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Kiene S, Albrecht M, Theurich S, Scheid C, Skoetz N, Holtick U. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2024; 11:CD010189. [PMID: 39508306 PMCID: PMC11542152 DOI: 10.1002/14651858.cd010189.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. OBJECTIVES To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. SEARCH METHODS For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. MAIN RESULTS The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. AUTHORS' CONCLUSIONS Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.
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Affiliation(s)
- Sinje Kiene
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Stem Cell Transplantation Program, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Melanie Albrecht
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Stem Cell Transplantation Program, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sebastian Theurich
- Department of Medicine III, University Hospital LMU, Ludwig-Maximilians-Universität München, Munich, Germany
- Cancer- and Immunometabolism Research Group, Gene Center LMU, Munich, Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, German Cancer Research Center, Heidelberg, Germany., Munich, Germany
| | - Christof Scheid
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Stem Cell Transplantation Program, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Nicole Skoetz
- Cochrane Evidence Synthesis Unit Germany, Institute of Public Health, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Udo Holtick
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Stem Cell Transplantation Program, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Hawsawi YM, Al-Zahrani F, Mavromatis CH, Baghdadi MA, Saggu S, Oyouni AAA. Stem Cell Applications for Treatment of Cancer and Autoimmune Diseases: Its Promises, Obstacles, and Future Perspectives. Technol Cancer Res Treat 2019; 17:1533033818806910. [PMID: 30343639 PMCID: PMC6198389 DOI: 10.1177/1533033818806910] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Since the original discovery of stem cells, a new era of promising results has emerged in the clinical application of stem cells for the treatment of several important diseases, including cancer and autoimmune diseases. The plentiful research on stem cells during the past decades has provided significant information on the developmental, morphological, and physiological processes that govern tissue and organ formation, maintenance, and regeneration; cellular differentiation; molecular processes; and tissue homeostasis. In this review, we present the history of the use of stem cells in different clinical applications. Furthermore, we discuss the various therapeutic options for stem cells in cancer, followed by the role of stem cells in the treatment of autoimmune disorders. Additionally, we highlight the risks of and obstacles to the application of stem cells in clinical practice. Ultimately, we show future perspectives in stem cell use, with an aim to improve the clinical usefulness of stem cells.
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Affiliation(s)
- Yousef M Hawsawi
- 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.,2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia.,3 Department of Epidemiology and Biostatistics, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
| | - Faisal Al-Zahrani
- 2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia
| | - Charalampos Harris Mavromatis
- 2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia
| | - Mohammed A Baghdadi
- 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.,3 Department of Epidemiology and Biostatistics, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
| | - Shalini Saggu
- 4 Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
| | - Atif Abdulwahab A Oyouni
- 4 Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
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3
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Amouzegar A, Dey BR, Spitzer TR. Peripheral Blood or Bone Marrow Stem Cells? Practical Considerations in Hematopoietic Stem Cell Transplantation. Transfus Med Rev 2018; 33:43-50. [PMID: 30528986 DOI: 10.1016/j.tmrv.2018.11.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 11/02/2018] [Accepted: 11/06/2018] [Indexed: 01/10/2023]
Abstract
Although peripheral blood stem cells (PBSC) have worldwide become the predominant source of progenitor cells for hematopoietic stem cell transplantation (HSCT), debate about their role compared with bone marrow (BM) has recently intensified, in large part based on the results of a multicenter Clinical Trials Network study which showed lower incidence of chronic graft-versus-host disease (cGVHD) and improved quality of life in recipients of myeloablative HLA-matched unrelated BM compared with PBSC transplants. However, in certain patient populations, PBSC may lead to improved clinical outcomes due to faster hematologic recovery, a lower risk of graft failure, and possibly a lower probability of relapse. This review will provide a comprehensive summary of studies comparing PBSC with BM as the graft source in terms of acute and chronic GVHD incidence, time to engraftment, and disease-free and overall survival probabilities after HLA-matched related and unrelated donor transplantation and haploidentical donor transplantation. Recommendations based on these studies regarding the use of PBSC versus BM for HSCT are offered.
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Affiliation(s)
- Afsaneh Amouzegar
- Department of Medicine, Bone Marrow Transplant Unit, Massachusetts General Hospital, Boston, MA
| | - Bimalangshu R Dey
- Department of Medicine, Bone Marrow Transplant Unit, Massachusetts General Hospital, Boston, MA
| | - Thomas R Spitzer
- Department of Medicine, Bone Marrow Transplant Unit, Massachusetts General Hospital, Boston, MA.
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4
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DeFilipp Z, Khoury HJ. Management of advanced-phase chronic myeloid leukemia. Curr Hematol Malig Rep 2016; 10:173-81. [PMID: 25929768 DOI: 10.1007/s11899-015-0249-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The management of chronic myeloid leukemia (CML) in accelerated or blast phase (advanced phase) remains a significant challenge despite the introduction of very effective tyrosine kinase inhibitors (TKIs). The biology of advanced-phase CML is complex and engages several pathways that are not optimally targeted by TKIs. Allogeneic stem cell transplantation remains the only potentially curative therapy, but the effectiveness of this conventional approach is limited. New strategies are required to improve the outlook for these patients.
