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Moghassemi S, Nikanfar S, Dadashzadeh A, Sousa MJ, Wan Y, Sun F, Colson A, De Windt S, Kwaspen L, Kanbar M, Sobhani K, Yang J, Vlieghe H, Li Y, Debiève F, Wyns C, Amorim CA. The revolutionary role of placental derivatives in biomedical research. Bioact Mater 2025; 49:456-485. [PMID: 40177109 PMCID: PMC11964572 DOI: 10.1016/j.bioactmat.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 04/05/2025] Open
Abstract
The human placenta is a transient yet crucial organ that plays a key role in sustaining the relationship between the maternal and fetal organisms. Despite its historical classification as "biowaste," placental tissues have garnered increasing attention since the early 1900s for their significant medical potential, particularly in wound repair and surgical application. As ethical considerations regarding human placental derivatives have largely been assuaged in many countries, they have gained significant attention due to their versatile applications in various biomedical fields, such as biomedical engineering, regenerative medicine, and pharmacology. Moreover, there is a substantial trend toward various animal product substitutions in laboratory research with human placental derivatives, reflecting a broader commitment to advancing ethical and sustainable research methodologies. This review provides a comprehensive examination of the current applications of human placental derivatives, explores the mechanisms behind their therapeutic effects, and outlines the future potential and directions of this rapidly advancing field.
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Affiliation(s)
- Saeid Moghassemi
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Saba Nikanfar
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Arezoo Dadashzadeh
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Maria João Sousa
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Yuting Wan
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Fengxuan Sun
- Department of Obstetrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Arthur Colson
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Obstetrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Sven De Windt
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Gynecology and Andrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Lena Kwaspen
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Gynecology and Andrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Marc Kanbar
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Gynecology and Andrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Keyvan Sobhani
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Jie Yang
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Hanne Vlieghe
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Yongqian Li
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Frédéric Debiève
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Obstetrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Christine Wyns
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Gynecology and Andrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Christiani A. Amorim
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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Haylock M, Kampkötter P, Macis M, Seitz S, Slonim R, Wienand E, Wiesen D, Schmidt AH. How perceptions of bone marrow donation costs affect donation behavior: survey evidence from a large donor registry. THE EUROPEAN JOURNAL OF HEALTH ECONOMICS : HEPAC : HEALTH ECONOMICS IN PREVENTION AND CARE 2025:10.1007/s10198-025-01785-4. [PMID: 40425906 DOI: 10.1007/s10198-025-01785-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 04/07/2025] [Indexed: 05/29/2025]
Abstract
Over the past three decades, advancements in collection methods for hematopoietic stem cell transplantation substantially reduced invasiveness and safety concerns. To what extent, however, registered donors are informed about extraction methods and how their beliefs drive their willingness to follow through with a donation is not well understood. Inaccurate beliefs about extraction methods may cause donors to overestimate their perceived cost, potentially reducing donations. In a survey with about 24,000 potential donors in Germany's largest stem-cell registry, we investigate how beliefs about extraction methods affect potential donors' willingness to follow through with a stem cell donation. We find widespread misconceptions about extraction methods, with many donors attributing a significant fraction of stem cell extractions to be coming from never-used methods. Importantly, a lack of knowledge and misconceptions about extraction methods persist among registered donors, often anchored to methods that prevailed at the time of registration. Exploring the link between donors' beliefs and their (stated) willingness to donate, we find that accurate beliefs about lower extraction costs correlate with a 2.2-2.9 percentage points higher willingness to donate, representing a 40% reduction in donor unavailability. Our results highlight the need for informational campaigns to correct donors' misconceptions and potentially save more lives among blood cancer patients.
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Affiliation(s)
| | - Patrick Kampkötter
- Faculty of Management, Economics and Social Sciences, Eberhard Karls University Tübingen, Nauklerstraße 47, 72074, Tübingen, Germany
| | - Mario Macis
- Johns Hopkins University, Carey Business School, IZA, and NBER, Baltimore, USA
| | - Susanne Seitz
- DKMS Group gGmbH Tübingen, Kressbach 1, 72072, Tübingen, Germany
| | - Robert Slonim
- University of Technology Sydney and IZA, Sydney, Australia
| | - Edith Wienand
- DKMS Group gGmbH Tübingen, Kressbach 1, 72072, Tübingen, Germany
| | - Daniel Wiesen
- University of Cologne, Department of Health Care Management and Erasmus University Rotterdam, Erasmus School of Health Policy and Management, Rotterdam, Netherlands
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3
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Hyder MA, Dimitrova D, Sabina R, DeVries A, McCune JS, McAdams MJ, Flomerfelt FA, McKeown C, Sadler JL, Chai A, Hughes TE, Napier S, Stokes A, Sponaugle J, Rechache K, Parta M, Cuellar-Rodriguez J, Figg WD, Choo-Wosoba H, Steinberg SM, Kanakry JA, Kanakry CG. Intermediate-dose posttransplantation cyclophosphamide for myeloablative HLA-haploidentical bone marrow transplantation. Blood Adv 2025; 9:2553-2569. [PMID: 39908565 DOI: 10.1182/bloodadvances.2024014879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/07/2025] Open
Abstract
ABSTRACT High-dose posttransplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase 1/2 trial to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity score was 3. The phase 1 dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n = 23), the phase 2 dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, nonrelapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n = 5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis/urethritis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. ID-PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. This trial was registered at www.clinicaltrials.gov as #NCT03983850.
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Affiliation(s)
- Mustafa A Hyder
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Dimana Dimitrova
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ruby Sabina
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ashley DeVries
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | | | - Meredith J McAdams
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Francis A Flomerfelt
- Clinical Research Correlatives Core, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Christi McKeown
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jennifer L Sadler
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Amy Chai
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Thomas E Hughes
- Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD
| | - Scott Napier
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Anita Stokes
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jennifer Sponaugle
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Kamil Rechache
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Mark Parta
- Clinical Research Directorate/Clinical Monitoring Research Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Bethesda, MD
| | | | - William D Figg
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Hyoyoung Choo-Wosoba
- Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jennifer A Kanakry
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Christopher G Kanakry
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Lassiter M, Lail C. Omidubicel-Onlv: The First Commercially Available Alternative Allogeneic Hematopoietic Stem Cell Transplantation Donor Source. Clin J Oncol Nurs 2025; 29:230-236. [PMID: 40401840 PMCID: PMC12124889 DOI: 10.1188/25.cjon.230-236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 01/07/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Although allogeneic hematopoietic stem cell transplantation (alloHSCT) can be a lifesaving therapy for patients with hematologic malignancies, only 30% of patients in need of transplantation will have a human leukocyte antigen matched related donor available. OBJECTIVES This article introduces an approved alternative donor stem cell source that is shown to provide earlier engraftment and decreased infections compared to dual or single umbilical cord blood transplantation. METHODS This article provides an overview of the pathophysiology, clinical trial results, and nursing management of the approved omidubicel-onlv cellular therapy product as an alternative donor source for patients undergoing alloHSCT. FINDINGS Omidubicel provides an alternative donor source for patients undergoing alloHSCT for whom there is no matched donor available. This need may be particularly great in ethnic and racial minority populations who may be underrepresented in the NMDP BioTherapies database.
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Morcos-Sandino M, Quezada-Ramírez SI, Gómez-De León A. Advances in the Treatment of Acute Myeloid Leukemia: Implications for Low- and Middle-Income Countries. Biomedicines 2025; 13:1221. [PMID: 40427048 PMCID: PMC12109363 DOI: 10.3390/biomedicines13051221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 05/09/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Acute myeloid leukemia (AML) presents a significant global health challenge due to its aggressive behavior and mortality rates. Traditionally, AML treatment has relied on intensive chemotherapy-anthracyclines and cytarabine. However, recent breakthroughs in targeted therapies are transforming clinical practices. This review examines current treatment strategies, including breakthrough therapies. Also, a global perspective on AML management includes the disparity in treatment availability, particularly the difficulties faced by low- and middle-income countries due to the high cost and restricted access to novel therapies.
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Affiliation(s)
| | | | - Andrés Gómez-De León
- Hematology Service, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León (UANL), Av. Madero y Gonzalitos S/N, Mitras Centro, Monterrey ZC 64460, Nuevo León, Mexico; (M.M.-S.); (S.I.Q.-R.)
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Kawamura S, Nakagawa D, Nagayama T, Katayama Y, Doki N, Takeda W, Nishida T, Matsuoka KI, Ikeda T, Ohigashi H, Sawa M, Fukushima K, Kanda J, Serizawa K, Onizuka M, Fukuda T, Atsuta Y, Kanda Y, Nakasone H. Impacts of donor age and HLA mismatch on HCT outcomes differ according to the donor CMV serostatus in unrelated allo-HCT. Blood Adv 2025; 9:2356-2365. [PMID: 39808797 DOI: 10.1182/bloodadvances.2024014408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/16/2025] Open
Abstract
ABSTRACT In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 patients with CMV seropositivity who received unrelated allo-HCT. We divided the entire cohort into 2 cohorts according to the donor CMV serostatus: CMV positive (DP) and negative (DN). We also stratified each cohort into 4 groups based on donor age (aged ≥40 or <40 years) and HLA parity (8/8 or 7/8): Young88 and Old88, and Young78 and Old78, respectively. In the CMV-DP cohort, the Old88 (hazard ratio [HR], 1.20; P = .012), Young78 (HR, 1.35; P < .001), and Old78 (HR, 1.60; P < .001) groups were associated with inferior overall survival (OS) than the Young88 group. In contrast, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP: HR, 1.19; P = .001; CMV-DN: HR, 1.04; P = .53; P for interaction, .070), as was the impact of HLA (CMV-DP: HR, 1.34; P < .001; CMV-DN: HR, 1.08; P = .23; P for interaction, .012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV-seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.
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Affiliation(s)
- Shunto Kawamura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Daishi Nakagawa
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Nagayama
- Division of Cell Transplantation and Transfusion, Jichi Medical University, Shimotsuke, Japan
| | - Yuta Katayama
- Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Wataru Takeda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Tetsuya Nishida
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Ken-Ichi Matsuoka
- Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
| | - Takashi Ikeda
- Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Ohigashi
- Department of Hematology, Hokkaido University Hospital, Sapporo, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Kentaro Fukushima
- Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan
| | - Junya Kanda
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kentaro Serizawa
- Division of Hematology and Rheumatology, Department of Internal Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Makoto Onizuka
- Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
- Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Division of Hematology, Jichi Medical University, Shimotsuke, Japan
| | - Hideki Nakasone
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
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Thordardottir TH, Rodenbach RA, Brauer M, Hall AC, Ward E, Smith CB, Campbell TC. 'A perfect match': how hematologists discuss donor options and risks with black and white patients considering allogeneic stem cell transplant. Leuk Lymphoma 2025:1-10. [PMID: 40331277 DOI: 10.1080/10428194.2025.2500625] [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: 03/15/2025] [Revised: 04/25/2025] [Accepted: 04/26/2025] [Indexed: 05/08/2025]
Abstract
Patients of racial minorities have lower chance of securing a suitable donor, essential part of successful allogeneic stem cell transplant. In this simulated interview study, we sought to examine how hematologists discuss donor options and risks with patients with high-risk myeloid neoplasm considering transplant. Thirty-seven US hematologists participated (65% male; 65% white, 24% Asian, none Black), randomly assigned to meet with a Black or white patient actor. The hematologists emphasized the benefits of a full match with the white patient and high chance of securing a donor. Conversely, with the Black patient, they tended not to ask about ancestry, discuss the donor registry, race implications or challenges with donor search. Knowing the patient had children, many recommended haploidentical transplant. The unique circumstances of transplant argue for a focused communication including discussing race. While conversations should be tailored to each patient, limiting essential information on donor options may contribute to disparities.
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Affiliation(s)
| | - Rachel A Rodenbach
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
- James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Markus Brauer
- Department of Psychology, University of Wisconsin, Madison, WI, USA
| | - Aric C Hall
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - Earlise Ward
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
- Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | | | - Toby C Campbell
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
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Madbouly A, Bashyal P, Banos A, Ramirez J, Whitaker C, Fernandez-Vina M, Springer B, Ybarra Y, Maiers M, Bolon YT. Profiling the genetic diversity of the HLA system in Mexico using 9-locus allele and haplotype frequencies from donors in the NMDP Mexico donor center. Hum Immunol 2025; 86:111324. [PMID: 40334347 DOI: 10.1016/j.humimm.2025.111324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 04/24/2025] [Accepted: 04/29/2025] [Indexed: 05/09/2025]
Abstract
Profiling the HLA diversity at the population level benefits multiple clinical and anthropological applications, such as tracing population migration, identifying genetic relationships between different groups, quantifying the added diversity in a global donor pool and matching for solid organ and stem cell transplantation. We calculated nine-locus HLA-A ∼ C ∼ B ∼ DRB1 ∼ DRB3/4/5 ∼ DQA1 ∼ DQB1 ∼ DPA1 ∼ DPB1 allele and haplotype frequencies in about 170,000 volunteer donor genotypes from the NMDP Mexico (NMDP MX, previously Be The Match Mexico) donor center. These donors are predominantly of Mexican ancestry recruited from multiple regions in Mexico. The goal of the study was to describe the HLA genetic profiles of the Mexican population and investigate the contribution of these donors' HLA in serving Mexican, US and international patients in need of hematopoietic cell transplants. Additionally, we estimated that almost all Mexican patients will have an available 5 of 8 or better matched donor in the NMDP MX donor center with matches also available for some of the Latino patients in the U.S. We demonstrate that Mexican populations clustered genetically and shared multiple frequent alleles and haplotypes with populations from the US Mexican or Chicano, US South/Central American Hispanic, and some Latino populations. Operationally, 78 % of NMDP Mexico donors contributed genotypes that were observed a total of three times or less on the registry, increasing the diversity of the overall NMDP registry. More than 300 donor collections were facilitated through the NMDP MX donor center serving mostly Hispanic/Latino patients in the US and abroad. This study highlights the importance of adding the NMDP MX donors to the worldwide donor pool and paves the way for a data-driven strategy for future planning and donor recruitment.
