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Woywodt, Alexander, Johanna Scheer, Lothar Hambach, Stefanie Buchholz, Arnold Ganser, Hermann Haller, Bernd Hertenstein, and Marion Haubitz. "Circulating endothelial cells as a marker of endothelial damage in allogeneic hematopoietic stem cell transplantation." Blood 103, no. 9 (May 1, 2004): 3603–5. http://dx.doi.org/10.1182/blood-2003-10-3479.
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Abstract Damage to endothelial cells is the common feature of vascular disorders associated with hematopoietic stem cell transplantation (HSCT). Elevated numbers of circulating endothelial cells reflect the extent of endothelial damage in a variety of disorders but their use in HSCT has not been investigated so far. We studied 39 patients undergoing allogeneic HSCT with different conditioning regimens and 22 healthy controls. Circulating endothelial cells were enumerated with immunomagnetic isolation during the course of HSCT. After conditioning, cell numbers were significantly elevated (median 44 cells/mL) compared with baseline (median 16 cells/mL) and controls (median 8 cells/mL). Patients who received radiation had an earlier peak when compared with patients who received chemotherapy. Patients who received reduced-intensity conditioning had significantly lower cell numbers (median 24 cells/mL) than those who received standard conditioning. These observations provide a novel marker to investigate microvascular endothelial damage and the effects of different conditioning regimens in patients undergoing HSCT. (Blood. 2004;103:3603-3605)
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Can, Sun, Lin Xia, Huang Yuxian, Chen Tuzhen, and Bingyi Wu. "More Intensity Immuno-Suppression In Conditioning Regimen may Favor Donor Stem Cell Sustained Engraftment In Allogeneic Stem Cell Transplantation For Acquired Severe Aplastic Anemia Patients." Blood 122, no. 21 (November 15, 2013): 5452. http://dx.doi.org/10.1182/blood.v122.21.5452.5452.
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Abstract Background Hematopoietic stem cell transplantation (HSCT) is the first-line therapy for patients younger less than 40 years old with severe aplastic anemia (SAA). And the long-term survival for patients with SAA who received HSCT reaches to 70%-90%. Cyclophosphamide-based conditioning regimen with or without antithymocyte globulin (ATG) has been adopted in majority of HSCT for SAA patients with HLA matched related donor. However the graft rejection and graft failure in HSCT for SAA with cyclophosphamide-based conditioning regimen is still as high as 5%-16%. The aim of this study is to explore whether more immue suppression in conditioning regimen could favor the donor stem cells sustained engraftment for severe aplastic anemia patients receiving allogeneic hematopoietic stem cell transplantation. Fludarabine and busulfan were added in cyclophosphamide-based conditioning regimen to intensity immune suppression in conditioning. Methods To analyze the outcomes and chimeras of 40 patients with SAA who received HLA matched allo-HSCT from 2000 to 2012 with either fludarabine-based conditioning regimen or cyclophosphamide-based conditioning regimen retrospectively and to explore the relationship between the chimeras and conditioning regimen. Results Forty patients with SAA who received HLA matched allo-HSCT From May, 2000 to Dec. 2012. Twelve patients ( median age 25 year old range 13-52, male 7, femal 5) received fludarabine-based conditioning regimen which composed of fludarabine (30 mg/m2/d ×5d), busulfan ( 3 mg/kg ×2d ), cyclophosphamide ( 60mg/kg/d×2d) and ATG (2.5mg/kg/d ×5d). Twenty patients( median age 23 year old range 12-42, male 19, femal 9) received cyclophosphamide-based conditioning regimen which composed of cyclophosphamide (50mg/kg/d ×4d )and ATG (2.5mg/kg/d ×2d ). The median dose of MNC were 4.5×108/kg (range 3.8-7.0×108/kg )and 3.58×108/kg (range 3.2-6.8×108/kg ) and CD34+ cells were 4.5×108/kg and 3.58×108/kg respectively. GVHD prophylaxis were cyclosporine and short-term course methotrexate. Donor chimera was detected on day+30, +90, +180, and 360 after HSCT by short tandem repeat polymerase chain reaction, or fluorescein in situ hybridization for X and Y chromosomes in cases when patients and donors were sex mismatched. Results All patients with fludarabine-based conditioning regimen were successful Hematopoietic reconstitution and no graft failure occurred in this group patients. But two patients could not get recovery in cyclophosphamid-based conditioning regimen group. And complete donor chimeras always present when chimeras were detected by STR-PCR or FISH at day 30,day 60, day 90 and d 180 post transplantation in fludarabine-based conditioning regimen group, while seven patients with cyclophosphamide-based conditioning regimen were mixed chimeras at day 30 post transplant. The graft was rejected in six of the seven patients at day 90 post transplant in cyclophosphamide-based conditioning regimen group. The complete donor chimera in fludarabine-based conditioning regimen group was obvious higher than that in cyclophosphamide-based conditioning regimen group ( p=0.037). The incidence of aGVHD in the fludarabine group was 16.7% and 10.7% in the cyclophosphamide-based group. There is no significant difference of aGVHD between two group (P = 0.627). The incidence of cGVHD was 8.3% and 10.7% respectively. The bacterial infections developed in 16.7% and 28.6% of patients respectively (P=0.693), The overall survival were 83.33% and 82.14% in fludarabine-based conditioning regimen group and cyclophosphamide-based group respectively (p=0.870). Conclusions More intensity immuno-suppression in conditioning regimen may favor donor stem cell sustained engraftment in allogeneic stem cell transplantation for acquired severe aplastic anemia patients. Disclosures: No relevant conflicts of interest to declare.
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Jadasz, Janusz Joachim, David Kremer, Peter Göttle, Nevena Tzekova, Julia Domke, Francisco J. Rivera, James Adjaye, Hans-Peter Hartung, Ludwig Aigner, and Patrick Küry. "Mesenchymal Stem Cell Conditioning Promotes Rat Oligodendroglial Cell Maturation." PLoS ONE 8, no. 8 (August 12, 2013): e71814. http://dx.doi.org/10.1371/journal.pone.0071814.
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Divito, Sherrie J., Christopher Elco, Indira Guleria, Edgar Milford, Corey Cutler, and Thomas S. Kupper. "Host skin T cells survive stem cell transplant conditioning and are functional during acute GVHD." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 82.13. http://dx.doi.org/10.4049/jimmunol.198.supp.82.13.
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Abstract Graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality in stem cell transplantation (SCT). Acute GVHD is thought to be mediated by donor T cells that target and destroy host tissues. Studies into the host immune system are limited, as it is assumed that host T cells in peripheral tissues such as skin are depleted by conditioning regimens in parallel to T cells in lymphoid organs and blood. However, it is recently appreciated that a high number of memory T cells reside long-term within the organs most affected by GVHD. We investigated whether host skin T cells survive SCT conditioning and are present during acute GVHD. To do so, excess skin biopsy tissue was obtained from patients with acute skin GVHD who had undergone myeloablative or non-myeloablative conditioning and allogeneic SCT with sex-mismatched donor cells. Tissue was stained for T cell markers via immunofluorescence concurrently with in situ hybridization for the X and Y chromosomes. All seventeen patients studied demonstrated persistence of host T cells in skin, often in equal or greater numbers than donor T cells. Host skin T cells survived regardless of myeloablative or non-myeloablative conditioning, of patient age, and of day post-SCT (samples ranged from 12–213 days post-SCT). Comparatively, blood T cell chimerism was 100% donor in nearly all samples, indicating diverging effects of conditioning on T cell compartments. Skin host T cells demonstrated pro-inflammatory cytokine production. These results provide a novel avenue of research into GVHD pathobiology and suggest that alternative conditioning regimens should be employed if host skin T cells are to be targeted.
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Yamamoto, Shuhei, Yasunori Mitani, Masayuki Watanabe, Akihiro Satake, and Yoshiaki Ushifusa. "Fuel Cell Co-generation and PCS Control for Suppressing Frequency and Voltage Fluctuation due to PV Power." International Journal of Electronics and Electrical Engineering 9, no. 2 (June 2021): 48–51. http://dx.doi.org/10.18178/ijeee.9.2.48-51.
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The purpose of this study is to control active power of fuel cell co-generation system and reactive power of power conditioning system to suppress frequency fluctuation in power system and voltage fluctuation in distribution system caused by variation of photovoltaic power. The governor-free control for fuel cell co-generation system is applied to reduce frequency fluctuation in power system. A method which controls power fluctuation in distribution system for power conditioning system is applied to reduce voltage fluctuation. The authors reveal the effectiveness of the method by a simulation model. The results suggest that fuel cell co-generation system and power conditioning system work to reduce each targeted fluctuation.
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Limerick, Emily, and Courtney Fitzhugh. "Choice of Donor Source and Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease." Journal of Clinical Medicine 8, no. 11 (November 15, 2019): 1997. http://dx.doi.org/10.3390/jcm8111997.
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In the United States, one out of every 500 African American children have sickle cell disease (SCD), and SCD affects approximately 100,000 Americans. Significant advances in the treatment of this monogenetic disorder have failed to substantially extend the life expectancy of adults with SCD over the past two decades. Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with SCD. While human leukocyte antigen (HLA) matched sibling HSCT has been successful, its availability is extremely limited. This review summarizes various conditioning regimens that are currently available. We explore recent efforts to expand the availability of allogeneic HSCT, including matched unrelated, umbilical cord blood, and haploidentical stem cell sources. We consider the use of nonmyeloablative conditioning and haploidentical donor sources as emerging strategies to expand transplant availability, particularly for SCD patients with complications and comorbidities who can undergo neither matched related transplant nor myeloablative conditioning. Finally, we show that improved conditioning agents have improved success rates not only in the HLA-matched sibling setting but also alternative donor settings.
