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1
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Ueki H, Ogawa C, Goto H, Nishi M, Yamanaka J, Mochizuki S, Nishikawa T, Kumamoto T, Nishiuchi R, Kikuta A, Yamamoto S, Igarashi S, Sato A, Hori T, Saito AM, Watanabe T, Deguchi T, Manabe A, Horibe K, Toyoda H. TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia. Int J Hematol 2024; 119:450-458. [PMID: 38267673 DOI: 10.1007/s12185-024-03710-6] [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: 04/26/2023] [Revised: 12/27/2023] [Accepted: 01/08/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.
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Affiliation(s)
- Hideaki Ueki
- Department of Pediatric Hematology/Oncology, Japanese Red Cross Narita Hospital, Narita, Japan
| | - Chitose Ogawa
- Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroaki Goto
- Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Masanori Nishi
- Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan
| | - Junko Yamanaka
- Department of Pediatrics, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shinji Mochizuki
- Department of Pediatrics, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takuro Nishikawa
- Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Tadashi Kumamoto
- Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ritsuo Nishiuchi
- Department of Pediatrics, Kochi Health Sciences Center, Kochi, Japan
| | - Atsushi Kikuta
- Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima, Japan
| | - Shohei Yamamoto
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Shunji Igarashi
- Department of Pediatric Hematology/Oncology, Japanese Red Cross Narita Hospital, Narita, Japan
| | - Atsushi Sato
- Department of Hematology/Oncology, Miyagi Children's Hospital, Sendai, Japan
| | - Toshinori Hori
- Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Akiko M Saito
- Clinical Research Center, NHO Nagoya Medical Center, Nagoya, Japan
| | - Tomoyuki Watanabe
- Department of Nutritional Science, Faculty of Psychological and Physical Science, Aichi Gakuin University, Nisshin, Japan
| | - Takao Deguchi
- Division of Cancer Immunodiagnostics, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Atsushi Manabe
- Department of Pediatrics, Hokkaido University, Sapporo, Japan
| | - Keizo Horibe
- Clinical Research Center, NHO Nagoya Medical Center, Nagoya, Japan
| | - Hidemi Toyoda
- Department of Pediatrics, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
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Wölfl M, Qayed M, Benitez Carabante MI, Sykora T, Bonig H, Lawitschka A, Diaz-de-Heredia C. Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia. Front Pediatr 2021; 9:784377. [PMID: 35071133 PMCID: PMC8771910 DOI: 10.3389/fped.2021.784377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022] Open
Abstract
Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality-which is predominantly caused by severe GvHD-is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.
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Affiliation(s)
- Matthias Wölfl
- Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, Würzburg University Hospital, Würzburg, Germany
| | - Muna Qayed
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, United States
| | - Maria Isabel Benitez Carabante
- Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Tomas Sykora
- Haematopoietic Stem Cell Transplantation Unit, Department of Pediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia
| | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, Frankfurt, Germany.,German Red Cross Blood Service BaWüHe, Frankfurt, Germany
| | - Anita Lawitschka
- Department of Pediatrics, St. Anna Kinderspital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria
| | - Cristina Diaz-de-Heredia
- Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
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3
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Ribera Santasusana JM, de Andrés Saldaña A, García-Muñoz N, Gostkorzewicz J, Martínez Llinàs D, Díaz de Heredia C. Cost-Effectiveness Analysis of Tisagenlecleucel in the Treatment of Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia in Children and Young Adults in Spain. CLINICOECONOMICS AND OUTCOMES RESEARCH 2020; 12:253-264. [PMID: 32523362 PMCID: PMC7237114 DOI: 10.2147/ceor.s241880] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/19/2020] [Indexed: 11/30/2022] Open
Abstract
Purpose Tisagenlecleucel, a chimeric antigen receptor T-cell (CAR-T) therapy, is a promising alternative for the management of children and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia (r/r ALL). The aim of this study was to determine whether treatment with tisagenlecleucel is a cost-effective intervention compared with salvage chemotherapy in paediatric and young adult patients with r/r ALL in Spain. Materials and Methods A partitioned survival model of monthly cycles with three health states was used (event-free survival, progressive/relapsed disease and death). A lifetime time horizon and the Spanish National Health System perspective were adopted. During the first 5 years, permanence in the different health states was determined according to the results in the clinical studies. In successive years, mortality tables of the Spanish general population adjusted by standardized mortality rate for survivors of childhood cancer were used. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. Only direct health costs (pharmacological costs and the costs derived from health resource use) were included. The robustness of the results was evaluated in a sensitivity analysis. Results This cost-effectiveness analysis showed a greater benefit (10.10 and 8.97 life-years gained [LYGs] and quality-adjusted life-years [QALYs] gained, respectively) and a higher cost (€ 258,378.40) for tisagenlecleucel compared to salvage chemotherapy. The resulting incremental cost-effectiveness and cost-utility ratios were € 25,576.80 per LYG and € 28,818.52 per QALY gained, respectively. In the sensitivity analysis, all the results were below € 50,000/QALY. Conclusion Tisagenlecleucel would represent a cost-effective intervention for the treatment of children and young adults with r/r ALL in Spain.
