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Rostami T, Rostami MR, Mirhosseini AH, Mohammadi S, Nikbakht M, Alemi H, Khavandgar N, Rad S, Janbabai G, Mousavi SA, Kiumarsi A, Kasaeian A. Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant? Stem Cell Res Ther 2024; 15:111. [PMID: 38644499 PMCID: PMC11034046 DOI: 10.1186/s13287-024-03726-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 04/10/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.
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Affiliation(s)
- Tahereh Rostami
- Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Rostami
- Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Mirhosseini
- Department of Internal Medicine, School of Medicine, Imam Ali Hospital, Alborz University of Medical Sciences, Alborz, Iran
| | - Saeed Mohammadi
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Nikbakht
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Alemi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Naghmeh Khavandgar
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Soroush Rad
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghasem Janbabai
- Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Seied Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Kiumarsi
- Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Pediatrics, School of Medicine, Childrens Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Amir Kasaeian
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
- Clinical Research Development Unit, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Aggeletopoulou I, Kalafateli M, Triantos C. Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand? Int J Mol Sci 2024; 25:2631. [PMID: 38473878 DOI: 10.3390/ijms25052631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/20/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge that urgently calls for innovative therapeutic strategies. Chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising avenue for HCC treatment. However, the therapeutic efficacy of CAR T immunotherapy in HCC patients is significantly compromised by some major issues including the immunosuppressive environment within the tumor, antigen heterogeneity, CAR T cell exhaustion, and the advanced risk for on-target/off-tumor toxicity. To overcome these challenges, many ongoing preclinical and clinical trials are underway focusing on the identification of optimal target antigens and the decryption of the immunosuppressive milieu of HCC. Moreover, limited tumor infiltration constitutes a significant obstacle of CAR T cell therapy that should be addressed. The continuous effort to design molecular targets for CAR cells highlights the importance for a more practical approach for CAR-modified cell manufacturing. This review critically examines the current landscape of CAR T cell therapy for HCC, shedding light on the changes in innate and adaptive immune responses in the context of HCC, identifying potential CAR T cell targets, and exploring approaches to overcome inherent challenges. Ongoing advancements in scientific research and convergence of diverse treatment modalities offer the potential to greatly enhance HCC patients' care in the future.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| | - Maria Kalafateli
- Department of Gastroenterology, General Hospital of Patras, 26332 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
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Ramanathan S, Lum SH, Nademi Z, Carruthers K, Watson H, Flood T, Owens S, Williams E, Hambleton S, Gennery AR, Slatter M. CD3+TCRαβ/CD19+ depleted mismatched family or unrelated donor salvage stem cell transplantation for graft dysfunction in inborn errors of immunity. Transplant Cell Ther 2023:S2666-6367(23)01321-0. [PMID: 37279857 DOI: 10.1016/j.jtct.2023.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/13/2023] [Accepted: 05/25/2023] [Indexed: 06/08/2023]
Abstract
BACKGROUND A minority of children experience significant graft dysfunction after an allogeneic hematopoietic stem cell transplant (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT is unclear with respect to conditioning regimen and stem cell source. This single-centre retrospective case series reports the outcomes of salvage CD3+TCRαβ/CD19 depleted mismatched family or unrelated donor stem cell transplantation (TCRαβ-SCT) between 2013 - 2022 for graft dysfunction in 12 children with IEI. OBJECTIVES Outcomes of interest were overall survival (OS), event free survival (EFS), graft-versus-host disease (GvHD)-free and event-free survival (GEFS), toxicities, GvHD, viremia and long-term graft function. STUDY DESIGN A retrospective audit of patients who underwent second CD3+TCRαβ/CD19 depleted mismatched donor graft using Treosulfan-based reduced toxicity myeloablative conditioning. RESULTS Median age at first HSCT was 8.76 months (range, 2.5 months - 6 years) and at second TCRαβ-SCT was 3.6 years (1.2 - 11 years). Median interval between first and second HSCT was 1.7 years (3 months - 9 years). The primary diagnoses were: severe combined immunodeficiency (SCID) (n=5) and non-SCID IEI (n=7). The indications for second HSCT were: primary aplasia (n=1), secondary autologous reconstitution (n=6), refractory aGVHD (n=3) and secondary leukemia (n=1). Donors were either haploidentical parental donors (n=10) or mismatched unrelated donors (n=2). All received TCRαβ/CD19-depleted-PBSC with a median CD34+ cell dose of 9.3 × 106/kg (2.8-32.3 × 106/kg) and a median TCRαβ+ cell dose of 4 × 104/kg (1.3-19.2 × 104/kg). All engrafted with median days to neutrophil and platelet recovery of 15 (12-24) and 12 (9-19). One developed secondary aplasia and one had secondary autologous reconstitution, but both underwent a successful third HSCT. Four (33%) had grade II aGvHD and none had grade III-IV aGvHD. None had cGvHD but one developed extensive cutaneous cGVHD after third HSCT using PBSC and ATG. Nine (75%) were noted to have at least one episode of blood viremia with HHV6 (n=6, 50%), adenovirus (n=6, 50%), EBV (n=3, 25%) or CMV (n=3; 25%). Median duration of follow-up was 2.3 years (range: 0.5 - 10 years) and the 2-year OS, EFS and GEFS were 100% (95% confidence interval, 0-100%), 73% (37-90%) and 73% (37%-90%) respectively. CONCLUSIONS TCRαβ-SCT from mismatched family or unrelated donors, using a chemotherapy only regimen, is a safe alternative donor salvage transplant strategy for second HSCT in patients without a suitably matched donor.