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Affiliation(s)
- Abeer Madbouly
- CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA; NMDP, Minneapolis, MN, USA
| | - Pradeep Bashyal
- CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA; NMDP, Minneapolis, MN, USA
| | | | | | | | | | | | | | - Martin Maiers
- CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA; NMDP, Minneapolis, MN, USA
| | - Yung-Tsi Bolon
- CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA; NMDP, Minneapolis, MN, USA
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9
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Maiers M, Greco‐Stewart V, Madbouly A, Robinson J, Eberhard H, Sauter J, Louzoun Y, Israeli S, Bolon Y, Pingel J, Schmidt AH, Spierings E, Leonhard‐Melief C, Foeken L, Schuit M, Venter A, Marsh SGE. The Registry of Unmet Need: A World Marrow Donor Association Analysis of Patients Without an HLA Match. HLA 2025; 105:e70255. [PMID: 40404178 PMCID: PMC12097852 DOI: 10.1111/tan.70255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/16/2025] [Accepted: 05/07/2025] [Indexed: 05/24/2025]
Abstract
While the World Marrow Donor Association global database currently offers approximately 42.7 million potential donors and cord blood units to patients in need of haematopoietic cell transplant, lack of eight HLA-matched donors remains a significant barrier. The Registry of Unmet Need (RUN) Project seeks to address disparities in transplant access for patients with rare HLA genotypes, particularly those from populations that have been historically underrepresented and underserved by global donor registries. Patients eligible for this study searched for an unrelated donor for transplant between 2015 and 2017 and, at that time, lacked a potential eight-of-eight HLA-matched unrelated donor (MUD). Sixteen donor registries contributed data from 3654 patients using standardised data-collection project templates. To address this unmet need, pooled data were analysed to identify trends and inform global recruitment strategies. Patient genotypes were queried against the global inventory at later timepoints in 2018 and 2023 to determine whether potential matches had been recruited within the years since the initial search. Patient haplotypes were imputed using an open-source method referencing US population frequencies. The imputation process used five continental reference populations and 21 detailed populations derived from the NMDP database. The method provided a Bayesian inference of population membership. A control group consisting of US patients that yielded 1000 or more potential matches was used for comparison. RUN patient haplotype and genotype frequencies were substantially lower compared with controls; both the more frequent and less frequent haplotypes in RUN patients were found to be approximately 100 times less common than those in the control group. We identified 782 potential cases in which a potential MUD was recruited after the initial RUN patient search was performed; while this result is being further investigated, clear patterns of where these new matches can be found have emerged; typically, new matches are found outside the country where the patient search was initiated. Our findings demonstrate that rare haplotypes are the primary barrier to identifying a MUD; the presence of rare alleles or haplotype combinations, as with multi-race ancestry, is rarely the cause. Although strategic donor recruitment efforts will help improve MUD access, patient transplants should not be delayed in pursuit of a MUD when viable alternative options are available.
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Affiliation(s)
- Martin Maiers
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDPMinneapolisMinnesotaUSA
| | - Valerie Greco‐Stewart
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDPMinneapolisMinnesotaUSA
| | - Abeer Madbouly
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDPMinneapolisMinnesotaUSA
| | - James Robinson
- Anthony Nolan Research InstituteLondonUK
- UCL Cancer Institute, Royal Free CampusLondonUK
| | | | | | - Yoram Louzoun
- Department of MathematicsBar‐Ilan UniversityRamat GanIsrael
| | - Sapir Israeli
- Department of MathematicsBar‐Ilan UniversityRamat GanIsrael
| | - Yung‐Tsi Bolon
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDPMinneapolisMinnesotaUSA
| | | | | | | | | | - Lydia Foeken
- World Marrow Donor AssociationLeidenthe Netherlands
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10
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Rodriguez-Torres JC, Pando-Caciano A, Future B, Guerrero ME, Saldarriaga T, Pereda MA, Murillo-Vizcarra SA. Haploidentical Stem Cell Transplantation With TCR-αβ + /CD19 + Depletion in High-risk Pediatric Leukemias: Experience From a Referral Center in Peru. J Pediatr Hematol Oncol 2025; 47:161-168. [PMID: 40167993 PMCID: PMC12002040 DOI: 10.1097/mph.0000000000003021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 01/31/2025] [Indexed: 04/02/2025]
Abstract
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using TCR αβ+/CD19+ depletion provides an alternative treatment for patients with high-risk (HR) leukemias without a matched donor, especially in developing nations with limited donor registries. We present the outcomes of 36 patients <16 years with HR leukemia who underwent haplo-HSCT with TCR αβ + /CD19 + depletion between 2018 and 2022 at a referral center in Peru. Survival probabilities and cumulative incidence functions were calculated using the Kaplan-Meier method. Patients were followed for a median of 17.38 months (range: 2.34 to 60.36 mo). The 5-year overall survival (OS), 5-year event-free survival (EFS), and non-relapse mortality rates were 72.1%, 72.2%, and 16.7%, respectively. The incidence of relapse for the entire group was 11.1%. Acute graft versus host disease (GvHD) was observed in 36.1% of the patients, with only 2.8% experiencing grade III-IV acute GvHD. No patients developed chronic GvHD. Among all patients, CMV reactivations were observed in 27.78%, HHV-6 reactivations in 33.33%, and ADV or BK virus reactivations in 16.67%. Our study suggests that haplo-HSCT with TCR αβ+/CD19+ depletion is a safe and effective treatment for HR pediatric leukemias. Adopting this approach in major transplant centers throughout the country could improve outcomes for this group of patients.
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Affiliation(s)
| | - Alejandra Pando-Caciano
- Sub Unidad de Investigación e Innovación Tecnológica, Instituto Nacional de Salud del Niño San Borja, Lima, Perú
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias e Ingeniería, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Benigno Future
- Servicio de Trasplante de Progenitores Hematopoyéticos, Instituto Nacional de Salud del Niño San Borja, Lima, Perú
| | - Marco E. Guerrero
- Servicio de Trasplante de Progenitores Hematopoyéticos, Instituto Nacional de Salud del Niño San Borja, Lima, Perú
| | - Tatiana Saldarriaga
- Servicio de Trasplante de Progenitores Hematopoyéticos, Instituto Nacional de Salud del Niño San Borja, Lima, Perú
| | - María A. Pereda
- Tulane University School of Medicine, Children’s Hospital New Orleans, New Orleans, LA
| | - Sergio A. Murillo-Vizcarra
- Servicio de Hematología Especializada, Trasplante de Progenitores Hematopoyéticos, Hospital Nacional Edgardo Rebagliati Martins, Lima, Perú
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11
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Abdelgawad HAH, Aboeldahab H, Belal MM, Bashir MN, Miller HK, Handgretinger R, Otto M. Comprehensive up-to-date analysis on TCRαβ/CD19-depleted hematopoietic stem cell transplantation in pediatric hematological malignancies. Transpl Immunol 2025; 90:102220. [PMID: 40107625 DOI: 10.1016/j.trim.2025.102220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 03/07/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
This meta-analysis assesses the efficacy of TCRαβ+/CD19+ depleted hematopoietic stem cell transplantation (HSCT) in pediatric patients with hematological malignancies, bridging the gap in the heterogeneous results of published studies. We analyzed post-HSCT complications and survival outcomes in 1068 children across 14 studies, using both aggregated and patient-level data from acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and acute lymphoblastic leukemia (ALL) studies, employing the IPDfromKM technique for time-to-event data reconstruction. The analysis reveals a 95 % engraftment success rate (95 % CI: 93-97) and 6-year overall survival and disease-free survival (DFS) rates of 67.2 % and 66.3 %, respectively, with no significant differences in DFS between haploidentical and unrelated donors (hazard ratio = 0.9, 95 % CI: 0.53-1.55). Acute graft-versus-host disease (GvHD) grades III-IV and chronic GvHD incidences were 8 % (95 % CI: 6-11) and 17 % (95 % CI: 10-27). The relapse rate was 27 % (95 % CI: 21-33), with relapse-related mortality at 21 % (95 % CI: 15-28) and HSCT-related mortality at 12 % (95 % CI: 7-19). Relapse was significantly lower in patients (mostly ALL) receiving total body irradiation (risk ratio = 0.53, P = 0.04). These findings underscore TCRαβ/CD19-depleted HSCT as a valuable option for patients without HLA-matched donors, highlighting the need for larger, multicenter studies.
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Affiliation(s)
- Hussien Ahmed H Abdelgawad
- Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine-Phoenix, AZ, USA.
| | - Heba Aboeldahab
- Biomedical Informatics and Medical Statistics Department, Medical Research Institute, Alexandria University, Egypt; Clinical Research Department, El-Gomhoria General Hospital, MOHP, Alexandria, Egypt
| | | | | | - Holly K Miller
- Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine-Phoenix, AZ, USA; Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Rupert Handgretinger
- Department of Hematology/Oncology, Children's University Hospital, Tuebingen, Germany; Department of Pediatrics, National University of Singapore, Singapore
| | - Mario Otto
- Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine-Phoenix, AZ, USA.
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12
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Marcoux C, Kebriaei P. SOHO State of the Art Updates and Next Questions | Transplant in Adult Acute Lymphoblastic Leukemia. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025:S2152-2650(25)00147-8. [PMID: 40383653 DOI: 10.1016/j.clml.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 05/20/2025]
Abstract
The landscape of acute lymphoblastic leukemia (ALL) treatment is rapidly evolving, with new therapies challenging traditional treatment paradigms. While allogeneic hematopoietic cell transplantation (allo-HCT) remains essential for many high-risk patients, advances in measurable residual disease (MRD) monitoring and the increasing use of immunotherapies in earlier treatment lines have reshaped transplant decision-making. Improvements in donor availability, conditioning strategies, and post-transplant care have expanded access and improved survival, yet relapse and toxicity remain major challenges. This review examines the evolving role of allo-HCT in ALL, highlighting key advancements and ongoing challenges.
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Affiliation(s)
- Curtis Marcoux
- Division of Hematology, Dalhousie University, Halifax, Canada
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
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13
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Raiola AM, Bruno B, Risitano AM, Mosna F, Cavattoni IM, Onida F, Saporiti G, Patriarca F, Battista ML, Pavone V, Mele A, Chiusolo P, Sica S, Loteta B, di Grazia C, Carella AM, Salvatore D, Morello E, Leoni A, Giaccone L, Bernasconi P, Terruzzi E, Mordini N, Borghero C, Zallio F, Luppi M, Grassi A, Olivieri A, Piras E, Sacchi N, Ciccone G, Castiglione A, Degrandi E, Angelucci E, Martino M, Bonifazi F. Posttransplant cyclophosphamide as GVHD prophylaxis in patients receiving mismatched unrelated HCT: the PHYLOS trial. Blood Adv 2025; 9:1966-1975. [PMID: 39928954 PMCID: PMC12018986 DOI: 10.1182/bloodadvances.2024015173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/24/2024] [Accepted: 01/08/2025] [Indexed: 02/12/2025] Open
Abstract
ABSTRACT Posttransplant high-dose cyclophosphamide (PTCy) is effective in overcoming the negative impact of HLA disparity in the haploidentical setting. In light of these results, we investigated the efficacy of PTCy, in improving clinical outcomes of hematopoietic stem cell transplantation (HSCT) from a mismatched unrelated donor (MMUD) in patients with acute myeloid malignancies by reducing the incidence and severity of acute graft-versus-host disease (aGVHD). A prospective, single-arm, phase 2 study (PHYLOS) was conducted by the Gruppo Italiano Trapianto di Midollo Osseo. The ethical committees of the participating centers approved the study (EURODRACT 2017-003530-85). A total of 77 consecutive patients (acute myeloid leukemia: 64; myelodysplastic syndrome: 13) were enrolled at 26 Italian transplant centers (January 2020-November 2022). Median age of the patients was 53 (range, 19-65) years. The 100-day cumulative incidence of grades 2 to 4 aGVHD was 18.2% (95% CI, 10.6-27.6) and of grades 3 to 4 was 6.5% (95% CI, 3.1-15.1). Seventy-one patients (92%) had full-donor chimerism with complete neutrophil engraftment by day +30. One-year cumulative incidence of chronic GVHD was 13.4% (95% CI, 6.9-22.1). One-year cumulative incidence of nonrelapse mortality was 9.1% (95% CI, 4.0-16.9), and the relapse rate was 23.8% (95% CI, 14.9-33.9). One-year overall survival and graft relapse-free survival were 78.6% (95% CI, 67.4-86.3) and 55.3% (95% CI, 43.4-65.7), respectively. Our study in a homogeneous patient cohort suggests that PTCy leads to a low rate of aGVHD and improves clinical outcomes of HSCT from MMUD. This trial was registered at www.clinicaltrials.gov as #NCT03270748.
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Affiliation(s)
- Anna Maria Raiola
- Department of Hematology and Cellular Therapy, Istituo di Ricovero E Cura A Carattere Scientifico, Ospedale Policlinico San Martino, Genoa, Italy
| | - Benedetto Bruno
- Division of Hematology, Azienda Ospedaliera Universitaria Citta' della Salute e della Scienza di Torino, and Department of Biotechnologies and Health Sciences, University of Torino, Turin, Italy
| | - Antonio Maria Risitano
- Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy
| | - Federico Mosna
- Hematology and Bone Marrow Transplantation Unit, Hospital of Bolzano (SABES-Azienda Sanitaria dell'Alto Adige), Teaching Hospital of Paracelsus Medical University, Bolzano, Italy
| | - Irene Maria Cavattoni
- Hematology and Bone Marrow Transplantation Unit, Hospital of Bolzano (SABES-Azienda Sanitaria dell'Alto Adige), Teaching Hospital of Paracelsus Medical University, Bolzano, Italy
| | - Francesco Onida
- Hematology and Bone Marrow Transplantation Unit, Azienda Socio Sanitaria Territoriale Fatebenefratelli-Sacco, University of Milan, Milan, Italy
- Centro Trapianti Midollo Osseo e Terapie Cellulari-Struttura Complessa Ematologia, Fondazione Istituo di Ricovero E Cura A Carattere Scientifico, Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giorgia Saporiti
- Centro Trapianti Midollo Osseo e Terapie Cellulari-Struttura Complessa Ematologia, Fondazione Istituo di Ricovero E Cura A Carattere Scientifico, Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Patriarca
- Division of Hematology, S. Maria della Misericordia Hospital, Dipartimento di Medicina, Università di Udine, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Marta Lisa Battista
- Division of Hematology, S. Maria della Misericordia Hospital, Dipartimento di Medicina, Università di Udine, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Vincenzo Pavone
- Unità Operativa Complessa Ematologia con Trapianto, Azienda Ospedale Car Panico Tricase (Lecce), Tricase, Italy
| | - Anna Mele
- Unità Operativa Complessa Ematologia con Trapianto, Azienda Ospedale Car Panico Tricase (Lecce), Tricase, Italy
| | - Patrizia Chiusolo
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze di laboratorio ed Ematologiche, Fondazione Policlinico A. Gemelli Istituo di Ricovero E Cura A Carattere Scientifico, Rome, Italy
| | - Simona Sica
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze di laboratorio ed Ematologiche, Fondazione Policlinico A. Gemelli Istituo di Ricovero E Cura A Carattere Scientifico, Rome, Italy
| | - Barbara Loteta
- Stem Cell Transplantation and Cellular Therapies Unit, Grande Ospedale Metropolitano, “Bianchi-Melacrino-Morelli,” Reggio Calabria, Italy
| | - Carmen di Grazia
- Department of Hematology and Cellular Therapy, Istituo di Ricovero E Cura A Carattere Scientifico, Ospedale Policlinico San Martino, Genoa, Italy
| | - Angelo Michele Carella
- Department of Hematology and Stem Cell Transplant Unit, Fondazione Istituo di Ricovero E Cura A Carattere Scientifico Casa Sollievo della Sofferenza, Foggia, Italy
| | - Dalila Salvatore
- Department of Hematology and Stem Cell Transplant Unit, Fondazione Istituo di Ricovero E Cura A Carattere Scientifico Casa Sollievo della Sofferenza, Foggia, Italy
| | - Enrico Morello
- Blood Diseases and Cell Therapies Unit, Bone Marrow Transplant Unit, “Azienda Socio Sanitaria Territoriale-Spedali Civili” Hospital of Brescia, Brescia, Italy
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Alessandro Leoni
- Blood Diseases and Cell Therapies Unit, Bone Marrow Transplant Unit, “Azienda Socio Sanitaria Territoriale-Spedali Civili” Hospital of Brescia, Brescia, Italy
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Luisa Giaccone
- Division of Hematology, Azienda Ospedaliera Universitaria Citta' della Salute e della Scienza di Torino, and Department of Biotechnologies and Health Sciences, University of Torino, Turin, Italy
| | - Paolo Bernasconi
- Hematopoietic Stem Cell Unit, Hematology Department, Fondazione Istituo di Ricovero E Cura A Carattere Scientifico Policlinico San Matteo, Pavia, Italy
| | - Elisabetta Terruzzi
- Haematology Unit, Istituo di Ricovero E Cura A Carattere Scientifico San Gerardo, Monza, Italy
| | - Nicola Mordini
- Division of Hematology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Carlo Borghero
- Hematology Department, “San Bortolo” Hospital, Vicenza, Italy
| | - Francesco Zallio
- Hematology Department, SS Antonio and Biagio and C. Arrigo Hospital, Alessandria, Italy
| | - Mario Luppi
- Ematologia, Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
| | - Anna Grassi
- Hematology-Bone Marrow Transplantation Unit Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Attilio Olivieri
- Clinica di Ematologia, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
| | - Eugenia Piras
- Hematology Unit, Businco Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Nicoletta Sacchi
- Italian Bone Marrow Donor Registry, E.O. Galliera Hospitals, Genoa, Italy
| | - Giovannino Ciccone
- Unit of Clinical Epidemiology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino e Centro Prevenzione Oncologica Piemonte, Turin, Italy
| | - Anna Castiglione
- Unit of Clinical Epidemiology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino e Centro Prevenzione Oncologica Piemonte, Turin, Italy
| | - Eliana Degrandi
- Trial Office Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali emopoietiche e terapia Cellulare, Bologna, Italy
| | - Emanuele Angelucci
- Department of Hematology and Cellular Therapy, Istituo di Ricovero E Cura A Carattere Scientifico, Ospedale Policlinico San Martino, Genoa, Italy
| | - Massimo Martino
- Stem Cell Transplantation and Cellular Therapies Unit, Grande Ospedale Metropolitano, “Bianchi-Melacrino-Morelli,” Reggio Calabria, Italy
| | - Francesca Bonifazi
- Istituo di Ricovero E Cura A Carattere Scientifico Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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14
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Merdin A, Aydın Ü. Evaluation of the Awareness and Approaches of People Between the Ages of 19-60 in a Rural Area of Antalya Province About Blood Stem Cell Donation and Bone Marrow Donation. Risk Manag Healthc Policy 2025; 18:1397-1405. [PMID: 40352113 PMCID: PMC12065113 DOI: 10.2147/rmhp.s514701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Purpose While hematopoietic stem cell transplantation is commonly associated with stem cell procedures in public discourse, "stem cell" remains a broad classification. More precise terminology such as "blood stem cell transplantation", "bone marrow transplantation", or "bone marrow stem cell transplantation" may better characterize hematopoietic stem cell procedures in both public and academic contexts. This study aimed to evaluate public comprehension of these specific terms and to assess awareness and attitudes toward stem cell donation, with particular focus on rural populations. Materials and Methods The study recruited 250 participants aged 19-60 years from rural Aksu District, Antalya Province. Individuals with a history of stem cell transplantation, those with a first-degree relative with a history of stem cell transplantation, and healthcare professionals were excluded from the study. The participants were asked 11 questions about their approach to stem cell donation and their thoughts on the subject. Results Among the 250 participants, 51.6% (n=129) expressed willingness to become stem cell donors, whereas 48.4% (n=121) reported no willingness to be a donor. Interestingly, 95.6% (n=239) of the participants stated that they would like to know the identity of the person to whom they would be donating stem cells. Conclusion This study underscores the need to revisit current anonymity regulations in stem cell transplantation, particularly when both donor and recipient express a desire for mutual identification. Updating regulatory protocols and codes to facilitate information exchange in such cases might be better. Moreover, if the recipient may require further donations from the same donor, the donor should be consulted pre-transplantation about their willingness to provide further support. Their preferences should also be considered in the treatment approach when necessary.