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Affiliation(s)
| | | | | | - Joana Gostkorzewicz
- Health Economics and Outcomes Research, Novartis Farmacéutica S.A., Madrid, Spain
| | | | - Cristina Díaz de Heredia
- Paediatric Oncology and Hematology Department - Hematopoietic Stem Cell Transplantation, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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Gabelli M, Veys P, Chiesa R. Current status of umbilical cord blood transplantation in children. Br J Haematol 2019; 190:650-683. [PMID: 31410846 DOI: 10.1111/bjh.16107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/19/2019] [Accepted: 06/19/2019] [Indexed: 12/19/2022]
Abstract
The first umbilical cord blood (UCB) transplantation was performed 30 years ago. UCB transplantation (UCBT) is now widely used in children with malignant and non-malignant disorders who lack a matched family donor. UCBT affords a lower incidence of graft-versus-host disease compared to alternative stem cell sources, but also presents a slower immune recovery and a high risk of infections if serotherapy is not omitted or targeted within the conditioning regimen. The selection of UCB units with high cell content and good human leucocyte antigen match is essential to improve the outcome. Techniques, such as double UCBT, ex vivo stem cell expansion and intra-bone injection of UCB, have improved cord blood engraftment, but clinical benefit remains to be demonstrated. Cell therapies derived from UCB are under evaluation as potential novel strategies to reduce relapse and viral infections following transplantation. In recent years, improvements within haploidentical transplantation have reduced the overall use of UCBT as an alternative stem cell source; however, each may have its relative merits and disadvantages and tailored use of these alternative stem cell sources may be the optimal approach.
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Affiliation(s)
- Maria Gabelli
- Bone Marrow Transplantation, Great Ormond Street Hospital, London, UK
| | - Paul Veys
- Bone Marrow Transplantation, Great Ormond Street Hospital, London, UK
| | - Robert Chiesa
- Bone Marrow Transplantation, Great Ormond Street Hospital, London, UK
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Hamidieh AA, Eslami Shahre Babaki A, Rostami T, Kasaeian A, Koochakzadeh L, Sharifi Aliabadi L, Behfar M, Ghavamzadeh A. A Single-Center Experience With Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia: A Modest Pitch for Non-Total Body Irradiation Conditioning Regimens. EXP CLIN TRANSPLANT 2018; 17:243-250. [PMID: 30295587 DOI: 10.6002/ect.2017.0226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Allogeneic hematopoietic stem cell transplantation has been used for several decades to treat patients with acute lymphoblastic leukemia. Total body irradiation has been promoted as an important component of conditioning regimens for this process; however, recent reports of chemotherapy-based conditioning regimens have shown comparable outcomes. MATERIALS AND METHODS We report our experience with radiation-free conditioning using busulfan and cyclophosphamide in 127 pediatric patients with acute lymphoblastic leukemia who were treated between 1997 and 2014. The median age was 11 years (range, < 1 to 15 y), 70% of patients were male, 81.1% received transplants from HLA-matched siblings, 83% received peripheral blood stem cells, 41% were in second complete remission at the time of transplant, and 83% had B-lineage immunophenotype. RESULTS In patients who were in complete remission at the time of transplant, 5-year overall survival, leukemia-free survival, and relapse rates were 62.48% (95% confidence interval, 52.29-71.09%), 49.43% (95% confidence interval, 39.57-58.53%), and 45.64% (95% confidence interval, 35.85-54.88%), respectively. We observed significant differences between outcomes in patients by time of transplant, presence of chronic graft-versus-host disease, and remission status. CONCLUSIONS Our relapse rates were comparable to those shown in recent studies, although the transplant-related mortality rate was lower. The results of our study showed that a busulfan/cyclophosphamide conditioning regimen has acceptable outcomes without the undesirable adverse effects of total body irradiation, particularly in pediatric patients. Large multicenter studies are needed to assess less toxic conditioning regimens with fewer adverse effects in these patients.