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Affiliation(s)
- Zachariah DeFilipp
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Road NE C5010, Atlanta, GA, 30322, USA,
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Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults—a systematic review and meta-analysis. Crit Rev Oncol Hematol 2015; 94:179-88. [DOI: 10.1016/j.critrevonc.2014.12.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 10/08/2014] [Accepted: 12/11/2014] [Indexed: 11/21/2022] Open
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Vonka V, Petráčková M. Immunology of chronic myeloid leukemia: current concepts and future goals. Expert Rev Clin Immunol 2015; 11:511-22. [PMID: 25728856 DOI: 10.1586/1744666x.2015.1019474] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although chronic myeloid leukemia is a rare malignancy, it has developed into a model system for the study of a variety of aspects of cancer biology and immunology. The introduction of tyrosine kinase inhibitors has resulted in a significant prolongation of the survival rates of chronic myeloid leukemia patients but has not resulted in a cure. There is a growing conviction that this aim can be achieved through immunotherapy. For this concept to be successful, a considerable increase in the present understanding of chronic myeloid leukemia immunology is required. The authors attempt to review and evaluate the current findings that demonstrate a number of immunological aberrations in patients prior to the start of any therapy and their normalization after achieving remission. They also discuss the recent clinical trials with experimental therapeutic vaccines and then present their own strategy on how to address the problem.
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Affiliation(s)
- Vladimír Vonka
- Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12820 Prague 2, Czech Republic
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Gupta A, Khattry N. Current status of hematopoietic stem cell transplant in chronic myeloid leukemia. Indian J Med Paediatr Oncol 2014; 35:207-10. [PMID: 25336791 PMCID: PMC4202616 DOI: 10.4103/0971-5851.142036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Indications for hematopoietic stem cell transplant (HSCT) in chronic myeloid leukemia (CML) have changed over time. This change has largely been influenced by the advent of tyrosine kinase inhibitors, increased understanding of the mechanisms underlying disease phase progression as well as drug resistance, refinement of transplant techniques and exploitation of graft versus leukemia effect in this disease. Here, we have discussed the status of HSCT in CML in the present era with regards to the current indications, factors determining outcome and management strategies for posttransplant relapse.
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Affiliation(s)
- Alok Gupta
- Department of Medical Oncology, Bone Marrow Transplant Unit, ACTREC, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Navin Khattry
- Department of Medical Oncology, Bone Marrow Transplant Unit, ACTREC, Tata Memorial Centre, Mumbai, Maharashtra, India
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Ohashi K, Nagamura-Inoue T, Nagamura F, Tojo A, Miyamura K, Mori T, Kurokawa M, Taniguchi S, Ishikawa J, Morishima Y, Atsuta Y, Sakamaki H. Effect of graft sources on allogeneic hematopoietic stem cell transplantation outcome in adults with chronic myeloid leukemia in the era of tyrosine kinase inhibitors: a Japanese Society of Hematopoietic Cell Transplantation retrospective analysis. Int J Hematol 2014; 100:296-306. [DOI: 10.1007/s12185-014-1632-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 07/01/2014] [Accepted: 07/02/2014] [Indexed: 11/27/2022]
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Holtick U, Albrecht M, Chemnitz JM, Theurich S, Skoetz N, Scheid C, von Bergwelt‐Baildon M, Cochrane Haematological Malignancies Group. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2014; 2014:CD010189. [PMID: 24748537 PMCID: PMC10612998 DOI: 10.1002/14651858.cd010189.pub2] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant disorders. In the past two decades, peripheral blood stem cells replaced bone marrow as stem cell source due to faster engraftment and practicability. Previous meta-analyses analysed patients treated from 1990 to 2002 and demonstrated no impact of the stem cell source on overall survival, but a greater risk for graft-versus-host disease (GvHD) in peripheral blood transplants. As transplant indications and conditioning regimens continue to change, whether the choice of the stem cell source has an impact on transplant outcomes remains to be determined. OBJECTIVES To assess the effect of bone marrow versus peripheral blood stem cell transplantation in adult patients with haematological malignancies with regard to overall survival, incidence of relapse and non-relapse mortality, disease-free survival, transplant-related mortality, incidence of GvHD and time to engraftment. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (from 1948 to February 2014), trial registries and conference proceedings. The search was conducted in October 2011 and was last updated in February 2014. We did not apply any language restrictions. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing bone marrow and peripheral blood allogeneic stem cell transplantation in adults with haematological malignancies. DATA COLLECTION AND ANALYSIS Two review authors screened abstracts and extracted and analysed data independently. We contacted study authors for additional information. We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS We included nine RCTs that met the pre-defined selection criteria, involving a total of 1521 participants. Quality of data reporting was heterogeneous among the studies. Overall, the risk of bias in the included studies was low.For the primary outcome overall survival, our analysis demonstrated comparable results between bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) (six studies, 1330 participants; hazard ratio (HR) 1.07; 95% CI 0.91 to 1.25; P value = 0.43; high-quality evidence).Disease-free survival (six studies, 1225 participants; HR 1.04; 95% CI 0.89 to 1.21; P value = 0.6; moderate-quality of evidence) and non-relapse or transplant-related mortality (three studies, 758 participants; HR 0.98; 95% CI 0.76 to 1.28; P = 0.91; high-quality evidence) were also comparable between transplantation arms.In the related-donor setting, data from two of eight studies with 211 participants (21%) indicated a higher relapse incidence in participants transplanted with bone marrow stem cells rather than peripheral blood stem cells (HR 2.73; 95% CI 1.47 to 5.08; P value = 0.001). There was no clear evidence of a difference in relapse incidence between transplantation groups in unrelated donors (HR 1.07; 95% CI 0.78 to 1.47; P value = 0.66). The difference between the donor-related and -unrelated subgroups (P-value = 0.008) was considered to be statistically significant.BMT was associated with lower rates of overall and extensive chronic GvHD than PBSCT (overall chronic GvHD: four studies, 1121 participants; HR 0.72; 95% CI 0.61 to 0.85; P value = 0.0001, extensive chronic GvHD: four studies, 765 participants; HR 0.69; 95% CI 0.54 to 0.9; P value = 0.006; moderate-quality evidence for both outcomes). The incidence of acute GvHD grades II to IV was not lower (six studies, 1330 participants; HR 1.03; 95% CI 0.89 to 1.21; P value = 0.67; moderate-quality evidence), but there was a trend for a lower incidence of grades III and IV acute GvHD with BMT than with PBSCT (three studies, 925 participants; HR 0.75; 95% CI 0.55 to 1.02; P value = 0.07; moderate-quality evidence).Times to neutrophil and platelet engraftment were longer with BMT than with PBSCT (neutrophil: five studies, 662 participants; HR 1.96; 95% CI 1.64 to 2.35; P value < 0.00001; platelet: four studies, 333 participants; HR 2.17; 95% CI 1.69 to 2.78; P value < 0.00001). AUTHORS' CONCLUSIONS This systematic review found high-quality evidence that overall survival following allo-HSCT using the current clinical standard stem cell source - peripheral blood stem cells - was similar to that following allo-HSCT using bone marrow stem cells in adults with haematological malignancies. We found moderate-quality evidence that PBSCT was associated with faster engraftment of neutrophils and platelets, but a higher risk of GvHD (in terms of more overall and extensive chronic GvHD). There was an imprecise effect on relapse and on severe (grades III to IV) acute GvHD. Quality of life, which is severely affected by GvHD, was not evaluated.Against the background of transplantation practices that have clearly changed over the past 10 to 15 years, our aim was to provide current data on the best stem cell source for allo-HSCT, by including the results of recently conducted trials. Our review includes participants recruited up to 2009, a proportion of whom were older, had received reduced-intensity conditioning regimens or had been transplanted with stem cells from unrelated donors. However, only one, large, study included relatively recently treated participants. Nevertheless, our findings are comparable to those of previous meta-analyses suggesting that our results hold true for today's practice.
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Affiliation(s)
- Udo Holtick
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramCologneGermany50924
| | - Melanie Albrecht
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramCologneGermany50924
| | - Jens M Chemnitz
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramCologneGermany50924
| | - Sebastian Theurich
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramCologneGermany50924
| | - Nicole Skoetz
- University Hospital of CologneCochrane Haematological Malignancies Group, Department I of Internal MedicineKerpener Str. 62CologneGermany50924
| | - Christof Scheid
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramCologneGermany50924
| | - Michael von Bergwelt‐Baildon
- University Hospital of CologneDepartment I of Internal Medicine, Stem Cell Transplantation ProgramCologneGermany50924
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Engineering human peripheral blood stem cell grafts that are depleted of naïve T cells and retain functional pathogen-specific memory T cells. Biol Blood Marrow Transplant 2014; 20:705-16. [PMID: 24525279 DOI: 10.1016/j.bbmt.2014.01.032] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 01/29/2014] [Indexed: 12/14/2022]
Abstract
Graft-versus-host disease (GVHD) is a frequent major complication of allogeneic hematopoietic cell transplantation (HCT). Approaches that selectively deplete T cells that cause GVHD from allogeneic stem cell grafts and preserve T cells specific for pathogens may improve HCT outcomes. It has been hypothesized that the majority of T cells that can cause GVHD reside within the naïve T cell (TN) subset, and previous studies performed in mouse models and with human cells in vitro support this hypothesis. As a prelude to translating these findings to the clinic, we developed and evaluated a novel 2-step clinically compliant procedure for manipulating peripheral blood stem cells (PBSC) to remove TN, preserve CD34(+) hematopoietic stem cells, and provide for a fixed dose of memory T cells (TM) that includes T cells with specificity for common opportunistic pathogens encountered after HCT. Our studies demonstrate effective and reproducible performance of the immunomagnetic cell selection procedure for depleting TN. Moreover, after cell processing, the CD45RA-depleted PBSC products are enriched for CD4(+) and CD8(+) TM with a central memory phenotype and contain TM cells that are capable of proliferating and producing effector cytokines in response to opportunistic pathogens.
