Browsing by Subject "Hematopoietic stem cell transplantation"

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    237: Unrelated Donor Cord Blood Stem Cell Transplantation for Leukocyte Adhesion Deficiency (LAD)
    (Elsevier, 2008-02-01) Robertson, K.A.; Goebel, W.S.; Renbarger, J.L.; Jude, V.; Gowan, D.; Towell, P.; Lorch, C.; Collura, J.; Haut, P.R.; Medicine, School of Medicine
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    A randomized double-blind placebo-controlled trial of intravenous thiamine for prevention of delirium following allogeneic hematopoietic stem cell transplantation
    (Elsevier, 2021) Nakamura, Zev M.; Deal, Allison M.; Park, Eliza M.; Quillen, Laura J.; Chien, Stephanie A.; Stanton, Kate E.; McCabe, Sean D.; Heiling, Hillary M.; Wood, William A.; Shea, Thomas C.; Rosenstein, Donald L.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Objective: To determine if high dose intravenous (IV) thiamine can prevent delirium during hospitalization following allogeneic HSCT. Secondarily, we evaluated the effects of high dose IV thiamine on thiamine levels and explored risk factors for delirium. Methods: Randomized, double-blind, placebo-controlled trial in patients undergoing allogeneic HSCT at a U.S. academic medical center between October 2017 and March 2020. 64 participants were randomized 1:1 to thiamine 200 mg IV three times daily for 7 days or placebo. We used the Delirium Rating Scale to assess for delirium. Delirium incidence was compared between groups using the chi-square test. Group differences in time to onset and duration of delirium were compared using the Kaplan-Meier method. Fisher's Exact and Wilcoxon Rank Sum tests were used to examine associations between pre-transplantation variables and delirium. Results: 61 participants were analyzed. Delirium incidence (25% vs. 21%, Chi-square (df = 1) = 0.12, p = 0.73), time to onset, duration, and severity were not different between study arms. Immediately following the intervention, thiamine levels were higher in the thiamine arm (275 vs. 73 nmol/L, t-test (df = 57) = 13.63, p < 0.0001), but not predictive of delirium. Variables associated with delirium in our sample included disease severity, corticosteroid exposure, infection, and pre-transplantation markers of nutrition. Conclusion: High dose IV thiamine did not prevent delirium in patients receiving allogeneic HSCT. Given the multiple contributors to delirium in this population, further research regarding the efficacy of multicomponent interventions may be needed.
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    Allogeneic T cells cause acute renal injury after hematopoietic cell transplantation
    (American Society of Hematology, 2023) Miyata, Masahiro; Matsuki, Eri; Ichikawa, Kazunobu; Takehara, Tomohiro; Hosokawa, Yuka; Sekiguchi, Erika; Peltier, Daniel; Reddy, Pavan; Ishizawa, Kenichi; Watanabe, Masafumi; Toubai, Tomomi; Pediatrics, School of Medicine
    Acute kidney injury (AKI) is a frequent complication of allogeneic hematopoietic cell transplantation (allo-HCT). There are many causes of AKI after allo-HCT, but it is unknown whether renal acute graft-versus-host disease (aGVHD) caused by direct allogeneic donor T-cell-mediated renal damage contributes. Here, we tested whether allogeneic donor T cells attack kidneys in murine models of aGVHD. To avoid confounding effects of nephrotoxic agents, we did not administer immunosuppressants for GVHD prophylaxis. We found that urinary N-acetyl-β-D-glucosaminidase, a marker of tubular injury, was elevated in allogeneic recipients on day 14 after allogeneic bone marrow transplantation. Donor major histocompatibility complex-positive cells were present and CD3+ T cells were increased in the glomerulus, peritubular capillaries, interstitium, and perivascular areas in the kidneys of allo-HCT recipient mice. These T cells included both CD4+ and CD8+ cells with elevated activation markers, increased exhaustion markers, and greater secretion of proinflammatory cytokines and cytotoxic proteins. Consistent with allo-T-cell-mediated renal damage, expression of neutrophil gelatinase-binding lipocalin, a marker of AKI, and elafin, a marker of aGVHD, were increased in renal tissue of allogeneic recipients. Because apoptosis of target cells is observed on histopathology of aGVHD target tissues, we confirmed that alloreactive T cells increased apoptosis of renal endothelial and tubular epithelial cells in cytotoxic T-lymphocyte assays. These data suggest that immune responses induced by donor T cells contribute to renal endothelial and tubular epithelial cell injury in allo-HCT recipients and that aGVHD may contribute to AKI after allo-HCT.
