scholarly journals Feasibility of Peripheral Blood Stem Cell Collection from Heterozygoussickle Cell Trait Donors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1171-1171
Author(s):  
Juergen Foell ◽  
Morad Morez ◽  
Anja Troeger ◽  
Katharina Kleinschmidt ◽  
Beatrix Pfirstinger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Safety Concern ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Sickle Cell Crisis ◽  
Family Donor ◽  
Peripheral Stem Cells

Introduction Allogeneic haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for sickle cell disease (SCD) offered to patients with a fully matched sibling (MSD) or matched unrelated donor (MUD). With a MSD/MUD donor availability of below 20% a haploidentical HSCT from a family donor either with post-transplant cyclophosphamide (post-cy) or with a TCRαß/CD19 depleted graft (T-haplo) is an increasingly successful alternative for the majority of patients. In contrast to post-cy where mostly bone marrow is used, T-haploHSCT requires the generation of a G-CSF stimulated peripheral stem cell grafts. Almost uniformly haploidentical relatives of SCD patients are heterozygous carriers of SC trait. For these donors with a genetically heterozygous sickle trait, G-SCF represents a major safety concern with regard to triggering a sickle cell crisis. Therefore, the use of sickle trait donors is prohibited or not recommended in several countries, and guidelines are currently not available due to lack of evidence. Methods Haploidentical related donors with heterozygousSCD (group S, n=13) as well as healthy donors (group O, n=9) were stimulated with G-CSF. In all donors a similar mobilizations schedule using G-CSF was applied. All donors were applied 10µg/kg body weight (Neupogen®or Granocyte®) sub cutaneous daily with first apheresis on day 5 and day 6 when necessary. The amount of mobilized CD34+ cells were assessed after mobilization. In addition, the harvested stem cell preparations were analysed for CD34 content after apheresis and patients monitored for potential serious adverse effects (AE) during and after the apheresis. Results Mobilization was tolerated well with only mild and typical AE related to apheresis procedure such as citrate reactions, joint pain, ostealgia and headache, observed equally in both groups. In most of the donors (n=13/13 and 8/9), we were able to collect a sufficient amount of CD34+peripheral stem cells (mean of 16.3 and 8.2 x 10^6/kg in group S and O, respectively). We observed slight increases in LDH and reticulocyte counts in few donors also without significant differences between both groups. In particular, there were no severe neurologic side effects and no problems like sickle cell crisis despite mean pre-apheresis hemoglobin concentrations of 14.1 (range 11.9-17.5) g/dL in group S. Conclusions Collectively, these data indicate that in the absence of a MSD or MUD donor, haploidentical family donors with heterozygoussickle cell trait provide a safe and effective alternative for collection of peripheral CD34+stem cells for a T-haplo HSCT. Disclosures No relevant conflicts of interest to declare.

Comparison of PBSC Vs Cord Blood (CB) As Stem Cells Source for Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Adult Patients with Haematological Diseases: A Single Centre Analysis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3108-3108
Author(s):  
Amandine Lebourgeois ◽  
Marion Loirat ◽  
Benoit Tessoulin ◽  
Elsa Lestang ◽  
Pierre Peterlin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cord Blood ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Single Centre ◽  
Stem Cell Source

