpoints included collection CD34+ yield and proportion who met the collection goal. Results 123 patients were included in the analysis. The median age was 65 (range: 34-77), 54% were male, and 84% were White. Twenty-two percent were stage I, 58% stage II, and 19% stage III by the Revised International Staging System. Forty-seven percent received daratumumab during induction. Of those, the median number of cycles administered was 4 (range: 1-5). Ninety percent received daratumumab in combination with bortezomib, lenalidomide and dexamethasone. The two cohorts were balanced in terms of age, gender, race, and exposure to lenalidomide, alkylators and radiation during induction. Patients with daratumumab exposure had a mean mobilization of 57.5 CD34+ cells/mcl compared to 96.4 for those without (p < 0.001). The mean CD34+ cell collection yield in 1 apheresis procedure was 6.0 x 106 cells/kg compared to 10.6 x 106 cells/kg (p < 0.001). Fifty-three percent of patients with daratumumab exposure met the collection goal compared to 80% of patients without (p < 0.001). Of the patients who did not meet the goal in one apheresis procedure, the majority were able to meet the goal with 1-3 additional days of apheresis (Figure 1). However, only 86% of patients with daratumumab exposure met the collection goal compared to 97% of those without (p < 0.001). Ten patients failed to collect 2.0 x 106 cells/kg, the institutional minimum for transplantation, 9 of which received daratumumab during induction. Eight were able to collect the minimum with an additional 1-3 days of apheresis; 2 patients required an additional mobilization procedure and collection but were able to proceed to transplantation. After adjusting for covariates including age, gender, race, weight, and exposure to lenalidomide, alkylators, and radiation, daratumumab exposure was associated with a 37.9 cells/mcl decrease in mean mobilization of CD34+ and 4.2 x 106 cells/kg decrease in CD34+ cell collection (both p < 0.001). Alkylator exposure was associated with a 43.3 cells/mcl decrease in mean mobilization of CD34+ (p = 0.040) and 4.1 x 106 cells/kg decrease in CD34+ cell collection (p = 0.057). Lenalidomide exposure was associated with a 103.4 cells/mcl decrease in mean mobilization of CD34+ (p <0.001) and 8.7 x 106 cells/kg decrease in CD34+ cell collection (p <0.001). Conclusion Inclusion of daratumumab in the induction regimen for transplant-eligible patients with MM resulted in a significant reduction in stem cell mobilization and stem cell yield, even with the use of plerixafor-containing mobilization regimens. This reduction was similar to alkylator exposure but less than lenalidomide exposure. With the increasing use of quadruplet induction regimens, the frequency of mobilization failure is likely to increase in the future and new mobilization regimens and approaches are needed to guarantee adequate cell yields without the need for additional days of apheresis and/or mobilizations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Venous Thromboembolism in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplant

Introduction: Venous thromboembolism (VTE) is a common complication that could affect multiple myeloma (MM) patients. Previous studies suggested the incidence of VTE in MM patients not on VTE prophylaxis to be as high as 10.7% in the peri-transplant period. Usage of antiplatelet or anticoagulant VTE prophylaxis is often a challenging clinical decision especially in patients with profound thrombocytopenia. Here, we aimed to explore the incidence and risk factors for VTE in MM patients undergoing AHCT. Methods: The electronic medical records of all MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th, 2021 were reviewed. We evaluated the incidence and type of venous thrombosis occurring in the immediate peri-transplant period, defined as extending from the start of stem cell apheresis up to 30 days post-AHCT. Baseline patient, demographic, disease, and transplant factors were evaluated to analyze risk factors for VTE occurrence within the studied period. Statistical Package for Social Sciences (SPSS) was used for statistical analysis. Results: A total of 493 patients with available records were