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Affiliation(s)
- Amir Ali Hamidieh
- From the Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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6
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Berghiche A, Khenenou T, Kouzi A, Labiad I. An investigation on the predominant diseases, its diagnosis, and commonly used drugs in the poultry farms in the North-Eastern regions of Algeria. Vet World 2018; 11:986-989. [PMID: 30147270 PMCID: PMC6097571 DOI: 10.14202/vetworld.2018.986-989] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/07/2018] [Indexed: 11/16/2022] Open
Abstract
Aim An investigation was carried out to assess the occurrence of diseases, its method of diagnosis, and commonly used drugs in poultry farms in North-Eastern regions of Algeria. Materials and Methods A total of 265 veterinary doctors were surveyed to obtain information on the dominant diseases, its frequency of occurrence, method of diagnosis, and commonly used drugs in poultry farms. Results A study revealed that about 68% of bacterial diseases are due to colibacillosis, mycoplasmosis, and salmonellosis, 22% of viral diseases are due to Newcastle, Gumboro, and infectious bronchitis, and 10% others including coccidiosis and ascites syndrome. The study also showed that about 57% of cases were diagnosed by clinical signs, 36% by necropsy findings, and the remaining 7% through therapeutic and laboratory analysis. Antibiotics, a predominance of the anarchic veterinary drugs, were massively used to control the diseases. Hence, there is a need for strict regulations on the use of veterinary drugs to guarantee food safety. Conclusion These results remain non-exhaustive but contribute strongly to determine the status of health of the birds in the region.
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Affiliation(s)
- Amine Berghiche
- Department of Veterinary Science, Institute of Agronomic and Veterinarian Sciences, University of Mohamed Cherif Messaâdia, Souk Ahras, Algeria
| | - Tarek Khenenou
- Laboratory of Animal Production, Biotechnology and Health, University of Mohamed Cherif Messaâdia, Souk Ahras, Algeria
| | - Ahmed Kouzi
- Laboratory of Animal Production, Biotechnology and Health, University of Mohamed Cherif Messaâdia, Souk Ahras, Algeria
| | - Ibtissem Labiad
- Laboratory of Science and Technique of Living, Institute of Agronomic and Veterinarian Sciences, University of Mohamed Cherif Messaâdia, Souk Ahras, Algeria
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7
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Gustafsson BM. Different aspects of stem cell procedures in children with poor responding AML: when is HSCT the best answer? Int J Hematol Oncol 2015. [DOI: 10.2217/ijh.15.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Acute myeloid leukemia in children is a heterogeneous disease with different morphological and cytogenetic features. New diagnostic tools and treatments, improved supportive care and the use of genomic tissue typing in selecting donors for hematopoietic stem cell transplantation (HSCT) adds to increased survival rates. Candidates to HSCT in first complete remission are patients with cytogenetic or molecular unfavorable prognostic markers, or blasts >15% after first induction. The use of minimal residual disease can also identify children benefiting from HSCT in first complete remission and the patients post HSCT with signs of relapse. The outcome and cure rate of acute myeloid leukemia, still remains poor and new diagnostic tools and treatments strategies need to be evaluated. In this management perspective, future management of novel minimal residual disease tools are discussed, conditioning therapies, as well as different transplantation procedures including haplo-transplantation and haplo-identical natural killer cell transplantation, but also altered graft-versus-host-disease treatments.
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Affiliation(s)
- Britt M Gustafsson
- Department of Clinical Science, Intervention & Technology, CLINTEC, Karolinska Institutet, SE141 86 Stockholm, Sweden
- Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
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8
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Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia. Ann Hematol 2014; 94:473-80. [DOI: 10.1007/s00277-014-2213-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 09/02/2014] [Indexed: 10/24/2022]
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9
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Cheuk DKL. Optimal stem cell source for allogeneic stem cell transplantation for hematological malignancies. World J Transplant 2013; 3:99-112. [PMID: 24392314 PMCID: PMC3879529 DOI: 10.5500/wjt.v3.i4.99] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 11/15/2013] [Accepted: 12/11/2013] [Indexed: 02/05/2023] Open
Abstract
Hematopoietic stem cell transplant (HSCT) is a standard treatment for many hematological malignancies. Three different sources of stem cells, namely bone marrow (BM), peripheral blood stem cells (PBSC) and cord blood (CB) can be used for HSCT, and each has its own advantages and disadvantages. Randomized controlled trials (RCTs) suggest that there is no significant survival advantage of PBSC over BM in Human Leukocyte Antigen-matched sibling transplant for adult patients with hematological malignancies. PBSC transplant probably results in lower risk of relapse and hence better disease-free survival, especially in patients with high risk disease at the expense of higher risks of both severe acute and chronic graft-versus-host disease (GVHD). In the unrelated donor setting, the only RCT available suggests that PBSC and BM result in comparable overall and disease-free survivals in patients with hematological malignancies; and PBSC transplant results in lower risk of graft failure and higher risk of chronic GVHD. High level evidence is not available for CB in comparison to BM or PBSC. The risks and benefits of different sources of stem cells likely change with different conditioning regimen, strategies for prophylaxis and treatment of GVHD and manipulation of grafts. The recent success and rapid advance of double CB transplant and haploidentical BM and PBSC transplants further complicate the selection of stem cell source. Optimal selection requires careful weighing of the risks and benefits of different stem cell source for each individual recipient and donor. Detailed counseling of patient and donor regarding risks and benefits in the specific context of the patient and transplant method is essential for informed decision making.