Abstract Abstract 3108 Introduction: RIC regimens are increasingly used for allo-SCT in older patients or patients with co-morbidities. The FB2 regimen (Fludarabine 120–150 mg/m2 + I.V. Busulfan 6.4 mg/Kg + ATG 5 mg/Kg) using PBSC as stem cell source is currently the most widely used RIC regimen in many European centres. On the other hand, in patients without a suitable HLA-matched donor, the use of umbilical cord blood stem cells for allo-SCT (uCBT) is increasingly considered, especially using the RIC regimen developed by the Minneapolis group. Series comparing PBSC vs CB as stem cells source for RIC allo-SCT are still scarce and using various RIC regimens before allo-SCT. Patients and Methods: This retrospective single centre analysis compared two homogeneously treated cohorts of patients who had received between January 2007 and November 2010 in our department either a FB2/PBSC allo-SCT (n=52, males: 61%; median age: 59 years (range: 22–70)) or a FC-TBI/uCBT (Fludarabine 200 mg/m2 + Cyclophosphamide 50 mg/Kg + TBI 2 Grays regimen; n=39, males 49%; median age 56 years (range: 22–70). Except for age (p=0.03), there were no significant differences between the 2 groups regarding patients and diseases characteristics: gender (p=0.22), interval between diagnosis and transplant (PBSC: 9 months vs CB: 10 months, p=0.85), disease type (PBSC: myeloid disease 63% vs CB: 67%, p=0.75), status at transplant (complete remission PBSC: 77% vs CB: 67%, p=0.28), prior auto-SCT (PBSC: 35% vs CB: 33%, p=0.90). Donors in the PBSC group were as follows: sibling donors, n=30; HLA-MUD n=20, mismatched unrelated n=2. All patients from the CB group received 2 CB units (HLA matching 4/6 n=25; 5/6 n=53). As for GVHD prophylaxis, patients received cyclosporine (CsA) alone in case of an HLA-identical sibling donor, and CsA+ mycophenolate mofetyl in all other cases. None of the patients from the PBSC group received G-CSF after transplant, while it was administered to all CB recipients. Results: Median follow-up was respectively 19 and 20 months for the PBSC and the CB groups (p=NS). Engraftment and median time for neutrophils recovery were similar between the 2 groups: PBSC: 96% vs CB: 90%, p=0.22; and 17 days (range: 0–39) vs 16 days (range: 8–60), p=0.88, respectively. The median time for platelets recovery (>20000/mm3) was significantly higher in the CB group: 38 days (range: 13–150) vs PBSC: 0 days (range: 0–186) (p<0.0001). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were comparable between both groups: PBSC: 31% and 15% vs CB: 26% and 8% (p=0.72 and p=0.28) as also the 2-years incidence of chronic GVHD: PBSC: 35% vs uCBT: 25%, p=0.54. 2-years NRM was significantly higher after uCBT: 26% vs 6%, p=0.02. Finally, there were no differences between the two groups in terms of 2-years OS, DFS and Relapse Incidence: PBSC: 62.3% vs CB: 60.8% (p=0.51); 58.7% vs 50.4% (p=0.43) and 36% vs 23% (p=0.31). In multivariate analysis, the source of stem cells (CB) remains associated with NRM (HR: 0.16, 95%CI: 0.05–0.5, p=0.001) but was not predictable for survivals. Conclusion: Our study suggests that RIC uCBT is a valid alternative in patients lacking an HLA-matched related or unrelated donor and candidate for RIC allo-SCT. Prospective and randomized studies are warranted in order to establish the definitive role of uCBT, especially in patients with acute leukemia, where CB cells may offer a rapidly available source of stem cells in diseases with high tumor kinetics. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4879-4879
Author(s):  
Omar Albanyan ◽  
Hyejeong Jang ◽  
Seongho Kim ◽  
Andrew Kin ◽  
Asif Alavi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Matched Donor

Abstract Introduction: Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment. Methods: We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis. Results: From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant). Conclusion: Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

scholarly journals Single Cell Phenotyping Reveals Heterogeneity among Haematopoietic Stem Cells Following Infection

2016 ◽  
Author(s):  
Adam L MacLean ◽  
Maia A Smith ◽  
Juliane Liepe ◽  
Aaron Sim ◽  
Reema Khorshed ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Single Cell ◽  
Life History Theory ◽  
Cell Function ◽  
Trichinella Spiralis ◽  
Haematopoietic Stem Cell ◽  
Haematopoietic Stem Cells ◽  
Hsc Niche

AbstractThe haematopoietic stem cell (HSC) niche provides essential micro-environmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, haematopoietic dynamics are perturbed, but it is not known whether changes to the HSC-niche interaction occur as a result. We visualise HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behaviour: (i) a pattern of revisiting previously explored space, and (ii) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (i), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC-niche micro-environments following infection.Author SummaryHaematopoietic stem cells reside in the bone marrow where they are crucially maintained by an incompletely-determined set of niche factors. Recently it has been shown that chronic infection profoundly affects haematopoiesis by exhausting stem cell function, but these changes have not yet been resolved at the single cell level. Here we show that the stem cell–niche interactions triggered by infection are heterogeneous whereby cells exhibit different behavioural patterns: for some, movement is highly restricted, while others explore much larger regions of space over time. Overall, cells from infected mice display higher levels of persistence. This can be thought of as a search strategy: during infection the signals passed between stem cells and the niche may be blocked or inhibited. Resultantly, stem cells must choose to either ‘cling on’, or to leave in search of a better environment. The heterogeneity that these cells display has immediate consequences for translational therapies involving bone marrow transplant, and the effects that infection might have on these procedures.

scholarly journals Haematopoietic stem cell transplantation in Nigerian sickle cell anaemia children patients

2015 ◽  
Vol 56 (3) ◽  
pp. 175 ◽  
Author(s):  
Antonella Isgro ◽  
Katia Paciaroni ◽  
Javid Gaziev ◽  
Pietro Sodani ◽  
Cristiano Gallucci ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Sickle Cell ◽  
Haematopoietic Stem Cell Transplantation ◽  
Sickle Cell Anaemia ◽  
Haematopoietic Stem Cell