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Affiliation(s)
- Subramaniam Ramanathan
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Su Han Lum
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Zohreh Nademi
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Kayleigh Carruthers
- Newcastle Advanced Therapies, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Helen Watson
- Blood Sciences, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Terence Flood
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Stephen Owens
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Eleri Williams
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Sophie Hambleton
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Andrew R Gennery
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom
| | - Mary Slatter
- Department of Paediatric Hematopoietic Stem Cell Transplant, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, United Kingdom.
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Chen YF, Li J, Xu LL, Găman MA, Zou ZY. Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities. World J Clin Cases 2023; 11:268-291. [PMID: 36686358 PMCID: PMC9850970 DOI: 10.12998/wjcc.v11.i2.268] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/02/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
As an important treatment for acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) plays an important role in reducing relapse and improving long-term survival. With rapid advancements in basic research in molecular biology and immunology and with deepening understanding of the biological characteristics of hematopoietic stem cells, allo-HSCT has been widely applied in clinical practice. During allo-HSCT, preconditioning, the donor, and the source of stem cells can be tailored to the patient's conditions, greatly broadening the indications for HSCT, with clear survival benefits. However, the risks associated with allo-HSCT remain high, i.e. hematopoietic reconstitution failure, delayed immune reconstitution, graft-versus-host disease, and post-transplant relapse, which are bottlenecks for further improvements in allo-HSCT efficacy and have become hot topics in the field of HSCT. Other bottlenecks recognized in the current treatment of individuals diagnosed with acute myeloid leukemia and subjected to allo-HSCT include the selection of the most appropriate conditioning regimen and post-transplantation management. In this paper, we reviewed the progress of relevant research regarding these aspects.
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Affiliation(s)
- Yong-Feng Chen
- Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Jing Li
- Department of Histology and Embryology, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Ling-Long Xu
- Department of Hematology, Taizhou Central Hospital, Taizhou 318000, Zhejiang Province, China
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
| | - Zhen-You Zou
- Department of Scientific Research,Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou 545005, Guangxi Zhuang Autonomous Region, China
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Sperl D, Lang P, Benesch M, Bainschab A, Urban C, Wilfing R, Feuchtinger T, Döring M, Seitz C, Strenger V, Lackner H, Seidel MG, Perwein T, Handgretinger R, Sipurzynski S, Rosskopf K, Schwinger W. Immunological recovery following HLA-matched CD3+ TCR αß+/CD19+ depleted hematopoietic stem cell transplantation in children. Pediatr Transplant 2022; 26:e14285. [PMID: 35441401 DOI: 10.1111/petr.14285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 02/08/2022] [Accepted: 03/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. METHODS Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαβ+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαβ+, and CD19+B-cells infused was 12.7 × 106 /kg, 16.8 × 103 /kg, and 96 × 103 /kg bodyweight. RESULTS With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal. CONCLUSIONS Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.
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Affiliation(s)
- Daniela Sperl
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Peter Lang
- Children's University Hospital University of Tuebingen, Tuebingen, Germany
| | - Martin Benesch
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Antonia Bainschab
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Christian Urban
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Roland Wilfing
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Tobias Feuchtinger
- Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Michaela Döring
- Children's University Hospital University of Tuebingen, Tuebingen, Germany
| | - Christian Seitz
- Children's University Hospital University of Tuebingen, Tuebingen, Germany
| | - Volker Strenger
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Herwig Lackner
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Markus G Seidel
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Thomas Perwein
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | | | - Sabine Sipurzynski
- Department of Blood Group Serology and Transfusion Medicine, Medical University Graz, Graz, Austria
| | - Konrad Rosskopf
- Department of Blood Group Serology and Transfusion Medicine, Medical University Graz, Graz, Austria
| | - Wolfgang Schwinger
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
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Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment. Cytotherapy 2022; 24:884-891. [PMID: 35705447 DOI: 10.1016/j.jcyt.2022.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 04/13/2022] [Accepted: 05/22/2022] [Indexed: 11/20/2022]
Abstract
Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.