included in our study. The median age was 61.4 years (range 33.1-77.7 years) at the time of AHCT with a male preponderance of 59%. Symptomatic VTE was recorded in 23 events involving 17 patients (3.5%) within the defined peri-transplant period, of which 34.8% of the events occurred between the start of stem cell apheresis and the date of transplant (i.e. day 0). Around 34.8% of VTE events, involving 6 (35.3%), patients occurred during hospitalization for the transplant procedure. All VTEs were non-catheter related, and most were lower extremity deep venous thromboses (DVT) (52.2%), followed by pulmonary emboli (17.4%), DVT of upper extremities (13%), internal jugular thromboses (13%) and superficial vein thrombosis (4.4%). Of the 17 VTE patients, 41% had history of previous VTE prior to the defined peri-transplant period, 88.2% were recently on immunomodulatory drugs (IMiD), 76.5% were on either antiplatelet (41.2%) or anticoagulant (53%) therapy or both (17.7%), while 23.5% were on none. Most of the VTE patients were never smokers (70.6%), while the rest (29.4%) were ex-smokers. Of note, 35.3% of VTE patients had thrombocytopenia (Platelets <150 x109/L) but median platelet count of 184 x109/L. Patients who developed VTE were of similar age (median 62.1 vs 61.4 years, P=0.9) but had a higher female preponderance (64.7 vs 40.1%, P=0.04) compared to those who did not. In addition, they had similar albumin levels at diagnosis (75 vs 71.7% ≥ 3.5 g/dL, P=0.8), similar cytogenetic risk categorization (high risk in 35.3 vs 25.8%, P=0.4), ISS stages (P=0.5), disease remission status prior to AHCT (P=0.3), mobilization regimens (G-CSF + Plerixafor in 88.2 vs 88.2%, P=0.1), and recent IMiD use (88.2 vs76.7, P=0.26) (Table 1). However, VTE patients were more likely to have IgG MM (70.6 vs 62%, P=0.06), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≥1 (100 vs 81.1%, P=0.05), infection at AHCT (12.5 vs 3.2%, P=0.05), longer length of AHCT hospital stay (median 17 vs 14.9 days, P<0.0001), and had higher prevalence of prior history of VTE (41.2 vs 11.6%, P<0.0001) (Table 1). With regards to prophylaxis therapy, VTE patients were less likely to be on antiplatelets (41.2 vs 65.6%, P=0.039), were on similar prophylactic anticoagulation (11.8 vs 19.5%, P=0.42), but were more likely to be on therapeutic anticoagulation (41 vs 14%, P=0.002) compared to non-VTE pts, suggesting a higher impact of a history of prior VTE than therapeutic anticoagulation on recurrence of VTE during the studied time period. Among patients with no history of previous VTE, non-VTE patients were more likely to be on either antiplatelet or prophylactic anticoagulation (82.6 vs 50%, P=0.02). Interestingly, no difference was seen in the incidence of VTE with antiplatelet vs prophylactic anticoagulation in patients without history of previous VTE (1.86 vs 0%, P=0.9). Moreover, among those with a history of previous VTE, the addition of antiplatelets to therapeutic anticoagulation did not significantly lower the risk of VTE recurrence in the studied time period (9 vs 16%, P=0.9). Conclusion: The use of VTE prophylaxis among MM patients undergoing AHCT may lower its incidence. The main risk factors for VTE are female sex, history of previous VTE, infections at AHCT, HCT-CI ≥1, and longer hospital stay. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chip-Derived Vs De Novo Treatment-Related Myeloid Neoplasms after Autologous Stem Cell Transplant for Lymphoid Disorders

Autologous stem cell transplant (ASCT) involves high intensity conditioning regimens with significant cytotoxicity. Therapy-related myeloid neoplasms (tMN) represent a serious complication characterized by high-risk features and poor treatment outcomes in patients potentially cured from their primary neoplastic disorders. While the 2016 WHO classification broadly divides tMN into MDS or AML, yet their heterogeneity warrants a more distinctive characterization based on specific prior exposures and subsequently-developed unique features, as emphasized by the updated 2022 WHO revision. We previously analyzed the genomics of tMN including features suggestive of their derivation from either CHIP or de novo driver mutations1. Specifically for tMN