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10
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Mårtensson T, Priftakis P, Casswall T, Ringdén O, Mattsson J, Remberger M, Hassan M, Gustafsson B. Increased risk of gastrointestinal acute GVHD following the addition of melphalan to busulfan/cyclophosphamide conditioning. Pediatr Transplant 2013; 17:285-93. [PMID: 23489519 DOI: 10.1111/petr.12061] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/24/2013] [Indexed: 11/30/2022]
Abstract
Risk factors associated with the development of aGVHD in the gastrointestinal tract have not been studied in depth. We retrospectively assessed 25 pediatric patients with MDS and JMML and compared the treatment outcome of two different conditioning regimens. Seventeen children (68%) underwent conditioning with busulfan (Bu), cyclophosphamide (Cy), and melphalan (Mel) and eight children (32%) with Bu and Cy. Gastrointestinal aGVHD stages II-IV (day 0-100) were observed in 47% (eight of 17) of the patients in the BuCyMel group and in none (0 of 8) in the BuCy group (p < 0.05). In patients who developed gastrointestinal aGVHD stages III-IV, a 24-h variation in the Bu concentration with a nighttime peak was noted. HC and liver aGVHD stages II-IV were observed in 47% (eight of 17) and 35% (six of 17) after BuCyMel conditioning and in 0% (0 of 17) and 12.5% (one of eight) after BuCy conditioning. The overall survival rate was 53% (nine of 17) in the BuCyMel group and 62.5% (five of eight) in the BuCy group. In conclusion, the addition of melphalan to the BuCy conditioning regimen resulted in severe gastrointestinal complications and did not improve overall survival.
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Affiliation(s)
- T Mårtensson
- Astrid Lindgren Children's Hospital and Karolinska University Hospital-Huddinge, Stockholm, Sweden.
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11
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Zhang H, Chen J, Que W. A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in acute leukemia patients. Biol Blood Marrow Transplant 2012; 18:1164-73. [PMID: 22289799 DOI: 10.1016/j.bbmt.2012.01.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2011] [Accepted: 01/24/2012] [Indexed: 11/29/2022]
Abstract
Umbilical cord blood has emerged as an alternative stem cell source to bone marrow or peripheral blood stem cells. Umbilical cord blood transplantation (UCBT) is also potentially curative for acute leukemia. However, the effect of unrelated donor bone marrow transplantation (UBMT) and UCBT on the outcome of patients with acute leukemia has not been systematically reviewed. In the present meta-analysis, we systematically searched Cochrane Library, MEDLINE, EMBASE, and CNKI up to May 2011. Two reviewers extracted data independently. Seven studies totaling 3389 patients have been assessed. Pooled results found that the incidence of engraftment failure and transplantation-related mortality were higher in UCBT than in UBMT, and relative risks (RRs) were 4.27 (95% confidence interval [CI], 2.94-6.21) and 1.27 (95% CI, 1.01-1.59), respectively. The rates of acute and chronic graft-versus-host disease (GVHD) in the UCBT group were significantly lower than that in the UBMT group, and RRs were 0.71 (95% CI, 0.65-0.79) and 0.69 (95% CI, 0.52-0.91), respectively. The relapse rate was similar between the UCBT and UBMT group. The leukemia-free survival (LFS) and overall survival (OS) were significantly lower in the UCBT group than in the UBMT group; RRs were 1.14 (95% CI, 1.07-1.22) and hazard ratios (HRs) were 1.31 (95% CI, 1.16-1.48), respectively. Subgroup analysis showed that in patients with acute lymphoblastic leukemia (ALL), the survival was similar between UCBT and UBMT.