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Antin, Joseph H. "Reduced-Intensity Stem Cell Transplantation." Hematology 2007, no. 1 (January 1, 2007): 47–54. http://dx.doi.org/10.1182/asheducation-2007.1.47.
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Abstract The recognition that the immune system can play a major role in the control and cure of transplantable disorders led to the development of reduced-intensity allogeneic transplantation. The notion is that a compromise can be made between the intensity of conditioning and the fostering of graft-versus-host disease/ graft-versus-leukemia (GVHD/GVL), allowing the use of less intense conditioning with concomitantly less intense immediate toxicity. Reduced-intensity conditioning regimens have allowed the application of transplantation to older patients and to patients with underlying medical problems that preclude full-dose transplantation. Clearly, in some settings in which dose intensity is important, reduced-intensity regimens are less useful. However, for diseases that are either indolent, highly susceptible to GVL, or under good control before entering transplantation, this approach appears to have substantial benefits. Although the therapy appears to be valuable, concerns about delayed immune reconstitution and GVHD remain.
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Granadier, David, Kirsten Cooper, Dante Dennis Acenas II, Lorenzo Iovino, Paul Deroos, Vanessa A. Hernandez, and Jarrod A. Dudakov. "Hematopoietic Stem Cell Transplantation (HCT) Conditioning Leads to NK Cell Cytotoxicity Limiting Endogenous Thymus Regeneration." Blood 142, Supplement 1 (November 28, 2023): 461. http://dx.doi.org/10.1182/blood-2023-188387.
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The thymus is highly sensitive to acute injury such as the cytoreductive conditioning given pre-hematopoietic stem cell transplant (HCT). The thymus is capable of regeneration, however its reparative capacity and T cell productivity decline with age. This leaves HCT recipients vulnerable to relapse of malignancy and opportunistic infection - the leading causes of post-HCT mortality - during a prolonged period of lymphopenia. Better understanding the endogenous mechanisms by which thymus regeneration is regulated may inform therapeutic interventions to improve T cell reconstitution in these patients. Here, we report that HCT conditioning leads to rises in stimulatory cytokine IL-18, subsequent activation of NK cells and increased cytotoxicity, which aberrantly suppresses organ recovery. Our group has reported that HCT-conditioning by ionizing radiation leads to increased Caspase-1 mediated immunogenic cell death within the thymus (Kinsella 2023 BioRxiv). Consistent with the cleavage of Caspase-1, we found an increase in release of the inflammatory cytokines IL-1b and IL-18. Although mice deficient for IL-1b signaling receptor ( Il1r -/-) did not show any modulation in their ability to regenerate after TBI, we found that mice deficient for IL-18 signaling (Il18 -/-) exhibited increased thymic cellularity one week following acute damage by sublethal irradiation (SL-TBI) (Fig. 1A left). This led us to conclude that post-damage activation and release of IL-18 suppresses thymus regeneration. We found that IL-18R was not expressed on most developing thymocytes and although a minority of thymic epithelial cells expressed the receptor, mice with a deficiency in IL-18R restricted to TECs ( Il18r1fl/fl:Foxn1-Cre +) showed no difference in regenerative capacity following conditioning. To rule out an effect on hematopoietic progenitors, for which IL-18R expression has been reported ( Silberstein 2016 Cell Stem Cell 6;19), we performed a competitive transplantation of Il18r1 -/- and WT bone marrow and measured T cell production, which showed no competitive advantage of Il18r1 -/- donor cells; this demonstrated that IL-18 does not directly regulate progenitor cells themselves, but rather, more likely acts via a bystander thymus-resident population. Within the thymus, IL-18R was expressed by highly radioresistant NK1.1 + NKT and NK cells. Depletion of both populations with anti-NK1.1 monoclonal antibody improved thymus cellularity in WT mice (Fig. 1A middle). Notably, NKT deficient CD1d -/- mice showed no defective repair which suggested that the depletion upon NK1.1 + cell depletion is largely mediated by NK cells. Depletion of NK1.1 + cells in Il18 -/- mice did not improve regeneration further, suggesting that NK-mediated suppression is IL-18 dependent. Given the known role of IL-18 in NK cell activation, we hypothesized that the HCT-conditioning resultant rise in IL-18 stimulates NK cells leading to “accidental” targeting of regeneration promoting cells. NK cell production of cytotoxic factors including IFNg, GzmB and Perforin increases following radiation conditioning, although only mice deficient for Perforin and not IFNg -exhibited improved thymus cellularity 7 days post HCT-conditioning (Fig 1A right). Further supporting this hypothesis, IL-18R +CD49b + NK cells isolated from the thymus 2-days post-irradiation induced more target cell death in head-to-head cytotoxicity assays compared to NK cells isolated pre-radiation (Fig 1B). Finally, we observe TEC downregulation of NK cytotoxicity inhibitory ligand MHC-I following radiation conditioning, suggesting that critical regeneration promoting stroma may be the targets of these activated NK cells. These findings suggest that, while necessary for successful transplantation, conditioning regimens may induce cytotoxicity of bystander NK cells which suppresses thymus recovery. Furthermore, we implicate conditioning induced immunogenic cell death and increased IL-18 in the stimulation of these suppressive cytotoxic cells and suggest that therapeutically targeting IL-18 and NK cell cytotoxicity may improve T cell reconstitution post-HCT.
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Limerick, Emily, and Allistair Abraham. "Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease." Journal of Clinical Medicine 11, no. 13 (July 3, 2022): 3856. http://dx.doi.org/10.3390/jcm11133856.
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One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD.
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Elsabbagh, Eman M., Osama Abunar, Ammar Habbal, Mohammad Tanbour, Ahmed Mansour, Mohamed Sarhan, Ahmed Elkaryoni, and Sherif M. Badawy. "Alternative-Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Pediatric Patients: A Systematic Review and Meta-Analysis." Blood 132, Supplement 1 (November 29, 2018): 5875. http://dx.doi.org/10.1182/blood-2018-99-119287.
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Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donor for patients with sickle cell disease (SCD) provides excellent curative potential with acceptable rates of graft rejection and other common post transplant complications. However, in the United States, only 18% of patients with SCD have an HLA-matched sibling donor. Hence, multiple studies adopted various strategies to figure out alternative donors with favorable outcomes. Poor engraftment, graft versus host disease (GVHD) and regimen related toxicities are the main obstacles following alternative-donor transplant. To overcome these complications, different modalities had been experimented targeting the source of the stem cell, CD34 and TNC cell counts, pre-transplant conditioning regimens and adding immunosuppressive drugs pre/post transplant. However, so far there is no worldwide consensus about robust strategy for alternative donor HSCT. Aim The aim of this review is to systematically evaluate the outcomes of alternative-donor HSCT in patients with SCD in pediatric population, and correlate the outcomes with experimented interventional regimens. Methods We searched PubMed, SCOPUS, Embase, Cochrane and Clinical trials.gov from 2000 till February 2018. We utilized the Systematic Reviews and Meta-Analyses guidelines for Preferred Reporting Results (PRISMA). Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality. Risk of bias in the included studies was assessed using ROBINS-I tool. Data of platelet/neutrophil recovery, acute/chronic GvHD incidence and overall survival were pooled in a single-arm meta-analysis approach. Results Of the 2886 records examined, 19 met predefined criteria. 16 studies were included in the meta-analysis. 12 clinical trials, 5 cohort observational studies and 2 case reports. All studies had a sample size <50. The pooled times of platelet and neutrophil recovery were 31.55 and 20.15 days, respectively. The pooled incidences of acute and chronic GvHD were 36.1% and 21.7, respectively (Figure 1). The pooled one-year overall survival was 90.3% and two-years was 88.3%. Neutrophil engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 16 days (7-32) compared to 23 days (12-42) after Myelo-ablative Conditioning, (P=0.013). Platelet engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 29 days (15-204) in comparison to 62 days (18-123) after Myelo-ablative Conditioning, (P=0.026). The median duration of neutrophil engraftment after mismatched related donors was 14 days (14-17), after unrelated donors was 14 days (9-25) , after haplo-identical transplantation was 14 days (12-16), after umbilical cord blood transplantation (UCBT) was 23 days (7-42), (P=0.001). The median duration of platelet engraftment after haplo-identical and mismatched related transplantation was 19 days, after matched unrelated donors was 19 days (18-24), after mismatched unrelated donors was 22 day (19-37) and after UCBT was 47 days (15-204), (P=.001). There was no significant difference in acute/chronic GvHD between different types of alternative donors but acute GvHD was significantly less in Myelo-ablative Conditioning compared to Reduced Intensity Conditioning (P=.036) Conclusion Our systematic review showed better outcomes with using Myelo-ablative Conditioning and post transplant cyclophosphamide in haplo-identical transplantation compared to using Reduced Intensity Conditioning. Adding pre-transplant immunosuppressive drugs in haplo-identical transplantation didn't significantly improve the outcomes. In unrelated donor no significant difference between Myelo-ablative Conditioning and Reduced Intensity Conditioning but adding Mesenchymal Stem Cell to the reduced intensity regimen improved the outcomes. In UCBT and mismatched related donors, Reduced Intensity Conditioning had better outcomes especially with high doses of TNC and CD34 cell counts and with applying Mesenchymal Stem Cell or adequate dose of Alemtuzumab. Randomized controlled trials are mandated to generate standardized regimen in the setting of alternative-donor HSCT. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Altmann, Daniel M., and Rosemary J. Boyton. "Reciprocal conditioning: T cells as regulators of dendritic cell function." Immunology 109, no. 4 (August 2003): 473–75. http://dx.doi.org/10.1046/j.1365-2567.2003.01698.x.
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Ebadi, Maryam, Xinyi Fan, Gary Schoch, Ted Gooley, Armin Rashidi, Stephen D. Smith, Mazyar Shadman, et al. "Total Body Irradiation Versus Chemotherapy-Only Conditioning in Autologous Hematopoietic Stem Cell Transplantation for Large B-Cell Lymphoma." Blood 142, Supplement 1 (November 28, 2023): 2224. http://dx.doi.org/10.1182/blood-2023-184728.
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Introduction Recent data suggest that compared with high-dose chemotherapy conditioning and autologous stem cell transplant (ASCT), CD19-chimeric antigen receptor (CAR) T-cell therapy as second-line therapy improves outcomes in patients with primary refractory or early relapsed large B-cell lymphoma (LBCL). However, more than half of patients will not attain a long-term remission with CAR T-cell therapy, and may subsequently be considered for ASCT, indicating an unmet need for alternative therapies including strategies to improve ASCT outcomes. Given that LBCL is radioresponsive, we evaluated whether total body irradiation (TBI)-based conditioning may improve outcomes compared to chemotherapy-only conditioning among LBCL patients who underwent peripheral blood ASCT at our institution. Methods We reviewed the records of adults with relapsed/refractory LBCL who underwent ASCT at Fred Hutch Cancer Center between 2012-2021. LBCL was categorized as de novo DLBCL, transformed DLBCL, and double-hit lymphoma (DHL). Patients with primary CNS lymphoma were excluded. Given that TBI is generally reserved for younger patients (≤ 60 years), we excluded patients in the chemo-only group older than the oldest patient in the TBI group (58.7 years) to reduce the bias due to age differences. The hazards for failure for progression-free survival (PFS) and for overall mortality (OM) were compared between TBI-based and chemo-only groups using Cox regression with adjustment for clinically important variables including age, sex, histology, LDH at ASCT, conditioning type, PET positivity at the time of ASCT and year of ASCT. LDH at ASCT, age and year of ASCT were modeled as continuous linear variables. Results Among 225 patients, we excluded 121 patients in the chemo-only group who were older than 58.7 years, leaving 104 patients for the analysis ( Table 1). A total of 48 (46%) patients received TBI-based and 56 (54%) received chemo-only conditioning. All patients in the TBI group received 12 Gy in 6-8 fractions. Most patients (n=46, 82.14%) in the chemo-only group received BEAM conditioning. Patients receiving TBI-based conditioning had more adverse features including male sex (72.9% vs 58.9%), DHL histology (31.3% vs 7.1%), and PET-positive disease at the time of ASCT (39.6% vs 23.2%). With a median follow-up of 51.2 months (range 1.3-134.2) among survivors, point estimates of PFS at 2 and 5 years were 74.3% and 66.3%, respectively among TBI patients and 68.5% and 64.0%, respectively among the chemo-only patients ( Figure 1). Time to engraftment was similar between the groups. On multivariable analysis, compared to chemo-only conditioning, TBI was not associated with improved PFS (TBI vs chemo-only: HR 1.02, 95%CI 0.45-2.31, P=0.96) or OS (HR 0.85, 95%CI 0.37-1.98, P=0.7). Predictors of worse PFS were PET positivity at the time of ASCT (HR 3.39, 95%CI 1.61-7.17, P < 0.01) and higher LDH (HR 1.0011, 95%CI 1.0002-1.0020, P=0.02). Similarly, both PET positivity (HR 3.12, 95%CI 1.47-6.63, P<0.01) and higher LDH (HR 1.0013, 95%CI 1.0003-1.0022, P <0.01) were associated with worse OS. Age, sex, histology and year of ASCT were not significant. Conclusions Despite worse prognostic factors, TBI-based conditioning yielded similar outcomes compared to chemo-only conditioning for patients with relapsed/refractory LBCL undergoing ASCT. These results confirm prior findings from a registry-based study. Although a proportion of patients may achieve a long-term remission with ASCT, other strategies are needed to improve ASCT outcomes.
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&NA;. "Conditioning regimen costs compared for cell transplants." Inpharma Weekly &NA;, no. 1602 (August 2007): 4. http://dx.doi.org/10.2165/00128413-200716020-00008.
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Aiuti, Alessandro, and Luigi Naldini. "Safer conditioning for blood stem cell transplants." Nature Biotechnology 34, no. 7 (July 2016): 721–23. http://dx.doi.org/10.1038/nbt.3629.
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Jurcic, Joseph G., and David A. Scheinberg. "Radionuclides as conditioning before stem cell transplantation." Current Opinion in Hematology 6, no. 6 (November 1999): 371. http://dx.doi.org/10.1097/00062752-199911000-00003.
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Barrett, A. John. "Conditioning regimens for allogeneic stem cell transplants." Current Opinion in Hematology 7, no. 6 (November 2000): 339–42. http://dx.doi.org/10.1097/00062752-200011000-00003.
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Wu, Kai Hong, Xu Ming Mo, Zhong Chao Han, and Bin Zhou. "Cardiac cell therapy: pre-conditioning effects in cell-delivery strategies." Cytotherapy 14, no. 3 (March 2012): 260–66. http://dx.doi.org/10.3109/14653249.2011.643780.
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Fischer, Lars, Olaf Penack, Chiara Gentilini, Eckhard Thiel, and Uharek Lutz. "Analysis of Factors Influencing Natural Killer (NK) Cell Activity during the Early Phase after Allogeneic Stem Cell Transplantation (SCT)." Blood 106, no. 11 (November 16, 2005): 2192. http://dx.doi.org/10.1182/blood.v106.11.2192.2192.
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Abstract Background: After allogeneic SCT, NK cell mediated cytotoxicity is an important defense mechanism against residual tumor cells and viral infections. Using a novel flow cytometric assay, which detects the lytic granule membrane protein CD107a as a marker for NK cell degranulation, we investigated the effect of in vivo T cell depletion and the type of conditioning on NK cell function in the early phase after transplantation. Methods: At day +30 and day +90 after allogeneic SCT with regular (n=14) and dose reduced conditioning (n=8), PBMCs were coincubated at 37°C for 3 h with the NK sensitive cell line HL60. 20μl of PE-Cy5 conjugated anti-CD107a monoclonal antibody (moAb) was added to each tube containing 400μl effector/target cell suspension (2x106 cells, E:T ratio 1:1) prior to incubation. After 1 hour, 10μl of monensin (2mM) was added. After incubation for 3 hours, the cells were stained with conjugated moAb (CD56, CD16, CD3) for flow cytometry. The percentage of CD107a expressing NK cells was assessed and the absolute number of degranulating NK cells /μl was calculated. Results were compared to values from 15 healthy controls. Results: Twenty two patients (pts.) were investigated. Fourteen pts. received a conventional conditioning regimen and eight a reduced intensity conditioning. T cell depletion was applied in 15/22 pts. (ATG n=12, alemtuzumab n=2, 1 OKT-3 n=1). The type of donor included MRD (n=7) and MUD (n=15). At day +30, the proportion of NK cells with cytotoxic activity (indicated by the mean percentage of degranulating CD107a+/CD56+ cells) was significantly reduced as compared to normal donors (2.6% vs. 5.6%, p<0.001). At day +90 the percentage of degranulating NK cells was still decreased compared to normal (3.5%, p=0.007). The predominant proportion of degranulating cells was in the CD56dim/CD16− subpopulation (mean 9.8%). After conventional conditioning, the mean percentage of CD107a+ cells was 1,9% at day +30, compared to 4,0% in patients with reduced intensity conditioning (p=0.21). The absolute number of degranulating NK cells was significantly reduced after conventional conditioning (4.1/μl vs. 19.8/μl, p=0.011). Interestingly, we found no influence of in vivo T cell depletion with ATG on the mean value for CD107a+ cells at day +30 (2.5% vs. 2.9%, p=0.77). Conclusion: Although the proportion of NK cells is increased after allogeneic SCT, our data suggest that the cytotoxic activity of these cells is considerably reduced. The absolute number of NK cells with cytotoxic activity is significantly higher after reduced intensity conditioning which may contribute to the effectiveness of these regimens. Antibody induced in vivo T cell depletion with ATG showed no impact on NK cell activity during the first two months post SCT.
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Iliev, I. D., E. Mileti, G. Matteoli, M. Chieppa, and M. Rescigno. "Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning." Mucosal Immunology 2, no. 4 (April 22, 2009): 340–50. http://dx.doi.org/10.1038/mi.2009.13.
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Thiele Orberg, Erik, Julius Clemens Fischer, Sascha Göttert, Florian Bassermann, and Hendrik Poeck. "Type I Interferon Signaling before Hematopoietic Stem Cell Transplantation Lowers Donor T Cell Activation Via Reduced Allogenicity of Recipient Cells." Blood 134, Supplement_1 (November 13, 2019): 4431. http://dx.doi.org/10.1182/blood-2019-128784.
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Background: Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterised. Methods: We applied selective RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Results: Using IFNAR1-deficient donor T and hematopoietic donor cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these respective cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c+ recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted T-cells after allo-HSCT. The reduced allogenicity of CD11c+ recipient cells was dependent on IFN-I signalling. Notably, this immunosuppressive function of DCs was restricted to a scenario of genotoxic tissue damage as neither RIG-I activation and IFN-I induction in naive (non-irradiated) mice altered allogeneic T cell activation. Conclusion: Our findings uncover a hitherto unknown IFN-I- and context dependent immunosuppressive function of dendritic cells. This needs to be considered in the development of IFN-I based therapeutic approaches to modulate donor T cell activation after allo-HSCT. Disclosures No relevant conflicts of interest to declare.
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Ward-Kavanagh, Lindsay, Timothy Cooper, and Todd Schell. "Host conditioning approach and choice of target epitope determine the success of adoptive T cell immunotherapy against oncogene-induced established tumors (P2068)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 132.24. http://dx.doi.org/10.4049/jimmunol.190.supp.132.24.
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Abstract Host conditioning regimens can dramatically enhance adoptive T cell-based therapies for some cancers. We investigated the unique and combined contributions of whole body irradiation (WBI) and agonist anti-CD40 conditioning to successful adoptive immunotherapy in a mouse model of autochthonous cancer. Line Rip1-Tag4 mice develop pancreatic islet cell tumors due to expression of the SV40 large T antigen oncogene from the rat insulin promoter. Using transfer of T cell receptor transgenic CD8+ T cells specific for two unique determinants in T antigen (designated TCR-I or TCR-IV), we demonstrate that successful control of established tumors in these mice is both regimen- and epitope-dependent. WBI conditioning alone minimally enhanced T cell accumulation and persistence, while anti-CD40 alone transiently enhanced the subdominant TCR-I but not the immunodominant TCR-IV response. Combining anti-CD40 with WBI conditioning enhanced the magnitude and duration of both T cell responses, but only TCR-I cells accumulated and persisted at high levels in the pancreas. Mice that received combined conditioning plus TCR-I transfer had an increased life span, and showed histological signs of anti-tumor immunity. Lack of therapeutic impact by TCR-IV T cells was associated with development of an unusual differentiation phenotype following antigen recognition in vivo. The results indicate that target selection and conditioning regimen dramatically influence the efficacy of adoptive T cell therapy.
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Zhang, Yintian, Min Dai, Ya Gao, Ying Xu, Weiru Li, Xiaoyin Bu, Jinman Zhong, et al. "DAC-Based Conditioning Regimen Versus Standard Conditioning Regimen for Myelodysplastic Syndrome." Blood 136, Supplement 1 (November 5, 2020): 31–32. http://dx.doi.org/10.1182/blood-2020-139518.
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B ackground : Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable way for Myelodysplastic syndromes (MDS). There are still some patients have a poor prognosis after transplantation, including high frequency of relapse, poor response to salvage therapy and short overall survival. This study aimed to investigate whether DAC-based conditioning regimen improves survival compared with standard conditioning regimen for MDS patients. Methods : One hundred and forty-seven patients with MDS were enrolled in this prospective multicenter study. Eligible patients were randomly assigned to DAC-based conditioning regimen or standard conditioning regimen before allo-HSCT in a 1:1 ratio. Patients in standard conditioning regimen group received busulfan (3.2 mg/kg/day on days -7 to -4) and cyclophosphamide (60 mg/kg/day on days -3 and -2) for allo-HSCT. DAC-based conditioning regimen comprising decitabine (20 mg/m2/day on days -14 to -10), busulfan (3.2 mg/kg/day on days -7 to -4), and cyclophosphamide (60 mg/kg/day on days -3 and -2). The primary endpoint was overall survival after randomization. This trial was registered at ClinicalTrials.gov (NCT 02744742). Results: The median time to neutrophil reconstitution was 12 (8-35) days and 12 (9-34) days in the DAC-based conditioning regimen and standard conditioning regimen groups, respectively (P=0.577). The median platelet reconstitution time was 14 (9-68) days and 14 (10-90) days in the DAC-based conditioning regimen and standard conditioning regimen groups, respectively (P=0.017). Median follow-up was 419 (range, 1-1697) days. Overall survival was longer for DAC-based conditioning regimen than for standard conditioning regimen (P=0.034). 3-year OS was 62% (95%CI 46-98%) in the DAC-based conditioning regimen group and 43% (95%CI 29-64%) in the standard conditioning regimen group. 3-year GRFS was 50% (95%CI 34-74%) and 39% (95%CI 26-58%) in the DAC-based conditioning regimen and standard conditioning regimen groups, respectively (P=0.183). 3-year relapse incidence was 12% (95%CI 3-11%) and 25% (95%CI 11-29%) in the DAC-based conditioning regimen and standard conditioning regimen groups, respectively (P=0.209). There were no significant differences in the incidence of graft-versus-host disease, the incidence of infections, and other adverse events between two groups. The treatment-related mortality rate at 3 years was 30% (95% CI 13-34%) and 45% (95% CI 30-67%) in DAC conditioning and standard conditioning group, respectively(P=0.061). Stratified and multivariable logistic regression analysis showed that DAC-based conditioning regimen is an independent favorable factor for OS for very poor risk patients (HR 0.42, 95% CI, 0.19-0.93, P= 0.03) and a protective factor for CIR for patients with high-risk karyotype(HR 0.56, 95% CI, 0.18-1.36, P=0.04). Conclusions: Our study demonstrates that DAC-based conditioning regimen had a survival benefit versus standard conditioning regimen in MDS patients, especially for very poor risk cases according to IPSS-R. DAC conditioning also has lower relapse for patients with high-risk karyotypes, shorter platelet reconstitution and tolerable toxicity. These results may contribute to improving the management of MDS patients for better survival. Disclosures No relevant conflicts of interest to declare.
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Bobreshova, Svetlana S., Svetlana V. Solov’eva, Evgeniya N. Bulasheva, O’lga N. Lepunova, Aleksandr D. Shalabodov, Andrey V. Elifanov, and Tat’yana A. Fisher. "White blood cell parameters and cortisol and thyroid-stimulating hormone levels in 4–6-year-old children doing cold conditioning." Journal of Medical and Biological Research, no. 3 (October 10, 2022): 232–40. http://dx.doi.org/10.37482/2687-1491-z111.
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The purpose of this paper was to analyse white blood cell parameters and certain hormone levels in children doing cold conditioning at a preschool. Materials and methods. The study group consisted of 4–6-year-old children (n = 12) who underwent cold conditioning 5 times a week according to a certain scheme of exposure to contrasting temperatures. The control group (4–6-year-old children; n = 12) was doing the usual kindergarten activities. Absolute and relative white blood cell count was determined; thyroid-stimulating hormone (TSH) and cortisol levels were studied using enzyme-linked immunosorbent assay. Results. Hormone levels in all the subjects were within normal limits and did not differ statistically significantly between the groups. The total white blood cell count in children of the conditioning group (7.81 ± 0.67∙109/l) was statistically significantly higher (p < 0.05) than in their peers from the control group (6.06 ± 0.50∙109/l). The increased white blood cell count in the conditioning group was due to the rise in absolute (p < 0.01) and relative (p < 0.001) monocyte count. At the same time, relative basophil count in children doing cold conditioning was lower (p < 0.01) than in the control group. In the conditioning group, we found a statistically significant correlation between TSH level and relative white blood cell count (r = 0.73, p < 0.01), between TSH level and relative neutrophil count, as well as between cortisol level and absolute white blood cell count (r = 0.61, p < 0.05) in the peripheral blood. The systematic character of cold conditioning contributed to the development of a certain stereotyped response to the stimulus. The research demonstrated that these comprehensive cold conditioning activities have been performed with adequate use of contrasting temperatures, resulting in stronger immune system, increased resistance and improved adaptive capabilities of the child body.
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Saraf, Santosh L., and Damiano Rondelli. "Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease." Journal of Clinical Medicine 8, no. 10 (October 1, 2019): 1565. http://dx.doi.org/10.3390/jcm8101565.
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Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and early mortality. Acute and chronic SCD-related complications increase with older age, and therapies are urgently needed to treat adults. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but has been used less frequently in adults compared to children. This is, in part, due to (1) greater chronic organ damage, limiting tolerability to myeloablative conditioning regimens, (2) a higher rate of HSCT-related complications in adults versus children with SCD, and (3) limited coverage by public and private health insurance. Newer approaches using nonmyeloablative and reduced-intensity conditioning HSCT regimens have demonstrated better safety and tolerability, with high rates of stable engraftment in SCD adults. This review will focus on the impacts of HSCT, using more contemporary approaches to SCD-related complications in adults.
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Rao, Kanchan, Persis J. Amrolia, Alison Jones, Catherine M. Cale, Paru Naik, Doug King, Graham E. Davies, H. Bobby Gaspar, and Paul A. Veys. "Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen." Blood 105, no. 2 (January 15, 2005): 879–85. http://dx.doi.org/10.1182/blood-2004-03-0960.
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Abstract The optimal approach to stem cell transplantation in children with immunodeficiency who lack a matched family donor is controversial. Unrelated donor stem cell transplantation gives equivalent outcome to mismatched family donor stem cell transplantation in severe combined immunodeficiency, whereas unrelated donors may be preferable in non–severe combined immunodeficiency children. However, unrelated donor stem cell transplantation with conventional conditioning regimens has been associated with significant treatment-related toxicity, particularly in non–severe combined immunodeficiency patients with preexisting organ dysfunction. We report the outcome of a series of 33 consecutive unrelated donor transplantations performed at our center in children with primary immunodeficiency using a reduced-intensity conditioning regimen between 1998 and 2001. We have compared these outcomes with a retrospective control cohort of 19 patients who underwent transplantation with myeloablative conditioning between 1994 and 1998. All children in both groups had primary engraftment. There was no statistical difference in the speed of immune reconstitution or incidence of graft-versus-host disease between the 2 groups. Overall survival was significantly better in the reduced-intensity conditioning group: 31 (94%) of 33 patients survived, compared with 10 (53%) of 19 in the myeloablative conditioning group (P = .014). We conclude that the reduced-intensity conditioning regimen results in improved survival and reduced transplantation-related mortality compared with myeloablative conditioning in high-risk patients undergoing unrelated donor transplantation.
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Bacher, Ulrike, Evgeny Klyuchnikov, Jeanette Carreras, Jennifer Le-Rademacher, Ginna G. Laport, Silvia Montoto, David G. Maloney, and Parameswaran Hari. "Conditioning Intensity in Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 118, no. 21 (November 18, 2011): 501. http://dx.doi.org/10.1182/blood.v118.21.501.501.
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Abstract Abstract 501 Non-myeloablative (NMC) and reduced intensity (RIC) conditioning approaches rely primarily on a graft-vs-lymphoma (GVL) effect and aim at reducing transplant-related mortality (TRM) associated with myeloablative conditioning (MAC). We analyzed outcomes for 396 adults (228 male) receiving alloHCT for DLBCL following MAC (n=165), RIC (n=143) or NMC (n=88) regimens between 2000 and 2009 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Conditioning regimens were classified using consensus criteria. Engraftment, cumulative incidences of acute and chronic graft-vs-host disease (GvHD), TRM, progression and probabilities of progression-free (PFS) and overall survival (OS) were compared between MAC and NMC/RIC. Common MAC regimens were cyclophosphamide (CY) + total body irradiation (TBI) (54%) and busulfan (BU) + CY (23%). Common RIC regimens were fludarabine (Flu) with melphalan (44%) or BU (39%) and for NMC, Flu with CY (48%) and low dose TBI (33%). Practice patterns changed with declining use of MAC regimens after 2003 (> 66% of total being MAC pre-2003 and <33% after). Donors were HLA matched siblings in 40%, 26%, 30% of MAC, RIC and NMC recipients, respectively, with 67% overall receiving unrelated donor (URD) grafts. Significant (p <0.05) baseline differences between the cohorts included: RIC and NMC recipients were older (54% and 58% >50 yrs vs 39% for MAC), more likely to have received prior autoHCT (36% and 51% vs 18%), prior radiation and more prior chemotherapy regimens (55 and 70% vs 44% with >3 regimens) than those with MAC. Recipients of RIC and NMC were less likely to have chemotherapy resistant disease (30% and 26% vs. 42% for MAC); and had a longer median interval from diagnosis to alloHCT (median 27 and 36 mo vs. 17 mo). Day 100 engraftment was more frequent in RIC and NMC recipients (99% and 97% with ANC >500/cu.mm vs. 88% for MAC, p <0.001). Acute (43–44%) and chronic GvHD incidence (37–42% at 5 years) was similar across the groups. Outcomes are summarized in Table 1. TRM at day +100 and at 5 years was significantly higher for MAC compared with RIC and NMC groups (See Table 1). Lymphoma relapse/progression at 5 years was significantly lower for MAC vs. RIC and NMC but 5 year PFS and OS at 5-years did not differ significantly. In multivariable analysis, NMC (HR 0.58, p=0.026) and later year of alloHCT (HR 0.49, p<0.001) were associated with lower TRM while Karnofsky status <90 (HR 1.51, p=0.011), chemo-resistant relapse (HR 2.79, p<0.001) and URD (HR 2.32, p<0.001) were associated with higher TRM. Higher incidence of relapse/progression was associated with NMC (HR 2.14, p=0.003), non-receipt of rituximab prior to alloHCT (HR 1.69, p=0.008) and chemo-resistant disease (HR 2.06, p=0.006). Conditioning intensity did not impact OS and PFS. In selected patients with advanced DLBCL, allogeneic HCT can induce long-term PFS irrespective of the intensity of conditioning with a lower incidence of TRM with RIC and NMC regimens. Due to increased toxicity, the use of MAC regimens has been declining in recent years. However, the incidence of RIC/NMC, risk of relapse/progression was concordantly higher in the RIC/NMC recipients so that survival did not differ significantly between conditioning regimens. Further studies are needed to clarify optimal conditioning strategies for advanced DLBCL aiming to further reduce TRM. Table 1: Parameter Intensity of Conditioning (95% CI) p-value MAC RIC NMC TRM @day +100 at 5 yrs 32% (25–39%) 24% (17–31%) 17% (10–26%) 0.029 56% (48–64%) 47% (38–56%) 36% (26–46%) 0.007 Relapse @ 5 yrs 26% (19–33%) 38% (30–46%) 40% (30–50%) 0.031 OS @ 5 yrs 18% (12–25%) 20% (13–29%) 26% (17–36%) 0.365 PFS @ 5 yrs 18% (12–24%) 15% (9–23%) 25% (16–34%) 0.309 Disclosures: Montoto: Genentech: Research Funding; Roche: Honoraria.
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Gilman, Andrew L., Michael J. Eckrich, Stacy Epstein, Carrie Barnhart, Mark Cannon, Tracy Fukes, Michelle Hyland, et al. "Alternative donor hematopoietic stem cell transplantation for sickle cell disease." Blood Advances 1, no. 16 (June 28, 2017): 1215–23. http://dx.doi.org/10.1182/bloodadvances.2017005462.
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Key Points A CD34-selected, T-cell–depleted alternative donor graft after a reduced conditioning regimen resulted in engraftment in patients with sickle cell. This approach was associated with a low incidence of acute and chronic graft-versus-host disease and very good survival.
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Krenger, Werner, Bruce R. Blazar, and Georg A. Holländer. "Thymic T-cell development in allogeneic stem cell transplantation." Blood 117, no. 25 (June 23, 2011): 6768–76. http://dx.doi.org/10.1182/blood-2011-02-334623.
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Abstract Cytoreductive conditioning regimens used in the context of allogeneic hematopoietic cell transplantation (HCT) elicit deficits in innate and adaptive immunity, which predispose patients to infections. As such, transplantation outcomes depend vitally on the successful reconstruction of immune competence. Restoration of a normal peripheral T-cell pool after HCT is a slow process that requires the de novo production of naive T cells in a functionally competent thymus. However, there are several challenges to this regenerative process. Most notably, advanced age, the cytotoxic pretransplantation conditioning, and posttransplantation alloreactivity are risk factors for T-cell immune deficiency as they independently interfere with normal thymus function. Here, we discuss preclinical allogeneic HCT models and clinical observations that have contributed to a better understanding of the transplant-related thymic dysfunction. The identification of the cellular and molecular mechanisms that control regular thymopoiesis but are altered in HCT patients is expected to provide the basis for new therapies that improve the regeneration of the adaptive immune system, especially with functionally competent, naive T cells.
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Klein Geltink, Ramon I., Joy Edwards-Hicks, Petya Apostolova, David O’Sullivan, David E. Sanin, Annette E. Patterson, Daniel J. Puleston, et al. "Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy." Nature Metabolism 2, no. 8 (August 2020): 703–16. http://dx.doi.org/10.1038/s42255-020-0256-z.
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Collin, Matthew P., Derek N. Hart, Graham H. Jackson, Gordon Cook, James Cavet, Stephen Mackinnon, and Anne M. Dickinson. "The Fate of Human Langerhans Cells in Hematopoietic Stem Cell Transplantation." Blood 106, no. 11 (November 16, 2005): 572. http://dx.doi.org/10.1182/blood.v106.11.572.572.
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Abstract The fate of Langerhans cells (LC) and other antigen-presenting cells (APC) in haematopoietic stem cell transplantation (HSCT), their depletion by conditioning regimens, reconstitution and chimerism are important factors in understanding graft versus host disease and the outcome of transplantation. Hitherto untested predictions in humans state that depletion of recipient LC may prevent acute graft versus host disease (GVHD), the acquisition of donor chimerism in LC may drive the evolution of clinical GVHD from acute to chronic and the persistence of recipient LC may explain late acute GVHD phenomena and donor lymphocyte infusion toxicity. Between April 2003 and June 2005 we obtained 184 skin biopsies from 76 patients at 4 UK centres. Using confocal microscopy of intact epidermal sheets to image up to 2000 LC at a time, we find that full intensity transplant (FIT) conditioning with TBI-based regimens or busulfan and cyclophosphamide depletes 55% of LC at day 0 (n 14; p 0.001). In contrast, fludarabine-based reduced intensity transplant (RIT) depletes only 9% of LC (n 23; p 0.061). A minimum LC density is reached at 14-21 days in both regimes with little difference at the nadir, suggesting that the effect on density at day 0 is primarily kinetic. Rapid recovery occurs by 40 days in the absence of acute cutaneous GVHD but is delayed beyond 100 days in the presence of GVHD (n 50; p 0.006) We assessed LC chimerism in sex-mismatched transplants by allowing single cells to migrate from small epidermal sheets in vitro and applying a two-step Giemsa/FISH assay. At 40 days median LC donor chimerism is 97% after FIT and 36.5% after RIT (n 11; p 0.004). At 100 days median donor chimerism is 100% after FIT and 97.5% after RIT (n 28; p 0.133.). The majority of transplants - 16/28 (57%) - achieve 100% LC donor chimerism at day 100 and all are at least 90%. Attainment of full donor chimerism at 100 days shows only a trend with FIT (p 0.133), and with complete myeloid chimerism in the blood (p 0.080) but is strongly associated with prior acute cutaneous GVHD (p 0.002). At one year post transplant it is possible to detect rare recipient cells in a minority of transplants (12/1746 interphase nuclei - less than 1%), confirming that LC may regenerate in the skin under quiescent conditions. In conclusion we find that: 1) recipient LC survive conditioning, especially after RIT, suggesting that targeted APC depletion might have potential as a novel means of preventing acute GVHD; 2) LC turnover is accelerated by full conditioning, complete myeloid chimerism and acute GVHD; 3) the majority of LC are donor-derived in all transplants at 100 days, consistent with the hypothesis that donor engraftment of APC drives the transition of acute to chronic GVHD. 4) there is little evidence using these conditioning regimens that acute GVHD or DLI-toxicity occurring after 100 days is related to the persistence of recipient APC.
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Matthes-Martin, Susanne, Anita Lawitschka, Gerhard Fritsch, Thomas Lion, Brigitte Grimm, Sabine Breuer, Heidrun Boztug, et al. "Stem cell transplantation after reduced-intensity conditioning for sickle cell disease." European Journal of Haematology 90, no. 4 (February 26, 2013): 308–12. http://dx.doi.org/10.1111/ejh.12082.
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Shizuru, Judith A. "Novel Conditioning Regimens for Blood Stem Cell Transplantation." Blood 130, Suppl_1 (December 7, 2017): SCI—21—SCI—21. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-21.sci-21.
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Hematopoietic stem cell (HSC) therapies rely on chemotherapy and/or radiation to overcome host barriers to permit cell engraftment and provide life-long donor derived hematopoiesis. In conventional allogeneic transplantation these modalities function to both suppress immune rejection and create sufficient niche space to allow HSC to engraft. For gene-corrected or gene-modified cells that are derived from autologous patient sources, access to the HSC niche constitutes the primary barrier. Non-genotoxic approaches are being developed with the goal to target molecules expressed on hematopoietic stem and progenitors. We have studied the use of monoclonal antibodies (mAbs) that target the molecule CD117, also known as cKit, to deplete endogenous stem cells and safely allow engraftment of purified HSC. CD117 is a cell surface molecule expressed at high levels on HSC and early myeloid progenitors as well as other non-hematopoietic cell types. It is a receptor tyrosine kinase that upon binding to its ligand, stem cell factor (SCF), propagates intracellular signaling pathways that regulate activities including cell survival, proliferation and differentiation. Studies in immune deficient mice showed that a single dose of anti-CD117 mAb transiently depletes HSC, creating a therapeutic window for donor HSC to engraft1. We have developed for use in clinical transplantation an anti-human CD117 (anti-hCD117) mAb. This antibody significantly inhibits in vitro proliferation of human HSC and effectively depletes human HSC in mice xenografted with human cord blood cells2, and is effective in depleting HSC and progenitors from the bone marrow of non-human primates (NHP). Although CD117 is expressed on non-hematopoietic cells including mast cells, melanocytes, and cells in the gastrointestinal tract, antibody administration in animals and in healthy human volunteers, show little to no off-target toxicity. We are currently testing in a Phase I clinical trial the anti-hCD117 mAb as the sole conditioning agent for the transplantation of children with severe combined immunodeficiency (SCID). We have observed that the effect of the mouse anti-CD117 mAb is more potent in immune deficient mice compared to immune sufficient wildtype mice as evidenced by markedly inferior HSC engraftment results in wildtype recipients. Thus, we are exploring next generation approaches to achieve deeper and more extended depletion of HSC and progenitors in immune competent animals. In vivo HSC clearance by the mouse anti-CD117 mAb is dependent on Fc-mediated antibody effector functions. We therefore tested combination therapy with anti-CD117 mAb plus biologic agents that inhibit CD47, a myeloid-specific immune checkpoint, with the goal to promote phagocytosis of target cells that bind the anti-CD117 mAb. The combined treatment led to elimination of >99% of host HSCs and robust multilineage blood reconstitution following HSC transplantation3. These studies show that a conditioning approach using anti-CD117 antibodies is feasible, and has the potential to replace genotoxic agents with targeted and safer biologic agents. 1. Czechowicz A, Kraft D, Weissman IL, et al, Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science. 2007; 318: 1296. 2. Logan AC, Czechowicz A, Kelley BV, et al. Anti-CD117 (c-Kit) monoclonal antibodies deplete human hematopoietic stem cells and facilitate their replacement in humanized NOD/SCID/IL2Rg-/- mice: A non-toxic conditioning regimen for allotransplantation. Blood . 2012; 120: 4099. 3. Chhabra A, Ring AM, Weiskopf K, et al.Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci Transl Med . 2016; 8: 351RA105. Disclosures No relevant conflicts of interest to declare.
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Zhang, Michelle M., and Ajay K. Gopal. "Radioimmunotherapy-Based Conditioning Regimens for Stem Cell Transplantation." Seminars in Hematology 45, no. 2 (April 2008): 118–25. http://dx.doi.org/10.1053/j.seminhematol.2008.02.002.
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Baker, K. Scott, and John E. Wagner. "Novel conditioning regimens and nonmyeloablative stem cell transplants." Current Opinion in Pediatrics 14, no. 1 (February 2002): 17–22. http://dx.doi.org/10.1097/00008480-200202000-00004.
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Estey, Elihu H. "Intensity of conditioning for allogeneic haemopoetic cell transplantation." Lancet Oncology 13, no. 10 (October 2012): 966–68. http://dx.doi.org/10.1016/s1470-2045(12)70374-1.
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Galler, Kerstin M., Rena N. D’Souza, Marianne Federlin, Adriana C. Cavender, Jeffrey D. Hartgerink, Stephanie Hecker, and Gottfried Schmalz. "Dentin Conditioning Codetermines Cell Fate in Regenerative Endodontics." Journal of Endodontics 37, no. 11 (November 2011): 1536–41. http://dx.doi.org/10.1016/j.joen.2011.08.027.
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Gojo, Satoshi, and Shunei Kyo. "Recipient Conditioning in Cell Transplantation for Cardiac Resurrection." Journal of Cardiac Failure 13, no. 6 (August 2007): S20—S21. http://dx.doi.org/10.1016/j.cardfail.2007.06.085.
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Contreras, Cristina F., Janel R. Long-Boyle, Kristin A. Shimano, Alexis Melton, Sandhya Kharbanda, Jasmeen Dara, Christine Higham, James N. Huang, Morton J. Cowan, and Christopher C. Dvorak. "Reduced Toxicity Conditioning for Nonmalignant Hematopoietic Cell Transplants." Biology of Blood and Marrow Transplantation 26, no. 9 (September 2020): 1646–54. http://dx.doi.org/10.1016/j.bbmt.2020.06.004.
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Aschan, Johan. "Risk assessment in haematopoietic stem cell transplantation: Conditioning." Best Practice & Research Clinical Haematology 20, no. 2 (June 2007): 295–310. http://dx.doi.org/10.1016/j.beha.2006.09.004.
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Gallicchio, Vincent S., and Emily McGill. "Stem cells in the treatment of sickle cell disease." Journal of Stem Cell Research & Therapeutics 6, no. 1 (February 17, 2020): 32–39. http://dx.doi.org/10.15406/jsrt.2020.06.00138.
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Sickle Cell Disease (SCD) is autosomal recessive disorder that is the result of a point mutation in the coding region of the beta globin gene. Polymerization of red blood cells with the sickle hemoglobin result in painful clinical symptoms and early death due to end organ failure. Improvement of treatment has extended the survival of adolescents into adulthood and offers relief of symptoms but does not offer a cure against the diagnosis being the inevitable cause of an early death. In addition, response to therapies vary between patients depending on their responsiveness and metabolism of medications. Hematopoietic stem cell transplantation offers reduction of recipient Hb S through replacing it with Hb A from the donor. Increased use of hematopoietic stem cell transplantation (HSCT) offers a curative therapy for patients with SCD that have access to an HLA-identical donor. However, limitations to indications for HSCT result due to associated toxicities with myeloablative conditioning and risk of graft failure. Reduced intensity and non-myeloablative conditioning look at reducing associated toxicities and making HSCT readily available for the adult population through mixed chimerism. In addition, clinical trials looking at alternative donors and gene therapies expand the availability of HSCT for the vast majority of patients without an HLA-identical donor.
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Vriesendorp, Huib M. "Aims of conditioning." Experimental Hematology 31, no. 10 (October 2003): 844–54. http://dx.doi.org/10.1016/s0301-472x(03)00229-7.
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Nickel, Robert Sheppard, Jacqueline Y. Maher, Michael H. Hsieh, Meghan F. Davis, Matthew M. Hsieh, and Lydia H. Pecker. "Fertility after Curative Therapy for Sickle Cell Disease: A Comprehensive Review to Guide Care." Journal of Clinical Medicine 11, no. 9 (April 21, 2022): 2318. http://dx.doi.org/10.3390/jcm11092318.
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Curative therapy for sickle cell disease (SCD) currently requires gonadotoxic conditioning that can impair future fertility. Fertility outcomes after curative therapy are likely affected by pre-transplant ovarian reserve or semen analysis parameters that may already be abnormal from SCD-related damage or hydroxyurea treatment. Outcomes are also likely affected by the conditioning regimen. Conditioning with myeloablative busulfan and cyclophosphamide causes serious gonadotoxicity particularly among post-pubertal females. Reduced-intensity and non-myeloablative conditioning may be acutely less gonadotoxic, but more short and long-term fertility outcome data after these approaches is needed. Fertility preservation including oocyte/embryo, ovarian tissue, sperm, and experimental testicular tissue cryopreservation should be offered to patients with SCD pursing curative therapy. Regardless of HSCT outcome, longitudinal post-HSCT fertility care is required.
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Mielcarek, Marco, Paul J. Martin, David G. Maloney, Rainer Storb, and Brenda M. Sandmaier. "Outcomes among Patients with Recurrent High-Risk Hematologic Malignancy after Nonmyeloablative Versus Myeloablative Allogeneic Hematopoietic Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 262. http://dx.doi.org/10.1182/blood.v108.11.262.262.
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Recurrence of high risk hematologic malignancy after allogeneic hematopoietic cell transplantation (HCT) indicates the persistence of malignant cells that are resistant to the conditioning regimen given before HCT and the immunologic effects of donor cells after HCT. Early recurrence of high-risk hematologic malignancy after myeloablative conditioning is associated with a very poor prognosis. Given the minimal exposure to cytotoxic therapy during and the lower burden of regimen-related toxicity after nonmyeloablative preparative regimens, we hypothesized that relapse-directed interventions would be more effective for patients with high-risk malignancy after HCT with nonmyeloablative conditioning compared to myeloablative conditioning. We retrospectively analyzed outcomes among 195 patients treated for acute leukemia (AML, n=123; ALL, n=28), chronic myeloid leukemia beyond accelerated phase (n=21), or high-risk myelodysplastic syndromes (n=23) that recurred after HCT with myeloablative or nonmyeloablative conditioning between 1995 and 2004. Relapse-directed interventions included withdrawal of immunosuppression (WIS), chemotherapy, and donor lymphocyte infusion (DLI) used singly or in combination as allowed by clinical circumstances. Interventions were used for 68% and 87% of patients who had recurrence < 100 days after HCT with myeloablative or nonmyeloablative conditioning, respectively, and for 83% and 95% of those who had recurrence ≥ 100 days after HCT. The incidence rates of life-threatening GVHD and remission were 6% and 25% among patients with myeloablative conditioning, compared to 19% and 26% among those with nonmyeloablative conditioning (Table 1). The incidence of remission was higher among patients who had recurrence ≥ 100 days after HCT as compared to < 100 days after HCT (p = 0.04). Contrary to our hypothesis, interventions were not more effective among patients with nonmyeloablative conditioning compared to myeloablative conditioning, as measured by remission rates (Table 1) or survival. The 2-year survival rates among patients with recurrence < 100 days after HCT were 4% and 0% among patients who had myeloablative and nonmyeloablative conditioning regimens, respectively. The corresponding 2-year survival rates among patients with recurrence ≥ 100 days after HCT were 12% and 5%. In summary, with either myeloablative or nonmyeloablative conditioning regimens, limited clinical benefit is gained from the interventions typically used for management of early recurrent high-risk hematologic malignancy after HCT. Thus, innovative and more effective strategies are needed for treatment of recurrent high-risk malignancy after allogeneic HCT. Interventions and outcomes among patients treated for recurrent high-risk hematologic malignancy after allogeneic HCT Total WIS Chemo DLI GVHD* CR *GVHD, life-threatening graft-versus-host disease; CR, complete remission. **Recurrence was detected at 100–200 days from HCT in 9 cases and >200 days in 11 cases. Myeloablative conditioning Recurrence < Day 100, n (%) 87 78 51 11 6 16 (90) (59) (13) (7) (18) Recurrence ≥ Day 100–200, n (%) 65 50 55 13 3 21 (77) (85) (20) (5) (32) Non-myeloablative conditioning Recurrence < Day 100, n (%) 23 18 13 5 5 5 (78) (57) (22) (22) (22) Recurrence ≥ Day 100, n (%)** 20 13 15 2 3 6 (65) (75) (10) (15) (30)
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Srinivasan, Anand, David Crawford, Sandra Bajana, Carrie Yuen, Xiao-Hong Sun, and Rikin Shah. "Recovery of innate lymphoid cells after allogeneic stem cell transplant: A single institution pilot study." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 87.25. http://dx.doi.org/10.4049/jimmunol.204.supp.87.25.
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Abstract The response of Innate Lymphoid Cells (ILCs) to conditioning regimens and subsequent recovery in the setting of allogeneic hematopoietic stem cell transplant (aHSCT) in pediatric patients is not known. The impact of this recovery pattern on graft versus host disease (GVHD) has not been prospectively studied. We aim to study the recovery of ILCs after aHSCT in children and discover its role in GVHD. Pediatric patients undergoing aHSCT were enrolled in a prospective translational study since May 2019. Patients blood were analysed by flow cytometry at following time points: prior to the conditioning regimen, weekly starting on day 0 until +30 (+/− 3 days), then +60, +90 and +180 days. Ten patients have been enrolled to date - demographics: median age 9.5 years; 4 malignant, 6 non-malignant; haploidentical donor (n=1), matched sibling (n=3), unrelated (n= 6). Graft source was bone marrow for all patients. Most common conditioning regimen was fludarabine, busulfan and rabbit antithymocyte globulin (40%). GVHD prophylaxis for most patients was tacrolimus with mini-methotrexate (90%). We saw substantial drop in number of ILCs in response to conditioning regimen in all patients, with nadir on +14 that plateaued through +30, followed by a spike on +60 and return to normal levels by +90. Similar trend was seen in type 1 ILCs (Lin− CD127+ CRTH2− CD117−) but showed a slower drop, reaching nadir on +21 with slow recovery by +60. Type 2 ILCs (Lin− CD127+ CRTH2+) and Type 3 ILCs (Lin− CD127+ CRTH2-ve CD117+) however showed a small increase on +7 compared to day 0 with both cell types recovering by +60. We showed that it is feasible to prospectively study the recovery of ILCs after aHSCT. Continued enrollment will allow us to evaluate the correlation between ILCs and GVHD.
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de Kerchove, Alexis J., and Menachem Elimelech. "Impact of Alginate Conditioning Film on Deposition Kinetics of Motile and Nonmotile Pseudomonas aeruginosa Strains." Applied and Environmental Microbiology 73, no. 16 (June 15, 2007): 5227–34. http://dx.doi.org/10.1128/aem.00678-07.
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ABSTRACT The initial deposition of bacteria in most aquatic systems is affected by the presence of a conditioning film adsorbed at the liquid-solid interface. Due to the inherent complexity of such films, their impact on bacterial deposition remains poorly defined. The aim of this study was to gain a better understanding of the effect of a conditioning film on the deposition of motile and nonmotile Pseudomonas aeruginosa cells in a radial stagnation point flow system. A well-defined alginate film was used as a model conditioning film because of its polysaccharide and polyelectrolyte nature. Deposition experiments under favorable (nonrepulsive) conditions demonstrated the importance of swimming motility for cell transport towards the substrate. The impact of the flagella of motile cells on deposition is dependent on the presence of the conditioning film. We showed that on a clean substrate surface, electrostatic repulsion governs bacterial deposition and the presence of flagella increases cell deposition. However, our results suggest that steric interactions between flagella and extended polyelectrolytes of the conditioning film hinder cell deposition. At a high ionic strength (100 mM), active swimming motility and changes in alginate film structure suppressed the steric barrier and allowed conditions favorable for deposition. We demonstrated that bacterial deposition is highly influenced by cell motility and the structure of the conditioning film, which are both dependent on ionic strength.
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Baron, Frederic, Brenda M. Sandmaier, Ted Gooley, Paul L. Martin, Mary E. D. Flowers, Michael L. Linenberger, Rainer F. Storb, Frederick R. Appelbaum, and Shelly Heimfeld. "Higher Doses of Transplanted T and B Cells Are Associated with Greater Incidence of Extensive Chronic GVHD after PBSC Transplantation from HLA-Identical Sibling Donors." Blood 110, no. 11 (November 16, 2007): 1077. http://dx.doi.org/10.1182/blood.v110.11.1077.1077.
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Abstract Background. We investigated the impact of graft composition on GVHD in 1520 allogeneic transplant recipients given PBSC. Methods. Graft composition was determined by FACS analyses and expressed as cells/kg of recipient weight. Cell types were defined as follows: CD3+ T cell (CD3+CD56−), CD4+ T cell (CD3+CD4+), CD8+ T cell (CD3+CD8+), natural killer (NK) cell (CD3−CD56+), NK/T cell (CD3+CD56+), B cell (CD20+), monocyte (CD14+), and CD34+ cells (CD34+CD14−). Cell doses were modeled as continuous linear variables or by quartiles. Cox (for chronic) and logistic (for acute) regression models were adjusted for conditioning regimen intensity, pt age, female donor to male recipient vs. other gender combination, and disease risk. Results. The median age among all pts was 52 (45 among myeloablative, 57 among nonmyeloablative); 27% of pts were male transplanted from a female donor; 66% of pts had high-risk disease; 49% were transplanted from an alternative donor (47% unrelated, 2% mismatched sibling); 51% received a nonmyeloablative conditioning. Table 1 shows graft composition and GVHD incidences according to donor type and conditioning intensity. There were no statistically significant associations between cell dose and acute GVHD, although there was a suggestion that the association of NK/T cell was dependent on conditioning. In particular, increasing NK/T cells were associated with an increased probability of grades 2–4 GVHD among myeloablative pts (p=.03) but not among nonmyeloablative pts. There were no statistically significant associations between cell dose and chronic GVHD, but several cell types showed evidence of an interaction between donor and cell dose. In particular, increasing B cells and CD3+, CD4+, and CD8+ T cells were associated with an increased risk of chronic GVHD among pts with an HLA-identical donor (p=.006, p=.0003, p=.0002, p=.02, respectively) while the associations among alternative donors were in the opposite direction and were not statistically significant (p=.68, p=.26, p=.44, and p=.15, respectively). Lack of correlation in the alternative donor group may reflect differences in T-cell responses to the greater minor histocompatability divergence, or changes in T-cell functionality associated with the dose of G-CSF (higher in sibling donors) used for mobilization. Increasing CD34+ cells was not statistically associated with chronic GVHD in either myeloablative (negative association, p=.10) or nonmyeloablative (positive association, p=.11) pts. Conclusions. Higher numbers of transplanted T and B cells were associated with an increased risk of extensive chronic GVHD in pts given grafts from HLA-identical siblings. Increasing CD34+ cells were not associated with a statistically significant increase in chronic GVHD. Further analyses looking at other clinical outcomes such as survival are forthcoming. Table 1. Graft composition and GVHD according to conditioning intensity and donor type Nonmyeloablative conditioning and HLA-id sibling Myeloablative conditioning and HLA-id sibling Nonmyeloablative conditioning and alternative donor Myeloablative conditioning and alternative donor Median # of T cell transplanted (× 108/Kg) 3.4 2.5 2.5 2.8 Median # of CD34+ cell transplanted (× 106/Kg) 8.6 7.5 6.9 7.5 Incidence of grade II–IV acute GVHD (%) 47 66 61 81 Incidence of extensive chronic GVHD (%) 40 54 41 49
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Erotocritou, P., H. Ahmed, S. S. Patel, I. Shergill, H. R. Patel, P. M. Shah, and M. Arya. "Nonmyeloablative Allogeneic Stem-Cell Transplantation for Metastatic Renal Cell Cancer: A Review and Update." Scientific World JOURNAL 6 (2006): 2519–28. http://dx.doi.org/10.1100/tsw.2006.391.
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Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy and radiotherapy. However, immunotherapy appears to be effective in 15—20% of cases, with interleukin-2 becoming the standard therapy for this disease. As a consequence of the immune susceptibility of RCC, other avenues of immunotherapy are being explored, such as nonmyeloablative allogeneic stem cell transplantation (NST). A number of trials have shown NST to be effective in varying degrees, causing partial or complete regression. Although nonmyeloablative conditioning is safer than myeloablative conditioning, its role has yet to be clearly proven as many studies have shown variable effect. Alongside this limitation, transplant-related toxicity also forms obstacles. Regardless of the limitation of NST, further refinement of the technique, with appropriate patient selection, may lead to this being an effective therapeutic choice for a significant number of individuals.
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Reston, James T., Stacey Uhl, Jonathan R. Treadwell, Richard A. Nash, and Karen Schoelles. "Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review." Multiple Sclerosis Journal 17, no. 2 (October 4, 2010): 204–13. http://dx.doi.org/10.1177/1352458510383609.
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Background and objectives: The purpose of this systematic review was to evaluate the safety and efficacy of autologous hematopoietic cell transplantation in patients with progressive multiple sclerosis (MS) refractory to conventional medical treatment. Methods: Eight case series met our a priori inclusion criteria for the primary outcome of progression-free survival. Individual study quality was rated using an 11-item scale for case series. The strength of the overall body of evidence for each outcome was rated using a system developed by the ECRI Institute. Data from different studies were statistically combined using meta-analysis. An additional six studies were included for a summary of mortality and morbidity. Results: For secondary progressive MS, immunoablative therapy with autologous bone marrow/peripheral blood stem cell transplantation was associated with higher progression-free survival (up to 3 years following treatment) when using intermediate-intensity conditioning regimens compared with high-intensity conditioning regimens. The evidence was insufficient to determine whether the treatment was effective in patients with other types of MS. Treatment-related mortality was about 2.7%. Conclusions: Patients with secondary progressive MS refractory to conventional medical treatment have longer progression-free survival following autologous stem cell transplantation with intermediate-intensity conditioning regimens than with high-intensity conditioning regimens.
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Tian, Chen, Yueyang Li, M. James You, Zhigang Zhao, Yizhuo Zhang, and Yafei WANG. "Modified Conditioning Regimen with Idarubicin Prior to Autologous Hematopoietic Stem Cell Transplantation in B-Cell Non-Hodgkin Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5349. http://dx.doi.org/10.1182/blood-2019-122089.
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High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) has become a standard consolidation treatment for patients with invasive lymphoma. The combination of cyclophosphamide, carmustine, and etoposide (CBV) is a commonly used conditioning regimen prior to auto-HSCT for patients with invasive lymphoma. Many modifications of the CBV regimen, including the addition of idarubicin, have been employed, with varying results. We retrospectively analyzed the clinical characteristics and treatment outcomes of 36 patients with invasive B-cell non-Hodgkin lymphoma treated with a conditioning regimen prior to auto-HSCT between January 2015 and June 2018. For our analysis, the patients were divided into two groups: one group received the classic CBV conditioning regimen and the other group received idarubicin at a dose of 8 mg/m2 for 3 days in addition to the CBV regimen. Overall survival (OS), median progression-free survival (PFS), adverse reactions, and hematopoietic reconstitution time were compared between the two groups. OS and PFS were analyzed using the Kaplan-Meier method, and the log-rank test was used for comparison between groups. Cox regression was used for multivariable analysis of other clinical factors. The median follow-up time was 29 months. Among the 36 patients in the cohort, 19 were male and 17 were female, with a male-to-female ratio of 1.12 to 1. The median age of onset was 39.5 years; 18 patients were older than 40 years and 18 were younger than 40 years. Twenty-six patients (72%) had an international prognostic index score of 0-2 and 10 patients (28%) had a score of 3-5. According to Ann Arbor staging criteria, 9 patients (25%) had stage I-II disease and 27 patients (75%) had stage III-IV disease. A total of 21 patients achieved complete remission and 15 patients achieved partial remission before transplantation. There were no significant differences between the groups in terms of neutrophil counts (P = 0.795) or platelet reconstitution time (P = 0.551). Also, there was no difference in adverse reactions between the two groups, suggesting that the addition of idarubicin to the conditioning regimen did not aggravate adverse reactions. OS and PFS were significantly longer in the idarubicin group than among patients who did not receive idarubicin. In the multivariable analysis, the use of idarubicin and complete remission state before auto-HSCT were associated with improved prognosis. These results indicate that the use of idarubicin with the CBV conditioning regimen prior to auto-HSCT is a safe and effective choice for patients with invasive B-cell non-Hodgkin lymphoma. Keywords: B-cell non-Hodgkin lymphoma; conditioning regimen; autologous hematopoietic stem cell transplantation; idarubicin Disclosures No relevant conflicts of interest to declare.
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Buchholz, Stefanie, Alexander Woywodt, Johanna Scheer, Lothar Hambach, Haytham Kamal, Hermann Haller, Marion Haubitz, Arnold Ganser, Bernd Hertenstein, and Mario von Depka. "Hemostatic Alterations in Patients Undergoing Hematopoietic Stem Cell Transplantation." Blood 104, no. 11 (November 16, 2004): 985. http://dx.doi.org/10.1182/blood.v104.11.985.985.
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Abstract Damage of endothelial cells (EC) is known to be involved in pathogenesis of microangiopathy, hepatic veno-occlusive disease, sepsis, capillary leak syndrome, and acute or chronic graft-versus-host disease (GvHD) as major causes of morbidity and mortality in patients after hematopoietic stem-cell transplantation (HSCT). We recently demonstrated in 39 patients undergoing allogeneic stem cell transplantation that numbers of circulating EC (CEC) increased significantly after conditioning regimens and that patients treated with reduced intensity conditioning (RIC) showed significantly lower cell numbers (Woywodt et al., Blood, 2004 May 1;103(9):3603-5). Here we report on the measurement of plasma levels of von Willebrand factor (vWF), thrombomodulin (TM), PAI-I and TAFI in the course of HSCT. Measurement of vWF, TM, PAI-I and TAFI was performed in the 39 patients (20 male, 19 female; n = 21: HLA-matched unrelated donor; n = 18: related donors). Blood samples were collected before starting conditioning regimen (day −7), the day before transplantation (day −1) and at day +7, +14 and +21 after transplantation. 28 patients received a conventional regimen with cyclophosphamide (120 mg/kg) and either total body irradiation with 12 Gy (n = 14) or busulfan (16 mg/kg, n = 14). 11 patients undergoing stem-cell transplantation were treated with reduced intensity conditioning with fludarabine (150 mg/m²) and busulfan (8 mg/kg body) or melphalan (120 mg/m²). Median baseline vWF was elevated (262%, range 68–612, normal range: 50–150). Median baseline PAI-I (11.3 U/l; range 1.8–34.4; normal range: < 20) and median baseline TAFI (90%; range 46–126; normal range: 70–120) were within normal limits. TM level was lower than normal values (median 3.95 ng/ml; range 2.69–9.36; normal range: 6.6–10.6). Levels of vWF increased after conditioning regimen and remained elevated until day +21 (day −1: median 262; day+7: 268; day +14: 327; day +21: 374; p < 0.01). Median TM remained low at all time points (day −1: median 4.26; day +7: 3.86; day +14: 3.97; day +21: 4.52). Levels of TAFI remained unchanged (day −1: median 82; day +7: median 91, day +14: median 88; day +21: median 89). There were also no differences in levels of PAI-I before or after conditioning regimen or after transplantation (day −1: median 11.4, day +7: median 10.8, day + 14: median 14, day + 21: median 11.8). There was no significant difference in vWF in patients undergoing reduced intensity conditioning compared to patients treated with conventional regimens. Interestingly, there was no correlation between the endothelial markers as vWF and TM and numbers of CEC. Our data indicate that significant alterations of the hemostatic system occur in patients undergoing HSCT. Further studies are warranted to define the clinical role of both, hemostatic alterations and CEC in the course of HSCT.