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    Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency
    (Massachusetts Medical Society, 2021-05-27) Kohn, Donald B.; Booth, Claire; Shaw, Kit L.; Xu-Bayford, Jinhua; Garabedian, Elizabeth; Trevisan, Valentina; Carbonaro-Sarracino, Denise A.; Soni, Kajal; Terrazas, Dayna; Snell, Katie; Ikeda, Alan; Leon-Rico, Diego; Moore, Theodore B.; Buckland, Karen F.; Shah, Ami J.; Gilmour, Kimberly C.; De Oliveira, Satiro; Rivat, Christine; Crooks, Gay M.; Izotova, Natalia; Tse, John; Adams, Stuart; Shupien, Sally; Ricketts, Hilory; Davila, Alejandra; Uzowuru, Chilenwa; Icreverzi, Amalia; Barman, Provaboti; Fernandez, Beatriz Campo; Hollis, Roger P.; Coronel, Maritess; Yu, Allen; Chun, Krista M.; Casas, Christian E.; Zhang, Ruixue; Arduini, Serena; Lynn, Frances; Kudari, Mahesh; Spezzi, Andrea; Zahn, Marco; Heimke, Rene; Labik, Ivan; Parrott, Roberta; Buckley, Rebecca H.; Reeves, Lilith; Cornetta, Kenneth; Sokolic, Robert; Hershfield, Michael; Schmidt, Manfred; Candotti, Fabio; Malech, Harry L.; Thrasher, Adrian J.; Gaspar, H. Bobby; Medicine, School of Medicine
    Background: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. Methods: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. Results: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. Conclusions: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution.
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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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    Biomarkers for Early Complications After Hematopoietic Stem Cell Transplantation
    (Elsevier, 2019-03) Rowan, Courtney M.; Paczesny, Sophie; Pediatrics, School of Medicine
    The advancement in technology, particularly in the field of omics, has led to numerous discoveries of biomarkers for early post-HSCT complications. Future research must include the testing of newly discovered biomarkers against existing, validated biomarkers. Work also needs to be done to implement the promising, validated biomarkers into clinical practice in a time-efficient and cost-effective manner. The prognostic biomarkers should be incorporated into clinical trials so that the effect of early recognition on the outcomes of HSCT recipients can be assessed. Diagnostic biomarkers can help to differentiate the complex variety of diseases that can be present in this population. Finally, biomarkers that can serve as therapeutic targets should be further studied. Many of these post-HSCT complications have limited or nonspecific therapeutic options. For example, corticosteroids are the first-line therapy for aGVHD. Using biomarkers to help identify underlying biologic pathways may open new therapeutic avenues that deserve investigation. This major advancement in technology allows for early diagnosis of complications, risk stratification for complications, and potential new therapeutic targets. All of these strides can improve the utilization of life-saving allogeneic HSCT while minimizing complications and mortality.
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    Characterization of Hepatic Dysfunction in subjects diagnosed with Chronic GVHD by NIH Consensus Criteria
    (Elsevier, 2022) Yang, Alexander H.; Han, Ma Ai Thanda; Samala, Niharika; Rizvi, Bisharah S.; Marchalik, Rachel; Etzion, Ohad; Wright, Elizabeth C.; Cao, Liang; Hakim, Frances T.; Jones, Elizabeth; Kapuria, Devika; Hickstein, Dennis D.; Fowler, Daniel; Kanakry, Jennifer A.; Kanakry, Christopher G.; Kleiner, David E.; Koh, Christopher; Pavletic, Steven Z.; Heller, Theo; Medicine, School of Medicine
    Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality.