pathobiology, ASCT may be very instructive due to the high dose therapy and repopulation of the hematopoiesis out of a limited number of transplanted hematopoietic stem cells. Post-ASCT tMN may be unique and possibly related to antecedent CHIP, CHIP induced by the procedure, or driver lesions. We took advantage of a large volume of ASCT performed at our institution along with excellent clinical annotations and long follow up to study the dynamics of tMN in this setting. We accrued a total of 1507 patients undergone ASCT, of whom 35 (2.3%) developed tMN at a median follow up time of 5.4 years following the procedure. The clinical and molecular phenotype of these index cases were then compared to a cohort of tMN patients (n=263) without prior history of ASCT. Of note, both groups had similar MDS/AML proportions. Compared to the rest of the ASCT cohort, patients developing tMN were older at the time of the transplant procedure (66 vs 46% ≥60 years, P=.02) and had a higher male preponderance (91 vs 59%, P<.0001). Post-ASCT tMN was more common following non-Hodgkin's lymphoma (NHL) than multiple myeloma (MM) (2.5 vs 1.1%, P=.0002) but similar between NHL and Hodgkin's disease (2.5 vs 1.5%, P=0.13). We then studied whether graft size and mobilization regimens could increase the risk of tMN. The incidence of this complications was higher with a mobilization involving GCSF (G), Etoposide (E) and Plerixafor (P) (GEP) rather than G, G+E or G+P (P=.0001), as well as when a CD34+ dose ≤3.5 x106 (4.1 vs 1.9%, P=.03) was infused. No difference was noted with respect to time to engraftment following ASCT. Multivariate analysis confirmed the independent influence of age ≥60 (HR 2.4, 95% CI 1.1-5.6), male sex (HR 7.1, 2.5-29.9), diagnosis (prior NHL vs MM; HR 3.3, 1.5-8.2) and mobilization scheme (GEP vs G+P; HR 4.7, 1.3-13.7). The caveat was the lack of significant effect of the graft size on tMN risk. When compared to non-transplanted cases, tMN following ASCT still showed a male preponderance (91 vs 51%, P<.0001) and exhibited a higher prevalence of high-risk (IPSS-R>3.5) MDS (79 vs 57%, P=.05). Furthermore, tMN arising post-ASCT appeared to follow a more aggressive course with a significantly shorter latency duration following the procedure (median 2.6 vs 6.5 years, P<.0001) and shorter overall survival (median 16 vs 58 months, P<.0001; Fig1). Cytogenetic profiling revealed higher frequencies of complex karyotype (49 vs 31%, P=.05), del(5q)/5- (26 vs 20%, P=.5), del(7q)/7- (46 vs 27.5%, P=.03), and del(17p)/17- (27 vs 6%, P=.0025) in the ASCT-exposed as opposed to non-transplanted cases. Subsequent analysis of isolated cytogenetic aberrations showed that isolated del(7q)/7- was significantly enriched in post-ASCT tMN (20 vs 6%, P=.0129). Mutational analysis revealed similar patterns with the exception of TP53, which was significantly more frequent in the ASCT-exposed group (41 vs 13%, P=.0028), mostly displaying a multi-hit configuration (32 vs 11%, P=.0178). We have previously shown that ancestral hits in DNMT3A, TET2, ASXL1 and JAK2 (CHIP-mutations) indicate derivation of disease from CHIP vsU2AF1, RUNX1 and STAG2 highlighted de novo cases, thereby prompting us to investigate whether CHIP may have been the originator of tMN post ASCT2. However, the frequencies of CHIP- and de novo -mutations were similar across the post-ASCT tMN and the non-ASCT tMN groups. Interestingly, within the post-ASCT tMN, patients who had CHIP-derived tMN had lower survival compared to the rest of the group (median 9 vs 25 months, P=.0079). Sequencing experiments on serial specimens are ongoing to determine whether CHIP- derived mutations were present prior to ASCT constituting a risk for tMN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I Safety and Feasibility Study to Evaluate Motixafortide (CXCR4/SDF-1 Inhibition) and Natalizumab (VLA-4/VCAM-1 Inhibition) As a Novel Regimen to Mobilize CD34+ Hematopoietic Stem Cells for Gene Therapy in Sickle Cell Disease