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Affiliation(s)
- Haoran Zhang
- Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian, China
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12
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Brunstein CG. Umbilical Cord Blood Transplantation for the Treatment of Hematologic Malignancies. Cancer Control 2011; 18:222-36. [DOI: 10.1177/107327481101800403] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background The use of unrelated umbilical cord blood (UCB) has grown as an allogeneic source of hematopoietic cells for transplantation of patients with hematologic malignancies. As the number of UCB transplantation procedures has grown, an increasing number of publications have focused on disease-specific outcomes. Methods This review focuses on the outcome data following UCB transplantation in subsets of hematologic malignancies in which experience with this graft source is greater. Results Registry and single-institution reports regarding the outcomes of children and adults with acute leukemias after UCB transplantation include many patients, while data on the clinical outcomes of other leukemias are limited due in part to the small number of patients with these diseases. UCB is now routinely used as a source of hematopoietic stem cells (HSCs) in pediatric allogeneic transplantation when a suitable sibling donor is not available. Data also support the use of UCB as an alternative source of HSC for transplantation of patients with hematologic malignancies who lack a more conventional donor. Current data also support UCB for patients who require an allograft in the setting of prospective clinical trials. Conclusions Along with safety and feasibility in UCB transplantation, continued study is needed that focuses on issues such as accelerating engraftment, extending access, ensuring quality, and examining outcomes in specific subgroups of patients.
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Affiliation(s)
- Claudio G. Brunstein
- Blood and Marrow Transplant Program and Division of Hematology, Oncology and Transplantation at the University of Minnesota, Minneapolis, Minnesota
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13
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Abstract
Once considered biological waste, umbilical cord blood (UCB) has become an accepted source of haematopoietic stem cells (HSCs). With initial success in the pediatric setting, UCB transplantation continues to gain favor in the adult patient population. Novel approaches to UCB transplantation include use of two units and a variety of graft manipulations. Additional uses for UCB are currently being explored and include applications in regenerative medicine and immunotherapy.
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Affiliation(s)
- D H McKenna
- Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, University of Minnesota, Saint Paul, MN 55108, USA.
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14
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McNeer JL, Kletzel M, Rademaker A, Alford K, O'Day K, Schaefer C, Duerst R, Jacobsohn DA. Early elevation of C-reactive protein correlates with severe infection and nonrelapse mortality in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16:350-7. [PMID: 20005964 DOI: 10.1016/j.bbmt.2009.10.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2009] [Accepted: 10/20/2009] [Indexed: 11/27/2022]
Abstract
C-reactive protein (CRP) is an acute phase reactant that is a reliable marker of systemic inflammation and has been associated with increased morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in adults. In this study, we evaluated whether early elevations of CRP were associated with various complications and nonrelapse mortality following HSCT in pediatric patients. Seventy pediatric patients had CRP levels drawn at regular time points during the first week following their transplants. Patients were followed for 100 days following transplant, and transplant-related complications were documented. Patients who subsequently developed severe infections had higher median CRP values than those without severe infections (median 8.03 mg/dL versus 1.64 mg/dL, P = .0008) as did those who suffered nonrelapse mortality compared with those who did not (12.6 mg/dL versus 2.44 mg/dL, P = .02). These findings suggest that elevated CRP values may be useful as a marker of individual pediatric patients with a higher risk for treatment-related morbidity and mortality.
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Affiliation(s)
- Jennifer L McNeer
- Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA
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15
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Schechter T, Ishaqi KM, Rojas M, Irina Z, Doyle JJ, Gassas A. Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission. Pediatr Transplant 2010; 14:377-82. [PMID: 19793223 DOI: 10.1111/j.1399-3046.2009.01245.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty-three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III-IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant-related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11-110), the event free survival and OS were 0.49 (95% CI: 0.31-0.67) and 0.53 (CI: 0.44-0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.
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Affiliation(s)
- Tal Schechter
- Division of Haematology/Oncology/BMT, Hospital for Sick Children, University of Toronto, ON, Canada.