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Affiliation(s)
- Alparslan Merdin
- Süleyman Demirel University Faculty of Medicine, Department of Internal Medicine, Division Hematology, Isparta, Turkey
| | - Ümit Aydın
- Süleyman Demirel University Faculty of Medicine, Department of Internal Medicine, Isparta, Turkey
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15
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Horwitz ME, Schiller GJ, Tsai SB, Rezvani AR, Maziarz RT, Goshen U, Levy S, Schwarzbach A, Mazor RD, Stiff PJ. Omidubicel-onlv Transplantation for Hematologic Malignancies: Results of a Multicenter Expanded Access Program. Transplant Cell Ther 2025:S2666-6367(25)01138-8. [PMID: 40204073 DOI: 10.1016/j.jtct.2025.04.005] [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: 01/17/2025] [Revised: 03/25/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Omidubicel-onlv is an FDA-approved, nicotinamide-modified, allogeneic hematopoietic progenitor cell therapy derived from umbilical cord blood (UCB). A phase 3 study demonstrated improved hematopoietic recovery and decreased infections with omidubicel compared with UCB allogeneic transplantation. We report results of an Expanded Access Program evaluating clinical outcomes in patients with hematologic malignancies following transplantation with omidubicel. Between August 2020 and May 2023, 29 patients were transplanted at 5 US sites. Patients received myeloablative conditioning, prophylactic and therapeutic medications, and supportive care per institutional guidelines, and were monitored for engraftment, infections, and graft-versus-host-disease (GVHD) for up to 2 years post-transplant. Results were compared with previously reported phase 3 outcomes. Omidubicel recipients had a median age of 39 (range 20-73, 62% male); 45% were non-White and 65.5% had acute leukemia. Median follow-up was 11.8 (range: .3-27.7) months. Median neutrophil and platelet engraftment times were 12 and 33.5 days, respectively. Acute GVHD (grade 3-4) at day 100 occurred in 19% of patients, with chronic GVHD at 1 year in 9% of patients, all of which were mild. First grade 2 to 3 bacterial infections through 100 days post-transplant and first grade 3 viral infection 1 year post-transplant occurred in 18% and 12% of patients, respectively. One-year disease-free survival and overall survival rates were 76% and 87%, respectively. This real-world study of omidubicel transplantation for hematologic malignancies finds that this graft source is commonly used for non-White allogeneic transplant recipients. The rapid engraftment kinetics observed following transplantation with omidubicel appears to have addressed excessive nonrelapse mortality that has been previously observed following myeloablative umbilical cord blood transplantation.
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Affiliation(s)
| | - Gary J Schiller
- David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
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16
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Dvorak CC, Cho S, Salinas Cisneros G, Higham CS, Chu J, Winestone LE, Temple WC, Kharbanda S, Shimano KA, Avagyan S, Pauerstein PT, Huang JN, Cheng G, Lalefar N, Aguayo-Hiraldo P, Keizer RJ, Pulsipher MA, Long-Boyle JR. High Melphalan Exposure Increases the Risk of Graft-Versus-Host Disease in Pediatric Patients Undergoing Alpha-Beta T-Cell Depleted Haploidentical Transplantation. Transplant Cell Ther 2025:S2666-6367(25)01115-7. [PMID: 40185404 DOI: 10.1016/j.jtct.2025.03.020] [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: 01/22/2025] [Revised: 03/19/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Melphalan is often used as the backbone agent for conditioning prior to A/B-T-cell depleted (A/B-TCD) hematopoietic cell transplant (HCT) due to lower rates of organ toxicity compared to busulfan or total-body irradiation, albeit with significant mucosal injury. Traditional dosing based on body-surface-area (BSA) may result in non-optimal melphalan exposure among certain patient subsets. OBJECTIVES As mucosal injury is linked to initiation of alloreactivity, we hypothesized that high exposure of melphalan predicted via a pharmacokinetic (PK) model would be associated with an increased risk of acute graft-versus-host disease (aGVHD). STUDY DESIGN We performed an analysis of 85 patients who underwent A/B-TCD haploidentical HCT on 2 prospective trials using melphalan-based conditioning for treatment of malignancy at 3 centers from 2015 to 2024. Most patients (61.2%) received a total dose of melphalan at 140 mg/m2 using actual body weight; others received a dose adjusted for obesity or age <2 years. We analyzed outcomes based on whether melphalan exposure was above or below the median exposure for the group. RESULTS The 100-day cumulative incidences of engraftment syndrome (ES), grade II-IV aGVHD, and grade III-IV aGVHD were 34.2%, 24.8%, and 17.1%, respectively. The 3-year cumulative incidence of chronic GVHD (cGVHD), non-relapse mortality (NRM), and relapse were 17.5%, 8.7%, 21.8%, respectively. The 3-year cumulative incidence of disease-free survival (DFS) and severe GVHD-relapse-free survival (GRFS) were 71.4% and 55.6%, respectively. ES was significantly associated with the subsequent development of aGVHD, both grade II-IV (41.4% vs. 17.3% in those with and without ES, P = .01) and grade III-IV (34.5% vs. 8.5% in those with and without ES; P = .003). Chronic GVHD occurred at significantly higher rates in patients with prior Grade II-IV (66.7% vs. 0% for Grade 0-I; P < .001) and Grade III-IV aGVHD (75% vs. 4.3% for Grade 0-II; P < .001). Compared to non-obese patients, the PK model predicted lower melphalan exposure (P = .02) in obese patients where adjusted ideal body weight was utilized, suggesting overcorrection of the dose. There was no impact of melphalan exposure on immunologic rejection. The median melphalan exposure was 6.81 mg*hr/L (range, 4.4-8.8). Compared to a melphalan exposure ≤6.8 mg*hr/L, a melphalan exposure >6.8 mg*hr/L was associated with a higher incidence of ES (48.8% vs. 19.1%; P = .005), grade II-IV aGVHD (39.3% vs. 10.1%; P = .002), and grade III-IV aGVHD (31.5% vs. 2.5%; P < .001). The 3-year incidence of cGVHD was 27.2% in those with high predicted melphalan exposure compared to 7.4% for low exposure (P = .03); with no difference in 3-year NRM incidence (9.2% vs. 7.7%; P = .82) or 3-year relapse incidence (16.8% vs. 27.6%; P = .31) for high compared to low exposure. However, GRFS was significantly worse in patients with high exposure (46.4%) vs. low exposure (64.6%; P = .02). CONCLUSIONS High melphalan exposure predicted by a validated population PK model is associated with an increased likelihood of developing ES and subsequently acute and chronic GVHD. Given that a substantial number of patients already require adjustment of standard BSA-based dosing for young age or obesity, a prospective trial of model-based dosing to individualize melphalan exposure is warranted to confirm these results.
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Affiliation(s)
- Christopher C Dvorak
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California.
| | - Soohee Cho
- Division of Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, Utah
| | - Gabriel Salinas Cisneros
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Christine S Higham
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Julia Chu
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Lena E Winestone
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - William C Temple
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Sandhya Kharbanda
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Kristin A Shimano
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Serine Avagyan
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Philip T Pauerstein
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California; Division of Pediatric Oncology, University of California San Francisco, San Francisco, California
| | - James N Huang
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California; Division of Pediatric Hematology, University of California San Francisco, San Francisco, California
| | - Geoffrey Cheng
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California
| | - Nahal Lalefar
- Division of Pediatric Hematology, University of California San Francisco, San Francisco, California
| | - Paibel Aguayo-Hiraldo
- Division of Pediatric Hematology, Oncology, and Transplantation and Cellular Therapy, University of Southern California, Children's Hospital Los Angeles, Los Angeles, California
| | | | - Michael A Pulsipher
- Division of Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, Utah
| | - Janel R Long-Boyle
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California; Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California
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17
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Ikeda S, Hasegawa K, Kogue Y, Arimori T, Kawamoto R, Wibowo T, Yaga M, Inada Y, Uehara H, Matsubara M, Tachikawa M, Suga M, Kida S, Shibata K, Tsutsumi K, Fukushima K, Fujita J, Ueda T, Kusakabe S, Hino A, Ichii M, Hirose A, Nakamae H, Hino M, Nakao T, Inoue M, Yoshihara K, Yoshihara S, Ueda S, Tachi T, Kuroda H, Murakami K, Kijima N, Kishima H, Igashira E, Murakami M, Takiuchi T, Kimura T, Hiroshima T, Kimura T, Shintani Y, Imai C, Yusa K, Mori R, Ogino T, Eguchi H, Takeda K, Oji Y, Kumanogoh A, Takagi J, Hosen N. CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant. NATURE CANCER 2025; 6:595-611. [PMID: 40128569 DOI: 10.1038/s43018-025-00934-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 02/19/2025] [Indexed: 03/26/2025]
Abstract
Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.
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MESH Headings
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/genetics
- Hematopoietic Stem Cell Transplantation/methods
- Animals
- Humans
- Mice
- Female
- Killer Cells, Natural/immunology
- HLA-DRB1 Chains/immunology
- HLA-DRB1 Chains/genetics
- Receptors, Chimeric Antigen/immunology
- Transplantation, Homologous
- Male
- Immunotherapy, Adoptive/methods
- T-Lymphocytes/immunology
- Antibodies, Monoclonal/immunology
- Middle Aged
- Adult
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Shunya Ikeda
- World Premier Interenational Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Kana Hasegawa
- World Premier Interenational Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Yosuke Kogue
- Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Company, Osaka, Japan
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takao Arimori
- Institute for Protein Research, Osaka University, Osaka, Japan
| | - Ryuhei Kawamoto
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tansri Wibowo
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Moto Yaga
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuri Inada
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hirofumi Uehara
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Miwa Matsubara
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mana Tachikawa
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Makiko Suga
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Kida
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kumi Shibata
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuhito Tsutsumi
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kentaro Fukushima
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Jiro Fujita
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tomoaki Ueda
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinsuke Kusakabe
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Akihisa Hino
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Michiko Ichii
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Asao Hirose
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hirohisa Nakamae
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masayuki Hino
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takafumi Nakao
- Department of Hematology, Osaka City General Hospital, Osaka, Japan
| | - Megumu Inoue
- Department of Hematology, Itami City Hospital, Hyogo, Japan
| | - Kyoko Yoshihara
- Department of Hematology, Hyogo Medical University Hospital, Hyogo, Japan
| | - Satoshi Yoshihara
- Department of Hematology, Hyogo Medical University Hospital, Hyogo, Japan
| | - Shuji Ueda
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Hyogo, Japan
| | - Tetsuro Tachi
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hideki Kuroda
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Koki Murakami
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Noriyuki Kijima
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Haruhiko Kishima
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Eri Igashira
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mari Murakami
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tsuyoshi Takiuchi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takashi Hiroshima
- Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Toru Kimura
- Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasushi Shintani
- Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Chihaya Imai
- Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Kosuke Yusa
- Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Ryota Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Takeda
- World Premier Interenational Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Yusuke Oji
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Kumanogoh
- World Premier Interenational Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Junichi Takagi
- Institute for Protein Research, Osaka University, Osaka, Japan
| | - Naoki Hosen
- World Premier Interenational Immunology Frontier Research Center, Osaka University, Osaka, Japan.
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan.
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18
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Feist WN, Luna SE, Ben-Efraim K, Filsinger Interrante MV, Amorin A, Johnston NM, Bruun TUJ, Utz A, Ghanim HY, Lesch BJ, McLaughlin TM, Dudek AM, Porteus MH. Multilayered HIV-1 resistance in HSPCs through CCR5 Knockout and B cell secretion of HIV-inhibiting antibodies. Nat Commun 2025; 16:3103. [PMID: 40164595 PMCID: PMC11958643 DOI: 10.1038/s41467-025-58371-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 03/19/2025] [Indexed: 04/02/2025] Open
Abstract
Allogeneic transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5-null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs engraft and reconstitute multiple hematopoietic lineages in vivo and can be engineered to express multiple antibodies simultaneously (in pre-clinical models). Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro. This work lays the foundation for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy of CCR5 KO HSPC transplantation.