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Gómez-Santos C, González-Vicent M, Molina B, Deltoro N, Herrero B, Ruiz J, Pérez-Martínez A, Diaz MA. Comparison of clinical outcomes between unrelated single umbilical cord blood and "ex-vivo" T-cell depleted haploidentical transplantation in children with hematological malignancies. World J Pediatr 2021; 17:609-618. [PMID: 34590210 DOI: 10.1007/s12519-021-00461-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/31/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND Over the last two decades, umbilical cord blood (UCB) and haploidentical transplantation (HaploHSCT) have emerged as alternative sources of hematopoietic stem cell for allogeneic transplantation. There are few retrospective studies and no prospective studies comparing both types of alternative transplantation in pediatric patients. RESULTS We analyzed the data of 134 children with hematological malignancies who received a hematopoietic stem cell transplantation from a single umbilical cord blood (UCB) (n = 42) or an "ex-vivo" T-cell depleted transplant from a haploidentical-related donor (HaploHSCT) (n = 92) between 1996 and 2014. Hematological recovery was faster after HaploHSCT than the UCB transplant group (median times to neutrophil and platelet recovery: 13 vs. 16 days, 10 vs. 57 days, respectively) (P < 0.001). The HaploHSCT group had a significantly early immune reconstitution based on NK and CD8 + T cells compared with the UCB group. However, after the first year post-transplantation, HaploHSCT had a lower number of CD4 + T and B lymphocytes compared with the UCB transplant recipients. The cumulative incidence of TRM was 29±8% in the HaploHSCT group versus 40±5% in the UCB group. Relapse incidence was 21±7% in the HaploHSCT group and 19±8% in the UCB group. Probability of DFS was 58±8% in the HaploHSCT group versus 40±9% in the UCB group (P = 0.051). CONCLUSIONS TCD haploidentical transplant is associated with advantages in terms of engraftment and early immune reconstitution kinetics. TCD haploidentical transplant was associated with lower incidence of infectious and non-infectious complications, especially in the early phases of the transplant compared with UCB transplant recipients. However, there are no advantages in transplant outcomes compared with UCB transplant.
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Affiliation(s)
- Carmen Gómez-Santos
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain
| | - Marta González-Vicent
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain
| | - Blanca Molina
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain
| | - Natalia Deltoro
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain
| | - Blanca Herrero
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain
| | - Julia Ruiz
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain
| | - Antonio Pérez-Martínez
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain.,Hospital Infantil Universitario "La Paz" Madrid, Madrid, Spain
| | - Miguel A Diaz
- Department of Pediatrics, Hematopoietic Stem Cell Transplantation Unit, Hospital Infantil Universitario "Niño Jesus", Menedez Pelayo 65, 28009, Madrid, Spain.
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8
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Seven Year Long Follow Up of Patient With Childhood Chronic Myeloid Leukemia Postsecond Haploidentical Stem Cell Transplant. J Pediatr Hematol Oncol 2021; 43:e1267-e1268. [PMID: 34673715 DOI: 10.1097/mph.0000000000002320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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9
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Duah M, Li L, Shen J, Lan Q, Pan B, Xu K. Thymus Degeneration and Regeneration. Front Immunol 2021; 12:706244. [PMID: 34539637 PMCID: PMC8442952 DOI: 10.3389/fimmu.2021.706244] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/16/2021] [Indexed: 01/08/2023] Open
Abstract
The immune system’s ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus’s development, factors causing thymic injury, and the strategies for improving thymus regeneration.
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Affiliation(s)
- Maxwell Duah
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Lingling Li
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Jingyi Shen
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Qiu Lan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Bin Pan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Kailin Xu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
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Albert MH, Sirin M, Hoenig M, Hauck F, Schuetz C, Bhattacharyya R, Stepensky P, Jacoby E, Güngör T, Beier R, Schulz A. Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders. Bone Marrow Transplant 2021; 56:2248-2258. [PMID: 33967276 PMCID: PMC8106764 DOI: 10.1038/s41409-021-01323-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/14/2021] [Accepted: 04/21/2021] [Indexed: 02/05/2023]
Abstract
Graft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20-24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7-95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15-61) and 39 days (15-191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.