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16
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Wang J, Zhan P, Ouyang J, Chen B, Zhou R, Yang Y. Unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients: A meta-analysis. Leuk Res 2009; 34:1018-22. [PMID: 20031212 DOI: 10.1016/j.leukres.2009.11.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Revised: 11/21/2009] [Accepted: 11/22/2009] [Indexed: 11/25/2022]
Abstract
The effect of unrelated donor bone marrow transplantation (UBMT) and unrelated donor cord blood transplantation (UCBT) on the outcome of patients with hematological diseases remains controversial. We conducted a meta-analysis using data from controlled clinical trials comparing UCBT to UBMT in patients undergoing hematopoietic stem cell transplantation. Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of chronic graft-versus-host disease (GVHD) was lower with UCBT (relative risk [RR]=0.41; 95% confidence interval [CI] (0.25, 0.68)), and the incidence of grades II-IV aGVHD was also significantly different (RR=0.69; 95% CI (0.55, 0.86)). The incidence of relapse was also lower with UCBT (RR=0.72; 95% CI (0.59, 0.87)). There was no difference in OS in children when studies were pooled (Hazard ratio [HR]=1.25; 95% CI (0.87, 1.78)). For adults, OS (HR=1.26; 95% CI (1.13, 1.40)) was statistically different. Thus, UCBT led to inferior outcomes than UBMT in adults.
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Affiliation(s)
- Jing Wang
- Department of Hematology, the Affiliated DrumTower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, PR China
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17
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Abstract
OBJECTIVE To investigate the cost-effectiveness of private umbilical cord blood banking. METHODS A decision-analytic model was designed comparing private umbilical cord blood banking with no umbilical cord blood banking. Baseline assumptions included a cost of $3,620 for umbilical cord blood banking and storage for 20 years, a 0.04% chance of requiring an autologous stem cell transplant, a 0.07% chance of a sibling requiring an allogenic stem cell transplant, and a 50% reduction in risk of graft-versus-host disease if a sibling uses banked umbilical cord blood. RESULTS Private cord blood banking is not cost-effective because it cost an additional $1,374,246 per life-year gained. In sensitivity analysis, if the cost of umbilical cord blood banking is less than $262 or the likelihood of a child needing a stem cell transplant is greater than 1 in 110, private umbilical cord blood banking becomes cost-effective. CONCLUSION Currently, private umbilical cord blood banking is cost-effective only for children with a very high likelihood of needing a stem cell transplant. Patients considering private blood banking should be informed of the remote likelihood that a unit will be used for a child or another family member. LEVEL OF EVIDENCE III.
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18
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Brunstein CG, Weisdorf DJ. Future of cord blood for oncology uses. Bone Marrow Transplant 2009; 44:699-707. [DOI: 10.1038/bmt.2009.286] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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19
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Jacobsohn DA, Tse WT, Chaleff S, Rademaker A, Duerst R, Olszewski M, Huang W, Chou PM, Kletzel M. High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival. Br J Haematol 2009; 146:669-74. [PMID: 19650884 DOI: 10.1111/j.1365-2141.2009.07770.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
WT1 gene expression has been proposed as a useful marker of minimal residual disease in leukaemia. Its utility in paediatric haematopoietic stem cell transplantation (HSCT) has not been studied. We studied the prognostic value of WT1 expression in peripheral blood prior to HSCT in 36 children with acute myeloid leukaemia (AML). Samples were obtained 2 weeks pre-transplant to determine the level of WT1 expression. WT1 expression was normalized using K562 cells as a control and a relative value of 0.5 was chosen as the cut-off point between high and low WT1 expression. The median level of pre-transplant WT1 expression in the 36 patients was 0.09 (range 0.0001-11.0), with 11 patients having WT1 >or= 0.5 and 25, WT1 < 0.5. After HSCT, 76% of patients with high pre-transplant WT1 expression relapsed, in contrast to 0% of the patients with low WT1 expression. Those with high WT1 expression had significantly lower 5-year event-free survival (EFS) (18%, 95% CI 0-40%) as compared to those with low WT1 expression (68%, 95% CI 50-86%, P = 0.007). Multivariate analysis showed that pre-transplant WT1 level is the only significant prognostic factor for the difference in EFS. Our finding suggests that elevated WT1 gene expression before HSCT in paediatric AML predicts relapse and poor long-term EFS. A larger prospective study is warranted to compare the value of high WT1 expression and other markers of minimal residue disease in predicting clinical outcomes after HSCT.
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Affiliation(s)
- David A Jacobsohn
- Children's Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60614, USA.
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Abstract
PURPOSE We used total body irradiation (TBI) as conditioning for cord blood transplantation studies in pigtailed macaques. In these studies, different doses of TBI were explored to obtain optimal myelosuppression with acceptable radiation-related side effects. METHODS Four macaques received TBI ranging from 800 to 1320 cGy, followed by standard post-transplant care. Hematopoietic recovery was monitored by CBC and donor contribution by variable number of tandem repeats analysis. RESULTS Animals receiving 800 or 1020 cGy TBI tolerated the irradiation well with autologous recovery of neutrophils within 24 days. At a dose of 1200 cGy, neither autologous recovery nor extramedullary toxicity was observed. A fourth animal received 1320 cGy of TBI and suffered significant toxicity necessitating termination of the study. CONCLUSIONS We conclude that previously considered myeloablative doses of TBI allowed for autologous recovery in the pigtailed macaque, and that a dose of 1200 cGy may be most appropriate, providing both myeloablation and acceptable non-hematopoietic toxicities.
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Affiliation(s)
- K L Watts
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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21
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Affiliation(s)
- Beth Percer
- Knoxville Women's Health Nurse Practitioner Program, University of Tennessee, TN, USA.
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22
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Shi-Xia X, Xian-Hua T, Xiang-Feng T. Unrelated umbilical cord blood transplantation and unrelated bone marrow transplantation in children with hematological disease: a meta-analysis. Pediatr Transplant 2009; 13:278-84. [PMID: 19032424 DOI: 10.1111/j.1399-3046.2008.01089.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
UCB has been used as an alternative source of HSC. Both unrelated donor BM and UCB are available as potential options for transplantation. However, there have been limited comparisons of the outcomes of unrelated donor UCBT vs. UBMT in the unrelated setting. Our aim is to observe the therapeutic efficacy of UCBT and UBMT for treatment of pediatric hematological diseases. We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and critically appraised all relevant articles (1989.1-2008.5). Comparative studies were carried out on clinical therapeutic effect of UCBT and UBMT with research on stem cells engraftment, complications, earlier mortality, and survival rate. We performed a meta-analysis using review manager 5.0 software (RevMan, The Nordic Cochrane Center, The Cochrane Collaboration) and adopted funnel plot regression to assess the publication bias. We obtained 324 records. Seven trials totaling 1453 patients have been assessed. Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of engraftment failure and earlier transplantation-related mortality were higher with UCBT because of its delay of hematological recovery [OR = 4.96, 95% CI (3.25, 7.59), p < 0.00001 and OR = 2.36, 95% CI (1.79, 3.11), p < 0.00001 respectively], but CMV infection didn't increase obviously. There was no difference in long disease-free survival rate [OR = 0.85, 95% CI (0.65, 1.01), p = 0.06] between UCBT and UBMT due to the decrease of GVHD in UCBT [OR = 0.45, 95% CI (0.34, 0.60), p < 0.0001]. Our meta-analysis confirmed that UCBT in children is also an effective way to treat children with hematological disease and has equivalent survival outcomes compared with UBMT.
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Affiliation(s)
- Xu Shi-Xia
- Department of Medical Information, Navy General Hospital, Beijing, China.
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23
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Outcome following unrelated cord blood transplant in 136 patients with malignant and non-malignant diseases: a report from the Australian and New Zealand children's haematology and oncology group. Bone Marrow Transplant 2008; 43:207-15. [DOI: 10.1038/bmt.2008.314] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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24
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Bailey LC, Lange BJ, Rheingold SR, Bunin NJ. Bone-marrow relapse in paediatric acute lymphoblastic leukaemia. Lancet Oncol 2008; 9:873-83. [PMID: 18760243 DOI: 10.1016/s1470-2045(08)70229-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Marrow relapse is the major obstacle to cure for 10-15% of young patients with acute lymphoblastic leukaemia (ALL). Recent investigations into the biology of minimal residual disease indicate that many early relapses derive from residual cells present at first diagnosis, but some late relapses might represent new mutations in leukaemic cells not eliminated by conventional therapy. Treatment of marrow relapse involves higher doses and more intensive schedules of the drugs used for initial therapy with or without haemopoietic stem cell transplantation. In most reports, transplantation is better than continuation chemotherapy in early marrow relapse, but its role in later relapse is less clear. Current therapy cures 10% of patients with early marrow relapses and 50% of those with late relapses, but outcomes have changed little in the past two decades. Understanding the molecular biology of ALL underlies development of improved risk stratification and new therapies. Although better drugs are needed, introduction of new agents into clinical trials in paediatric disease has been difficult. Innovative trial designs and use of valid surrogate endpoints may expedite this process.