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Affiliation(s)
- William N Feist
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Sofia E Luna
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Kaya Ben-Efraim
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Maria V Filsinger Interrante
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA
- Stanford ChEM-H, Stanford University, Stanford, CA, USA
| | - Alvaro Amorin
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Nicole M Johnston
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Theodora U J Bruun
- Stanford ChEM-H, Stanford University, Stanford, CA, USA
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - Ashley Utz
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Hana Y Ghanim
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Benjamin J Lesch
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA
| | | | - Amanda M Dudek
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
| | - Matthew H Porteus
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
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19
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Afranie-Sakyi JA, Randall E, Fasano R, McLemore ML, El Rassi F. The Mortality of Adults With Sickle Cell Disease at a Comprehensive Sickle Cell Center. Eur J Haematol 2025; 114:663-671. [PMID: 39748504 DOI: 10.1111/ejh.14360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 01/04/2025]
Abstract
INTRODUCTION Sickle cell disease (SCD) is the most common hemoglobinopathy in North America. The life expectancy of SCD has extended into adulthood with screenings, preventative care, and hydroxyurea. However, comorbidities arise as adults with SCD age, leading to early mortality. METHODS We conducted a retrospective chart review of the Georgia Comprehensive Sickle Cell Center at Grady Health System, analyzing records of deceased SCD patients from 2013 to 2020. RESULTS Amongst the 72 patients analysed, majority had severe complications from SCD and at least 1 cardiovascular comorbidity. The median age of death was 44 (STD = 15.5) for all genotypes with the median age of death at 39 (STD = 14.26) for SS and Sβ0 genotypes (n = 51). There was no difference in the median age of death for patients who maintained regular clinic visits (a visit in the last 6 months prior to death) compared to those who did not. Despite hydroxyurea's known benefits in reducing SCD morbidity and mortality, less than 50% of patients had a prescription. CONCLUSION As new therapies are approved, their impact on SCD-related morbidity and mortality must be evaluated. Improving access to, and education about, disease-modifying therapies like hydroxyurea for both patients and clinicians is essential to improving outcomes.
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Affiliation(s)
- Jennifer A Afranie-Sakyi
- Department of Internal Medicine, Morehouse School of Medicine, Atlanta, Georgia, USA
- Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Eldrida Randall
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA
| | - Ross Fasano
- Georgia Comprehensive Sickle Cell Center at Grady Health System, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Morgan L McLemore
- Georgia Comprehensive Sickle Cell Center at Grady Health System, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Fuad El Rassi
- Georgia Comprehensive Sickle Cell Center at Grady Health System, Emory University School of Medicine, Atlanta, Georgia, USA
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20
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Rotz SJ, Wiener L, Baker KS, Choi SW, Phelan R, Cuvelier GDE, Duncan C, Williams KM, Qayed M. Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part IV. Patient Important Outcomes. Transplant Cell Ther 2025; 31:224.e1-224.e13. [PMID: 39733839 PMCID: PMC11957933 DOI: 10.1016/j.jtct.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/13/2024] [Accepted: 12/20/2024] [Indexed: 12/31/2024]
Abstract
Chronic graft-versus-host disease (cGVHD) occurs in approximately 1 in 5 pediatric allogeneic HCT patients and is a leading cause of late morbidity and mortality. Late effects of hematopoietic cell transplantation (HCT) may lead to long-term chronic health conditions and shortened life expectancy. In addition to direct physiologic challenges from cGVHD and other late effects, numerous patient-important outcomes impact the quality of life (QOL) of patients and their families. The Research and Education towards Solutions for Late Effects to Innovate, Excel, and Nurture (RESILIENT) after GVHD Consensus Conference was convened to better understand the overlap of cGVHD and late effects in pediatric HCT survivors. Working Committee IV: Patient Important Outcomes identified 4 key areas for focus: (1) What are the key mental health and QOL concerns of survivors of pediatric cGVHD? (2) What is the impact of cGVHD on cognitive performance and social development? (3) What multilevel social determinants of health impact cGVHD survivors, families, and communities? (4) What is the role of racial, ethnic, and socioeconomic factors on the development of cGVHD and the risk for adverse outcomes related to survivorship? For each focus area, the Working Committee reviewed the current state of the field, developed recommendations for clinical practice, and highlighted areas to prioritize for future research. Eleven recommendations were adapted and approved. Substantial overlap exists between the role of cGVHD and late effects on the QOL and mental health of childhood HCT survivors. Recommendations based on available data and consensus opinion may be helpful to improve outcomes for these patients. However, several gaps remain that need further study.
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Affiliation(s)
- Seth J Rotz
- Division of Pediatric Hematology, Oncology, and Blood and Marrow Transplantation, Cleveland Clinic, Cleveland, Ohio.
| | - Lori Wiener
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - K Scott Baker
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Sung Won Choi
- Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, Michigan
| | - Rachel Phelan
- Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Geoffrey D E Cuvelier
- Department of Pediatric Oncology and Transplantation, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | | | - Kirsten M Williams
- Aflac Blood and Cancer Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Muna Qayed
- Aflac Blood and Cancer Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
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21
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Khaseb S, Kohansal Vajari M, Soufi Zomorrod M, Rezai Rad M, Ajami M, Ajami M, Sadeghpour S, Atashi A. Effect of fibrin on the expression of adhesion molecules (ICAM-1, ITGAV, and ITGB3) in unrestricted somatic stem cells. Hematol Transfus Cell Ther 2025; 47:103827. [PMID: 40315755 PMCID: PMC12098137 DOI: 10.1016/j.htct.2025.103827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/18/2024] [Accepted: 11/10/2024] [Indexed: 05/04/2025] Open
Abstract
BACKGROUND Hematopoietic stem cell expansion relies on direct cell-cell interactions mediated by adhesion molecules, integrins, and cytokines. Unrestricted somatic stem cells have emerged as novel stromal cells supporting hematopoietic stem cell expansion in co-culture conditions via secretion of hematopoiesis-related cytokines and the expression of adhesion molecules. Previous research showed fibrin increased hematopoiesis-related gene expression in these cells. This study focused on the adhesive characteristics of unrestricted somatic stem cells on 3D fibrin scaffolds. METHODS Unrestricted somatic stem cells were isolated from umbilical cord blood and characterized using flow cytometry and multilineage differentiation assays. Scanning electron microscopy and DAPI staining were employed to analyze cell attachment to fibrin. Viability on fibrin was assessed through MTT assays. Quantitative polymerase chain reaction was conducted to evaluate the expression of intercellular adhesion molecule 1 (ICAM-1), integrin subunit αv (ITGAV), and integrin subunit β3 (ITGB3) in cells cultured on 3D fibrin scaffolds. RESULTS Cells were positive for CD73, CD105, and CD166 but negative for CD45. Alizarin red and Oil red O stains confirmed calcium deposition and lipid vacuoles. MTT assays revealed that fibrin positively impacts viability. ITGAV expression was significantly increased in cells cultured on fibrin compared to those cultured on plastic tissue culture plates (Control Group). Furthermore, ITGB3 expression showed no significant change in both groups, while ICAM-1 expression was downregulated in cells cultured on fibrin. CONCLUSIONS Our study revealed that fibrin has a positive impact on the expression of ITGAV, which plays a crucial role in direct cell-cell interactions affecting hematopoietic stem cell expansion.
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Affiliation(s)
- Sanaz Khaseb
- Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran
| | - Mahdi Kohansal Vajari
- Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran; School of Allied Medical Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Maryam Rezai Rad
- Research Institute for Dental Sciences, Dental Research Center, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Monireh Ajami
- Faculty of Paramedical Sciences, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Mansoureh Ajami
- School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Saba Sadeghpour
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Atashi
- Stem Cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
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22
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Liu YC, Lin TA, Fan NW, Ko PS, Wang HY, Tsai CK, Chien SH, Liu CJ, Hsiao LT. Incidence and impact of invasive fungal infection comparing post-transplant cyclophosphamide with cyclosporine plus methotrexate GVHD prophylaxis in allogeneic HSCT. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2025; 58:226-232. [PMID: 39627110 DOI: 10.1016/j.jmii.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 11/13/2024] [Accepted: 11/28/2024] [Indexed: 03/18/2025]
Abstract
BACKGROUND In recent years, haploidentical hematopoietic stem cell transplantation (haploHSCT) with post-transplant cyclophosphamide (PTCy) has become increasingly prevalent. However, the precise impact of invasive fungal disease (IFD) in relation to graft-versus-host disease (GVHD) prophylaxis and donor type remains to be elucidated. METHODS In this study, we analyzed data from 580 HSCT patients, comprising 80 patients who received haploidentical grafts and 500 patients who received grafts from other donor types. PTCy was exclusively administered to haploidentical HSCT recipients, while cyclosporine A (CsA) in combination with short-course methotrexate (scMTX) was used for patients receiving grafts from other donors. RESULTS The IFD rate by PTCy and CsA plus scMTX was 15 % and 15.6 %, respectively. At 6 months and 1 year post-transplant, the cumulative incidence of IFD was 9.4 % and 14.8 % for the PTCy group, and 7.9 % and 12.3 % for the CsA plus scMTX group, respectively. Both groups exhibited poor survival outcomes associated with IFD. Identified risk factors for IFD included age ≥ 45 years, disease relapse, and grade III-IV acute GVHD. Aspergillus spp. and Candida spp. were the most commonly isolated pathogens. High rate of cytomegalovirus reactivation was also noticed in PTCy or CsA plus scMTX group, but not a risk factor for IFD. CONCLUSION The similar IFD rate between haploHSCT with PTCy and others with CsA plus scMTX was documented, with Aspergillus spp. and Candida spp. as the most common pathogens. Further research is needed to investigate IFD following haploHSCT with PTCy and to explore differences with other types of allogeneic HSCT.
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Affiliation(s)
- Yao-Chung Liu
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan.
| | - Ting-An Lin
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Nai-Wen Fan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Po-Shen Ko
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Hao-Yuan Wang
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Chun-Kuang Tsai
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Sheng-Hsuan Chien
- School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan; Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Chia-Jen Liu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan; Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Liang-Tsai Hsiao
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
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23
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Takahashi T, Wachter F, Alvarez Calderon F, Kapadia M, Qayed M, Keating AK. Umbilical Cord Blood Reduced Relapse but Increased Nonrelapse Mortality Compared to Matched Unrelated Donor Transplantation in Pediatric Acute Myeloid Leukemia With Active Disease: A CIBMTR 2008 to 2017 Analysis of Donor Source and Residual Disease. Transplant Cell Ther 2025; 31:261.e1-261.e15. [PMID: 39938807 DOI: 10.1016/j.jtct.2025.01.889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/23/2024] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
Umbilical cord blood (UCB) and matched unrelated donors (MUD) are common alternative donor options in children with high-risk acute myeloid leukemia (AML). Emerging evidence suggests an augmented graft-versus-leukemia (GVL) effect of UCB, but uncertainties persist due to the heterogeneity of the hematopoietic cell transplantation (HCT) characteristics in the previous studies. We reviewed 1148 patients aged ≤18 years with AML, who underwent the first HCT between 2008 to 2017, using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry data. Multivariable analyses evaluated predictors of DFS and other clinical outcomes, factoring in graft source, conditioning regimen, patient age, cytogenetic risk, and HCT year (significance at P < .01). Residual disease status was assessed both as a covariate and as a stratifying factor. Additionally, the differential effects of conditioning regimens were analyzed specifically within the UCB cohort. UCB was used most frequently (33.8%) followed by MUD (29.1%), both of which had comparable DFS and overall survival. In patients with minimal residual disease or not in remission prior to HCT, human-leukocyte antigen (HLA) ≤5/8 matched UCB was associated with lower relapse rates than MUD (hazard risk [HR]: 0.25 and 0.29, P = .005 and .006, respectively) but with increased nonrelapse mortality (HR: 32.8 and 7.5, P = .001 and .012, respectively). Conditioning regimens varies by graft type; total body irradiation (TBI)-based regimens, primarily combined with cyclophosphamide and fludarabine, were more common in the UCB cohort (45% in UCB versus 19% in the other grafts, P < .001). Within the 388 patients received UCB, multivariable analysis demonstrated comparable DFS and OS across variable busulfan- and TBI-based regimens, with no trend of superiority for either approach. In conclusion, highly HLA-mismatched UCB reduced relapse in pediatric AML with higher disease burden but increased nonrelapse mortality, resulting in similar DFS to MUD. Improved supportive care and toxicity mitigation may improve the outcomes of UCB transplant. Overall, UCB should be considered a viable alternative graft source with equally favorable outcomes to MUD. Further research is warranted to refine conditioning regimen, including TBI- and busulfan-based strategies, mitigate toxicity, and improve supportive care to optimize UCB HCT outcomes.
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Affiliation(s)
- Takuto Takahashi
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Franziska Wachter
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Francesca Alvarez Calderon
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Malika Kapadia
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Muna Qayed
- Division of Pediatric Hematology/Oncology, Emory University School of Medicine, Atlanta, Georgia; Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Amy K Keating
- Stem Cell Transplant, Boston Children's Hospital, Boston, Massachusetts; Pediatric Stem Cell Transplant, Dana-Farber Cancer Institute, Boston, Massachusetts
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24
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Bernardo VS, Torres FF, Zucão ACA, Chaves NA, Santana ILR, da Silva DGH. Disrupted homeostasis in sickle cells: Expanding the comprehension of metabolism adaptation and related therapeutic strategies. Tissue Cell 2025; 93:102717. [PMID: 39805212 DOI: 10.1016/j.tice.2024.102717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/02/2024] [Accepted: 12/29/2024] [Indexed: 01/16/2025]
Abstract
Sickle cell disease (SCD) is a hereditary hemolytic anemia associated with the alteration of the membrane composition of the sickle erythrocytes, the loss of glycolysis, dysregulation of the pyruvate phosphatase pathway, and changes in nucleotide metabolism of the sickle red blood cell (RBC). This review provides a comprehensive overview of the impact of the presence of Hb S, which leads to the disruption of the normal RBC metabolism. The intricate interplay between the redox and energetic balance in erythrocytic cells, where the glycolysis, pentose phosphate pathway, and methemoglobin reductase pathways are all altered in sickle RBC, is a key focus. Moreover, this review summarizes the current knowledge about the disease-modifying agents and their action mechanisms based on the sickle RBC alterations previously mentioned (i.e., their association with beneficial effects on the sickle cells' membrane, to their RBCs' energy metabolism, and to their oxidative status). Therefore, providing a comprehensive understanding of how sickle cells cope with the disruption of metabolic homeostasis and the most promising therapeutic agents able to ameliorate the various consequences of abnormal sickle RBC alterations.
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Affiliation(s)
| | | | | | - Nayara Alves Chaves
- Department of Biology, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
| | | | - Danilo Grünig Humberto da Silva
- Department of Biology, Universidade Estadual Paulista (UNESP), São Paulo, Brazil; Campus de Três Lagoas, Universidade Federal de Mato Grosso do Sul (CPTL/UFMS), Mato Grosso do Sul, Brazil.