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11
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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: 36] [Impact Index Per Article: 3.0] [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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Sohn SK, Moon JH. Adoptable strategic approaches to improve outcomes of allogeneic peripheral blood stem cell transplantations from unrelated donors. Transfusion 2013; 54:1673-80. [PMID: 24261633 DOI: 10.1111/trf.12503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 10/21/2013] [Accepted: 10/22/2013] [Indexed: 11/27/2022]
Abstract
While previous studies have shown comparable clinical results for related and unrelated bone marrow transplantation (BMT), the transplantation outcomes for related and unrelated peripheral blood stem cell transplantation (PBSCT) may not follow the same pattern due to a higher incidence of graft-versus-host disease (GVHD)-related morbidity and mortality in the case of long-term survival after unrelated PBSCT. Thus, given the higher possibility of an impaired quality of life due to severe GVHD in long-term survivors who receive unrelated PBSCT, the selection of the stem cell source needs to be decided very carefully. In addition, strategic approaches, such as the extended use of immunosuppressant as a GVHD prophylaxis, the use of antithymocyte globulins (ATGs), choosing a younger donor, and optimizing the CD34+ cell dose, need to be adopted to improve the transplantation outcomes by minimizing GVHD-related morbidity and mortality in an unrelated PBSCT setting. This review article provides a comparison of BMT and PBSCT, and related and unrelated PBSCT, plus introduces several adoptable strategies to improve the outcomes of unrelated PBSCT.
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Affiliation(s)
- Sang Kyun Sohn
- Department of Hematology/Oncology, Kyungpook National University Hospital, Daegu, South Korea
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13
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Pavlů J, Apperley JF. Allogeneic stem cell transplantation for chronic myeloid leukemia. Curr Hematol Malig Rep 2013; 8:43-51. [PMID: 23275177 DOI: 10.1007/s11899-012-0149-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In recent years new, more potent tyrosine-kinase inhibitors have been introduced to accompany imatinib for the treatment of chronic myeloid leukemia. Most patients in chronic phase obtain an optimal response to these oral agents with minimal toxicity. Allogeneic stem cell transplantation is therefore indicated only in a minority of patients who do not achieve an adequate response to first, second or third generation agents. Patients in accelerated phase have a lower chance of achieving an optimal response on these drugs. For patients in blast phase, transplantation remains the only therapy with curative potential, although now it is increasingly used in combination with tyrosine-kinase inhibitors. In this review we address the role of allogeneic stem cell transplantation in the treatment of this disease and how patients should be transplanted.
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Affiliation(s)
- Jiří Pavlů
- Imperial College London at Hammersmith Hospital, London, UK.
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Abstract
Tyrosine kinase inhibitor (TKI) therapy has revolutionized the therapy of chronic myeloid Leukemia (CML). Thus, while in the near past allogeneic transplantation was the curative option for CML, imatinib, nilotinib, and dasatinib have pushed transplantation to the role of salvage therapy in CML. Still, TKI therapy still fails some patients, and so the clinical challenge is to integrate transplantation in a safe and sane manner. This manuscript reviews the data on the variables that have an influence on outcome following transplantation, and discusses the variables to consider in determining who and when patients should receive transplantation.
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Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367:1487-96. [PMID: 23075175 PMCID: PMC3816375 DOI: 10.1056/nejmoa1203517] [Citation(s) in RCA: 676] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).
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Affiliation(s)
- Claudio Anasetti
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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16
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Zhang H, Chen J, Que W. Allogeneic peripheral blood stem cell and bone marrow transplantation for hematologic malignancies: Meta-analysis of randomized controlled trials. Leuk Res 2012; 36:431-7. [DOI: 10.1016/j.leukres.2011.10.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2011] [Revised: 10/03/2011] [Accepted: 10/16/2011] [Indexed: 11/28/2022]
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17
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Nagler A, Labopin M, Shimoni A, Niederwieser D, Mufti GJ, Zander AR, Arnold R, Greinix H, Cornelissen JJ, Jackson GH, Craddock C, Bunjes DW, Ganser A, Russell NH, Kyrcz-Krzemien S, Rocha V, Mohty M. Mobilized peripheral blood stem cells compared with bone marrow as the stem cell source for unrelated donor allogeneic transplantation with reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission: an analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012; 18:1422-9. [PMID: 22446014 DOI: 10.1016/j.bbmt.2012.02.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 02/26/2012] [Indexed: 12/12/2022]
Abstract
Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC-alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient's age was higher in the PBSC versus BM groups 57 (range, 17-77 years) and 51 (range, 17-76 years), respectively (P < .0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (aGVHD) grade >II was significantly higher in the PBSC group: 27% versus 12% in the BM group (P < .002). Similarly, chronic graft-versus-host disease (cGVHD; at 2 years) was somewhat higher in the PBSC group with 43% ± 3% versus 35% ± 6% in the BM group, respectively (P = .04). The 2-year probabilities of leukemia-free survival (LFS) were 46% ± 3% for the PBSC group in comparison to 43% ± 6% for the BM transplant group (P = NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% ± 6% versus 32% ± 3%, respectively (P = .014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% ± 2% versus 13% ± 4%, respectively (P = .004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of aGVHD (grade II-IV; hazard ratio [HR] = 2.33; P = .06), higher NRM (HR = 2.3; P = .015), and a decreased relapse incidence (HR, 0.61; P = .02) with no statistical difference of LFS between the 2 groups (P = .88). In conclusion, our results indicate significantly higher incidence of aGVHD and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT.