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    Collection and Processing of Mobilized Mouse Peripheral Blood at Lowered Oxygen Tension Yields Enhanced Numbers of Hematopoietic Stem Cells
    (SpringerLink, 2020-10) Aljoufi, Arafat; Cooper, Scott; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Mobilized peripheral blood (mPB) hematopoietic stem (HSCs) and progenitor (HPCs) cells are primary sources for hematopoietic cell transplantation (HCT). Successful HCT requires threshold numbers of high-quality HSCs to reconstitute hematopoiesis long-term. Nevertheless, considerable percentages of patients and healthy donors fail to achieve required thresholds of HSCs with current mobilization regimens. In this present study we demonstrate that similar to mouse bone marrow (BM) and human cord blood, collection and processing of mouse Granulocyte Colony Stimulating Factor (G-CSF)-, AMD3100/Plerixafor- or G-CSF plus AMD3100/Plerixafor-mobilized HSCs in 3% O2 results in enhanced numbers of rigorously-defined phenotypic and for G-CSF - and G-CSF plus AMD3100/Plerixafor - mPB enhanced functionally-engrafting HSCs. These results may be of potential clinical utility.
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    Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT
    (American Society of Clinical Oncology, 2020-06-20) Mehta, Rohtesh S.; Holtan, Shernan G.; Wang, Tao; Hemmer, Michael T.; Spellman, Stephen R.; Arora, Mukta; Couriel, Daniel R.; Alousi, Amin M.; Pidala, Joseph; Abdel-Azim, Hisham; Agrawal, Vaibhav; Ahmed, Ibrahim A.; Al-Homsi, Samer; Aljurf, Mahmoud; Antin, Joseph H.; Askar, Medhat; Auletta, Jeffery J.; Bhatt, Vijaya Raj; Chee, Lynette; Chhabra, Saurabh; Daly, Andrew; DeFilipp, Zachariah; Gajewski, James; Gale, Robert Peter; Gergis, Usama; Hematti, Peiman; Hildebrandt, Gerhard C.; Hogan, William J.; Inamoto, Yoshihiro; Martino, Rodrigo; Majhail, Navneet S.; Marks, David I.; Nishihori, Taiga; Olsson, Richard F.; Pawarode, Attaphol; Diaz, Miguel Angel; Prestidge, Tim; Rangarajan, Hemalatha G.; Ringden, Olle; Saad, Ayman; Savani, Bipin N.; Schoemans, Hélène; Seo, Sachiko; Schultz, Kirk R.; Solh, Melhem; Spitzer, Thomas; Storek, Jan; Teshima, Takanori; Verdonck, Leo F.; Wirk, Baldeep; Yared, Jean A.; Cahn, Jean-Yves; Weisdorf, Daniel J.; Medicine, School of Medicine
    Purpose: There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. Methods: We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. Results: In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. Conclusion: Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.
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    Counteracting the enzymatic activity of dipeptidylpeptidase 4 for potential therapeutic advantage, with an emphasis on cord blood transplantation
    (Korean Association of Internal Medicine, 2013) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Dipeptidylpeptidase (DPP) 4, also known as CD26, is an enzyme present on the surface of a number of different cell types. It is also found within cells and as a soluble protein in body fluids. It can specifically truncate proteins at the penultimate N-terminus residue for some amino acids, such as alanine, proline, serine, and perhaps others. DPP4 has been implicated in regulating the in vitro and in vivo functional activities of a number of hematopoietically active molecules, and this information, along with that on inhibition of DPP4, has been studied in efforts to enhance hematopoietic cell transplantation (HCT), hematopoiesis after stress in mouse models, and in the clinical setting of single-unit cord blood (CB) HCT. This article reviews the current status of this compound's effects on regulatory proteins, the field of CB HCT, a potential role for modulating DPP4 activity in enhancing single-unit CB HCT in adults, and future aspects in context of other cellular therapies and the area of regenerative medicine.