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25
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Abboud R, Schroeder MA, Rettig MP, Jayasinghe RG, Gao F, Eisele J, Gehrs L, Ritchey J, Choi J, Abboud CN, Pusic I, Jacoby M, Westervelt P, Christopher M, Cashen A, Ghobadi A, Stockerl-Goldstein K, Uy GL, DiPersio JF. Itacitinib for prevention of graft-versus-host disease and cytokine release syndrome in haploidentical transplantation. Blood 2025; 145:1382-1394. [PMID: 39576962 DOI: 10.1182/blood.2024026497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/24/2024] Open
Abstract
ABSTRACT Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly used treatment for hematologic malignancies. Although posttransplant cyclophosphamide (PtCy) has improved graft-versus-host disease (GVHD) prophylaxis in haplo-HCT, patients continue to experience life-threatening complications. Interferon gamma and interleukin-6 are central in the pathophysiology of GVHD and cytokine release syndrome (CRS), and both cytokines signal through Janus kinase 1 (JAK-1). We tested the effect of adding the JAK-1 selective inhibitor, itacitinib, to PtCy-haplo-HCT to mitigate these complications and improve overall survival (OS). This open-label, single-arm study evaluated the safety and efficacy of itacitinib combined with standard GVHD prophylaxis after haplo-HCT. A total of 42 patients were treated with itacitinib 200 mg daily from day -3 through +100 or +180, followed by a taper. Itacitinib resulted in low CRS grades, all patients had grade 0 (22%) or grade 1 (78%) CRS and there were no cases of grade 2 to 5 CRS. There were no cases of primary graft failure. No patients developed grade 3 to 4 acute GVHD (aGVHD) through day +180. The cumulative incidence of grade 2 aGVHD at day +100 was 21.9%. The 1-year cumulative incidence of moderate or severe chronic GVHD was 5%. The cumulative incidence of relapse at 2 years was 14%. OS at 1 year was 80%. The cumulative incidence of nonrelapse mortality (NRM) at day 180 was 8%. Itacitinib, when added to standard GVHD prophylaxis, was well tolerated and resulted in low rates of CRS, acute and chronic GVHD, and NRM, and encouraging rates of GVHD-free relapse-free survival and OS after haplo-HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03755414.
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Affiliation(s)
- Ramzi Abboud
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Mark A Schroeder
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Michael P Rettig
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Reyka G Jayasinghe
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Feng Gao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Jeremy Eisele
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Leah Gehrs
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Julie Ritchey
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Jaebok Choi
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Camille N Abboud
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Iskra Pusic
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Meagan Jacoby
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Peter Westervelt
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Matthew Christopher
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Amanda Cashen
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Armin Ghobadi
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Keith Stockerl-Goldstein
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Geoffrey L Uy
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - John F DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
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26
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Rassek K, Misiak J, Ołdak T, Rozwadowska N, Basak G, Kolanowski T. New player in CAR-T manufacture field: comparison of umbilical cord to peripheral blood strategies. Front Immunol 2025; 16:1561174. [PMID: 40191201 PMCID: PMC11968755 DOI: 10.3389/fimmu.2025.1561174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 02/28/2025] [Indexed: 04/09/2025] Open
Abstract
One of the most successful treatments in hematologic cancer is chimeric antigen receptor (CAR)-T cell-based immunotherapy. However, CAR-T therapy is not without challenges like the costly manufacturing process required to personalize each treatment for individual patients or graft-versus-host disease. Umbilical cord blood (UCB) has been most commonly used for hematopoietic cell transplant as it offers several advantages, including its rich source of hematopoietic stem cells, lower risk of graft-versus-host disease, and easier matching for recipients due to less stringent HLA requirements compared to bone marrow or peripheral blood stem cells. In this review, we have discussed the advantages and disadvantages of different CAR-T cell manufacturing strategies with the use of allogeneic and autologous peripheral blood cells. We compare them to the UCB approach and discuss ongoing pre-clinical and clinical trials in the field. Finally, we propose a cord blood bank as a readily available source of CAR-T cells.
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Affiliation(s)
- Karolina Rassek
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | | | - Tomasz Ołdak
- FamicordTx, Warsaw, Poland
- Polish Stem Cell Bank (PBKM), Warsaw, Poland
| | - Natalia Rozwadowska
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
- FamicordTx, Warsaw, Poland
| | - Grzegorz Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Kolanowski
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
- FamicordTx, Warsaw, Poland
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27
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Gedeon C, Rodenbach R, Campbell TC, Thordardottir TH, Brauer M. Racial Disparities in Doctor-Patient Communication: Examining Doctors' Encounters with Black and White Patients. J Racial Ethn Health Disparities 2025:10.1007/s40615-025-02374-0. [PMID: 40072799 DOI: 10.1007/s40615-025-02374-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025]
Abstract
Healthcare disparities persist in the USA, with Black patients often receiving lower-quality care. Effective doctor-patient communication is crucial for influencing satisfaction, adherence to treatment, and overall health outcomes. This study examined racial disparities in doctor-patient communication, focusing on encounters with Black and White patients recently diagnosed with myelodysplastic neoplasm (MDS). Thirty-seven oncologists participated in simulated encounters with trained actors portraying either Black or White patients. Using an innovative approach combining the comparison of communication characteristics, thematic content, and linguistic analyses, we observed significant disparities in time allocation, linguistic complexity, and relation-building efforts. Encounters with Black patients were notably shorter, with doctors using fewer words per sentence, asking fewer questions, and employing less inclusive and optimistic language. Doctors also had less thorough discussions about transplant options and used fewer words communicating authenticity when talking with Black patients. The post-encounter surveys revealed that doctors were not aware of their shortcomings when interacting with Black patients. The findings provide important insights for the development of training programs aimed at improving healthcare outcomes for marginalized communities and reducing racial healthcare disparities.
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Affiliation(s)
- Cassandra Gedeon
- LAPSCO UMR6024, University Clermont Auvergne, Clermont-Ferrand, France
| | - Rachel Rodenbach
- James P. Wilmot Cancer Center, University of Rochester, Rochester, USA
| | - Toby C Campbell
- Department of Medicine, Division of Hematology, Medical Oncology and Palliative Care, University of Wisconsin-Madison, Madison, USA
| | - Thorunn H Thordardottir
- Department of Medicine, Division of Hematology, Medical Oncology and Palliative Care, University of Wisconsin-Madison, Madison, USA
| | - Markus Brauer
- Department of Psychology, University of Wisconsin-Madison, 1202 West Johnson St., Madison, WI, 53706, USA.
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28
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Walters MC, Eapen M, Liu Y, El Rassi F, Waller EK, Levine JE, Strouse JJ, Antin JH, Parikh SH, Bakshi N, Dampier C, Jaroscak JJ, Bergmann S, Wong T, Kota V, Pace B, Lekakis LJ, Lulla P, Nickel RS, Kasow KA, Popat U, Smith W, Yu L, DiFronzo N, Geller N, Kamani N, Klings ES, Hassell K, Mendizabal A, Sullivan K, Neuberg D, Krishnamurti L. Hematopoietic cell transplant compared with standard care in adolescents and young adults with sickle cell disease. Blood Adv 2025; 9:955-965. [PMID: 39471440 PMCID: PMC11907447 DOI: 10.1182/bloodadvances.2024013926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/17/2024] [Accepted: 09/23/2024] [Indexed: 11/01/2024] Open
Abstract
ABSTRACT Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2 years after biologic assignment to a donor or no donor (SOC) arm based on the availability of an HLA-matched sibling or unrelated donor (BMT CTN 1503). A donor search was commenced after eligibility confirmation. The primary end point was a comparison of survival between the treatment arms 2 years after biologic assignment. Power calculations required 60 participants in the donor arm and 140 in the no donor arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives were a comparison of the changes in SCD-related events, functional outcomes, and organ function. The data were analyzed according to the intent-to-treat principle. A total of 113 participants were enrolled with 28 in the donor arm and 85 in the no donor arm. The 2-year probabilities of survival were 89% and 93%, in the donor vs no donor arms. Vaso-occlusive pain (VOC) was less frequent in the donor arm in the second year after biologic assignment (P < .001). Based on PROMIS-57 surveys, there was a decrease in fatigue (P = .003) and an increase in the ability to participate in social roles and activities (P = .003) in the donor arm 2 years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the donor arm led to improvements in VOC, fatigue, and social function. This trial was registered at www.clinicaltrials.gov as #NCT02766465.
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Affiliation(s)
- Mark C. Walters
- Department of Pediatrics, Division of Hematology, University of California San Francisco, San Francisco, CA
| | - Mary Eapen
- Department of Medicine, Division of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI
| | - Yiwen Liu
- Department of Data Science, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA
| | - Fuad El Rassi
- Department of Hematology and Medical Oncology, Division of Hematology, Emory University, Atlanta, GA
| | - Edmund K. Waller
- Department of Hematology and Medical Oncology, Division of Hematology, Emory University, Atlanta, GA
| | - John E. Levine
- Department of Pediatrics, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - John J. Strouse
- Department of Medicine, Division of Hematology Oncology, Duke University Medical Center, Durham, NC
| | - Joseph H. Antin
- Hematologic Oncology Treatment Program, Dana-Farber Cancer Institute, Boston, MA
| | - Suhag H. Parikh
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA
| | - Nitya Bakshi
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA
- Department of Pediatrics, Division of Hematology/Oncology/BMT, Yale School of Medicine, New Haven, CT
| | - Carlton Dampier
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA
| | - Jennifer J. Jaroscak
- Department of Pediatrics, Division of Hematology/Oncology/BMT, Medical University of South Carolina, Charleston, SC
| | - Shayla Bergmann
- Department of Pediatrics, Division of Hematology/Oncology/BMT, Medical University of South Carolina, Charleston, SC
| | - Trisha Wong
- Division of Hematology and Oncology, School of Medicine, Oregon Health & Science University, Portland, OR
| | - Vamsi Kota
- Department of Medicine, Division of Hematology and Oncology, Medical College of Georgia, Augusta University, Augusta, GA
| | - Betty Pace
- Department of Pediatrics, Division of Hematology and Oncology, Medical College of Georgia, Augusta University, Augusta, GA
| | - Lazaros J. Lekakis
- Department of Medicine, Division of Hematology/Oncology/BMT, University of Miami, Miami, FL
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX
| | - Robert S. Nickel
- Department of Pediatrics, Division of Hematology, Children’s National Hospital, Washington, DC
| | - Kimberly A. Kasow
- Department of Pediatrics, Division of Hematology/Oncology/BMT, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Uday Popat
- Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wally Smith
- Department of Medicine, Division of General Internal Medicine, Virginia Commonwealth University, Richmond, VA
| | - Lolie Yu
- Department of Pediatrics, Division of Hematology/Oncology/BMT, Children’s Hospital of New Orleans, New Orleans, LA
| | - Nancy DiFronzo
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Nancy Geller
- National Heart, Lung, and Blood Institute, Division of Intramural Research, National Institutes of Health, Bethesda, MD
| | - Naynesh Kamani
- Department of Pediatrics, Division of Immunology, Children’s National Hospital, Washington, DC
| | - Elizabeth S. Klings
- Department of Medicine, Division of Hematology and Medical Oncology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
| | - Kathryn Hassell
- Department of Medicine, Division of Hematology, University of Colorado, Denver, CO
| | | | - Keith Sullivan
- Department of Medicine, Division of Hematologic Malignanices and Cellular Therapy, Duke University Medical Center, Durham, NC
| | - Donna Neuberg
- Department of Data Science, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA
| | - Lakshmanan Krishnamurti
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA
- Department of Pediatrics, Division of Hematology/Oncology/BMT, Yale School of Medicine, New Haven, CT
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29
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Kajdic A, Deuitch NT, Bresciani E, Davis J, Craft K, Chong S, Liu Y, Young DJ, Kanakry CG, Cunningham L, Liu P. Genetic testing to identify hereditary predispositions to haematological malignancy is critical prior to allogenic haematopoietic cell transplant. Br J Haematol 2025; 206:1000-1003. [PMID: 39865735 DOI: 10.1111/bjh.19989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 12/26/2024] [Indexed: 01/28/2025]
Affiliation(s)
- Amra Kajdic
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
| | - Natalie T Deuitch
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
| | - Erica Bresciani
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
| | - Joie Davis
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
| | - Kathleen Craft
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
| | - Shawn Chong
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
| | - Yi Liu
- Genetics Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - David J Young
- Translational Stem Cell Biology Branch, National Heart Lung, and Blood Institute (NHLBI), Bethesda, Maryland, USA
| | - Christopher G Kanakry
- Center for Immuno-Oncology, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | - Lea Cunningham
- Immune-Deficiency Cellular Therapy Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | - Paul Liu
- Oncogenesis and Development Section, Translational and Functional Genomics Branch (TFGB), National Human Genome Research Institute (NHGRI), Bethesda, Maryland, USA
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30
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Xiao J, Yang X, Wu N, Fan S, Liu Z, Jiang F, Chen J, Wei J, Sun Y. Modified G-CSF/ATG-Based Haploidentical Transplantation Protocol in Pediatric Primary Hemophagocytic Lymphohistiocytosis: A Long-Term Follow-Up Single-Center Experience. Pediatr Blood Cancer 2025; 72:e31495. [PMID: 39704507 DOI: 10.1002/pbc.31495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/12/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by immune dysregulation. Hematopoietic stem cell transplantation (HSCT) represents the only option for long-term cure for primary HLH. However, only around 25% of patients have a fully HLA-matched donor. METHODS In this retrospective study, we analyzed 42 pediatric patients with primary HLH who underwent haplo-SCT using the modified granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol. The conditioning regimen included 300-600 mg/m2 etoposide (VP16), along with low doses of busulfan (Bu) (0.8-1.2 mg/kg every 6 hours on Days -8 to -6), cyclophosphamide (Cy) (10 mg/kg/day on Days -4 to -3), fludarabine (Flu) (30 mg/m2/day on Days -5 to -3), and ATG (8-9 mg/kg total dose on Days -5 to -2) to reduce complications. RESULTS All 42 patients achieved successful engraftment. Following a median follow-up period of 48.7 months, 32 of the 42 patients remained alive and disease free. The 2-year overall survival (OS) rate was 78.4%, and the 5-year OS rate was 73.7%. The 2-year failure-free survival (FFS) rate was 71.3%, and the 5-year FFS rate was 66.5%. Patients who achieved complete remission at the time of HSCT showed better OS (p < 0.05). The incidence of Grade III-IV acute graft-versus-host disease (GVHD) was 26.2%, and severe chronic GVHD was observed in 11.9% of patients. Thrombotic microangiopathy occurred in 13 patients, and veno-occlusive disease in two patients. CONCLUSIONS This modified G-CSF/ATG-based haploidentical protocol demonstrates significant potential for pediatric patients with primary HLH, exhibiting commendable effectiveness and safety.