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Affiliation(s)
- Michael H Albert
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
| | - Mehtap Sirin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Manfred Hoenig
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Fabian Hauck
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Munich, Germany
| | - Catharina Schuetz
- Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Rajat Bhattacharyya
- Haematology Oncology Service, Department of Paediatric subspecialties, KK Women's and Children's Hospital, Bukit Timah, Singapore
| | - Polina Stepensky
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Bone Marrow Transplantation, Hadassah Medical Center, Jerusalem, Israel
| | - Elad Jacoby
- Division of Pediatric Hematology Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tayfun Güngör
- Department of Hematology/Oncology/Immunology, Gene-therapy, and Stem Cell Transplantation, University Children's Hospital Zürich - Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland
| | - Rita Beier
- Department of Pediatric Hematology and Oncology, University Duisburg-Essen, Essen, Germany
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Ansgar Schulz
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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11
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Kindwall-Keller TL, Ballen KK. Umbilical cord blood: The promise and the uncertainty. Stem Cells Transl Med 2020; 9:1153-1162. [PMID: 32619330 PMCID: PMC7519764 DOI: 10.1002/sctm.19-0288] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 05/05/2020] [Accepted: 05/10/2020] [Indexed: 12/16/2022] Open
Abstract
Unfortunately, many patients referred for hematopoietic cell transplant will not have a fully matched related donor, and finding matched unrelated donors through the registry may be difficult, especially if the recipient is not of Northern European descent [N Engl J Med 2014;371:339‐348]. Umbilical cord blood (UCB) has been an available graft source for hematopoietic cell transplant for more than 30 years, since the first UCB transplant was performed in the late 1980s [N Engl J Med 1989;321:1174‐1178]. UCB is readily available, has low immunogenicity, and does not require as strict of human leukocyte antigen (HLA) matching compared to other graft sources [N Engl J Med 2004;351:2265‐2275]. According to data from the Center for International Blood and Marrow Transplant Research (CIBMTR), an estimated 500 patients in the US will have received a UCB transplant in 2018. Since 2014, haploidentical transplants have surpassed UCB transplants performed in the United States (CIBMTR Summary Slides, 2018, available at https://www.cibmtr.org). Increased use of haploidentical transplants has brought to light concerns about UCB transplants, including delayed engraftment and graft failure, increased nonrelapse mortality, increased infection risk, and UCB acquisition costs [Lancet Oncol 2010;11:653‐660; Biol Blood Marrow Transplant 2019;1456‐1464]. These concerns will need to be addressed for UCB to remain a viable option as a graft source for hematopoietic cell transplant. Other promising therapeutic benefits for UCB, in addition to hematopoietic cell transplant, is its use in regenerative medicine and immune modulation, which is currently being evaluated in ongoing clinical trials.
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Affiliation(s)
| | - Karen K Ballen
- Division of Hematology/Oncology, University of Virginia, Charlottesville, Virginia, USA
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12
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Giver CR. Antiviral Immune Monitoring and Support in Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 2020; 26:e92-e93. [PMID: 32188575 DOI: 10.1016/j.bbmt.2020.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 11/18/2022]
Affiliation(s)
- Cynthia R Giver
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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13
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Pérez‐Martínez A, Ferreras C, Pascual A, Gonzalez‐Vicent M, Alonso L, Badell I, Fernández Navarro JM, Regueiro A, Plaza M, Pérez Hurtado JM, Benito A, Beléndez C, Couselo JM, Fuster JL, Díaz‐Almirón M, Bueno D, Mozo Y, Marsal J, Gómez López A, Sisinni L, Heredia CD, Díaz MÁ. Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH). Am J Hematol 2020; 95:28-37. [PMID: 31625177 DOI: 10.1002/ajh.25661] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 12/22/2022]
Abstract
A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+ CD19+ depletion, TCRαβ+ CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.
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Affiliation(s)
- Antonio Pérez‐Martínez
- Pediatric Hemato‐OncologyLa Paz University Hospital Madrid Spain
- Faculty of MedicineAutonomous University of Madrid
| | | | | | | | - Laura Alonso
- Pediatric Hemato‐OncologyHospital Vall d'Hebron Barcelona Spain
| | - Isabel Badell
- Pediatric Hemato‐OncologyHospital Santa Creu I Sant Pau Barcelona Spain
| | | | - Alexandra Regueiro
- Pediatric Hemato‐OncologyUniversity of Santiago Clinical Hospital Santiago de Compostela Spain
| | - Mercedes Plaza
- Pediatric Hemato‐OncologyVirgen de la Arrixaca University Clinical Hospital; Biomedical Research Institute of Murcia (IMIB)
| | | | - Ana Benito
- Pediatric Hemato‐OncologyHospital of Salamanca Salamanca Spain
| | | | - José Miguel Couselo
- Pediatric Hemato‐OncologyUniversity of Santiago Clinical Hospital Santiago de Compostela Spain
| | - José Luis Fuster
- Pediatric Hemato‐OncologyVirgen de la Arrixaca University Clinical Hospital; Biomedical Research Institute of Murcia (IMIB)
| | | | - David Bueno
- Pediatric Hemato‐OncologyLa Paz University Hospital Madrid Spain
| | - Yasmina Mozo
- Pediatric Hemato‐OncologyLa Paz University Hospital Madrid Spain
| | - Julia Marsal
- Pediatric Hemato‐OncologyHospital Sant Joan de Déu Barcelona Spain
| | | | - Luisa Sisinni
- Pediatric Hemato‐OncologyHospital Santa Creu I Sant Pau Barcelona Spain
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14
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Admiraal R, Jol-van der Zijde CM, Furtado Silva JM, Knibbe CAJ, Lankester AC, Boelens JJ, Hale G, Etuk A, Wilson M, Adams S, Veys P, van Kesteren C, Bredius RGM. Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Clin Pharmacokinet 2019; 58:1609-1620. [PMID: 31131436 PMCID: PMC6885503 DOI: 10.1007/s40262-019-00782-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. METHODS A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers. RESULTS Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. CONCLUSION The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.