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Affiliation(s)
- Arnon Nagler
- Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
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18
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Chronic myelogenous leukemia: role of stem cell transplant in the imatinib era. Hematol Oncol Clin North Am 2012; 25:1025-48, vi. [PMID: 22054733 DOI: 10.1016/j.hoc.2011.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In the pre-tyrosine kinase (TKI) era, allogeneic stem cell transplant (allo-SCT) was the front-line treatment of choice for young patients with chronic myelogenous leukemia (CML). Today, imatinib is well established as front-line therapy for CML, with excellent long-term outcomes. This has changed the role of allo-SCT and the number of patients undergoing allo-SCT has declined dramatically. Allo-SCT is currently recommended for patients in accelerated/blast phase disease, those who have failed a second-generation TKI and those with TKI-resistant mutations such as T315I. The role of allo-SCT in the management of CML will require continual reappraisal as medical therapies continue to evolve.
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19
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Allogeneic bone marrow transplantation compared to peripheral blood stem cell transplantation for the treatment of hematologic malignancies: a meta-analysis based on time-to-event data from randomized controlled trials. Ann Hematol 2011; 91:427-37. [PMID: 21789620 DOI: 10.1007/s00277-011-1299-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 07/13/2011] [Indexed: 01/20/2023]
Abstract
Controversy remains regarding the transplant outcomes of human leukocyte antigen-identical related bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) for the treatment of patients with hematological malignancies. To provide an estimate of the effect of BMT and PBSCT on clinical outcomes in patients with hematological malignancies, we conducted a meta-analysis based on time-to-event data from 17 randomized controlled trials. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), from 1972 through July 2010, and conference proceedings through July 2009 and reference lists, without any language restriction, of randomized trials that compared the transplant outcomes after BMT and PBSCT in patients with hematological malignancies were searched for details. Two independent reviewers extracted the data. The outcomes examined were engraftment, graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), leukemia-free-survival (LFS), and overall survival (OS). Compared to PBSCT, BMT had lower neutrophil (HR, 2.08; 95% CI, 1.80 to 2.42; p < 0.00001) and platelet (HR, 2.77; 95% CI, 1.78 to 4.30; p < 0.00001) engraftment. BMT was associated with a significant decrease in the development of grades II-IV (HR, 0.75; 95% CI, 0.63 to 0.90; p = 0.002) and III-IV (HR, 0.63; 95% CI, 0.47 to 0.84; p = 0.001) acute GVHD as well as overall (HR, 0.70; 95% CI, 0.59 to 0.83; p < 0.0001) and extensive (HR, 0.60; 95% CI, 0.39 to 0.91; p = 0.002) chronic GVHD. BMT was associated with a higher incidence of relapse (HR, 1.91; 95% CI, 1.34 to 2.74; p = 0.0004). Comparable TRM (1.08; 95% CI, 0.56 to 2.10; p = 0.81), LFS (HR, 1.04; 95% CI, 0.83 to 1.30; p = 0.73), and OS (HR, 1.06; 95% CI, 0.81 to 1.39; p = 0.65) were demonstrated for both treatments. An inverse linear relationship was observed between the acute GVHD difference (PBSCT minus BMT) and the outcome of OS (p = 0.016). Our meta-analysis suggest that BMT leads to slower hematological recovery, increasing rates of relapse, and a lower risk of GVHD, but no significant difference in LFS and OS. A lower incidence of acute GVHD is associated with a superior OS.
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20
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Abstract
Tyrosine kinase inhibitor (TKI) therapy has revolutionized the therapy of chronic myeloid leukemia (CML). Thus, while in the near past allogeneic transplantation was the curative option for CML, imatinib, nilotinib, and dasatinib have pushed transplantation to the role of salvage therapy in CML. Still, TKI therapy still fails some patients, and so the clinical challenge is to integrate transplantation in a safe and sane manner. This article reviews the data on the variables that influence outcome following transplantation, and discusses the variables to consider in determining which patients should receive transplantation and when.
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Affiliation(s)
- Jerald Radich
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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21
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Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:9. [PMID: 21241480 PMCID: PMC3033847 DOI: 10.1186/1756-9966-30-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 01/17/2011] [Indexed: 12/11/2022]
Abstract
Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a correct view of the available stem cell subtypes and their rational use in the medical area, with a specific focus on their therapeutic benefits and side effects. We have reviewed the main clinical trials dividing them basing on their clinical applications, and taking into account the ethical issue associated with the stem cell therapy.