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Affiliation(s)
- Juan Xiao
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
| | - Xingcheng Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Nanhai Wu
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
| | - Shifen Fan
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
| | - Zhouyang Liu
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
| | - Fan Jiang
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
| | - Jiao Chen
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
| | - Jia Wei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuan Sun
- Department of Hematology and Oncology, Beijing Jingdu Children's Hospital, Beijing, China
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Yu S, Huang F, Xu N, Zhang Z, Liu C, Xu X, Fan Z, Zeng X, Liu Q, Qiu G, Xi X, Lin R, Liang X, Jiang Y, Dai M, Jin H, Li X, Wang S, Wu M, Sun J, Xuan L, Liu Q. Haploidentical peripheral blood stem cells combined with bone marrow or unrelated cord blood as grafts for haematological malignancies: an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol 2025; 12:e190-e200. [PMID: 39919775 DOI: 10.1016/s2352-3026(24)00372-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 02/09/2025]
Abstract
BACKGROUND Retrospective studies suggested that haploidentical transplantation combined with unrelated cord blood might improve survival for patients with haematological malignancies. We aimed to assess whether transplantation of haploidentical peripheral blood stem cells (PBSCs) plus unrelated cord blood would achieve superior disease-free survival compared with transplantation of haploidentical PBSCs plus bone marrow in this population. METHODS We did an open-label, randomised, phase 3 trial at seven hospitals in China. Eligible patients (aged 18-65 years) had a diagnosis of haematological malignancy, an Eastern Cooperative Oncology Group performance status of 0-2 and transplant comorbidity index of 0-2, and were receiving their first allogenic haematopoietic stem cell transplant. Patients were randomly assigned (1:1) to receive transplantation of haploidentical PBSCs plus bone marrow or haploidentical PBSCs plus unrelated cord blood. The primary endpoint was 1-year disease-free survival. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT05290545) and is complete. FINDINGS Between March 5, 2022, and Jan 2, 2023, 357 participants were screened for eligibility, and 314 were randomly assigned to receive transplantation of haploidentical PBSCs plus unrelated cord blood (n=157) or haploidentical PBSCs plus bone marrow (n=157). Median follow-up was 17·2 months (IQR 10·0-20·8) after random assignment. 1-year disease-free survival was 82·2% (95% CI 75·2-87·3) in the group receiving haploidentical PBSCs plus unrelated cord blood (PBSCs plus unrelated cord blood group) and 65·6% (57·6-72·5) in the group receiving haploidentical PBSCs plus bone marrow ([PBSCs plus bone marrow group] hazard ratio [HR] 0·47, 95% CI 0·30-0·74; p=0·0010). The most common grade 3-5 adverse events within 100 days of transplantation in participants in the PBSCs plus unrelated cord blood and PBSCs plus bone marrow groups were infections (58 [37%] of 157 vs 77 [49%] of 157, p=0·030), acute graft-versus-host disease (49 [31%] vs 61 [39%]), and gastrointestinal disorders (38 [24%] vs 38 [24%]). Seven (4%) patients in the PBSCs plus unrelated cord blood group and 17 (11%) in the PBSCs plus bone marrow group died of transplantation-related causes within 100 days of transplantation. Causes of deaths in the PBSCs plus unrelated cord blood group versus the PBSCs plus bone marrow group included infections (four [3%] vs 11 [7%]), acute graft-versus-host disease (one [1%] vs three [2%]), vascular disorders (two [1%] vs one [1%]), cardiac disorders (none vs one [1%]), and respiratory disorders (none vs one [1%]). INTERPRETATION Transplantation of haploidentical PBSCs plus unrelated cord blood achieved superior 1-year disease-free survival compared with transplantation of haploidentical PBSCs plus bone marrow in patients with haematological malignancies, with a more satisfactory safety profile. Our results suggest that combining haploidentical PBSCs with unrelated cord blood, rather than with bone marrow, could be a better treatment option for this population. FUNDING None.
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Affiliation(s)
- Sijian Yu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Fen Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Na Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Zhongming Zhang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Can Liu
- Department of Hematology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Xiaojun Xu
- Department of Hematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Zhiping Fan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Xiangzong Zeng
- Department of Hematology, The People's Hospital of Qingyuan, Qingyuan, China
| | - Qiong Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Guo Qiu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Xu Xi
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Xinquan Liang
- Department of Hematology, The First People's Hospital of Chenzhou, Chenzhou, China
| | - Yirong Jiang
- Department of Hematology, Dongguan People's Hospital, Affiliated Dongguan People's Hospital of Southern Medical University, Dongguan, China
| | - Min Dai
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Hua Jin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Xiaofang Li
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Shunqing Wang
- Department of Hematology, The First People's Hospital of Guangzhou, Guangzhou, China
| | - Meiqing Wu
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jing Sun
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Li Xuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China.
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de Franceschi L, Locatelli F, Rees D, Chabannon C, Dalle J, Rivella S, Iolascon A, Lobitz S, Abboud MR, de la Fuente J, Flevari P, Angelucci E, de Montalembert M. Selecting patients with sickle cell disease for gene addition or gene editing-based therapeutic approaches: Report on behalf of a joint EHA Specialized Working Group and EBMT Hemoglobinopathies Working Party consensus conference. Hemasphere 2025; 9:e70089. [PMID: 40084235 PMCID: PMC11904809 DOI: 10.1002/hem3.70089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 11/05/2024] [Accepted: 12/09/2024] [Indexed: 03/16/2025] Open
Abstract
Sickle cell disease (SCD) remains associated with reduced life expectancy and poor quality of life despite improvements observed in the last decades mostly related to comprehensive care, use of hydroxycarbamide, screening to identify patients at risk of strokes, and implementation of safe transfusion protocols. The course of the disease is highly variable, making it difficult to predict severity and response to therapy. Allogeneic hematopoietic stem cell transplantation potentially provides a cure with a relatively low rate of complications, but few patients have an HLA-identical sibling. The hopes of patients and healthcare providers have been raised after the initial excellent results of gene therapy studies. However, there is a strong contrast between the high expectations of families and patients and the limited availability of the product, which is technically complex and very expensive. In light of this consideration and of the limited data available on the long-term efficacy and toxicity of different gene therapy approaches, the European Hematology Association Red Cell & Iron Specialized Working Group (EHA SWG) and the hemoglobinopathy working part of the European Blood & Marrow Transplant (EBMT) Group have prioritized the development of recommendations for selection of patients with SCD who are good candidates for gene therapy. The decision-making algorithm was developed by a panel of experts in hemoglobinopathies and/or transplantation chosen by EHA SWG and EBMT, to discuss the selection of SCD patients for gene therapy and draw notes on the related clinical problems.
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Affiliation(s)
- Lucia de Franceschi
- Department of Engineering for Innovative MedicineUniversity of VeronaVeronaItaly
- Azienda Ospedaliera Universitaria integrata di VeronaVeronaItaly
| | - Franco Locatelli
- IRCCS Bambino Gesù Children's HospitalCatholic University of the Sacred HeartRomeItaly
| | - David Rees
- School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences Medicine, King's College London, and Department of Haematological MedicineKing's College HospitalLondonUK
| | - Christian Chabannon
- Institut Paoli‐Calmettes Comprehensive Cancer Center and Module Biotherapies du Centre d'Investigations Cliniques de Marseille, INSERM‐Aix‐Marseille Université AP‐HM‐IPCCBT‐1409MarseilleFrance
| | - Jean‐Hugues Dalle
- Pediatric Hematology and Immunoloy Department, Robert‐Debré Academic HospitalGHU AP‐HP Nord Université Paris CitéParisFrance
| | - Stefano Rivella
- Department of PediatricsHematology, The Children's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
- Penn Institute for RNA InnovationUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Penn Institute for Regenerative Medicine (IRM)University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Achille Iolascon
- Dipartimento di Medicina Molecolare e Biotecnologie MedicheUniversità degli Studi di Napoli Federico IINaplesItaly
- CEINGE Biotecnologie AvanzateNaplesItaly
| | - Stephan Lobitz
- Pediatric Hematology & Oncology, Gemeinschaftsklinikum MittelrheinKoblenzGermany
| | - Miguel R. Abboud
- Department of Pediatrics and Adolescent MedicineAmerican University of BeirutBeirutLebanon
| | - Josu de la Fuente
- Department of Immunology and InflammationCentre for Haematology, Imperial College LondonLondonUK
- Department of PaediatricsImperial College Healthcare NHS TrustLondonUK
| | - Pagona Flevari
- Thalassemia Unit—Center of Expertise in Haemoglobinopathies, Laiko General HospitalAthensGreece
| | - Emanuele Angelucci
- UO Ematologia e Terapie Cellulari, IRCCS Ospedale Policlinico San MartinoGenovaItaly
| | - Mariane de Montalembert
- Department of General Pediatrics and Pediatric Infectious Diseases, Sickle Cell Center, Necker‐Enfants Malades Hospital, Assistance Publique—Hôpitaux de Paris (AP‐HP)Université Paris CitéParisFrance
- Laboratory of Excellence GR‐ExParisFrance
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Jones RJ, Kassim AA, Brodsky RA, DeBaun MR. Is allogeneic transplantation for sickle cell disease still relevant in the era of gene therapy? Blood Adv 2025; 9:877-883. [PMID: 39602668 PMCID: PMC11875129 DOI: 10.1182/bloodadvances.2024013693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/04/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
ABSTRACT Sickle cell disease (SCD) is the most common inherited blood disease. Disease-modifying therapy and supportive care have improved the survival of children with SCD in the United States and Europe. Yet, adults with SCD continue to have high risks of morbidity and early death. Recently, 2 US Food and Drug Administration-approved genetic therapies offer the potential for a short-term decrease in acute vaso-occlusive pain events if not cure. Allogeneic hematopoietic cell transplantation (allo-HCT) is also curative but, until recently, was constrained by limited donor availability and the risks of graft-versus-host disease, graft rejection, and death. Importantly, recent advances have attenuated these barriers. Here, we discuss the current state of therapies with curative intent for SCD. Both genetic therapy and allo-HCT offer the potential for cure for most with SCD. However, the cost (∼5 times higher), the current need for myeloablation, and associated late-health effects may make genetic therapies less favorable choices than allo-HCT.
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Affiliation(s)
- Richard J. Jones
- Departments of Oncology and Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, MD
| | - Adetola A. Kassim
- Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN
| | - Robert A. Brodsky
- Departments of Oncology and Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, MD
| | - Michael R. DeBaun
- Departments of Pediatrics and Medicine, Vanderbilt University School of Medicine, Nashville, TN
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Herrity E, Singhabahu S, Remberger M, Alfaro Moya T, Novitzky Basso I, Pasic I, Lam W, Law AD, Viswabandya A, Gerbitz A, Kumar R, Kim DD, Lipton JH, Mattsson J, Michelis FV. Exploring Outcomes by Ethnicity in Allogeneic Hematopoietic Cell Transplantation. Cancers (Basel) 2025; 17:651. [PMID: 40002246 PMCID: PMC11853299 DOI: 10.3390/cancers17040651] [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: 01/23/2025] [Revised: 02/06/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Clinical outcome disparities among racial and ethnic groups have been described following allogeneic hematopoietic cell transplantation (HCT). This study investigated the impact of race and ethnicity on HCT outcomes in a multi-ethnic single-center population. METHODS We analyzed outcomes of 709 allogeneic HCT patients, stratified by racial and ethnic groups, who underwent allogeneic HCT between January 2018 and April 2022. Outcomes examined included overall survival (OS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and graft-versus-host disease/relapse-free survival (GRFS). RESULTS No significant differences in OS, CIR, NRM, GRFS, acute GVHD (aGVHD), or chronic GVHD (cGVHD) were observed. Significant differences in age, use of human leukocyte antigen-mismatched donors (HLA-MM), and HCT-CI comorbidity scores ≥ 3 across racial and ethnic groups were observed. Overall mean age was 58 years, with Black patients having the youngest mean age of 43 (range 22-73) and White patients the highest mean age of 59 (range 18-76) (p < 0.001). HCT-CI score ≥ 3 was seen in 35.9% of the entire cohort, varying by race and ethnicity: 60.5% in Black, 41.4% in South Asian, 31.5% in White, and 29.0% in East Asian patients (p < 0.001). Utilization of HLA-MM donors (including haploidentical) was 29.2% overall, with highest frequencies in Black (65.1%) and East Asian (45%) patients, and lowest in White patients (20.4%) (p < 0.001). CONCLUSIONS Statistically significant differences were observed across self-identified racial and ethnic groups regarding age, HCT-CI ≥ 3, and the use of HLA-MM donors. However, post-allogeneic HCT outcomes did not differ significantly by race or ethnicity. Larger prospective trials are warranted to validate our findings.
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Affiliation(s)
- Elizabeth Herrity
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Sanjay Singhabahu
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Mats Remberger
- Clinical Research and Development Unit, Department of Medical Sciences, Uppsala University Hospital, Uppsala University, 752 37 Uppsala, Sweden;
| | - Tommy Alfaro Moya
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Igor Novitzky Basso
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Ivan Pasic
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Wilson Lam
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Arjun D. Law
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Auro Viswabandya
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Armin Gerbitz
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Rajat Kumar
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Dennis D. Kim
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Jeffrey H. Lipton
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Jonas Mattsson
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
| | - Fotios V. Michelis
- Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada; (E.H.); (S.S.); (T.A.M.); (I.N.B.); (I.P.); (W.L.); (A.D.L.); (A.V.); (A.G.); (R.K.); (D.D.K.); (J.H.L.); (J.M.)
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35
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Weiss-Haug AV, Haraszti RA, Hug S, Faul C, Bethge WA, Lengerke C. Allogeneic Hemopoietic Cell Transplantation as a Paradigm for Cellular Immunotherapy. Oncol Res Treat 2025; 48:280-293. [PMID: 39907999 DOI: 10.1159/000543928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 11/18/2024] [Indexed: 02/06/2025]
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (alloHCT) is an established curative treatment for hematological malignancies and other severe blood disorders. However, alloHCT is also known for its significant side effects. SUMMARY Here we review recent advances in targeted molecular therapy, immunotherapy, infectiology, and diagnostics that have enhanced the tolerability and efficacy of alloHCT, expanding its use to less fit and elderly patients. We analyze developments in conditioning regimens, donor selection, and the management of graft versus host disease (GVHD) and infections and discuss posttransplantation strategies to prevent relapse. KEY MESSAGE In a fresh perspective, alloHCT can serve as a platform to enhance the potential of emerging targeted and immune therapies.
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Affiliation(s)
- Alisha Vanessa Weiss-Haug
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Reka Agnes Haraszti
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
- Gene and RNA Therapy Center, Faculty of Medicine, University of Tuebingen, Tuebingen, Germany
| | - Stefan Hug
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Christoph Faul
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Wolfgang Andreas Bethge
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Claudia Lengerke
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
- Gene and RNA Therapy Center, Faculty of Medicine, University of Tuebingen, Tuebingen, Germany
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Takahashi T, Watkins B, Bratrude B, Neuberg D, Hebert K, Betz K, Yu A, Choi SW, Davis J, Duncan C, Giller R, Grimley M, Harris AC, Jacobsohn D, Lalefar N, Farhadfar N, Pulsipher MA, Shenoy S, Petrovic A, Schultz KR, Yanik GA, Blazar BR, Horan JT, Langston A, Kean LS, Qayed M. The Adverse Event Landscape of Stem Cell Transplant: Evidence for AGVHD Driving Early Transplant Associated Toxicities. Transplant Cell Ther 2025; 31:109.e1-109.e13. [PMID: 38583802 DOI: 10.1016/j.jtct.2024.03.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 03/26/2024] [Accepted: 03/30/2024] [Indexed: 04/09/2024]
Abstract
Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (AGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of AGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 AGVHD, only AGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 AGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified AGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between AGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant AGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).
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Affiliation(s)
- Takuto Takahashi
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Benjamin Watkins
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, and Emory University, Atlanta, Georgia
| | - Brandi Bratrude
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Donna Neuberg
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kyle Hebert
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kayla Betz
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Alison Yu
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Jeffrey Davis
- BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christine Duncan
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Roger Giller
- Center for Cancer and Blood Disorders, Children Hospital of Colorado, University of Colorado, Aurora, Colorado
| | - Michael Grimley
- University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Andrew C Harris
- Memorial Sloan Kettering Cancer Center, New York City, New York
| | - David Jacobsohn
- Children's National Health System, Washington, District of Columbia
| | - Nahal Lalefar
- University of California San Francisco, UCSF Benioff Children's Hospital Oakland, Oakland, California
| | | | - Michael A Pulsipher
- Spencer Fox Eccles School of Medicine at the University of Utah, Intermountain Primary Children's Hospital, Salt Lake City, Utah
| | - Shalini Shenoy
- Washington University School of Medicine, St Louis, Missouri
| | - Aleksandra Petrovic
- Seattle Children's Hospital and Fred Hutch Cancer Center, Seattle, Washington
| | - Kirk R Schultz
- BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - John T Horan
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Amelia Langston
- Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Leslie S Kean
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Muna Qayed
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, and Emory University, Atlanta, Georgia
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Orvain C, Milano F, Rodríguez-Arbolí E, Othus M, Petersdorf EW, Sandmaier BM, Appelbaum FR, Walter RB. Relationship between donor source, pre-transplant measurable residual disease, and outcome after allografting for adults with acute myeloid leukemia. Leukemia 2025; 39:381-390. [PMID: 39668236 DOI: 10.1038/s41375-024-02497-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/25/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024]
Abstract
Lack of HLA-matched related/unrelated donor remains a barrier to allogeneic hematopoietic cell transplantation (HCT) for adult acute myeloid leukemia (AML), with ongoing uncertainty about optimal donor type if more than one alternative donor is available. To assess the relationship between donor type, pre-HCT measurable residual disease (MRD), and post-HCT outcomes, we retrospectively analyzed 1265 myelodysplastic neoplasm (MDS)/AML and AML patients allografted in first or second remission with an HLA-matched sibling (MSD) or unrelated donor (MUD), HLA-mismatched unrelated donor (MMD), an HLA-haploidentical donor, or umbilical cord blood (UCB) at a single institution. Relapse risk was non-significantly higher after HLA-haploidentical and lower after UCB HCT. Non-relapse mortality (NRM) was significantly higher in patients undergoing MMD HCT, HLA-haploidentical HCT, and UCB, translating into significantly lower relapse-free survival (RFS) and overall survival for MMD and HLA-haploidentical HCT. There was a significant interaction between conditioning intensity and post-HCT outcomes for UCB HCT with better RFS for UCB HCT after MAC but higher NRM after non-MAC. In patients with pre-HCT MRD receiving MAC, relapse risk was significantly lower and RFS higher in those who underwent UCB HCT in comparison to MSD/MUD. Together, UCB HCT is a valuable alternative for MAC HCT, particularly in patients with pre-HCT MRD.
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Affiliation(s)
- Corentin Orvain
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Maladies du Sang, CHU d'Angers, Angers, France
- Fédération Hospitalo-Universitaire Grand-Ouest Acute Leukemia, FHU-GOAL, Angers, France
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, Angers, France
| | - Filippo Milano
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA
| | - Eduardo Rodríguez-Arbolí
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), University of Seville, Seville, Spain
| | - Megan Othus
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Effie W Petersdorf
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA
| | - Brenda M Sandmaier
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA
| | - Frederick R Appelbaum
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Roland B Walter
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA.
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
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Gomez-Arteaga A, Chokr N, Auletta JJ. Precision medicine results from equitable representation. Bone Marrow Transplant 2025; 60:122-127. [PMID: 39433911 DOI: 10.1038/s41409-024-02430-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/21/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024]
Abstract
In this special issue of Bone Marrow Transplantation, investigators report the impact of IDH1 [1], IDH2 [2], and FLT3-TKD [3] measurable residual disease (MRD) pre-hematopoietic cell transplantation (HCT) in predicting relapse of acute myeloid leukemia (AML) in adults receiving allogeneic HCT. The patient population for these retrospective cohorts, reflecting clinical transplant practice patterns and research biobank participation, was 84-86% non-Hispanic White (NHW) in each study. In this commentary, we explore the implications of racial and ethnic disparities in access to both HCT and HCT-related research and propose strategies to promote representation in precision medicine, given the emerging impact of the field on HCT outcomes.
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Affiliation(s)
- Alexandra Gomez-Arteaga
- Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medicine/NewYork Presbyterian Hospital, New York, NY, USA.
| | - Nora Chokr
- Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medicine/NewYork Presbyterian Hospital, New York, NY, USA
| | - Jeffery J Auletta
- NMDP, Minneapolis, MN, USA
- Hematology/Oncology/Blood and Marrow Transplant and Infectious Diseases, Nationwide Children's Hospital, Columbus, OH, USA
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da Silva JS, Visentainer JEL, Fabreti-Oliveira RA, de Souza FCB, Silva MNP, da Costa Sena A, Goldenstein M, Claudino RE, de Souza Mendonça-Mattos PJ, Motta JPR, Secco DA, Oliveira D, Porto LC. Common, Intermediate and Well-Documented HLA Alleles in the Brazilian Population: An Analysis of the Brazilian Bone Marrow Donor Registry (REDOME). HLA 2025; 105:e70051. [PMID: 39933824 DOI: 10.1111/tan.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/02/2025] [Accepted: 01/26/2025] [Indexed: 02/13/2025]
Abstract
This study investigates the HLA allele diversity in Brazil, a reflection of the country's unique history of population admixture. The international comparison of findings emphasises the importance of incorporating underrepresented populations into global HLA databases. We present a comprehensive analysis of HLA alleles within the Brazilian population, utilising high-resolution sequencing data from 298,000 unrelated haematopoietic stem cell volunteer donors registered with the Brazilian Bone Marrow Donor Registry (REDOME). Our research encompasses donors from all regions of Brazil, identifying HLA alleles that are catalogued as common, intermediate or well-documented (CIWD Version 3.0). We evaluated the alleles of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1. At a two-field resolution, we identified 1969 alleles: 418 were classified as common, 358 as intermediate and 1193 as non-CIWD in Brazil. Notably, we report HLA alleles that, while not classified as common or intermediate in the CIWD 3.0 catalogue, are prevalent within the Brazilian population. A detailed list of alleles from the registry, presented at a two-field resolution and supplemented with grouped ARD levels, including three- or four-field resolution when available, serves as an essential reference for HLA typing frequencies specific to the Brazilian population.
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Affiliation(s)
- Jose Samuel da Silva
- Instituto de Imunogenética - IGEN, Associação de Fundo de Incentivo à Pesquisa - AFIP, São Paulo, Brazil
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Forbes J, Rice P, Groarke J, Berry E, Graham H, Graham‐Wisener L. Factors influencing unrelated stem cell donation a mixed-methods integrated systematic review. Br J Health Psychol 2025; 30:e12758. [PMID: 39449116 PMCID: PMC11586825 DOI: 10.1111/bjhp.12758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 08/14/2024] [Indexed: 10/26/2024]
Abstract
PURPOSE There is an imbalance between demand for and availability of stem cell donors worldwide. The purpose of this systematic review is to provide the first comprehensive understanding of facilitators and barriers influencing unrelated stem cell donation (USCD) in adults, through a data synthesis of qualitative and quantitative evidence. Identification of the facilitators and barriers associated with stem cell donation intention and behaviour is essential to inform the development of behaviour change interventions to meet the current demand. METHODS Four databases were searched (Embase, PsycINFO, MEDLINE and CINAHL) and the last search was in February 2021. The search was limited to studies written in English and published from 1980 to present. Screening, quality assessment, data extraction and data synthesis incorporating the COM-B model were undertaken in line with the Joanna Briggs Institute methodology for an integrated mixed-methods review. RESULTS Fifty studies were included in the review, analysis and mapping produced four integrated findings. Donation-related knowledge was a facilitator and conversely, lack of knowledge was a barrier to donation related behaviours. Perceived convenience, positive social influences, religious beliefs and the accessibility of positive donation-related social norms promoted positive donation related behaviours. Altruism and sense of duty were the most commonly cited motives for donation related behaviours.Through mapping to the COM-B model, Communication/Marketing, and Service Provision are the primary policy categories that can be used to change donation related behaviours. CONCLUSION Future interventions should focus on targeted education regarding unrelated stem cell donation and creating recruitment campaigns that emphasise the life-saving potential of donation.
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Affiliation(s)
- Jessica Forbes
- Centre for Improving Health‐Related Quality of Life, School of PsychologyQueen's University BelfastBelfastNorthern Ireland
| | - Paul Rice
- Centre for Improving Health‐Related Quality of Life, School of PsychologyQueen's University BelfastBelfastNorthern Ireland
| | - Jenny Groarke
- Centre for Improving Health‐Related Quality of Life, School of PsychologyQueen's University BelfastBelfastNorthern Ireland
- School of PsychologyNational University of Ireland GalwayGalwayIreland
| | - Emma Berry
- Centre for Improving Health‐Related Quality of Life, School of PsychologyQueen's University BelfastBelfastNorthern Ireland
| | - Henrietta Graham
- The Centre of Lifestyle Medicine and Behaviour, School of Sport Exercise and Health SciencesLoughborough UniversityLoughboroughUK
| | - Lisa Graham‐Wisener
- Centre for Improving Health‐Related Quality of Life, School of PsychologyQueen's University BelfastBelfastNorthern Ireland
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Xiao H, Huang Q, Lai Y, Liu R. Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Transfusion-Dependent Thalassemia: A Systematic Review and Meta-Analysis. Transplant Cell Ther 2025; 31:101.e1-101.e12. [PMID: 39647520 DOI: 10.1016/j.jtct.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/26/2024] [Accepted: 12/01/2024] [Indexed: 12/10/2024]
Abstract
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) presents a promising therapeutic option for pediatric transfusion-dependent thalassemia, particularly in the scarcity of matched donors. Despite its potential, the comprehensive evaluation of this method through large-scale prospective studies remains lacking. This study aims to systematically summarize the efficacy and safety of haplo-HSCT in thalassemia, thereby providing further evidence-based insights for clinical practice. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science databases through June 2024 to ensure a robust analysis of the available evidence. Data extraction was independently performed by 2 reviewers. The analysis utilized the inverse variance method with a 95% confidence interval (95% CI) to calculate the pooled proportion. To assess the heterogeneity among the studies, Cochran's Q test and Higgins' I-squared statistical methods were utilized. A random-effects model was employed to accommodate the variability between study results. Furthermore, subgroup analyses were explored differences in outcomes based on conditioning regimens and graft versus host disease (GVHD) prophylaxis. Conditioning regimens were categorized into reduced-intensity conditioning and myeloablative conditioning regimens. GVHD prophylaxis was classified into post-transplantation cyclophosphamide and non-post-transplantation cyclophosphamide. In this meta-analysis, we reviewed data from 10 studies encompassing 356 patients with thalassemia who underwent haplo-HSCT. Out of these, 328 patients survived until the follow-up date, resulting in a pooled overall survival rate of 92.4% (95% CI, 86.9-96.7; I² = 54.32%). The thalassemia-free survival was 84.5% (95% CI, 75.3-91.9; I² = 77.64%), and the graft failure rate was 8.1% (95% CI, 2.5-16.4; I² = 81.78%). The transplantation-related mortality stood at 7.4% (95% CI, 3.6-12.5; I² = 55.74%), with infections noted as the primary cause of death. The pooled proportion of acute graft versus host disease (aGVHD), grade 2-4 aGVHD, and grade 3-4 aGVHD were 29.6% (95% CI, 16.7-42.5, I² = 92.48%), 22.3% (95% CI, 10.1-42.1, I² = 80.06%), and 9.1% (95% CI, 2.8-17.7, I² = 67.92%), respectively. Subgroup analyses revealed no significant differences in these outcomes when comparing myeloablative conditioning to reduced-intensity conditioning, or post-transplantation cyclophosphamide to non-post-transplantation cyclophosphamide prophylaxis. However, variations in sample size, patient's age and geographic region among the studies suggest these factors as potential sources of heterogeneity. Haploidentical hematopoietic stem cell transplantation utilizes donors who are partially HLA-matched, typically family members, making it a viable option for transfusion-dependent thalassemia when fully matched donors are not available.
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Affiliation(s)
- Hongwen Xiao
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qiulin Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yongrong Lai
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; NHC Key Laboratory of Thalassemia Medicine, Nanning, Guangxi, China; Guangxi Key laboratory of Thalassemia Research, Nanning, Guangxi, China
| | - Rongrong Liu
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; NHC Key Laboratory of Thalassemia Medicine, Nanning, Guangxi, China; Guangxi Key laboratory of Thalassemia Research, Nanning, Guangxi, China.
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Hong KT, Kim BK, An HY, Choi JY, Song SH, Yu KS, Jang IJ, Kang HJ. Comparing haploidentical transplantation with post-transplantation cyclophosphamide and umbilical cord blood transplantation using targeted busulfan in children and adolescents with hematologic malignancies. Blood Res 2025; 60:7. [PMID: 39847190 PMCID: PMC11757842 DOI: 10.1007/s44313-025-00057-7] [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: 11/26/2024] [Accepted: 01/10/2025] [Indexed: 01/24/2025] Open
Abstract
PURPOSE This study compared the outcomes of haploidentical-related donor (HRD) and umbilical cord blood (UCB) hematopoietic stem cell transplantation (HSCT) in pediatric patients with hematologic malignancies. METHODS Data on patients who underwent HRD HSCT with post-transplant cyclophosphamide (n = 41) and UCB HSCT (n = 24) after targeted busulfan-based myeloablative conditioning with intensive pharmacokinetic monitoring between 2009 and 2018 were retrospectively analyzed. RESULTS The median follow-up durations in the HRD and UCB groups were 7.0 and 10.9 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV and moderate-to-severe chronic GVHD did not differ significantly between the groups. However, the HRD group demonstrated significantly lower rates of acute GVHD grades III-IV (4.9% vs. 29.2%, p = 0.009) and non-relapse mortality (2.6% vs. 34.2%, p < 0.001) but a higher relapse incidence (32.1% vs. 8.8%, p = 0.004) than the UCB group. The 5-year event-free and overall survival rates were 65.8% and 54.2% (p = 0.204) and 78.0% and 65.7% (p = 0.142) for the HRD and UCB groups, respectively. Multivariate analysis identified disease status as a significant risk factor for overall survival (hazard ratio, 3.24; p = 0.016). Additionally, UCB HSCT exhibited a trend toward worse event-free survival compared to HRD HSCT (hazard ratio, 2.63; p = 0.05). CONCLUSIONS These findings indicate that HRD HSCT with post-transplant cyclophosphamide provides promising outcomes compared to UCB HSCT in pediatric patients, with a trend toward improved survival over a long-term follow-up period exceeding a median of 7 years. Thus, HRD HSCT may be a valuable option for pediatric patients without human leukocyte antigen-matched donors.
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Affiliation(s)
- Kyung Taek Hong
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Bo Kyung Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Hong Yul An
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Jung Yoon Choi
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Sang Hoon Song
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyoung Jin Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea.