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Affiliation(s)
- Rick Admiraal
- Division of Stem Cell Transplantation, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands
- Pediatric Blood and Marrow Transplantation Program, Prinses Maxima Center, Utrecht, The Netherlands
| | - Cornelia M Jol-van der Zijde
- Division of Stem Cell Transplantation, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Catherijne A J Knibbe
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands
- Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Arjan C Lankester
- Division of Stem Cell Transplantation, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Jaap Jan Boelens
- Pediatric Blood and Marrow Transplantation Program, Prinses Maxima Center, Utrecht, The Netherlands
- Stem Cell Transplant and Cellular Therapies, Memorial Sloane Kettering Cancer Center, New York, NY, USA
| | | | - Aniekan Etuk
- Department of Haematology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London, UK
| | - Melanie Wilson
- Department of Haematology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London, UK
| | - Stuart Adams
- Department of Haematology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London, UK
| | - Paul Veys
- Bone Marrow Transplantation Department, Great Ormond Street Hospital, London, UK
| | - Charlotte van Kesteren
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands
- Pediatric Blood and Marrow Transplantation Program, Prinses Maxima Center, Utrecht, The Netherlands
| | - Robbert G M Bredius
- Division of Stem Cell Transplantation, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
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15
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Yanir AD, Martinez CA, Sasa G, Leung K, Gottschalk S, Omer B, Ahmed N, Hegde M, Eunji J, Liu H, Heslop HE, Brenner MK, Krance RA, Naik S. Current Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphocytic Leukemia: Success, Failure and Future Perspectives—A Single-Center Experience, 2008 to 2016. Biol Blood Marrow Transplant 2018; 24:1424-1431. [DOI: 10.1016/j.bbmt.2018.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 03/02/2018] [Indexed: 12/11/2022]
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16
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Hoare RL, Veys P, Klein N, Callard R, Standing JF. Predicting CD4 T-Cell Reconstitution Following Pediatric Hematopoietic Stem Cell Transplantation. Clin Pharmacol Ther 2017; 102:349-357. [PMID: 28074473 PMCID: PMC5579758 DOI: 10.1002/cpt.621] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/03/2017] [Accepted: 01/06/2017] [Indexed: 11/10/2022]
Abstract
Hematopoietic stem cell transplantation (HSCT) is an increasingly common treatment for children with a range of hematological disorders. Conditioning with cytotoxic chemotherapy and total body irradiation leaves patients severely immunocompromised. T-cell reconstitution can take several years due to delayed restoration of thymic output. Understanding T-cell reconstitution in children is complicated by normal immune system maturation, heterogeneous diagnoses, and sparse uneven sampling due to the long time spans involved. We describe here a mechanistic mathematical model for CD4 T-cell immune reconstitution following pediatric transplantation. Including relevant biology and using mixed-effects modeling allowed the factors affecting reconstitution to be identified. Bayesian predictions for the long-term reconstitution trajectories of individual children were then obtained using early post-transplant data. The model was developed using data from 288 children; its predictive ability validated on data from a further 75 children, with long-term reconstitution predicted accurately in 81% of the patients.
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Affiliation(s)
- RL Hoare
- Centre for Mathematics and Physics in the Life Sciences and Experimental BiologyUniversity College LondonLondonUnited Kingdom
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUnited Kingdom
| | - P Veys
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUnited Kingdom
- Great Ormond Street Hospital for Children NHS TrustLondonUnited Kingdom
| | - N Klein
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUnited Kingdom
- Great Ormond Street Hospital for Children NHS TrustLondonUnited Kingdom
| | - R Callard
- Centre for Mathematics and Physics in the Life Sciences and Experimental BiologyUniversity College LondonLondonUnited Kingdom
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUnited Kingdom
| | - JF Standing
- Centre for Mathematics and Physics in the Life Sciences and Experimental BiologyUniversity College LondonLondonUnited Kingdom
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUnited Kingdom
- Great Ormond Street Hospital for Children NHS TrustLondonUnited Kingdom
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17
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de Koning C, Admiraal R, Nierkens S, Boelens JJ. Immune reconstitution and outcomes after conditioning with anti-thymocyte-globulin in unrelated cord blood transplantation; the good, the bad, and the ugly. Stem Cell Investig 2017; 4:38. [PMID: 28607912 DOI: 10.21037/sci.2017.05.02] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 04/17/2017] [Indexed: 01/07/2023]
Abstract
Unrelated umbilical cord blood transplantation (UCBT) exhibits a low risk of graft-versus-host-disease (GvHD) and has unique potent anti-virus and anti-leukemia effects. Anti-thymocyte globulin (ATG) in the conditioning regimen for UCBT is successful in reducing graft rejection and GvHD. Nevertheless, this beneficial effect of ATG coincides with its detrimental effect on immune reconstitution. The latter directly relates to a high incidence of viral infections and leukemia relapses. ATG has been used in transplant patients for over 30 years. In recent years, the knowledge on the mechanisms of action of ATG and its implementation in the UCBT setting has increased dramatically. Important data became available showing the highly variable pharmacokinetics (PK) of ATG and its consequence on outcome measures. Here, we review the effects of ATG on immune reconstitution and subsequent outcomes after UCBT, and describe the mechanisms causing these effects. We highlight the importance of optimizing ATG exposure before and after UCBT and discuss strategies to maintain the 'good' and overcome the 'bad and ugly' effects of ATG on UCBT outcome.