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Affiliation(s)
- Daniele Lodi
- Department of Nephrology, Dialysis and Transplantation, University of Modena and Reggio Emilia Medical School, Modena, Italy
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22
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Venepalli N, Rezvani K, Mielke S, Savani BN. Role of allo-SCT for CML in 2010. Bone Marrow Transplant 2010; 45:1579-86. [DOI: 10.1038/bmt.2010.138] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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23
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A retrospective comparison of allogeneic peripheral blood stem cell versus bone marrow transplantation. Hematol Oncol Stem Cell Ther 2010; 2:272-7. [PMID: 20063557 DOI: 10.1016/s1658-3876(09)50037-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Disease evolution depends in part on the source of transplanted cells. Therefore, we compared outcomes after allogeneic bone marrow (BM) and peripheral blood stem cell (PBSC) transplantation in patients who underwent transplant at Hospital das Clinicas of the Federal University of Minas Gerais, Brazil. PATIENTS AND METHODS We studied 364 patients who received allogeneic BM (n = 142) or PBSC transplantation (n = 222) between July 1995 and May 2005. The median age of the patients was 31 years (range, 3.1-58 years). Chronic myeloid leukemia was the predominant diagnosis (41.2%). A conditioning regimen with cyclosphosphamide and busulfan was used in 79.4% (n = 289) and graft-versus-host disease (GVHD) prophylaxis was cyclosporine/methotrexate in 95.9% (n = 349) of cases. RESULTS The patients in the PBSC group had faster neutrophil (P < .001) and platelet engraftment (P = .03) but increased rates of acute GVHD (P < .001) vs. those in the BM group. There was no significant difference between the groups in chronic GVHD, transplant-related mortality, relapse and survival rates. CONCLUSIONS Although allogeneic PBSC transplant results in a faster hematopoietic engraftment, there was an increase in acute GVHD. There was no clear benefit in relapse rate and no evidence that transplantation with PBSC benefits patient survival in our institution.
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24
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Williams KM, Gress RE. Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation. Best Pract Res Clin Haematol 2008; 21:579-96. [PMID: 18790456 PMCID: PMC2577193 DOI: 10.1016/j.beha.2008.06.003] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Recovery of a fully functional immune system is a slow and often incomplete process following allogeneic stem cell transplantation. While innate immunity reconstitutes quickly, adaptive B- and especially T-cell lymphopoeisis may be compromised for years following transplantation. In large part, these immune system deficits are due to the decrease, or even absence, of thymopoiesis following transplantation. Thereby, T-cell reconstitution initially relies upon expansion of mature donor T cells; a proliferation driven by high cytokine levels and the presence of allo-reactive antigens. This peripheral mechanism of T-cell generation may have important clinical consequences. By expanding tumouricidal T cells, it may provide a venue to enhance T-cellular immunotherapy following transplantation. Alternatively, decreased thymic function may impair long-term anti-tumour immunity and increase the likelihood of graft-versus-host disease.
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Affiliation(s)
- Kirsten M Williams
- Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, CRC-3E-3300, 10 Center Drive, Bethesda, MD 20892, USA
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25
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Tan SS, Uyl-de Groot CA, Huijgens PC, Fibbe WE. Stem cell transplantation in Europe: trends and prospects. Eur J Cancer 2007; 43:2359-65. [PMID: 17919900 DOI: 10.1016/j.ejca.2007.08.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2007] [Revised: 08/21/2007] [Accepted: 08/24/2007] [Indexed: 11/17/2022]
Abstract
The aim of the present study was to identify trends in numbers of European patients treated with autologous and allogeneic haematopoietic stem cell transplantation (HSCT) as well as to provide anticipated transplant rates for the upcoming years. The following indications were considered: haematological malignancies (acute leukaemias, myeloproliferative disorders, lymphoproliferative disorders and multiple myeloma), solid tumours and non-malignant diseases. Numbers of patients treated from 1990 to 2004 were extracted from the European Group for Blood and Marrow Transplantation database, extrapolated to 2012 using mathematic models and adjusted to the literature study and expert opinion. In Europe, a 13% raise in HSCT utilisation is to be expected from 2005 to 2010, mostly due to the growing application of reduced-intensity conditioning regimens followed by allogeneic HSCT. Growing transplant rates are likely to exert health expenditure budgets and put pressure on health care providers and health insurers in Europe. Therefore, the rapid expansion would ideally imply a simultaneous increase in HSCT budgets.
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Affiliation(s)
- S S Tan
- Erasmus MC University Medical Center, Institute for Medical Technology Assessment, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
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26
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Hart DP, Peggs KS. Current status of allogeneic stem cell transplantation for treatment of hematologic malignancies. Clin Pharmacol Ther 2007; 82:325-9. [PMID: 17637786 DOI: 10.1038/sj.clpt.6100283] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Bone marrow transplantation has evolved significantly over the past 40 years. The initial rationale of using donor bone marrow to guarantee a supply of hematopoietic stem cells uncontaminated by tumor remains a relevant principle today. However, the donor hematopoietic cells also exert an important immunological, therapeutic effect in the recipient. This synopsis will consider the balance of conditioning therapy intensity and immunological effect of allogeneic stem cell transplantation, informing the positioning of these approaches in current treatment algorithms.
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Affiliation(s)
- D P Hart
- Department of Haematology, University College London Hospital, London, UK
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27
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Sagar J, Chaib B, Sales K, Winslet M, Seifalian A. Role of stem cells in cancer therapy and cancer stem cells: a review. Cancer Cell Int 2007; 7:9. [PMID: 17547749 PMCID: PMC1894783 DOI: 10.1186/1475-2867-7-9] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2006] [Accepted: 06/04/2007] [Indexed: 12/12/2022] Open
Abstract
For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future.