Background: Sickle cell disease (SCD) is one of the most common genetic diseases globally. Clinical manifestations of SCD commonly include anemia, pain, vaso-occlusive events and cumulative end organ damage leading to significant morbidity and mortality. Historically, allogeneic hematopoietic cell transplantation (HCT) represented the only curative therapy for SCD, but is associated with significant HCT-related morbidity and mortality which limit its use (PMID: 8663884, PMID: 20007560). Autologous hematopoietic stem cell (HSC) -based gene therapies now offer curative potential with decreased toxicity (PMID: 28249145). However, effective HSC-based gene therapy depends on collection of sufficient HSCs (ideally >10x106 CD34+ cells/kg), typically from peripheral blood (PB) (PMID: 33956057). G-CSF and CXCR4 inhibition (CXCR4i) with plerixafor are the most widely used mobilization strategies (PMID: 19363221, PMID: 19720922). However, G-CSF is associated with risk of fatal vaso-occlusive events in SCD (PMID: 9734950, PMID: 11368061, PMID: 19513902). Meanwhile, short-acting CXCR4i with plerixafor alone does not reliably yield optimal HSC numbers for gene therapy applications (PMID: 30282642, PMID: 29419425, PMID: 29472357). Therefore, developing novel HSC mobilization regimens to rapidly and reliably mobilize optimal CD34+ HSCs for gene therapy in SCD represents an unmet need. Motixafortide (M) is a high-affinity, long-acting CXCR4 inhibitor. The recent Phase III, randomized, controlled GENESIS Trial demonstrated combination M+G-CSF resulted in 88.8% of patients collecting ≥6x106 CD34+ cells/kg (median 10.8x106) within 1 leukapheresis (LP) for HCT. This compares favorably to historical data with plerixafor+G-CSF where 54.2% collected to goal in 1 LP. Motixafortide also mobilized more immunophenotypically primitive HSCs and multi-potent progenitors compared to plerixafor. Meanwhile, transcriptional profiling by single-cell RNA sequencing revealed HSCs mobilized with M have gene expression profiles associated with enhanced regeneration and self-renewal, compared to G-CSF or plerixafor (DOI: 10.1182/blood-2021-144296). Motixafortide alone also mobilized an average of 11.6×106 CD34+ cells/kg in healthy volunteers, while mobilizing 91.6% of allogeneic HSC donors to goal in ≤2 LPs (median 6.07x106) (DOI: 10.1182/blood-2018-99-109701, PMID: 28835380). Natalizumab (N) is a monoclonal antibody to the a4 integrin subunit of a4b1 (VLA-4) capable of VLA4 inhibition (VLA4i). In mice and primates, N led to an ~8-fold increase in PB CD34+ HSCs in 24 hrs (PMID: 7692447). In humans, a single N infusion resulted in a 5- to 6-fold increase PB CD34+ HSCs. Meanwhile, the average PB CD34+ HSC levels after a single dose were similar to levels with repeated doses, indicating rapid mobilization of maximal PB HSCs by 24 hrs after N infusion (PMID: 18195093). Combination CXCR4i and VLA-4i has been well-tolerated and resulted in synergistic mobilization of HSCs in preclinical studies (PMID: 21886173). Therefore, we hypothesize that combination CXCR4i and VLA-4i with M+N represents a safe and effective strategy for robust, rapid and synergistic mobilization of HSCs to PB in patients with SCD. Study Design and Methods: This is a single center, single-arm, dose de-escalation, Phase 1 safety and feasibility study. Key eligibility criteria include patients with SCD (SS or Sβ0) age 18-35 years receiving automated RBC exchanges. Patients with prior HCT or gene therapy will be excluded. We estimate 5 patients in this pilot feasibility study will provide sufficient safety and preliminary efficacy data to guide further development of this novel mobilization strategy. All patients will have baseline labs prior to M (1.25mg/kg, subcutaneous), N (300mg, IV) and M+N dosing. Each patient will then undergo mobilization and LP (1 blood volume), per protocol (see Figure 1). The primary outcome will be to assess the safety and tolerability of M, N and M+N in each SCD patient, defined by dose-limiting toxicities and maximum tolerated dose. Key secondary outcomes include: kinetics of CD34+ HSC mobilization to PB (CD34+ cells/uL), number of CD34+ HSCs collected via LP (CD34+ cells/kg/L), incidence of AEs, pharmacokinetics and the recommended phase 2 dose. Correlative studies include immunophenotypic and single cell transcriptional profiling of CD34+ HSCs from LP product mobilized with M, N and M+N. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal