Browsing by Subject "Transplantation conditioning"

Now showing 1 - 3 of 3
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    A biomarker panel for risk of early respiratory failure following hematopoietic cell transplantation
    (American Society of Hematology, 2022) Rowan, Courtney M.; Smith, Lincoln; Sharron, Matthew P.; Loftis, Laura; Kudchadkar, Sapna; Duncan, Christine N.; Pike, Francis; Carpenter, Paul A.; Jacobsohn, David; Bollard, Catherine M.; Cruz, Conrad Russell Y.; Malatpure, Abhijeet; Farag, Sherif; Renbarger, Jamie; Little, Morgan R.; Gafken, Phillip R.; Krance, Robert A.; Cooke, Kenneth R.; Paczesny, Sophie; Pediatrics, School of Medicine
    Plasma biomarkers associated with respiratory failure (RF) following hematopoietic cell transplantation (HCT) have not been identified. Therefore, we aimed to validate early (7 and 14 days post-HCT) risk biomarkers for RF. Using tandem mass spectrometry, we compared plasma obtained at day 14 post-HCT from 15 patients with RF and 15 patients without RF. Six candidate proteins, from this discovery cohort or identified in the literature, were measured by enzyme-linked immunosorbent assay in day-7 and day-14 post-HCT samples from the training (n = 213) and validation (n = 119) cohorts. Cox proportional-hazard analyses with biomarkers dichotomized by Youden's index, as well as landmark analyses to determine the association between biomarkers and RF, were performed. Of the 6 markers, Stimulation-2 (ST2), WAP 4-disulfide core domain protein 2 (WFDC2), interleukin-6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), measured at day 14 post-HCT, had the most significant association with an increased risk for RF in the training cohort (ST2: hazard ratio [HR], 4.5, P = .004; WFDC2: HR, 4.2, P = .010; IL-6: HR, 6.9, P < .001; and TFNR1: HR, 6.1, P < .001) and in the validation cohort (ST2: HR, 23.2, P = .013; WFDC2: HR, 18.2, P = .019; IL-6: HR, 12.2, P = .014; and TFNR1: HR, 16.1, P = .001) after adjusting for the conditioning regimen. Using cause-specific landmark analyses, including days 7 and 14, high plasma levels of ST2, WFDC2, IL-6, and TNFR1 were associated with an increased HR for RF in the training and validation cohorts. These biomarkers were also predictive of mortality from RF. ST2, WFDC2, IL-6 and TNFR1 levels measured early posttransplantation improve risk stratification for RF and its related mortality.
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    CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation
    (Oxford University Press, 2020-07) Singh, Pratibha; Mohammad, Khalid S.; Pelus, Louis M.; Microbiology and Immunology, School of Medicine
    The bone marrow (BM) microenvironment/niche plays a key role in regulating hematopoietic stem and progenitor cell (HSPC) activities; however, mechanisms regulating niche cell function are not well understood. In this study, we show that niche intrinsic expression of the CXCR4 chemokine receptor critically regulates HSPC maintenance during steady state, and promotes early hematopoietic regeneration after myeloablative irradiation. At steady state, chimeric mice with wild-type (WT) HSPC and marrow stroma that lack CXCR4 show decreased HSPC quiescence, and their repopulation capacity was markedly reduced. Mesenchymal stromal cells (MSC) were significantly reduced in the BM of CXCR4 deficient mice, which was accompanied by decreased levels of the HSPC supporting factors stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF). CXCR4 also plays a crucial role in survival and restoration of BM stromal cells after myeloablative irradiation, where the loss of BM stromal cells was more severe in CXCR4-deficient mice compared to WT mice. In addition, transplantation of WT donor HSPC into CXCR4-deficient recipient mice demonstrated reduced HSPC homing and early hematopoietic reconstitution. We found that CXCR4 signaling attenuates irradiation-induced BM stromal cell loss by upregulating the expression of the antiapoptotic protein Survivin via the PI3K pathway. Our study suggests that SDF-1-CXCR4 signaling in the stromal microenvironment cells plays a crucial role in maintenance of HSPCs during homeostasis, and promotes niche regeneration and early hematopoietic reconstitution after transplantation. Modulation of CXCR4 signaling in the HSPC microenvironment could be a means to enhance hematopoietic recovery after clinical hematopoietic cell transplantation.
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    Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
    (Elsevier, 2020-08) Im, Annie; Rashidi, Armin; Wang, Tao; Hemmer, Michael; MacMillan, Margaret L.; Pidala, Joseph; Jagasia, Madan; Pavletic, Steven; Majhail, Navneet S.; Weisdorf, Daniel; Abdel-Azim, Hisham; Agrawal, Vaibhav; Al-Homsi, A. Samer; Aljurf, Mahmoud; Askar, Medhat; Auletta, Jeffery J.; Bashey, Asad; Beitinjaneh, Amer; Bhatt, Vijaya Raj; Byrne, Michael; Cahn, Jean-Yves; Cairo, Mitchell; Castillo, Paul; Cerny, Jan; Chhabra, Saurabh; Choe, Hannah; Ciurea, Stefan; Daly, Andrew; Perez, Miguel Angel Diaz; Farhadfar, Nosha; Gadalla, Shahinaz M.; Gale, Robert; Ganguly, Siddhartha; Gergis, Usama; Hanna, Rabi; Hematti, Peiman; Herzig, Roger; Hildebrandt, Gerhard C.; Lad, Deepesh P.; Lee, Catherine; Lehmann, Leslie; Lekakis, Lazaros; Kamble, Rammurti T.; Kharfan-Dabaja, Mohamed A.; Khandelwal, Pooja; Martino, Rodrigo; Murthy, Hemant S.; Nishihori, Taiga; O'Brien, Tracey A.; Olsson, Richard F.; Patel, Sagar S.; Perales, Miguel-Angel; Prestidge, Tim; Qayed, Muna; Romee, Rizwan; Schoemans, Hélène; Seo, Sachiko; Sharma, Akshay; Solh, Melhem; Strair, Roger; Teshima, Takanori; Urbano-Ispizua, Alvaro; Van der Poel, Marjolein; Vij, Ravi; Wagner, John L.; William, Basem; Wirk, Baldeep; Yared, Jean A.; Spellman, Steve R.; Arora, Mukta; Hamilton, Betty K.; Medicine, School of Medicine
    Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.