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Affiliation(s)
- Jayesh Sagar
- Academic Department of Surgery, Royal Free Hospital, London, UK
- University College of London, London, UK
| | | | | | - Marc Winslet
- Academic Department of Surgery, Royal Free Hospital, London, UK
- University College of London, London, UK
| | - Alexander Seifalian
- Academic Department of Surgery, Royal Free Hospital, London, UK
- University College of London, London, UK
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28
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Small TN, Young JW, Castro-Malaspina H, Prockop S, Wilton A, Heller G, Boulad F, Chiu M, Hsu K, Jakubowski A, Kernan NA, Perales MA, O'Reilly RJ, Papadopoulos EB. Intravenous Busulfan and Melphalan, Tacrolimus, and Short-Course Methotrexate Followed by Unmodified HLA-Matched Related or Unrelated Hematopoietic Stem Cell Transplantation for the Treatment of Advanced Hematologic Malignancies. Biol Blood Marrow Transplant 2007; 13:235-44. [PMID: 17241929 DOI: 10.1016/j.bbmt.2006.10.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2006] [Accepted: 10/10/2006] [Indexed: 12/31/2022]
Abstract
Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and -DRbeta1-matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had > or = 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (< or = RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.
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Affiliation(s)
- Trudy N Small
- Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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29
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Bensinger W. Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration. Bone Marrow Transplant 2006; 38:539-46. [PMID: 16953207 PMCID: PMC1910698 DOI: 10.1038/sj.bmt.1705488] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The effects of immunosuppressive regimens on the outcomes of patients with hematological malignancies undergoing allogeneic stem cell transplantation remain uncertain. We conducted an individual patient data meta-analysis using data from nine randomized trials comparing allogeneic peripheral blood stem cell (PBSCT) transplants to bone marrow (BMT) transplants, focusing on the administration of three vs four doses of methotrexate (MTX) as part of a regimen for graft-versus-host-disease (GVHD) prophylaxis which included cyclosporine. Six trials containing 573 patients prescribed four doses of MTX while three trials containing 534 patients prescribed three doses of MTX. Four doses of MTX conferred a statistically significant survival advantage, resulting in death odds ratio (OR) 0.67 (CI 0.52-0.88) (P=0.0036) for recipients of PBSC compared to BM; with three doses, there was no statistically significant difference. In the four-dose studies relapse rates were 36.6% among recipients of BM compared to 19.2% among recipients of PBSC (P=0.0015). The rates of relapse in the three dose studies were 26% for both PBSC and BM. We hypothesize that the fourth dose of MTX provides extra immunosuppression among BM recipients resulting in a reduced anti-leukemic effect. This hypothesis can only be proved or disproved by a prospective, randomized trial.
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Affiliation(s)
- W Bensinger
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
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30
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Grigg A, Hughes T. Role of Allogeneic Stem Cell Transplantation for Adult Chronic Myeloid Leukemia in the Imatinib Era. Biol Blood Marrow Transplant 2006; 12:795-807. [PMID: 16864049 DOI: 10.1016/j.bbmt.2006.03.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2006] [Accepted: 03/29/2006] [Indexed: 11/29/2022]
Abstract
Due to superior survival in the short to medium term, the first-generation ABL kinase inhibitor imatinib mesylate has generally supplanted all other therapies as the initial treatment of choice in chronic phase chronic myeloid leukemia. The role of allogeneic stem cell transplantation (alloSCT) has shifted from a preferred first-line therapy to a possible second- or third-line therapy. However, despite generally excellent responses to imatinib, some patients respond poorly or lose response, and the risk-benefit equation in these cases may rapidly shift in favor of the alloSCT option. These patients need to be identified as soon as possible so that the alloSCT option can be applied while they are still in controlled chronic phase. Monitoring of imatinib response in patients who have suitable donors and are potentially eligible for alloSCT needs to be frequent, sensitive, and accurate. Clear criteria for switching from imatinib therapy to the alloSCT option should be established for each patient according to the specific risk profile of the transplant. The potential efficacy and safety of clinical trials combining reduced intensity alloSCT with ABL kinase inhibitor therapy warrants further consideration.
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MESH Headings
- Adult
- Benzamides
- History, 20th Century
- History, 21st Century
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/history
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Piperazines/history
- Piperazines/therapeutic use
- Protein Kinase Inhibitors/history
- Protein Kinase Inhibitors/therapeutic use
- Proto-Oncogene Proteins c-abl/antagonists & inhibitors
- Pyrimidines/history
- Pyrimidines/therapeutic use
- Stem Cell Transplantation
- Transplantation, Homologous
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Affiliation(s)
- Andrew Grigg
- Department of Clinical Haematology and Bone Marrow Transplantation, Royal Melbourne Hospital, Melbourne, Australia.
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31
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Mauro MJ, Maziarz RT. Stem cell transplantation in patients with chronic myelogenous leukemia: when should it be used? Mayo Clin Proc 2006; 81:404-16. [PMID: 16529146 DOI: 10.4065/81.3.404] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Hematopoietic stem cell transplantation has been a cornerstone of therapy for chronic myelogenous leukemia (CML) for more than 15 years and is still a standard treatment option for patients with CML. The advent of imatinib mesylate, an inhibitor of the molecular defect driving CML, the BCR-ABL tyrosine kinase, has rewritten treatment algorithms for this disease and has shifted focus away from allografting. Despite advances in stem cell transplantation, such as broader availability with the use of modified conditioning regimens, use of allografting has diminished. Also, the nearly universal patient exposure to imatinib or other kinase inhibitors before transplantation may affect the biology of the disease that is currently being treated with an allograft and ultimately may affect outcomes. Exceedingly high rates of meaningful and stable response with longer follow-up continue to drive enthusiasm for imatinib use, and understanding of resistance mechanisms has driven rapid investigation of second-generation tyrosine kinase inhibitors to address imatinib failure and suboptimal response. In most patients, imatinib reduces CML to a minimal residual disease state in which options to further deepen remission, such as immunotherapy, are sought; monitoring techniques and interpretation of response advance in parallel to meet demands; and uncertainty remains as a new natural history of CML is defined in an era of kinase inhibitor therapy. This review summarizes the state of transplant and nontransplant therapy for CML and discusses the decision making for patients with an aim to optimize the use of our best therapies for CML in an era of uncertainty.