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Affiliation(s)
- L Charles Bailey
- Division of Oncology, Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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Brunstein CG, Setubal DC, Wagner JE. Expanding the role of umbilical cord blood transplantation. Br J Haematol 2007; 137:20-35. [PMID: 17359369 DOI: 10.1111/j.1365-2141.2007.06521.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Umbilical cord blood has become a valuable alternative source of haematopoietic stem cells for allogeneic transplantation. However, largely because of the impact of cell dose on engraftment, risk of transplant-related mortality and survival, progress in the field has been largely restricted to children. Nevertheless, substantial clinical experience with umbilical cord blood transplantation clearly establishes its safety and effectiveness in young patients with a variety of malignant and non-malignant diseases. Although less well established in adults, new strategies are now being explored to address the obstacle of cell dose. This article reviews the state of the art and future directions with umbilical cord blood as a source of haematopoietic stem cells for transplantation in both children and adults.
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Affiliation(s)
- Claudio G Brunstein
- Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA.
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Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis 2007; 2:35. [PMID: 17784964 PMCID: PMC2018687 DOI: 10.1186/1750-1172-2-35] [Citation(s) in RCA: 154] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Accepted: 09/04/2007] [Indexed: 11/10/2022] Open
Abstract
Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. About 35%-50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used. Given the number of transplants performed, we can expect about 5500 patients/year to develop acute GVHD. Patients can have involvement of three organs: skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). One or more organs may be involved. GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome. Generally the patient is treated by optimizing their immunosuppression and adding methylprednisolone. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative to better define second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD. About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD.
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Affiliation(s)
- David A Jacobsohn
- Robert H Lurie Comprehensive Cancer Center and Division of Hematology/Oncology/Transplant, Children's Memorial Hospital, Chicago, IL, USA
| | - Georgia B Vogelsang
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Affiliation(s)
- Young-Ho Lee
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
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29
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Petropoulos D, Chan KW. Umbilical cord blood transplantation. Curr Hematol Malig Rep 2006; 1:197-200. [PMID: 20425351 DOI: 10.1007/s11899-996-0008-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Over the past decade umbilical cord blood has been established as a viable source of hematopoietic stem cells for allogeneic transplantation. Early experience with umbilical cord blood transplantation (CBT) demonstrated a lower incidence of graft-versus-host disease even though the procedure was performed with HLA-disparate grafts. The overall outcome of CBT appears similar to that of allogeneic bone marrow transplantation. The expansion of the donor selection is particularly beneficial to ethnic minorities, whose representation in the marrow registries is relatively small. The major drawbacks of CBT are slow hematopoietic recovery and a high incidence of graft failure, as a result of a lower number of progenitors infused. This paper reviews the current results of CBT and ongoing investigations to increase its availability to a larger number of recipients.
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Affiliation(s)
- Demetrios Petropoulos
- Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
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Abstract
Umbilical cord blood transplantation (UCBT) is an expanding practice for both pediatric and adult patients. Rapid availability, low risk of infectious disease transmission, lower risk of graft-versus-host disease, and lack of risk for the donor makes UCB an attractive alternative source of hematopoietic stem cells for transplantation. We review the state of the art of pediatric and adult UCBT and important aspects of UCB banking. Current strategies to improve clinical results and expand access to UCBT to a larger number of adult patients are discussed. New approaches to enhance hematopoietic recovery by the use of accessory cells or direct intra-bone marrow injection are also reviewed.
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Affiliation(s)
- Claudio G Brunstein
- Department of Medicine, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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31
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Abstract
Over the past decade umbilical cord blood has been established as a viable source of hematopoietic stem cell for allogeneic transplantation. Early experience with umbilical cord blood transplantation (CBT) demonstrated a lower incidence of graft-versus-host disease even though the procedure was performed with HLA-disparate grafts. The overall outcome of CBT appears similar to that of allogeneic bone marrow transplant. The expansion of the donor selection is particularly beneficial to ethnic minorities, whose representation in the marrow registries is relatively small. The major drawbacks of CBT are slow hematopoietic recovery and a high incidence of graft failure, as a result of a lower number of progenitors infused. This paper reviews the current results of CBT and ongoing investigations to increase its availability to a larger number of recipients.
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Affiliation(s)
- Demetrios Petropoulos
- Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 87, Houston, TX 77030, USA.
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Affiliation(s)
- Süreyya Savaşan
- Children's Hospital of Michigan, Hematology/Oncology Division, 3901 Beaubien Blvd., Detroit, MI 48301, USA
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Current Awareness in Hematological Oncology. Hematol Oncol 2005. [DOI: 10.1002/hon.729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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