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Affiliation(s)
- Coco de Koning
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Rick Admiraal
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.,Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Stefan Nierkens
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jaap Jan Boelens
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.,Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, the Netherlands
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18
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Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation. Blood 2016; 128:2734-2741. [PMID: 27702800 DOI: 10.1182/blood-2016-06-721936] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 09/21/2016] [Indexed: 12/18/2022] Open
Abstract
Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host disease and graft failure, negatively influences T-cell IR. We studied the relationships among ATG exposure, IR, and clinical outcomes. All pediatric patients receiving a first CBT between 2004 and 2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated pharmacokinetics model. Main outcome of interest was early CD4+ IR, defined as CD4+ T-cell counts >50 × 106/L twice within 100 days after CBT. Other outcomes of interest included event-free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, with a median age of 7.4 years (range, 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the cord blood transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced by 26% for every 10-point increase in AUC after CBT (hazard ratio [HR], 0.974; P < .0001). The chance of EFS was higher in patients with successful CD4+ IR (HR, 0.26; P < .0001) and lower ATG exposure after CBT (HR, 1.005; P = .0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure or, in selected patients, omission of ATG may contribute to improved outcomes in pediatric CBT.
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19
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Leukemia-free survival in myeloid leukemia, but not in lymphoid leukemia, is predicted by early CD4+ reconstitution following unrelated cord blood transplantation in children: a multicenter retrospective cohort analysis. Bone Marrow Transplant 2016; 51:1376-1378. [PMID: 27159172 DOI: 10.1038/bmt.2016.116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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20
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Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI. Bone Marrow Transplant 2016; 51:687-91. [DOI: 10.1038/bmt.2015.351] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/27/2015] [Accepted: 12/16/2015] [Indexed: 11/08/2022]
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21
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de Koning C, Plantinga M, Besseling P, Boelens JJ, Nierkens S. Immune Reconstitution after Allogeneic Hematopoietic Cell Transplantation in Children. Biol Blood Marrow Transplant 2015; 22:195-206. [PMID: 26341398 DOI: 10.1016/j.bbmt.2015.08.028] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 08/25/2015] [Indexed: 12/14/2022]
Abstract
Allogeneic (allo) hematopoietic cell transplantation (HCT) has evolved into a potent curative treatment option for a variety of malignant and nonmalignant diseases. The occurrence of complications and mortality after allo-HCT is, however, still high and is strongly associated with immune reconstitution (IR). Therefore, detailed information on IR through immunomonitoring is crucial to improve survival chances after HCT. To date, information about the reconstituting immune system after allo-HCT in pediatric patients is mostly derived from routine standard-of-care measurements. More profound knowledge on IR may provide tools to better predict and modulate adverse reactions and, subsequently, improve survival chances. Here, we provide an overview of IR (eg, immune cell subsets and circulating chemokines/cytokines) after allo-HCT in children, taking into account different cell sources and serotherapy, and discuss strategies to enhance immunomonitoring. We conclude that available IR data after allo-HCT contain limited information on immune cell families (mostly only generic T, B, and NK cells), which would improve with more detailed information on reconstituting cell subsets or effector cell functionality at earlier time points (<1 month). In addition, secretome data (eg, multiplex cytokine/chemokine profiles) could add to the understanding of IR mechanisms and cell functionality and may even provide (early) biomarkers for individual disease outcome, such as viral reactivity, graft-versus-host disease, or graft-versus-leukemia. The present data and suggestions for more detailed, standardized, and harmonized immunomonitoring in future (pediatric) allo-HCT studies will pave the path to "precision transplantation:" an individualized HCT approach (including conditioning), based on detailed information on IR and biomarkers, aiming to reduce transplantation related mortality and relapse, and subsequently improve survival chances.
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Affiliation(s)
- Coco de Koning
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Maud Plantinga
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Paul Besseling
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Jaap Jan Boelens
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands; Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Stefan Nierkens
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
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22
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Admiraal R, van Kesteren C, Jol-van der Zijde CM, Lankester AC, Bierings MB, Egberts TCG, van Tol MJD, Knibbe CAJ, Bredius RGM, Boelens JJ. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. LANCET HAEMATOLOGY 2015; 2:e194-203. [PMID: 26688094 DOI: 10.1016/s2352-3026(15)00045-9] [Citation(s) in RCA: 226] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 02/27/2015] [Accepted: 03/02/2015] [Indexed: 02/01/2023]
Abstract
BACKGROUND Anti-thymocyte globulin (ATG) was introduced into the conditioning regimen in haemopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. However, ATG can also cause delayed immune reconstitution of donor T cells. We studied the relation between exposure to active ATG and clinical outcomes in children. METHODS In this retrospective analysis, all patients (age 0·2-23 years) receiving their first HCT between April 1, 2004, and April 1, 2012, who received ATG (thymoglobulin) in two Dutch paediatric HCT programmes were included. The cumulative dose of ATG was chosen according to local protocols and was given intravenously over 4 days consecutively. ATG exposure measures (maximum concentration, concentration at time of HCT, clearance, days to reach a concentration below the lympholytic concentration of one arbitrary unit [AU] per mL, total area under the curve [AUC], AUC before HCT, and AUC after HCT) were calculated using a validated population pharmacokinetic model. The main outcome of interest was immune reconstitution (defined as CD4+ T cells >0·05 × 10(9) cells per L in two consecutive measurements within 100 days). Other outcomes of interest were survival, acute and chronic GvHD, and graft failure. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regressions for analyses. FINDINGS 251 patients were included. The chance of successful immune reconstitution decreased as the ATG AUC after HCT increased (odds ratio 0·991, 95% CI 0·987-0·996; p<0·0001). Within the cord blood group, we noted decreased immune reconstitution above the lowest AUC quartile (≥ 20 AU × day/mL; p=0·0024), whereas in the bone marrow or peripheral blood stem cell group, decreased immune reconstitution was noted only in the highest quartile (≥ 100 AU × day/mL; p=0·0024). Successful immune reconstitution by day 100 was associated with increased overall survival (hazard ratio [HR] 0·49, 95% CI 0·29-0·81; p=0·0047) caused by reduced non-relapse mortality (0·40, 0·21-0·77; p=0·0062), and relapse-related mortality in myeloid leukaemia (0·25, 0·08-0·76; p=0·015). An AUC before transplantation of at least 40 AU × day/mL resulted in a lower incidence of acute GvHD (grade 2-4 HR 0·979, 95% CI 0·963-0·994; p=0·0081; and grade 3-4 0·975, 0·952-0·998; p=0·033), chronic GvHD (0·983, 0·968-0·998; p=0·029), and graft failure (0·981, 0·965-0·997; p=0·020) compared with an AUC of less than 40 AU × day/mL. INTERPRETATION These results stress the importance of improving the efficacy and safety of ATG in HCT by amending dosage and timing. Individualised dosing and timing of ATG to aim for optimum exposure before and after HCT could result in improved outcomes after paediatric HCT. FUNDING Dutch Organization for Scientific Research.
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Affiliation(s)
- Rick Admiraal
- Paediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht, Netherlands; U-DANCE, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands; Department of Paediatrics, Leiden University Medical Center, Leiden, Netherlands; Department of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, Netherlands
| | - Charlotte van Kesteren
- Paediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht, Netherlands; U-DANCE, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands; Department of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, Netherlands
| | | | - Arjan C Lankester
- Department of Paediatrics, Leiden University Medical Center, Leiden, Netherlands
| | - Marc B Bierings
- Paediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht, Netherlands
| | - Toine C G Egberts
- Department of Clinical Pharmacology and Pharmacoepidemiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Maarten J D van Tol
- Department of Paediatrics, Leiden University Medical Center, Leiden, Netherlands
| | - Catherijne A J Knibbe
- Department of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, Netherlands; Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, Netherlands
| | - Robbert G M Bredius
- Department of Paediatrics, Leiden University Medical Center, Leiden, Netherlands
| | - Jaap J Boelens
- Paediatric Blood and Marrow Transplant Program, University Medical Center Utrecht, Utrecht, Netherlands; U-DANCE, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
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23
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Park SS, Bauer G, Abedi M, Pontow S, Panorgias A, Jonnal R, Zawadzki RJ, Werner JS, Nolta J. Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings. Invest Ophthalmol Vis Sci 2014; 56:81-9. [PMID: 25491299 DOI: 10.1167/iovs.14-15415] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
PURPOSE Because human bone marrow (BM) CD34+ stem cells home into damaged tissue and may play an important role in tissue repair, this pilot clinical trial explored the safety and feasibility of intravitreal autologous CD34+ BM cells as potential therapy for ischemic or degenerative retinal conditions. METHODS This prospective study enrolled six subjects (six eyes) with irreversible vision loss from retinal vascular occlusion, hereditary or nonexudative age-related macular degeneration, or retinitis pigmentosa. CD34+ cells were isolated under Good Manufacturing Practice conditions from the mononuclear cellular fraction of the BM aspirate using a CliniMACs magnetic cell sorter. After intravitreal CD34+ cell injection, serial ophthalmic examinations, microperimetry/perimetry, fluorescein angiography, electroretinography (ERG), optical coherence tomography (OCT), and adaptive optics OCT were performed during the 6-month follow-up. RESULTS A mean of 3.4 million (range, 1-7 million) CD34+ cells were isolated and injected per eye. The therapy was well tolerated with no intraocular inflammation or hyperproliferation. Best-corrected visual acuity and full-field ERG showed no worsening after 6 months. Clinical examination also showed no worsening during follow-up except among age-related macular degeneration subjects in whom mild progression of geographic atrophy was noted in both the study eye and contralateral eye at 6-month follow-up, concurrent with some possible decline on multifocal ERG and microperimetry. Cellular in vivo imaging using adaptive optics OCT showed changes suggestive of new cellular incorporation into the macula of the hereditary macular degeneration study eye. CONCLUSIONS Intravitreal autologous BM CD34+ cell therapy appears feasible and well tolerated in eyes with ischemic or degenerative retinal conditions and merits further exploration. (ClinicalTrials.gov number, NCT01736059.).