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Affiliation(s)
- Michael J Mauro
- Center for Hematologic Malignancies, Oregon Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN73C, Portland, OR 97239, USA.
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Peggs KS. Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans. Cytotherapy 2006; 8:427-36. [PMID: 17050247 DOI: 10.1080/14653240600851938] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment modality for a number of hematologic malignancies, as well as inherited immunodeficiencies and hemoglobinopathies, and may also have a role in selected acquired autoimmune disorders. The complete or near-complete ablation of host immunity and subsequent establishment of donor-derived immunity that is required for successful engraftment and long-term outcomes provide a major obstacle to such transplantation approaches. A delicate balance exists between the need for the reconstituted donor-derived immunity to provide both protection against pathogenic challenges and graft-versus-malignancy activity, and the potentially harmful expansion of alloreactive T-cell clones mediating GvHD. The search for interventions that would allow more rapid and selective reconstitution of beneficial immune specificities continues to be informed by the development of new tools enabling a more precise dissection of the kinetics of reconstituting populations. This review summarizes more recent data on immune reconstitution following allogeneic transplantation in humans.
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Affiliation(s)
- K S Peggs
- Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
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Abstract
This article is a broad overview of hematopoietic stem cell transplantation, covering topics such as indications for transplantation, types of transplantation procedures, HLA matching of donors and recipients, procurement of stem cells from donors, and outcomes of transplantation. The major complications of transplantation, such as graft-versus-host disease, and the mechanisms of tissue injury after transplantation are discussed, as are the nature of immunologic impairment and reconstitution after transplantation. Finally future directions in stem cell transplantation are discussed.
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Griffith LM, Pavletic SZ, Tyndall A, Bredeson CN, Bowen JD, Childs RW, Gratwohl A, van Laar JM, Mayes MD, Martin R, McSweeney PA, Muraro PA, Openshaw H, Saccardi R, Sandmaier BM, Forman SJ, Nash RA. Feasibility of Allogeneic Hematopoietic Stem Cell Transplantation for Autoimmune Disease: Position Statement from a National Institute of Allergy and Infectious Diseases and National Cancer Institute–Sponsored International Workshop, Bethesda, MD, March 12 and 13, 2005. Biol Blood Marrow Transplant 2005; 11:862-70. [PMID: 16275589 DOI: 10.1016/j.bbmt.2005.07.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2005] [Accepted: 07/14/2005] [Indexed: 12/29/2022]
Affiliation(s)
- Linda M Griffith
- Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Morris ES, MacDonald KPA, Rowe V, Banovic T, Kuns RD, Don ALJ, Bofinger HM, Burman AC, Olver SD, Kienzle N, Porcelli SA, Pellicci DG, Godfrey DI, Smyth MJ, Hill GR. NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. J Clin Invest 2005; 115:3093-103. [PMID: 16224535 PMCID: PMC1253626 DOI: 10.1172/jci25249] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2005] [Accepted: 08/09/2005] [Indexed: 01/02/2023] Open
Abstract
NKT cells have pivotal roles in immune regulation and tumor immunosurveillance. We report that the G-CSF and FMS-like tyrosine kinase 3 ligand (Flt-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to alpha-galactosylceramide. In a murine model of allogeneic stem cell transplantation, donor NKT cells promoted host DC activation and enhanced perforin-restricted CD8+ T cell cytotoxicity against host-type antigens. Following leukemic challenge, donor treatment with progenipoietin-1 significantly improved overall survival when compared with G-CSF or control, attributable to reduced graft-versus-host disease mortality and paradoxical augmentation of graft-versus-leukemia (GVL) effects. Enhanced cellular cytotoxicity was dependent on donor NKT cells, and leukemia clearance was profoundly impaired in recipients of NKT cell-deficient grafts. Enhanced cytotoxicity and GVL effects were not associated with Flt-3L signaling or effects on DCs but were reproduced by prolonged G-CSF receptor engagement with pegylated G-CSF. Thus, modified G-CSF signaling during stem cell mobilization augments NKT cell-dependent CD8+ cytotoxicity, effectively separating graft-versus-host disease and GVL and greatly expanding the potential applicability of allogeneic stem cell transplantation for the therapy of malignant disease.
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Affiliation(s)
- Edward S Morris
- Queensland Institute of Medical Research, Brisbane, Queensland, Australia
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McGlave P. Allogeneic transplantation for chronic myelogenous leukemia. Hematology 2005; 10 Suppl 1:15-8. [PMID: 16188624 DOI: 10.1080/10245330512331389764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Philip McGlave
- Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, 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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