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Adoncecchi G, Kumar A, Mogili K, Faramand R, Liu H, Khimani F, Mishra A, Nieder M, Nishihori T, Hansen D, Jain M, Lazaryan A, Perez L, Pidala J, Locke F, Anasetti C, Bejanyan N, Elmariah H. Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients. Cancers (Basel) 2025; 17:310. [PMID: 39858092 PMCID: PMC11763395 DOI: 10.3390/cancers17020310] [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: 11/04/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Previous studies have shown that allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA haploidentical (haplo) donor followed by graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) results in lower relapse rates and improved DFS when compared to haplo bone marrow transplant (BMT) with PTCy. However, PBSCT leads to higher rates of GVHD. It is unknown whether the benefits of haplo PBSCT may be nullified in older patients (>60 years) by a higher susceptibility to GVHD and transplant related toxicity. Thus, we sought to determine if older patients receiving haplo PBSCT with PTCy experience significantly worse outcomes than younger patients. METHODS We evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic haplo PBSCT followed by PTCy and compared outcomes of patients ≥60 years (n = 55) versus patients <60 years (n = 66). RESULTS The cumulative incidence of non-relapse mortality (NRM) from the competing risk regression analysis was worse for the older patient group (SHR = 4.05, 95% CI: 1.43-11.47, p = 0.008). However, there was no significant difference between groups in graft-versus-host disease (GVHD), relapse, disease-free survival (DFS), or overall survival (OS). Instead, hematopoietic comorbidity index (HCT-CI) ≥ 3 was associated with worse DFS (HR = 1.87, 95% CI: 1.04-3.34, p = 0.035) and OS (HR = 1.98, 95% CI: 1.03-3.84, p-value = 0.042). Subgroup analysis of patients ≥60 years showed a trend toward improved 2-year OS with fludarabine/cyclophosphamide/total body irradiation (Flu/Cy/TBI) versus fludarabine/busulfan: 71% versus 53% (HR = 0.47, p = 0.121). In patients over 70 years (n = 14), NRM was 8% and OS was 76% at 1 year. CONCLUSION Given similar OS and DFS between patients aged >60 years and those <60, haplo PBSCT with PTCy appears to be an appropriate transplant platform for older patients.
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Affiliation(s)
- Giacomo Adoncecchi
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Ambuj Kumar
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
| | - Krishnakar Mogili
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Rawan Faramand
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Hien Liu
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Farhad Khimani
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Asmita Mishra
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Michael Nieder
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Taiga Nishihori
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Doris Hansen
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Michael Jain
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Aleksandr Lazaryan
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Lia Perez
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Joseph Pidala
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Frederick Locke
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Claudio Anasetti
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Nelli Bejanyan
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
| | - Hany Elmariah
- Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (G.A.); (D.H.); (F.L.)
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Kaur M, Horowitz MM, Mendizabal A, Chen M, Foley A, Auletta JJ, Devine S, D'Souza A. Representativeness of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Trial Participants. Transplant Cell Ther 2025; 31:49-57. [PMID: 39489220 PMCID: PMC11735273 DOI: 10.1016/j.jtct.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Underrepresentation by race and ethnicity in oncology clinical trials, including those of hematopoietic cell transplantation (HCT), is a known challenge. This analysis studied accrual on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials conducted in 2014 to 2020 by race/ethnicity, age, and sex, comparing these characteristics with those of potentially eligible patients identified from the Surveillance, Epidemiology, and End Results (SEER) and Center for International Blood and Marrow Transplant Research (CIBMTR) databases for the disease, age, and years of interest of BMT CTN studies. Five BMT CTN trials met the inclusion criteria, including 1 autologous HCT trial and 4 allogeneic HCT trials. Two studies focused on multiple myeloma (BMT CTN 1302 and 1401), 2 studies focused on graft-versus-host disease (GVHD) treatment (BMT CTN 1301 and 1501), and 1 study focused on post-HCT maintenance therapy in FLT3+ acute myelogenous leukemia (BMT CTN 1506). A decline in the proportion of patients from minority racial and ethnic groups was seen from the SEER population to trial enrollees, with the largest drop seen between the SEER population and all patients who underwent HCT (on or off trial) at US transplant centers. Allogeneic HCT trials that allowed alternative donor graft sources had less decrease from the SEER population. No decrease in clinical trial enrollment was seen with respect to older age and female HCT recipients. This study provides insight into the underrepresentation of racial and ethnic minority patients in BMT CTN clinical trials, owing largely to lack of access to HCT in general. Pathways expanding access to donors and improving the outreach of HCT programs to underserved populations are needed to improve access to clinical trials.
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Affiliation(s)
- Manmeet Kaur
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Mary M Horowitz
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Min Chen
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Amy Foley
- Center for International Blood and Marrow Transplantation Research/National Marrow Donor Program, Minneapolis, Minnesota
| | - Jeffery J Auletta
- Center for International Blood and Marrow Transplantation Research/National Marrow Donor Program, Minneapolis, Minnesota
| | - Steven Devine
- Center for International Blood and Marrow Transplantation Research/National Marrow Donor Program, Minneapolis, Minnesota
| | - Anita D'Souza
- Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
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Oved JH, Russell A, DeZern A, Prockop SE, Bonfim C, Sharma A, Purtill D, Lakkaraja M, Bidgoli A, Bhoopalan SV, Soni S, Boelens JJ, Abraham A. The role of the conditioning regimen for autologous and ex vivo genetically modified hematopoietic stem cell-based therapies: recommendations from the ISCT stem cell engineering committee. Cytotherapy 2025; 27:78-84. [PMID: 39320295 DOI: 10.1016/j.jcyt.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND The advent of autologous gene modified cell therapies to treat monogenic disorders has been a major step forward for the field of hematopoietic stem cell transplantation (HCT) and cellular therapies. The need for disease-specific conditioning to enable these products to provide a potential cure has required extrapolation from experience in myeloablative and non-myeloablative HCT for these disorders. METHODS In this manuscript, we review the current datasets and clinical experience using different conditioning regimens for autologous gene therapies in hemoglobinopathies, metabolic and lysosomal disorders, inborn errors of immunity (IEI) and bone marrow failure (BMF) syndromes. RESULTS The disease specific and unique conditioning requirements of each disorder are considered in order to achieve maximal benefit while minimizing associated toxicities. CONCLUSIONS Standardized recommendations based on these data are made for each set of disorders to harmonize treatment. Future directions and the possibility of non-genotoxic conditioning regimens for autologous gene therapies are also discussed. Ethical Statement: The authors followed all relevant ethical considerations in writing this manuscript.
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Affiliation(s)
- Joseph H Oved
- Transplant and Cellular Therapies, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center New York, New York, USA.
| | - Athena Russell
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amy DeZern
- Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Susan E Prockop
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA
| | - Carmem Bonfim
- Pediatric Blood and Marrow Transplantation Division and Pelé Pequeno Príncipe Research Institute, Hospital Pequeno Príncipe, Curitiba, Brazil
| | - Akshay Sharma
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Duncan Purtill
- Department of Haematology, Fiona Stanley Hospital and PathWest Laboratory Medicine, Perth, Western Australia, Australia
| | - Madhavi Lakkaraja
- Fred Hutchinson Cancer Center, Seattle, Washington, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Alan Bidgoli
- Division of Blood and Marrow Transplantation, Children's Healthcare of Atlanta, Aflac Blood and Cancer Disorders Center, Emory University, Atlanta, Georgia, USA
| | - Senthil Velan Bhoopalan
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Sandeep Soni
- Pediatrics, University of California, San Francisco, California, USA; Crispr Therapeutics AG, Boston, Massachusetts, USA; ISCT Immune-Gene Therapy Committee, ISCT, Vancouver, California, USA
| | - Jaap Jan Boelens
- Transplant and Cellular Therapies, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center New York, New York, USA
| | - Allistair Abraham
- Center for Cancer and Immunology Research, CETI, Children's National Hospital, Washington, District of Columbia, USA
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Beeraka NM, Basappa B, Nikolenko VN, Mahesh PA. Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia. Stem Cell Rev Rep 2025; 21:2-27. [PMID: 38976142 DOI: 10.1007/s12015-024-10761-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.
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Affiliation(s)
- Narasimha M Beeraka
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA.
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia.
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India.
| | - Basappa Basappa
- Department of Studies in Organic Chemistry, Laboratory of Chemical Biology, University of Mysore, Mysore, Karnataka, 570006, India
| | - Vladimir N Nikolenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia
| | - P A Mahesh
- Department of Pulmonary Medicine, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
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Dvorak CC, Long-Boyle JR, Holbrook-Brown L, Abdel-Azim H, Bertaina A, Vatsayan A, Talano JA, Bunin N, Anderson E, Flower A, Lalefar N, Higham CS, Kapoor N, Klein O, Odinakachukwu MC, Cho S, Jacobsohn DA, Collier W, Pulsipher MA. Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19-depleted pediatric haploidentical HCT for hematologic malignancy. Blood Adv 2024; 8:6003-6014. [PMID: 39042892 PMCID: PMC11629297 DOI: 10.1182/bloodadvances.2024012670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/06/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
ABSTRACT We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19-depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (<12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D- serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was associated with inferior DFS following AB-TCD haploidentical HCT for pediatric patients with hematologic malignancies. Model-based dosing of rATG to achieve optimal exposure may improve DFS. These trials were registered at www.ClinicalTrials.gov as #NCT02646839 and #NCT04337515.
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Affiliation(s)
- Christopher C. Dvorak
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children’s Hospitals, San Francisco, CA
| | - Janel R. Long-Boyle
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children’s Hospitals, San Francisco, CA
| | - Lucia Holbrook-Brown
- Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children’s Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT
| | - Hisham Abdel-Azim
- Cancer Center, Children’s Hospital and Medical Center, Loma Linda University School of Medicine, Loma Linda, CA
| | - Alice Bertaina
- Division of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Anant Vatsayan
- Division of Blood and Marrow Transplantation, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Julie-An Talano
- Division of Pediatric Hematology, Oncology, and Blood and Marrow Transplant, Medical College of Wisconsin, Milwaukee, WI
| | - Nancy Bunin
- Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Eric Anderson
- Division of Pediatric Hematology-Oncology, Rady Children’s Hospital, University of California San Diego, San Diego, CA
| | - Allyson Flower
- Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, New York Medical College, Valhalla, NY
| | - Nahal Lalefar
- Division of Hematology, University of California San Francisco Benioff Children’s Hospitals, Oakland, CA
| | - Christine S. Higham
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children’s Hospitals, San Francisco, CA
| | - Neena Kapoor
- Division of Pediatric Hematology, Oncology, and Transplantation and Cellular Therapy, University of Southern California Children’s Hospital Los Angeles, Los Angeles, CA
| | - Orly Klein
- Division of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Maryanne C. Odinakachukwu
- Division of Blood and Marrow Transplantation, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Soohee Cho
- Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children’s Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT
| | - David A. Jacobsohn
- Division of Blood and Marrow Transplantation, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Willem Collier
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA
| | - Michael A. Pulsipher
- Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children’s Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT
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Marcoux C, Kebriaei P. Transplant in ALL: who, when, and how? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:93-101. [PMID: 39644076 DOI: 10.1182/hematology.2024000533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a cornerstone in the treatment of high-risk acute lymphoblastic leukemia (ALL), yet optimal patient selection is challenging in the era of rapidly changing modern therapy. Refined molecular characterization allows for better risk assessment, sparing low-risk patients from allo-HCT toxicity while identifying those who may benefit from intensified approaches. Measurable residual disease (MRD) has emerged as a powerful predictor of relapse irrespective of treatment strategy, challenging the necessity of transplant in MRD-negative patients. Further, expanded donor options, particularly haploidentical transplantation coupled with reduced intensity conditioning, have extended the applicability of allo-HCT to a broader range of patients. Finally, immunotherapies and targeted treatments are increasingly integrated into both initial and relapsed treatment protocols yielding deep remission and allowing for successful transplant in patients with a history of advanced disease. In this review, we provide an overview of the contemporary role of transplant in adult patients with ALL, focusing on indications for allo-HCT in first remission, optimal sequencing of transplant with novel therapies, and advancements in donor selection and conditioning regimens.
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Affiliation(s)
- Curtis Marcoux
- Division of Hematology, Dalhousie University, Halifax, Canada
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
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Lee-Won RJ, Holt LF. Harnessing Hope in Digital Spaces for Health Equity: How Group Comparison Information and Supportive Comments Influence Bone Marrow Donor Intentions for African Americans. CYBERPSYCHOLOGY, BEHAVIOR AND SOCIAL NETWORKING 2024; 27:910-918. [PMID: 39324346 DOI: 10.1089/cyber.2023.0598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
Pursuing health equity necessitates recognizing health disparities that disproportionately impact disadvantaged groups and eliminating their barriers to essential health resources. Interactive digital technologies-specifically, popular social media platforms such as blogs and social networks-can be leveraged to engage underserved minority populations in collective social action aimed at addressing key determinants of health disparities and promoting equitable health outcomes. The present research focuses on the plight of African Americans-a minority group facing significant health disparities. Particularly in the domain of bone marrow donation, African Americans remain the group least likely to find a matching donor. Guided by the social comparison framing literature, we conducted an online experiment to investigate how group comparison information (GCI) emphasizing group-based disparities and supportive user comments on social media platforms influence African Americans' intentions to join a bone marrow registry. In doing so, we considered hope as a mediator and group identification as a moderator. Results based on a conditional process analysis showed that GCI led to greater bone marrow donor intentions in the presence of supportive comments through elicitation of hope, particularly among those low in group identification. The current findings demonstrate that it is important to consider the role of supportive message environments and group identification when addressing health disparities with GCI. Theoretical and practical implications are discussed.
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Affiliation(s)
- Roselyn J Lee-Won
- School of Communication, The Ohio State University, Columbus, Ohio, USA
| | - Lanier F Holt
- School of Communication, The Ohio State University, Columbus, Ohio, USA
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50
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Mohty R, Al Kadhimi Z, Kharfan-Dabaja M. Post-transplant cyclophosphamide or cell selection in haploidentical allogeneic hematopoietic cell transplantation? Hematology 2024; 29:2326384. [PMID: 38597828 DOI: 10.1080/16078454.2024.2326384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 02/28/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND One major limitation for broader applicability of allogeneic hematopoietic cell transplantation (allo-HCT) in the past was the lack of HLA-matched histocompatible donors. Preclinical mouse studies using T-cell depleted haploidentical grafts led to an increased interest in the use of ex vivo T-cell depleted (TCD) haploidentical allo-HCT. TCD grafts through negative (T-cell depletion) or positive (CD34+ cell selection) techniques have been investigated to reduce the risk of graft-versus-host disease (GVHD) given the known implications of alloreactive T cells. A more practical approach to deplete alloreactive T cells in vivo using high doses of cyclophosphamide after allografting has proved to be feasible in overcoming the HLA barrier. Such approach has extended allo-HCT feasibility to patients for whom donors could not be found in the past. Nowadays, haploidentical donors represent a common donor source for patients in need of an allo-HCT. The broad application of haploidentical donors became possible by understanding the importance of depleting alloreactive donor T cells to facilitate engraftment and reduce incidence and severity of GVHD. These techniques involve ex vivo graft manipulation or in vivo utilization of pharmacologic agents, notably post-transplant cyclophosphamide (PTCy). DISCUSSION While acknowledging that no randomized controlled prospective studies have been yet conducted comparing TCD versus PTCy in haploidentical allo-HCT recipients, there are two advantages that would favor the PTCy, namely ease of application and lower cost. However, emerging data on adverse events associated with PTCy including, but not limited to cardiac associated toxicities or increased incidence of post-allograft infections, and others, are important to recognize.
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Affiliation(s)
- Razan Mohty
- Division of Hematology Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Zaid Al Kadhimi
- Division of Hematology Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Mohamed Kharfan-Dabaja
- Division of Hematology-Oncology, Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL, USA
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