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Affiliation(s)
- Susanna S Park
- Department of Ophthalmology and Vision Science, University of California-Davis Eye Center, Sacramento, California, United States
| | - Gerhard Bauer
- Institute for Regenerative Cures, University of California-Davis School of Medicine, Sacramento, California, United States
| | - Mehrdad Abedi
- Division of Hematology and Oncology, University of California-Davis Cancer Center, Sacramento, California, United States
| | - Suzanne Pontow
- Institute for Regenerative Cures, University of California-Davis School of Medicine, Sacramento, California, United States
| | - Athanasios Panorgias
- Department of Ophthalmology and Vision Science, University of California-Davis Eye Center, Sacramento, California, United States
| | - Ravi Jonnal
- Department of Ophthalmology and Vision Science, University of California-Davis Eye Center, Sacramento, California, United States
| | - Robert J Zawadzki
- Department of Ophthalmology and Vision Science, University of California-Davis Eye Center, Sacramento, California, United States
| | - John S Werner
- Department of Ophthalmology and Vision Science, University of California-Davis Eye Center, Sacramento, California, United States
| | - Jan Nolta
- Institute for Regenerative Cures, University of California-Davis School of Medicine, Sacramento, California, United States
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24
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Haploidentical SCT: the mechanisms underlying the crossing of HLA barriers. Bone Marrow Transplant 2014; 49:873-9. [PMID: 24566712 DOI: 10.1038/bmt.2014.19] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 12/23/2013] [Accepted: 01/06/2014] [Indexed: 12/29/2022]
Abstract
Research on the different mechanisms for crossing HLA barriers has progressed over the past 10 years. General outlines have come into view for a solution to this issue and are often presented as 'haploidentical SCT' immunology. In this review, we discuss several mechanisms that have recently been described in ex vivo and in vivo settings that can either avoid GVHD or promote hematopoietic reconstitution in haploidentical settings. The host and donor T-cell responses to allogeneic HLA molecules are a fundamental obstacle to the successful application of haploidentical transplantation, which results in unacceptably high incidences of GVHD and graft rejection. Thus, the T-cell response is a central factor in the establishment of a novel haploidentical transplant protocol with superior outcomes.
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25
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Tripura C, Pande G. Applications of human hematopoietic stem cells isolated and expanded from different tissues in regenerative medicine. Regen Med 2013; 8:783-95. [DOI: 10.2217/rme.13.75] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Bone marrow transplantation is a well-established stem cell-based therapy for the management of malignant and nonmalignant hematological disorders. In addition to the bone marrow, therapeutic hematopoietic stem cells (HSCs) can also be obtained from umbilical cord blood and mobilized peripheral blood. Transplantation of HSCs isolated from these tissues can be carried out with or without prior enrichment of specific cell types. New methodologies have been developed for lineage-specific HSC expansion and their transplantation as a supplementary treatment to whole bone marrow transplantation. In this review we have described the current methodologies for isolating and processing HSCs from various tissues, and discussed strategies to generate sufficient and functional HSCs for clinical and preclinical applications by expansion ex vivo. The various disease conditions in which these cells could be used, and the methods for delivering the cells into patients, are also discussed.
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Affiliation(s)
| | - Gopal Pande
- Centre for Cellular & Molecular Biology, Uppal Road, Hyderabad 500 007, India
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26
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Locatelli F, Lucarelli B, Merli P. Current and future approaches to treat graft failure after allogeneic hematopoietic stem cell transplantation. Expert Opin Pharmacother 2013; 15:23-36. [DOI: 10.1517/14656566.2014.852537] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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27
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Barrett AJ. Immune recovery in pediatric transplantation: can T cell-depleted peripheral blood stem cell transplantation beat cord blood transplantation? Biol Blood Marrow Transplant 2013; 19:1531-2. [PMID: 24035781 DOI: 10.1016/j.bbmt.2013.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 09/04/2013] [Indexed: 10/26/2022]
Affiliation(s)
- A John Barrett
- Allogeneic Stem Cell Transplantation Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
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28
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Booth C, Lawson S, Veys P. The current role of T cell depletion in paediatric stem cell transplantation. Br J Haematol 2013; 162:177-90. [DOI: 10.1111/bjh.12400] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 03/07/2013] [Indexed: 02/03/2023]
Affiliation(s)
- Claire Booth
- Molecular Immunology Unit; Institute of Child Health; University College London; London UK
| | - Sarah Lawson
- Department of Haematology; Birmingham Children's Hospital NHS Foundation Trust; Birmingham UK
| | - Paul Veys
- Molecular Immunology Unit; Institute of Child Health; University College London; London UK
- Department of Blood and Marrow Transplantation; Great Ormond Street Hospital for Children NHS Foundation Trust; London UK
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