Adenosine from Niche-Associated Tregs Maintains Hematopoietic Stem Cell Quiescence

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 91-91
Author(s):  
Yuichi Hirata ◽  
Kazuhiro Furuhashi ◽  
Hiroshi Ishi ◽  
Hao-Wei Li ◽  
Sandra Pinho ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pool Size ◽  
Immune Privilege ◽  
Haematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Conditional Deletion ◽  
Radiation Induced

Abstract A crucial player in immune regulation, FoxP3+ regulatory T cells (Tregs) are drawing attention for their heterogeneity and noncanonical functions. For example, specific subsets of Tregs in the adipose tissue control metabolic indices; muscle Tregs potentiate muscle repair, and lung Tregs prevent tissue damage. These studies, together with a previous finding that Tregs are enriched in the primary site for hematopoiesis, the bone marrow (BM), prompted us to examine whether there is a special Treg population which controls hematopoietic stem cells (HSCs). We showed that HSCs within the BM were frequently adjacent to distinctly activated FoxP3+ Tregs which highly expressed an HSC marker, CD150. Moreover, specific reduction of BM Tregs achieved by conditional deletion of CXCR4in Tregs, increased reactive oxygen species (ROSs) in HSCs. The reduction of BM Tregs further induced loss of HSC quiescence and increased HSC numbers in a manner inhibited by anti-oxidant treatment. Additionally, this increase in HSC numbers in mice lacking BM Tregs was reversed by transfer of CD150high BM Tregs but not of CD150low BM Tregs. These results indicate that CD150high niche-associated Tregs maintain HSC quiescence and pool size by preventing oxidative stress. We next sought to identify an effector molecule of niche Tregs which regulates HSCs. Among molecules highly expressed by niche Tregs, we focused on CD39 and CD73, cell surface ecto-enzymes which are required for generation of extracellular adenosine, because 1) CD39highCD73high cells within the BM were prevalent among CD150high Tregs and 2) HSCs highly expressed adenosine 2a receptors (A2AR). We showed that both conditional deletion of CD39 in Tregs and in vivo A2AR antagonist treatment induced loss of HSC quiescence and increased HSC pool size in a ROS-dependent manner, which is consistent with the findings in mice lacking BM Tregs. In addition, transfer of CD150high BM Tregs but not of CD150low BM Tregs reversed the increase in HSC numbers in FoxP3cre CD39flox mice. The data indicate that niche Treg-derived adenosine regulates HSCs. We further investigated the protective role of niche Tregs and adenosine in radiation injury against HSCs. Conditional deletion of CD39 in Tregs increased radiation-induced HSC apoptosis. Conversely, transfer of as few as 15,000 CD150high BM Tregs per B6 mouse (iv; day-1) rescued lethally-irradiated (9.5Gy) mice by preventing hematopoiesis failure. These observations indicate that niche Tregs protect HSCs from radiation stress. Finally, we investigated the role of niche Tregs in allogeneic (allo-) HSC transplantation. Our previous study showed that allo-hematopoietic stem and progenitor cells but not allo-Lin+ cells persisted in the BM of non-conditioned immune-competent recipients without immune suppression in a manner reversed by systemic Treg depletion1. This observation suggests that HSCs have a limited susceptibility to immune attack, as germline and embryonic stem cells are located within immune privileged sites. Because the study employed systemic Treg depletion and non-conditioned recipients, it remains unknown whether niche Tregs play a critical role in immune privilege of HSCs and in allo-HSC engraftment following conditioning. We showed here that the reduction of BM Tregs and conditional deletion of CD39 in Tregs abrogated allo-HSC persistence in non-conditioned immune-competent mice as well as allo-HSC engraftment following nonmyeloablative conditioning. Furthermore, transfer of CD150high BM Tregs but not of other Tregs (15,000 cells/recipient; day -2) significantly improved allo-HSC engraftment. This effect of niche Treg transfer is noteworthy given that 1-5 million Tregs per mouse were required in case of transfer of spleen or lymph node Tregs. These observations suggest that niche Tregs maintain immune privilege of HSCs and promote allo-HSC engraftment. In summary, our studies identify a unique niche-associated Treg subset and adenosine as regulators of HSC quiescence, numbers, stress response, engraftment, and immune privilege, further highlighting potential clinical utility of niche Treg transfer in radiation-induced hematopoiesis failure and in allo-HSC engraftment (under revision in Cell Stem Cell). 1 Fujisaki, J. et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature474, 216-219, doi:10.1038/nature10160 (2011). Disclosures No relevant conflicts of interest to declare.

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